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Shukui Qin,1 Rui-Hua Xu,2 Lin Shen,3 Jianming Xu,4 Yuxian Bai,5 Lei Yang,6 Yanhong Deng,7 Zhen-dong Chen,8 Haijun Zhong,9 Hongming Pan,10 Weijian Guo,11 Yongqian Shu,12 Ying Yuan,13 Jianfeng Zhou,14 Nong Xu,15 Tianshu Liu,16 Dong Ma,17 Changping Wu,18 Ying Cheng,19 Donghui Chen,20 Wei Li,21 Sanyuan Sun,22 Zhuang Yu,23 Peiguo Cao,24 Haihui Chen,25 Jiejun Wang,26 Shubin Wang,27 Hongbing Wang,28 Ning Wang,29 Bin Zhang,29 Qiang Zhang,29 Weiguo Su,30 Xiaojun Guo,30 Jin Li31 1Cancer Center, Jinling Hospital, Nanjing, People’s Republic of China; 2Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 3Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 4Department of Medical Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 6Department of Medical Oncology, Nantong Cancer Hospital, Nantong, People’s Republic of China; 7Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 8Department of Medical Oncology, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China; 9Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China; 10Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 11Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 12Department of Medical Oncology, Jiangsu Provincial Hospital, Nanjing, People’s Republic of China; 13Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 14Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 15Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People’s Republic of China; 16Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, People’s Republic of China; 17Department of Medical Oncology, Guangdong Provincial People’s Hospital, Guangzhou, People’s Republic of China; 18Department of Medical Oncology, The First People’s Hospital of Changzhou, Changzhou, People’s Republic of China; 19Department of Medical Oncology, Jilin Province Cancer Hospital, Changchun, People’s Republic of China; 20Department of Medical Oncology, Shanghai Jiaotong University Affiliated First People’s Hospital, Shanghai, People’s Republic of China; 21Department of Medical Oncology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 22Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, People’s Republic of China; 23Department of Medical Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao, People’s Republic of China; 24Department of Medical Oncology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 25Department of Medical Oncology, Liuzhou Worker’s Hospital, Liuzhou, People’s Republic of China; 26Department of Medical Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, People’s Republic of China; 27Department of Medical Oncology, Peking University Shenzhen Hospital, Beijing University, Shenzhen, People’s Republic of China; 28Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou Medical College, Xuzhou, People’s Republic of China; 29Eli Lilly and Company, Shanghai, People’s Republic of China; 30Hutchison MediPharma Limited, Shanghai, People’s Republic of China; 31Department of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Jin LiDepartment of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaTel +8613761222111Email lijin@csco.org.cnObjective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45– 0.77, P< 0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17– 0.30; P< 0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.ClinicalTrials.gov Identifier: NCT02314819.Keywords: colorectal cancer, FRESCO trial, fruquintinib, liver metastasis

Ji Li,1,* Wang Jing,2,* Xiaoyang Zhai,2 Wenxiao Jia,2 Hui Zhu,2 Jinming Yu1 1Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, 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 China*These authors contributed equally to this workCorrespondence: Hui Zhu; Jinming Yu Tel +86-531-67626782; +86-531-67626947Email drzhuh@126.com; sdyujinming@163.comPurpose: A new tool based on clinical characteristics and molecular factors (Lung-molGPA) was developed to predict the survival of patients with non-small-cell lung cancer but was has not been validated. This study aims to validate the feasibility of the Lung-molGPA in NSCLC.Patients and Methods: Patients diagnosed NSCLC between Feb 2012 and July 2018 were retrospectively reviewed and scored using the Lung-molGPA tool to compare clinical outcomes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by Cox regression analyses.Results: A total of 618 patients (524 adenocarcinoma [ADC], 94 non-adenocarcinoma [non-ADC]) were collected. For all patients, the median survival time (MST) was 33.0 months (33.6 and 28 months in the ADC and non-ADC groups, respectively; p = 0.21). In the ADC group, the MST for patients with a Lung-molGPA score of 3.5 to 4 was more than 4 years, while the MST was only 25 months in patients scoring 0– 1, 30.0 months in patients scoring 1.5– 2, and 35.0 months for scores of 2.5– 3 (p = 0.048). For the non-ADC group, the MST for scores 0– 1, 1.5– 2, 2.5– 3, and 3.5– 4 were 12.0, 20.2, 29.0, and 33.0 months, respectively (p = 0.017).Conclusion: Our findings provided evidence validating the Lung-molGPA score as a useful tool to determine treatment strategies and to predict prognosis. The model is still exploratory and needs to be evaluated further in combination with additional prognostic markers.Keywords: NSCLC, GPA, brain metastasis, survival, prognosis

Guannan Wang,* Xu Wang,* Meng Han, Xiaoming Wang Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoming WangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, No. 2 Zheshan West Road, Jinghu District, Wuhu, 241000, Anhui Province, People’s Republic of ChinaEmail wangxiaoming0203@sina.comObjective: Resistance to chemotherapeutic drugs, such as cisplatin, has been one of the major problems adversely affecting the clinical prognosis of patients with gastric cancer (GC). Disabled Homolog 2-Interacting Protein (DAB2IP) status is one of the major factors involved in sensitivity to chemotherapy in multiple cancer types. In the present study, we aimed to investigate the potential roles of DAB2IP in GC cell proliferation and cisplatin resistance.Materials and Methods: DAB2IP expression was detected in human GC tissues using immunohistochemistry (IHC). The role of DAB2IP in regulating GC cell proliferation and cisplatin resistance was explored by genetic manipulation. Western blot analysis was used to determine the molecular signaling to explain the mechanism of the observed DAB2IP effects in GC.Results: DAB2IP expression was downregulated in human GC tissues and low DAB2IP expression predicted poor prognosis. Moreover, our data provided evidence that DAB2IP upregulation impaired cell proliferation property and sensitized GC cells to cisplatin while DAB2IP depletion possessed the opposite effects. Mechanistically, we showed that DAB2IP could inhibit the phosphorylation and activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK), and the enhanced proliferation ability induced by DAB2IP knockdown was greatly impaired after incubation with AKT or ERK inhibitor.Conclusion: DAB2IP modulates GC cell proliferation and sensitivity to cisplatin potentially via regulation of AKT and ERK signaling pathway, indicating that DAB2IP may serve as a potential prognostic biomarker and therapeutic target for treatment of GC.Keywords: DAB2IP, proliferation, chemoresistance, gastric cancer

Teodora Statuto,1,* Fiorella D’Auria,2,* Luigi Del Vecchio3,4,†, Giovanna Rosaria Mansueto,5 Oreste Villani,5 Anna Vittoria Lalinga6,†, Luciana Possidente,6 Filomena Nozza,1 Gabriella Vona,1 Luciana Rago,7 Giovanni Storto,8 Vanessa Rebecca Gasparini,9 Renato Zambello,10 Giovanni D’Arena,5,* Luciana Valvano1,* 1Laboratory of Clinical Research and Advanced Diagnostics, Centro Di Riferimento Oncologico Della Basilicata (IRCCS-CROB), Rionero in Vulture, Pz, Italy; 2Unit of Clinical Pathology, Centro Di Riferimento Oncologico Della Basilicata (IRCCS-CROB), Rionero in Vulture, Pz, Italy; 3CEINGE Biotecnologie Avanzate S.c.a.r.l, Federico II University, Naples, Italy; 4Department of Molecular Medicine and Medical Biotechnology (DMMBM), Federico II University, Naples, Italy; 5Hematology Department of Basilicata, Centro Di Riferimento Oncologico Della Basilicata (IRCCS-CROB), Rionero in Vulture, Pz, Italy; 6Pathology Unit, Centro Di Riferimento Oncologico Della Basilicata (IRCCS-CROB), Rionero in Vulture, Pz, Italy; 7Radiotherapy Unit, Centro Di Riferimento Oncologico Della Basilicata (IRCCS-CROB), Rionero in Vulture, Pz, Italy; 8Department of Nuclear Medicine, Centro Di Riferimento Oncologico Della Basilicata (IRCCS-CROB), Rionero in Vulture, Pz, Italy; 9Department of Medicine, University of Padova - Veneto Institute of Molecular Medicine, VIMM, Padova, PD, Italy; 10Hematology and Clinical Immunology, Department of Medicine, Padua School of Medicine, Padova, PD, Italy†Anna Vittoria Lalinga passed away on January 26, 2020 and Luigi Del Vecchio passed away on August 16, 2018*These authors contributed equally to this workCorrespondence: Luciana ValvanoLaboratory of Clinical Research and Advanced Diagnostics, Centro Di Riferimento Oncologico Della Basilicata (IRCCS-CROB), Rionero in Vulture, Pz, ItalyTel +39 0972 726395Fax +39 0972 723509Email luciana.valvano@crob.itAbstract: Lymphoproliferative disorders are a heterogeneous group of malignant clonal proliferations of lymphocytes whose diagnosis remains challenging, despite diagnostic criteria are now well established, due to their heterogeneity in clinical presentation and immunophenotypic profile. Lymphoid T-cell disorders are more rarely seen than B-cell entities and more difficult to diagnose for the absence of a specific immunophenotypic signature. Flow cytometry is a useful tool in diagnosing T-cell lymphoproliferative disorders since it is not only able to better characterize T-cell neoplasms but also to resolve some very complicated cases, in particular those in which a small size population of neoplastic cells is available for the analysis. Here, we report three patients with mature T-cell neoplasms with atypical clinical and biological features in which analysis of peripheral blood and bone marrow specimens by means of multicolor flow cytometry was very useful to identify and characterize three rare T-cell lymphoproliferative disorders, such as angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and T-cell prolymphocytic leukemia. The aim of this case series report is not only to describe three rare cases of lymphoproliferative neoplasms but also to raise awareness that a fast, highly sensitive, and reproducible procedure, such as flow cytometry immunophenotyping, can have a determinant diagnostic role in these patients.Keywords: flow cytometry, immunophenotype, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, T-cell prolymphocytic leukemia, diagnosis

Carmen Salvador-Coloma,1,2,* María Saigí,3,* Roberto Díaz-Beveridge,1 Rosa María Penín,4 María Pané-Foix,4 Empar Mayordomo,5 Marcos Melián,1 Mona Schuler,6 Xavier García Del Muro,3 Jaime Font de Mora2 1Department of Medical Oncology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; 2Laboratory of Cellular and Molecular Biology, Clinical and Translational Research in Cancer, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; 3Department of Medical Oncology, Institut Català Oncologia, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain; 4Department of Pathology, Hospital Universitari de Bellvitge, Barcelona, Spain; 5Department of Pathology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; 6Department of Cardiac Surgery, Hospital Universitari i Politècnic La Fe, Valencia, Spain*These authors contributed equally to this workCorrespondence: Carmen Salvador-ColomaJaime Font de Mora Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell, 106, Torre A, 5-07, Valencia 46026 SpainTel +34-961246646Email salvadorcoloma@gmail.comBackground: Primary cardiac tumors are extremely rare; most are myxomas with a benign prognosis. However, primary sarcomas are highly aggressive and treatment options are limited. Radical surgery is often not feasible and conventional therapies provide only modest results. Due to the rare nature of primary cardiac tumors, there are no proper randomized studies to guide treatment. Their complexity requires alternative approaches in order to improve treatment efficacy.Methods: We isolated DNA from 5 primary cardiac sarcomas; the quality of DNA from 3 of them was sufficient to perform high-resolution single nucleotide polymorphism (SNP) array analysis.Results: In the present study, molecular karyotyping revealed numerous segmental chromosomal alterations and amplifications affecting actionable genes that may be involved in disease initiation and/or progression. These include chromosomal break flanking AKT2 in undifferentiated pleomorphic rhabdomyosarcoma, chromosomal break in promoter of TERT, and gain of CDK4 and amplification of MDM2 in inflammatory myofibroblastic tumor. We detected segmental break flanking MOS in high-grade myxofibrosarcoma. In addition, the high number of chromosomal aberrations in high-grade myxofibrosarcoma may cause multiple tumor-specific epitopes, supporting the study of immunotherapy treatment in this type of aggressive tumor.Conclusion: Our results provide a genetic rationale that supports an alternative, personalized therapeutic management of primary cardiac sarcomas.Keywords: primary cardiac sarcomas, molecular karyotype, actionable genes

Shu Liao,1,* Chaxiu Yu,2,* Hucheng Liu,3,* Congkai Zhang,1 Yong Li,1 Xiaojun Zhong1 1Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; 2Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; 3Department of Osseous and Soft Tissue Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China *These authors contributed equally tothis work Background: This study aimed to explore the effect of long non-coding RNA (LncRNA) H19 on the proliferation and invasion of lung carcinoma cells A549, and to determine its molecular targets. Methods: A549 cells were with either LncRNA H19 or LncRNA H19 shRNA, and the expression levels of LncRNA H19 were evaluated by quantitative real-time PCR (RT-PCR). We measured cell proliferation using the CCK-8 assay, cell counting assays, and colony formation assay in response to shLncRNA H19-2. Cell migration and invasion were assessed by wound healing assay and Transwell assay, respectively. The mRNA and protein expression levels of E-cadherin, N-cadherin, and vimentin were determined by RT-PCR and western blot, respectively. Results: The three LncRNA H19 shRNAs used in our study significantly reduced the expression levels of LncRNA H19 in A549 cells (P

Ge Gao,1,* Dianhui Xiu,2,* Bin Yang,3 Daju Sun,1 Xin Wei,4 Youpeng Ding,4 Yanan Ma,4 Zhixin Wang4 1Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China; 2Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China; 3Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China; 4Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China *These authors contributed equally to this work Background: Prostate cancer is one of the most commonly diagnosed diseases in males. Methods: RT-qPCR was used to detect miR-129-5p expression in tumor tissues and adjacent normal tissues from patients with prostate cancer. The cell proliferation assay and colony forming assay were used to study the role of miR-129-5p in mediating prostate cancer cell growth. Bioinformatic analysis and dual luciferase assay were performed to predict and confirm ETV1 as a target gene of miR-129-5p. Results: We found that miR-129-5p levels were decreased significantly in human prostate cancer tissues compared with matched normal tissues from patients with prostate cancer. Overexpression of miR-129-5p suppressed prostate cancer cell growth while antagonist of miR-129-5p promoted cell proliferation in immortal prostate cell line RWPE-1. In addition, elevation of miR-129-5p decreased ETV1 expression in prostate cancer cells while downregulation of miR-129-5p increased ETV1 expression in RWPE-1. Mechanistically, ETV1 is confirmed a direct target of miR-129-5p in prostate cancer cells. Through repression of ETV1 expression, miR-129-5p could inactivate YAP signaling in prostate cancer cells. In addition, overexpression of ETV1 attenuated miR-129-5p induced cell proliferation in prostate cancer cells. Correlation analysis further revealed that there was a negative correlation between miR-129-5p levels and ETV1 mRNA levels in tumor tissues from patients with prostate cancer. Conclusion: Our results identified miR-129-5p as a tumor suppressor in prostate cancer via repression of ETV1. Keywords: microRNA, prostate cancer, ETV1, proliferation

Meng Yang,1 Chen Zeng,1 Peiting Li,1 Liyuan Qian,1 Boni Ding,1 Lihua Huang,2 Gang Li,1 Han Jiang,1 Ni Gong,3 Wei Wu1 1Department of Breast Thyroid Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Central Laboratory, The Third Xiangya Hospital of Central South University, Changsha, Hunan410013, People’s Republic of China; 3Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic ofChina Background: Breast cancer is one of the most common malignancies threatening women’s health. Triple-negative breast cancer (TNBC) is a special type of breast cancer with high invasion and metastasis. CXCL12 and its receptors CXCR4 and CXCR7 play a crucial role in the progress of breast cancer. The aim of this study was to investigate the effect of CXCR4 and CXCR7 on the function of TNBC. Materials and methods: We used the CRISPR/Cas9 technique to carry out a single knockout of the CXCR4 or CXCR7 gene and co-knockout of CXCR4 and CXCR7 genes in the TNBC cell line (MDA-MB-231). The single knockout and co-knockout cells were screened and verified by PCR sequencing and Western blot assay, the effect of single knockout and co-knockout on the proliferation of TNBC cells was examined using the Cell Counting Kit-8 and colony formation assays, the migration and invasion of TNBC cells were examined by the transwell and wound-healing assays, the changes in the cell cycle distribution after knockout were detected by flow cytometry, and the difference in the migration and invasion of single knockout and co-knockout induced by CXCL12 was observed by adding CXCL12 in the experimental group. Results: The single knockout of the CXCR4 or CXCR7 gene significantly reduced the cell proliferation, growth, migration, and invasion and delayed the conversion of the G1/S cycle, while the co-knockout inhibited these biological abilities more significantly. In both the knockout and control groups, the migration and invasion of CXCL12-added cells were significantly stronger than those of the non-CXCL12-added cells, and CXCL12 induced lesser migration and invasion in the CXCR4 and CXCR7 co-knockout group than in the single knockout groups. Conclusion: The knockout of the CXCR4 and CXCR7 genes affects the binding capacity and functions of CXCL12, inhibits the malignant progression of TNBC cells significantly, and may become a potential target for the treatment of TNBC. Keywords: triple-negative breast cancer cells, TNBC, CXCR4, CXCR7, CXCL12, CRISPR/Cas9

Chengyin Weng,1–3,* Yong Chen,1,* Yong Wu,2,3 Xia Liu,2,3 Haibo Mao,2,3 Xisheng Fang,2,3 Baoxiu Li,2,3 Lina Wang,2,3 Mingmei Guan,2,3 Guolong Liu,2,3 Lin Lu,2,3 Yawei Yuan1,41Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 2Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, People’s Republic of China; 3Department of Medical Oncology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, People’s Republic of China; 4Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, People’s Republic of China *These authors contributed equally to this work Aim: The human ubiquitination factor E4B (UBE4B) gene is frequently amplified in some solid cancers. However, the role of UBE4B in nasopharyngeal carcinoma (NPC) has not yet been investigated.Methods: Firstly, we analyzed the expression of UBE4B in NPC samples using real-time quantitative PCR and Western blot analysis. After knocking down UBE4B using small interfering RNA technology, the functions of UBE4B on cell proliferation, apoptosis, and cell cycle, as well as underlying mechanism, were investigated.Results: Compared with matched adjacent non-tumor tissues, both protein and mRNA levels of UBE4B were much higher in most NPC cancerous specimens. Deficiency of UBE4B could significantly inhibit tumor cell growth and induce cell apoptosis. Knocking down UBE4B could promote the expression of cleaved caspase3 and p53, and inhibition of caspase3 could prevent cell apoptosis induced by the deficiency of UBE4B.Conclusion: These results indicate that expression of UBE4B was higher in most NPC tissues compared to adjacent non-tumoral tissues, and that knockdown of UBE4B inhibited the cell growth and induced apoptosis in NPC cells. This process was regulated by the activation of caspase3 and p53. Thus, UBE4B gene might act as a potential molecular target to develop novel strategy for NPC patients. Keywords: UBE4B, nasopharyngeal cancer, apoptosis, caspase3, p53

Yan Qu,1 Na Shao,2 Wenjing Yang,1 Jianbo Wang,1,* Yufeng Cheng1,* 1Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China; 2Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People’s Republic of China *These authors contributed equally to this work Objective: The main aim of this study was to investigate the association of polymorphisms in long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) with the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population.Methods: A total of 245 ESCC patients and 490 gender- and age-matched cancer-free controls were genotyped for four tag single nucleotide polymorphisms (SNPs) of MALAT1 (rs3200401 C>T, rs1122709 C>G, rs664589 C>G, and rs619586 A>G). Statistical analyses including chi-squared test and logistic regression were performed to identify the association between the tag SNPs and risk of ESCC, and false discovery rate (FDR) T polymorphism of MALAT1 was significantly associated with increased risk of ESCC (CT vs CC: adjusted OR =1.59, 95% CI =1.07–2.35, P=0.021; TT vs CC: adjusted OR =2.27, 95% CI =1.04–4.96, P=0.039; dominant model [CT+TT vs CC]: adjusted OR =1.68, 95% CI =1.16–2.43, P=0.006). In the stratified analysis, rs3200401 TT and CT/TT genotypes were associated with increased risk of ESCC compared with CC genotype in subgroup of never drinking (TT vs CC: adjusted OR =2.34, 95% CI =1.02–5.34, P=0.044; CT/TT vs CC: adjusted OR =1.52, 95% CI =1.02–2.26, P=0.041). However, compared with AA genotype, MALAT1 rs619586 GG was associated with decreased risk of ESCC in ever drinking subgroup (GG vs AA: adjusted OR =0.38, 95% CI =0.15–0.99, P=0.049). The results remained significant after FDR adjustment (FDR value T in MALAT1 gene is associated with increased risk of ESCC. Since the association between rs619586 A>G polymorphism and ESCC risk was not significant after FDR adjustment, there was a minor possibility that rs619586 A>G might be a protective factor for ESCC. Keywords: MALAT1, polymorphism, esophageal squamous cell carcinoma, single nucleotide polymorphism, susceptibility

Caijun Dong,1 Xingwang Liu,2 Huisheng Wang,3 Jutao Li,4 Lei Dai,5 Jun Li,6 Zhen Xu1 1Department of Cardiothoracic Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, People’s Republic of China; 2Sports Medicine Center, Department of Sports Medicine and Arthroscopy Surgery, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Orthopedics, The People’s Hospital of China Medical University, Shenyang, People’s Republic of China; 4Department of Hand and Foot Surgery I, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Liaoning, People’s Republic of China; 5Department of Thyroid Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, People’s Republic of China; 6Department of General Surgery II, Taihe Hospital, Shiyan, Hubei, People’s Republic of China Purpose: To explore the effects of hypoxic non-small-cell lung cancer (NSCLC)-derived exosomes on NSCLC resistance to cisplatin.Materials and methods: Exosomes were isolated by differential centrifugation and characterized by transmission electron microscope and Western blotting. Quantitative real-time PCR was used to measure miR-21 levels. MTT assays and colony formation assays were performed to investigate the effects of hypoxia-induced exosomes on cisplatin resistance.Results: Hypoxic NSCLC cell-derived exosomes facilitate normoxic cell resistance to cisplatin. In addition, hypoxia enhanced the miR-21 expression in NSCLC cells and cell-derived exosomes. Interestingly, changes in miR-21 levels in the hypoxia-induced exosomes affected the sensitivity of recipient cells to cisplatin. Mechanically, exosomal miR-21 promoted cisplatin resistance by downregulating phosphatase and tensin homolog (PTEN). The expression of miR-21 in tumor cell lines and clinical NSCLC tumor samples was positively correlated with hypoxia-inducible factor-1α and negatively correlated with PTEN. Moreover, high miR-21 expression was associated with shorter median survival period in patients undergoing pharmacotherapy, but no association was observed in patients who were not under pharmacotherapy.Conclusion: Exosomal miR-21 derived from hypoxic NSCLC cells may promote cisplatin resistance, which indicates that exosomal miR-21 might be a potential biomarker and therapeutic target to address NSCLC chemoresistance. Keywords: non-small-cell lung cancer, exosomes, miR-21, cisplatin resistance, PTEN &nbsp

Hui Zhao, Yue He, Shu-Li Yang, Qun Zhao, Yu-Mei Wu Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China Aim: This systematic review was designed to evaluate the efficacy of neoadjuvant chemotherapy with radical surgery vs radical surgery alone for cervical cancer.Methods: A computerized search was done for trials from PubMed, EMBASE, CENTRAL, and Cochrane Database of Systematic Reviews. The trials included neoadjuvant chemotherapy plus radical surgery vs radical surgery alone. We measured overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), local and distant recurrence, lymph node metastasis, and parametrial infiltration per patient.Results: In all, 13 studies involving 2,158 subjects were included. In regard to OS, DFS, PFS, local and distant recurrence, and parametrial infiltration, neoadjuvant chemotherapy plus radical surgery was similar to radical surgery alone. Among them, subgroup analysis of eight studies involving 1,544 patients with locally advanced cervical cancer (FIGO stage IB2–IIB) showed that neoadjuvant chemotherapy (NACT) plus radical surgery significantly improved OS, and decreased local and distant recurrence rates, lymph node metastasis rate, and the level of parametrial infiltration compared to radical surgery alone.Conclusion: The present study demonstrates that preoperative NACT is now an accepted effective procedure in selected patients with locally advanced cervical cancer (FIGO stage IB2–IIB). However, the relationship between NACT and longer DFS and PFS cannot be demonstrated by this meta-analysis. Thus, the decision to use or not to use NACT before radical surgery depends on the surgeon’s experience and clinical judgment. Nevertheless, further research in this field is urgently needed to confirm it. Keywords: neoadjuvant chemotherapy, surgery, cervical cancer, meta-analysis &nbsp

Fei Yang,1,* Jian Zhang,1,* Xinyou Zhang,2,* Mengli Tian,1 Jingjing Wang,1 Liqing Kang,3 Huiying Qiu,1 Depei Wu1 1Department of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Hematology, The Second Clinical Medical College of Jinan University (Shenzhen People’s Hospital), Jinan University, Shenzhen, Guangdong Province, People’s Republic of China; 3Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: CD19-modified CAR-T cells greatly influence responses in patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, recurrence remains a challenge, and reinfusion of CAR-T cells is not always effective. Sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells may overcome this issue and induce remission.Methods: We examined treatment with sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells in a patient with relapsed ALL previously exposed to murine-derived anti-CD19 CAR-T cells.Results: At ~6weeks after treatment, repeated bone marrow smear and flow cytometry analysis revealed no lymphoblasts.Conclusion: Our results suggest that sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells is a valuable option for relapsed patients with prior infusion of murine-derived, CD19-directed CAR-T cells. Keywords: chimeric antigen receptor, anti-CD19, anti-CD22, humanized, acute lymphoblastic leukemia, relapsed

Zhouxun Chen,1,* Jiahao Lin,2,* Shuyi Feng,2,* Xuxu Chen,2 Hanzhang Huang,3 Chen Wang,3 Yujun Yu,3 Yu He,3 Shaoliang Han,3 Linfeng Zheng,4 Guoyu Huang3 1Department of Colorectal and Anal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; 2School of The First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China; 3Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; 4Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China *These authors contributed equally to this work Background: SIRT4, a protein localized in the mitochondria, is one of the least characteristic members of the sirtuin family. It is known that SIRT4 has deacetylase activity and plays a role in energy metabolism, but little is known about its possible role in carcinogenesis. Recently, several studies have suggested that SIRT4 may function as either a tumor oncogene or a tumor suppressor gene. However, its relationship with thyroid cancer remains unclear. Methods: We stably overexpressed SIRT4 or silenced its expression in the human thyroid cancer cell line BCPAP by means of lentiviral vectors. We conducted a variety of tests, such as CCK-8, wound healing, migration, and invasion assays, to investigate the role of SIRT4 in the proliferation, migration, and invasion abilities of thyroid cancer cells. We also investigated the effects of SIRT4 overexpression on cell cycle progression and apoptosis of BCPAP cells and studied the role of glutamine metabolism in the effects of SIRT4 on BCPAP cell migration and invasion. Finally, we analyzed SIRT4 expression levels in thyroid cancer specimens by immunohistochemistry and investigated their association with clinicopathological features. Results: Overexpression of SIRT4 inhibited the proliferation, migration, and invasion abilities of BCPAP thyroid cancer cells, blocked the cell cycle in the G0/G1 phase, and induced apoptosis. Mechanistically, SIRT4 inhibited BCPAP migration and invasion by inhibiting glutamine metabolism. Moreover, we found that SIRT4 protein levels in thyroid cancer tissues were markedly lower than in their non-neoplastic tissue counterparts (P

San-Gang Wu,1,* Wen-Wen Zhang,2,* Jun Wang,1 Yong Dong,3 Yong-Xiong Chen,4 Zhen-Yu He2 1Department of Radiation Oncology, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen 361003, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, People’s Republic of China; 3Department of Oncology, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan 523326, People’s Republic of China; 4Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Medical College, Xiamen University, Xiamen 361005, People’s Republic of China *These authors contributed equally to this work Aim: We aimed to assess the role of 21-gene recurrence score (RS) in the decision-making for surgical treatment in early stage breast cancer and compared the outcomes between breast-conserving surgery (BCS) and mastectomy (MAST) among various 21-gene RS groups. Methods: We included patients with stage T1-2M0M0 and estrogen receptor-positive breast invasive ductal carcinoma who underwent BCS + radiotherapy or MAST between 2004 and 2012 as part of the Surveillance, Epidemiology, and End Results program. Data were analyzed using binomial logistic regression, multivariate Cox proportional hazards models, and propensity score matching (PSM). Results: We enrolled 34,447 patients including 22,681 (65.8%) and 11,766 (34.2%) who underwent BCS and MAST, respectively. Patients with high-risk RS were more likely to receive MAST. Multivariate analysis indicated that patients with intermediate-risk (P

Yong-jun Guan,1 Shi-ying Fang,2 Lin-lin Chen,3 Zheng-dong Li2,3 1Department of General Surgery, Yan Da International Hospital, Langfang, Hebei 065000, China; 2Department of General Surgery, West Anhui Health Vocational College, Luan, Anhui 237000, China; 3Department of General surgery, The Second People’s Hospital of Luan City, Luan, Anhui 237000, China Background: This aim of study was to develop and validate clinical nomograms to predict the survival of patients with medullary thyroid cancer. Patients and methods: Patient data were collected from the Surveillance, Epidemiology, and End Results database between 2004 and 2013. All included patients were randomly assigned into the training and validation sets. Multivariate analysis using Cox proportional hazards regression was performed, and nomograms were constructed. Model performance was evaluated by discrimination and calibration plots. Results: A total of 1,657 patients were retrospectively analyzed. The multivariate Cox model identified age, tumor size, extrathyroidal extension, N stage, and M stage as independent covariates associated with overall survival (OS) and cancer-specific survival (CSS). Nomograms predicting OS and CSS were constructed based on these covariates. The nomograms predicting both OS and CSS exhibited superior discrimination power to that of TNM staging system in the training and validation sets. Calibration plots indicated that both the nomograms in OS and CSS exhibited high correlation to actual observed results. Conclusion: The nomograms established in this study provided an alternative tool for prognostic prediction, which may thereby improve individualized assessment of survival risks and lead to the creation of additional clinical therapies. Keywords: medullary thyroid cancer, nomogram, overall survival, cancer-specific survival

Kazuto Tajiri, Yuka Futsukaichi, Saito Kobayashi, Kohei Nagata, Satoshi Yasumura, Terumi Takahara, Masami Minemura, Ichiro Yasuda Department of Gastroenterology, Toyama University Hospital, Toyama, Japan Purpose: The purpose of this study was to evaluate the effectiveness and tolerability of “on-demand” combination therapy with sorafenib and hepatic arterial treatments, such as transarterial chemoembolization and hepatic arterial infusion chemotherapy, in patients with hepatocellular carcinoma (HCC). Patients and methods: Eighty consecutive patients with advanced HCC, 58 administered sorafenib monotherapy and 22 administered on-demand combination therapy, were retrospectively evaluated. Results: The disease control rate was significantly higher in the combination group than in the monotherapy group (86.3% vs 51.7%, p=0.01). Elevated alanine aminotransferase levels were significantly more frequent in the combination group (40.9% vs 12.1%, p=0.01), but it was tolerable. Progression-free survival (180 vs 45days, p=0.045) and overall survival (983 vs 452days, p=0.004) were significantly longer in the combination group, as was the duration of sorafenib treatment (367 vs 66days, p400ng/mL was negatively prognostic. In patients receiving combination therapy, male sex, hepatitis B virus infection, performance status deterioration, Barcelona clinic liver cancer-B, and major vascular invasion were prognostic of survival. Conclusion: On-demand combination therapy was tolerated and may be a therapeutic option for patients with advanced HCC. Keywords: hepatocellular carcinoma, sorafenib, combination therapy, transarterial chemoembolization, hepatic arterial infusion chemotherapy

Shuang Gao,1,* Xiaohui Cheng,2,* Jinhua Li3 1Ultrasound Department, Guilin People’s Hospital, Guilin, Guangxi 541002, China; 2Department of Clinical Pharmacy, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, China; 3Traditional Chinese Medicine Department, Gansu Provincial Hospital, Lanzhou, Gansu 730000, China *These authors contributed equally to this work Purpose: Herein, this study is to prepare folic acid (FA)-conjugated lipid nanobubbles (NBs) that highly load artesunate (Arte; FA-ALNBs), as an ultrasound (US)-triggered Arte delivery system for imaging-guided, tumor-targeted chemotherapy.Materials and methods: The morphology, size, zeta potential, and stability of the FA-ALNBs were detected by optical microscopy and dynamic light scattering analysis. The cellular uptake of the FA-ALNBs was evaluated by confocal laser scanning microscopy and flow cytometry.Results: The FA-ALNBs showed uniform spheroidal structure, with 781.2±5.3 nm in average diameter, great physiological stability, and ~91.9%±1.1% encapsulation efficiency of Arte. Using focused US, about 36.1%±2.5% of the entrapped Arte was trigger-released from the FA-ALNBs. Owing to the US contrast property, FA-ALNBs showed an enhanced US signal in vitro when using an ultrasonic diagnostic apparatus with a 1-MHz linear transducer. Due to the FA receptor-mediated endocytosis effect, FA-ALNBs can be efficiently internalized by cells, showing an uptake ratio of about 56.4%±3.1%. FA-ALNBs showed an enhanced, dose-dependent cell-killing ability, while FA-ALNBs plus US irradiation exhibited a stronger anticancer effect in vitro. Post intravenous injection into tumor-bearing mice, FA-ALNBs showed an enhanced US contrast effect with increase in time, indicating the increasing accumulation of FA-ALNBs in tumor tissue, which peaked at 4 hours post injection. Focused US irradiation was conducted on the tumor region at 4 hours post injection of FA-ALNBs, which showed a greater tumor suppression effect after 30 days of treatment compared with all other treatment groups. Moreover, FA-ALNBs showed negligible systemic toxicity in vivo.Conclusion: This versatile US-triggered drug delivery system with great anticancer efficacy was assessed both in vitro and in vivo, revealing great potential as a cancer theranostic agent for future application. Keywords: nanobubbles, artesunate, ultrasound imaging, ultrasound-triggered drug release, cancer theranostics &nbsp

Yi Hou, Chunna Lan, Ying Kong, Chunjiao Zhu, Wenna Peng, Zhichao Huang, Changjie Zhang Department of Rehabilitation, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China Background and objective: Transcriptional coactivator with PDZ-binding motif (TAZ) has been found to be associated with tumor progression. Mitochondrial homeostasis regulates cancer cell viability and metastasis. However, the roles of TAZ and mitochondrial homeostasis in liver cancer viability have not been explored. The aim of our study was to investigate the influence of TAZ on HepG2 liver cancer cell apoptosis.Materials and methods: HepG2 liver cancer cell was used in the present study, and shRNA against TAZ was transfected into HepG2 cell to knockdown TAZ expression. Mitochondrial function was analyzed using Western blotting, immunofluorescence assay, and flow cytometry. Pathway blocker was used to confirm the role of CaMKII pathway in TAZ-mediated cancer cell death.Results: Our results indicated that TAZ deletion induced death in HepG2 cell via apoptosis. Biological analysis demonstrated that mitochondrial stress, including mitochondrial bioenergetics disorder, mitochondrial oxidative stress, and mitochondrial apoptosis, were activated by TAZ deletion. Furthermore, we found that TAZ affected mitochondrial stress by triggering mitochondrial elongation factor 1 (MIEF1)-related mitochondrial dysfunction. The loss of MIEF1 sustained mitochondrial function and promoted cancer cell survival. Molecular investigation illustrated that TAZ regulated MIEF1 expression via the CaMKII signaling pathway. Blockade of the CaMKII pathway prevented TAZ-mediated MIEF1 upregulation and improved cancer cell survival.Conclusion: Taken together, our results highlight the key role of TAZ as a master regulator of HepG2 liver cancer cell viability via the modulation of MIEF1-related mitochondrial stress and the CaMKII signaling pathway. These findings define TAZ and MIEF1-related mitochondrial dysfunction as tumor suppressors that act by promoting cancer apoptosis via the CaMKII signaling pathway, with potential implications for new approaches to liver cancer therapy. Keywords: TAZ, liver cancer, death, MIEF1, CaMKII signaling pathway

Liangyu Li,1,* Jing Chen,2,* Chao Ge,2 Fangyu Zhao,2 Taoyang Chen,3 Hua Tian,2 Jinjun Li,2 Hong Li2 1Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 2State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3Qi Dong Liver Cancer Institute, Qi Dong, Jiangsu Province, People’s Republic of China *These authors contributed equally to this work Introduction: CD24 is known as a heavily glycosylated cell surface molecule that is highly expressed in a wide variety of human malignancies. Previous studies have shown that CD24 plays an important role in self-renewal, proliferation, migration, invasion and drug resistance of hepatocellular carcinoma (HCC). However, little is known about the expression and function of CD24 isoform a (CD24A) and CD24 isoform b (CD24B) in HCC. Materials and methods: Quantitative real-time polymerase chain reaction (qPCR) and Western blotting were performed to detect CD24 and EGR1 expression in HCC cells and tissue. The function of CD24 in cell proliferation was verified with MTT assays, colony formation assays and tumor xenograft models. Wound healing assays and invasion assays were performed to clarify the function of CD24 in the regulation of cell migration and invasion in HCC. A dual luciferase reporter assay and chromatin immunoprecipitation assay were used to analyze the regulation mechanism of CD24A. Results: CD24A but not CD24B, which was barely detected by qPCR and Western blotting, is significantly upregulated in HCC tissue. Both CD24A and CD24B contribute to HCC cell proliferation, migration and invasion, but CD24A is more effective than CD24B. EGR1 downregulates CD24A and exerts transcription-promoting activity on the CD24A promoter. Furthermore, EGR1 represses HCC cell proliferation via downregulation of CD24A. Conclusion: CD24A is the predominant CD24 isoform in HCC and plays a major role in cell proliferation, migration, and invasion. EGR1 can exert its antitumor effect through transcriptional downregulation of CD24A in HCC. Keywords: CD24A, CD24B, EGR1, proliferation, hepatocellular carcinoma

Gang Liu,* Qiaosheng Wu,* Yili Wang, Qiuyun Xiong, Feiguo Fu Department of Breast Surgery, The Third Hospital of Nanchang City, Key Laboratory of Breast Diseases, Nanchang, Jiangxi 330009, China *These authors contributed equally to this work Background: Deleted in breast cancer 1 (DBC1) is believed to be involved in human cancers. However, it is still uncertain whether DBC1 expression can be regarded as a prognostic factor in patients with various cancers. This meta-analysis aimed to evaluate the relationship between high levels of DBC1 and prognosis in tumor patients. Methods: Electronic databases were searched and 14 studies meeting the selection criteria were included. Overall survival (OS), relapse-free survival (RFS), and 95% CIs were extracted and analyzed. HRs from individual studies were pooled using fixed- or random-effects models, depending on the heterogeneity of the included studies, and publication bias analyses were also performed to increase the reliability of the results. Results: A total of 2,254 patients with tumors from 14 published studies were included in the meta-analysis. DBC1 overexpression was associated with worse OS (univariate analysis: HR=2.94; 95% CI: [2.38–3.63]; multivariate analysis: HR=1.98, 95% CI: [1.21–3.25]) and RFS (univariate analysis: HR=2.83, 95% CI: [2.30–3.49]; multivariate analysis: HR=2.71, 95% CI: [2.07–3.53]) for various tumors. No publication bias was observed according to test of funnel plot asymmetry and Egger’s test. Conclusion: Current evidence supports the conclusion that the upregulation of DBC1 is correlated with poor survival among tumor patients, suggesting that DBC1 represents an independent prognostic factor significantly associated with OS and RFS, and could serve as a novel therapeutic target in patients with tumors. Nevertheless, further large-scale prospective trials and well-designed studies are warranted to confirm this finding. Keywords: deleted in breast cancer 1, breast cancer, prognosis, survival analysis, meta-analysis

Guosheng Xiong,1,* Liyin Li,2,* Xiaobo Chen,1 Sinuo Song,3 Yunping Zhao,1 Wenke Cai,4 Jingping Peng4 1Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, People’s Republic of China; 2Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, People’s Republic of China; 3Department of Medical Management, Kunming General Hospital, Kunming, Yunnan 650032, People’s Republic of China; 4Department of Cardiovascular and Thoracic, Kunming General Hospital, Kunming, Yunnan 650032, People’s Republic of China *These authors contributed equally to this work Aim: The purpose of this study is to consider the function of cytoskeleton-associated protein 2-like (CKAP2L) in lung adenocarcinoma (LAD) development and its prognostic value. Methods: The mRNA expression of CKAP2L and its correlation with clinical factors in LAD patients were analyzed from the data taken from The Cancer Genome Atlas and The First Affiliated Hospital of Kunming Medical University. We constructed H460 and A549 cell lines with silenced CKAP2L using RNA interference. Cell counting kit-8 assay and colony formation assays were carried out to determine the function of CKAP2L in H460 and A549 cell proliferation. Transwell and wound healing assays were applied to determine the effect of CKAP2L on H460 and A549 cell invasion and migration. The influences of CKAP2L on mitogen-activated protein kinase signaling pathway-related proteins were tested by Western blotting. Results: CKAP2L expression is enhanced in LAD tissues and is predictive of poor prognosis in LAD patients. High expression of CKAP2L is associated with stage (P

Katarzyna Niebudek, Ewa Balcerczak, Marek Mirowski, Jacek Pietrzak, Izabela Zawadzka, Marta Å»ebrowska-Nawrocka Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Interfaculty Cathedral of Laboratory and Molecular Diagnostics, Medical University of Lodz, Lodz 90-151, Poland Background: Breast cancer resistance protein BCRP, belonging to superfamily G of the adenosine triphosphate-binding cassette (ABC) transporters, is an efflux pump and plays a critical role in protecting cells against xenobiotics and toxic compounds including (pro)carcinogens. BCRP is expressed in many tissues, including hematopoietic stem cells. Genetic variants such as single nucleotide polymorphisms (SNPs) can change the gene expression and/or reduce their products’ activity which may affect an individual’s susceptibility to xenobiotics and the development of carcinoma. These changes may affect the exposure of blood cells to toxic compounds, which increases the risk of multiple myeloma. The aim of this study was to determine polymorphisms at positions G34A and C421A of the ABCG2 gene in multiple myeloma in the Polish population for the first time. Materials and methods: Material for the study included DNA isolated from nucleus of cells of peripheral blood of patients diagnosed with multiple myeloma (investigated group N=181) and from healthy people (control group N=97). Research into the polymorphisms was conducted using the polymerase chain reaction-restriction fragment length polymorphism technique. Results: The present study showed a statistically significant association between SNP C421A of the ABCG2 gene and the risk of developing multiple myeloma (P=0.0218). No statistically significant relationship was found for the other parameters analyzed, such as age, gender, or type of secreted immunoglobulin. Conclusion: Preliminary studies indicate that SNP C421A may become a potential predictor for the development of multiple myeloma. Keywords: BCRP, polymorphism, ABCG2, multiple myeloma risk, plasma cell myeloma, single nucleotide polymorphism

Ran-ran Ding,1,2,* Jian-ling Yuan,2,* Ya-nan Jia,2,3 Xiao-min Liao,2 Si-si Wang,2 Zhong-ming Shao,2 Mu-yin Feng,2 Wei Jie,2 Zhi-hua Shen2 1Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; 2Department of Pathology, School of Basic Medicine Sciences, Guangdong Medical University, Zhanjiang 524023, China; 3Department of Pathology, Dongguan People’s Hospital, Dongguan 523059, China *These authors contributed equally to this work Background: Epstein–Barr virus-encoded LMP1 plays a critical role in the carcinogenesis of nasopharyngeal carcinoma (NPC), but the mechanism remains elusive. We aimed to analyze the expression and clinical pathological significance of provirus integration site for Moloney murine leukemia virus 1 (Pim1) in clinical NPC, and to elucidate the effect of LMP1 on Pim1 expression and its mechanism. Methods: Immunohistochemical staining was used to detect the expression of Pim1 in clinical NPC tissues and control nasopharyngeal chronic inflammation (NPI) tissues, and the correlation between Pim1 and clinical parameters of NPC patients was analyzed. The LMP1 stable expression cell line CNE1-LMP1-OV was constructed through infecting the well-differentiated nasopharyngeal carcinoma cells CNE1 with LMP1 overexpressing lentivirus. Then the invivo experiments were conducted. Results: Among 89 NPC patients, 48 cases (53.93%) were positive for Pim1, while only one case was Pim1 positive in 15 NPI controls (6.67%). Pim1 expression was not correlated with gender, age, smoking status and clinical classification of NPC patients, but positively correlated with T, N and M classification. CNE1-LMP1-OV cell line was successfully established, which displayed a higher cell proliferation ability and Pim1 expression. NF-κB inhibitor PDTC, PKC inhibitor GF109203X and STAT3 inhibitor Stattic significantly attenuated LMP1-induced Pim1 expression, and while AP-1 inhibitor SR11302 showed no inhibitory effect. Interestingly, Pim1 inhibitor quercetagetin significantly inhibited the proliferation of CNE1-LMP1-OV cells. Conclusion: LMP1 mediates Pim1 expression through NF-κB, PKC and STAT3 signaling, which promotes the proliferation of NPC cells and participate in the clinical progression ofNPC. Keywords: nasopharyngeal carcinoma, Pim1, LMP1, cell proliferation

Xialin Chen,1,2 Xiang Zhu,3 Jianfang Wang,1,2 Jianjiang Liu,1,2 Rong Ji4 1Department of Oncology, Shaoxing People’s Hospital, Shaoxing, Zhejiang 312000, China; 2Department ofOncology, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, China; 3Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; 4Department of Radiation Oncology, Shaoxing Second Hospital, Shaoxing, Zhejiang 312000, China Purpose: The outcomes and safety profiles of neoadjuvant chemotherapy (NACT) + intensity modulated radiotherapy (IMRT) or NACT + IMRT + concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients were retrospectively analyzed.Patients and methods: Between 2010 and 2014, 125 patients with stage III–IVb NPC, who were treated with IMRT (36, 28.8%) or IMRT + CCRT (89, 71.2%) following NACT, participated in the research. There were grade 3–4 toxicities during NACT or radiotherapy (RT) in NACT + IMRT group and NACT + IMRT +CCRT group.Results: MRI within 3 months demonstrated that no patient suffered with progressive disease, 116 patients (92.8%) achieved a response rate (RR) with the complete response (CR) rate of 70.4% (88/125) and partial response (PR) rate of 22.4% (28/125), and nine patients (7.2%) showed stable disease (SD) at the primary site and metastatic nodes. Compared with NACT + IMRT group, patients in NACT + IMRT + CCRT group did not show significantly better RR (93.3% vs 91.7%, P=1.00), CR rate (71.9% vs 66.7%, P=0.67), or PR rate (21.4% vs 25%, P=0.81). There was no significant difference in overall survival (OS, P=0.114), local relapse-free survival (LRFS, P=0.124), distant metastasis-free survival (DMFS, P=0.668) or progression-free survival (PFS, P=0.475) between NACT + IMRT group and NACT + IMRT + CCRT group. T classification (P=0.042) and N classification (P=0.021) were independent prognostic factors for DMFS.Conclusion: To sum up, no significant difference was observed in combined RR, CR rate, LRFS, DMFS, PFS, or OS between the two groups. Keywords: advanced nasopharyngeal carcinoma, intensity modulated radiotherapy, concurrent chemoradiotherapy, neoadjuvant chemotherapy

Bingqing Hui,1,2,* Yetao Xu,3,* Benpeng Zhao,4,* Hao Ji,1,2 Zhonghua Ma,1,2 Shufen Xu,1,2 ZhenYu He,1,5 Keming Wang,1,2 Jianwei Lu6 1Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu, China; 2Department of Oncology, Second Clinical Medical College of Nanjing Medical University, Nanjing 210000, Jiangsu, China; 3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China; 4Basic Medicine Faculty of Shanghai Jiaotong University, Core Facility of Basic Medical Sciences, Shanghai 200000, China; 5Department of General Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu, China; 6Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing 210000, Jiangsu, China *These authors contributed equally to this work Background: Long noncoding RNAs (lncRNAs) are involved in various human diseases, including cancers. However, their mechanisms remain undocumented. We investigated alterations in lncRNA that may be related to pancreatic cancer (PC) through analysis of microarray data. Methods: In the present study, quantitative real-time PCR analysis was used to examine the expression of taurine upregulated 1 (TUG1) in PC tissue samples and PC cell lines. In PC cell lines, MTT assays, colony formation assays, and flow cytometry were used to investigate the effects of TUG1 on proliferation, cell cycle regulation, and apoptosis. Moreover, we established a xenograft model to assess the effect of TUG1 on tumor growth in vivo. The molecular mechanism of potential target genes was detected through nuclear separation experiments, RNA immunoprecipitation (RIP), chromatin immunoprecipitation assays (ChIP), and other experimental methods. Results: The findings suggest that the abnormally high expression of TUG1 in PC tissues was associated with tumor size and pathological stage. Knockdown of TUG1 blocked the cell cycle and accelerated apoptosis, thereby inhibiting the proliferation of PC cells. In addition, RIP experiments showed that TUG1 can recruit enhancer of zeste homolog 2 (EZH2) to the promoter regions of Rho family GTPase 3 (RND3) and metallothionein 2A (MT2A) and inhibit their expression at the transcriptional level. Furthermore, ChIP experiments demonstrated that EZH2 could bind to the promoter regions of RND3 and MT2A. The knockdown of TUG1 reduced this binding capacity. Conclusion: In conclusion, our data suggest that TUG1 may regulate the expression of PC-associated tumor suppressor genes at the transcriptional level and these may become potential targets for the diagnosis and treatment of PC. Keywords: LncRNA, ncRNA, regulate, mechanism, cancer, EZH2, transcriptional level, tumor suppressor genes

Shen-Cun Fang,1,2 Wen Huang,2 Ying-Ming Zhang,1 Hai-Tao Zhang,1 Wei-Ping Xie2 1Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu, China; 2Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China Background: Hypertension (HTN) is a common adverse event of the vascular endothelial growth factor pathway inhibitor apatinib. This study was conducted to evaluate the association of apatinib-induced HTN with clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). Methods: We retrospectively analyzed 110 consecutive patients with advanced NSCLC who were treated with apatinib from August 2014 to January 2018. All patients were classified as normotensive or hypertensive based on blood pressure measurements after initiating therapy. Therapeutic response, progression-free survival (PFS), and overall survival (OS) were evaluated. Univariate and multivariate analyses were performed using the Cox proportional hazards method. Results: A total of 46 patients (42%) were diagnosed with HTN. The median PFS for the hypertensive and normotensive groups were 5.6 months and 4.2 months, respectively (P=0.0027). The median OS times for the hypertensive and normotensive groups were 9.9 months and 7.8 months, respectively (P=0.005). Thirty percent of patients who experienced HTN showed partial response to apatinib as compared with 6.3% of non-hypertensive patients (P=0.002). HTN was independently associated with improved PFS and OS on both univariate and multivariate analyses. Conclusion: Apatinib-induced HTN may be an inexpensive, valid, and easily measurable biomarker for apatinib antitumor efficacy in patients with advanced NSCLC. Keywords: biomarker, hypertension, apatinib, non-small-cell lung cancer, clinical outcomes

Wei Zheng,1 Lin Cao,2 Linna Ouyang,1 Qian Zhang,3 Bofeng Duan,1 Wei Zhou,4 Shan Chen,5 Wei Peng,1 Yi Xie,1 Qing Fan,6 Daoxing Gong7 1Department of Thyroid and Breast Surgery, The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong 518112, China; 2Department of Breast Surgery, Maternal and Child Health Care Hospital of Hunan Province, Changsha, Hunan 410008, China; 3School of Clinical Medicine, Xiangnan University, Chenzhou, Hunan 423000, China; 4Department of Medical Examination, Zhuzhou Central Hospital, Zhuzhou, Hunan 412007, China; 5Department of General Surgery, The Third Hospital of Changsha, Changsha, Hunan 410013, China; 6Department of Gastrointestinal and Breast and Thyroid Surgery, Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital), Changsha, Hunan 410100, China; 7Department of Surgery, The Medical School, University of South China, Hengyang, Hunan 421000, China Purpose: Breast cancer is the most common cancer among women with ~1.67 million cases diagnosed annually worldwide, and ~1 in 37 women succumbed to breast cancer. Over the past decades, new therapeutic strategy has substantially improved the curative effect for women with breast cancer. However, the currently available ER-targeted and HER-2-based therapies are not effective for triple-negative breast cancer patients, which account for ~15% of total breast cancer cases.Materials and methods: We reported that 1,25-(OH)2D3, a biologically active form of vitamin D3, exhibited a strong anticancer effects on the proliferation, migration, invasion, cell cycle arrest, and apoptosis of both ER-positive (MCF-7) and ER-negative breast cancer cells (MDA-MB-453).Results: The anticancer effect of 1,25-(OH)2D3 was more potent compared to the classical chemotherapeutics tamoxifen in MDA-MB-453 cells. Furthermore, we also found that 1,25-(OH)2D3 decreased the expression of Ras and resulted in decrease of the phosphorylation of downstream proteins MEK and ERK1/2, indicating that 1,25-(OH)2D3 plays its anticancer roles through targeting the Ras/MEK/ERK signaling pathway. In addition, Ras overexpression abrogated 1,25-(OH)2D3-induced G0/G1 cell cycle arrest and apoptosis of breast cancer cells, as well as the suppression of proliferation, migration, and invasion. Our study suggested that 1,25-(OH)2D3 suppressed breast cancer tumorigenesis by targeting the Ras/MEK/ERK signaling pathway.Conclusion: 1,25-(OH)2D3 might serve as a promising supplement for breast cancer drug therapy, especially for the ER-negative breast cancer and drug-resistant breast cancer. Keywords: breast cancer, 1,25-(OH)2D3, ER-negative, cell apoptosis, cell proliferation

Miaomiao Gou,* Yong Zhang,* Haiyan Si,* Guanghai Dai Department of Medical Oncology, Chinese People’s Liberation Army General Hospital, Beijing 100853, People’s Republic of China *These authors contributed equally to this work Objective: PD-1 inhibitors have improved efficacy in many cancers. There are currently no reports of the use of PD-1 inhibitors, such as nivolumab, for metastatic biliary tract cancer (mBTC). This study reviewed the efficacy and safety of nivolumab for mBTC with the aim of exploring ways to improve efficacy and survival. Methods: Thirty patients with mBTC were voluntarily treated with nivolumab at the PLA General Hospital. Nivolumab 3 mg/kg was administered. Progression-free survival (PFS) and overall survival were evaluated by Kaplan–Meier and univariate and multivariate analyses were carried out for clinical characteristics. Objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs) were also evaluated. Results: The median treatment cycle is four cycles. One case was complete response, 5 cases partial response, 12 cases stable, and 12 cases progression. ORR was 20%, DCR was 60%, and PFS was 3.1 months (95% CI: 2.13–4.06). The AEs of nivolumab monotherapy were fatigue (three cases), fever (two cases), hypothyroidism (one case), skin reaction (one case), and liver injury (one case). Nivolumab combined with chemotherapy related grade 1–2 hematologic toxicity were leukopenia (five cases) and thrombocytopenia (two cases), and grade 3–4 were leukopenia (three cases). Non-hematologic toxicity grade 1–2 were nausea and vomiting (four cases), fatigue (four cases), fever (three cases), peripheral neurotoxicity (three cases), and hypothyroidism (one case). Univariate analysis showed that PFS of nivolumab combined with chemotherapy was statistically significant compared with that of nivolumab monotherapy (4.1 vs 2.3 months, P=0.031). Programmed death-ligand 1 (PD-L1) expression positively has no relationship with better PFS in contrast with PD-L1 negatively (3.6 vs 3.0 months P>0.05). Multivariate analysis show nivolumab combined with chemotherapy was only the independent factor for longer PFS (HR: 0.432, P

Lu Chen, Xin Jiang, Haoyue Chen, Qiaoyan Han, Chunhua Liu, Miao Sun Department of Hematology, Jingjiang People’s Hospital, The Seventh Affiliated Hospital of Yangzhou University, Jiangsu 214500, P.R. China Background: A variety of microRNAs (miRNAs) are aberrantly expressed in acute myeloid leukemia (AML), and these dysregulated miRNAs perform crucial roles in tumorigenesis and progression of AML. miR-628-3p (miR-628), one of the miRNAs dysregulated in multiple types of human cancers, exerts antitumor roles in different cancer types. However, no specific study has explored the expression pattern and role of miR-628 in AML. Materials and methods: In this study, RT-qPCR was performed to detect miR-628 expression in AML tissues and cell lines. CCK-8 assay, flow cytometry analysis and xenograft tumor experiment was carried out to determine the functions of miR-628 in AML cells. The possible mechanism underlying the activity of miR-628 in AML cells was also explored using a series of experiments. Results: Our results revealed the downregulated expression of miR-628 in patients with AML and AML cell lines. Ectopic expression of miR-628 resulted in the inhibition of AML cell proliferation and induction of cell cycle arrest and apoptosis in vitro and attenuation of tumor growth in vivo. Insulin-like growth factor 1 receptor (IGF-1R) was identified as a direct target gene of miR-628 in AML cells. IGF-1R expression was upregulated in patients with AML and upregulation of IGF-1R expression inversely correlated with miR-628 level. Furthermore, IGF-1R knockdown imitated the tumor suppressive effect of miR-628 in AML cells. Restoration of IGF-1R expression abrogated the effects of miR-628 on the proliferation, cycle status, and apoptosis rate of AML cells. miR-628 inhibited the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) pathway in AML cells both in vitro and in vivo through the inhibition of IGF-1R expression. Conclusion: Our results demonstrate that miR-628 exhibits antitumor effects in AML through the direct targeting of IGF-1R and regulation of PI3K/Akt pathway, suggestive of its potential role as a therapeutic target in patients with this aggressive hematological malignant tumor. Keywords: acute myeloid leukemia, microRNA-628, proliferation, cell cycle, apoptosis, insulin-like growth factor 1 receptor, PI3K/Akt pathway

Zhitao Jiang,1,* Qianyu Cao,2,* Guoliang Dai,3 Jianchun Wang,1 Chundi Liu,1 Lingyan Lv,1 Jinhuo Pan4 1Department of Pharmacy Office, Zhangjiagang Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China; 2The First Clinical College, Nanjing University of Chinese Medicine, Nanjing, China; 3Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; 4College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China *These authors contributed equally to this work Background: There are few clinical challenges associated with the treatment of colorectal cancer (CRC). Studies have shown that TGF-β plays a crucial role in CRC. Importantly, celastrol, a major components of the root extract of the traditional Chinese herb Tripterygium wilfordii Hook F, has been shown to inhibit the growth, adhesion, and metastasis of human CRC cells through the inhibition of TGF-β1/Smad signaling.Materials and methods: Real-time PCR and Western blot tests were proceeded to present TGF-β1, TGF-β receptor type I (TGFβRI), TGF-β receptor type II (TGFβRII), Smad2/3, p-Smad2/3, Smad4, and glyceraldehyde-3-phosphate dehydrogenase expression in human colon cancer cell samples.Results: Our results indicated that celastrol can reduce the expression levels of TGF-β1, TGFβRI, and TGFβRII in HCT116 and SW620 cells. Furthermore, celastrol could also prevent the increase in Smad4 and p-Smad2/3 in HCT116 and SW620 cells.Conclusion: Celastrol could inhibit tumor growth through TGF-β1/Smad signaling and might be a promising therapeutic component against CRC. Keywords: celastrol, colorectal cancer, TGF-β1, Smad&nbsp

Lijie Zhao,1 Yuhua Zheng,1 Yong Ji,2 Xiaoying Zhang3 1Department of Gynecology, Maternal and Child Health Hospital of Foshan, Foshan 528000, Guangdong, China; 2Department of Surgery, The First People’s Hospital of Foshan, Foshan 528000, Guangdong, China; 3Department of Gynecology, Jiashi County People’s Hospital of Kashi Region, Kashi, Xinjiang 844000, China Background: The oncogenic potential of special AT-rich binding protein 1 (SATB1) has been reported in various types of cancer, but its function in cervical cancer remains not fully investigated. This study aimed to investigate the effect of SATB1 mRNA expression on tumor progression and outcomes in the cervical cancer patients. Methods: A total of 33 cervical cancer patients treated in our hospital from September 2012 to December 2015 were included. The mRNA expression level of STAB1 in cervical cancer tissue was determined by real-time PCR, and the patients were divided into dichotomous groups based on their SATB1 expression level. Clinical characteristics, recurrence, and survival outcomes were compared between groups. Results: Compared with the SATB1-low group, the SATB1-high group had significantly advanced International Federation of Gynecology and Obstetrics (FIGO) stages (P=0.037) and histologic grade (P=0.036). Kaplan–Meier analysis showed that SATB1-high group had a worse overall survival (P=0.078, marginal significant). In the subgroup analysis of pathological types, adenocarcinomas group (n=8) had a significantly higher SATB1 expression level as compared with the squamous cell carcinomas (n=18) and adenosquamous carcinomas (n=7) groups (both P

Zhaojun Yin, Weiru Ren Gynaecology Ward of Maternal and Child Health Hospital, Shizhong District, Zaozhuang 277100, Shandong, People’s Republic of China Background: MicroRNA-217 (miR-217) has been demonstrated to participate in the tumorigenesis and progression of various types of cancers. Nevertheless, the role of miR-217 in cervical carcinoma still remains not fully elucidated. This current work sought to investigate the role of miR-217 in the growth, migration, and invasion of cervical carcinoma and detect the role of miR-217 in the chemosensitivity of cervical carcinoma cell to cisplatin.Materials and methods: The levels of miR-217 in 65 pairs of cervical carcinoma tissues and matched normal tissues were detected using quantitative real-time-PCR assay. The roles of miR-217 on the growth, apoptosis, migration, and invasion of cervical cancer SiHa and Ca-Ski cells were analyzed using Cell Counting Kit-8, flow cytometry, wound healing, and Transwell invasion assays, respectively. The target of miR-217 was identified using the online analysis tool TargetScan (http://www.targetscan.org/vert_72/) and was verified by luciferase reporter and immunoblotting assays. The xenograft tumor model was constructed to explore the impact of miR-217 on the growth of cervical carcinoma cell in vivo.Results: The level of miR-217 was remarkably lower in cervical carcinoma tissues than that in noncancerous tissues. Overregulation of miR-217 markedly suppressed the aggressiveness of cervical cancer cell and induced cell apoptosis through regulating V-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Finally, upregulation of miR-217 enhanced the chemosensitivity of both SiHa and Ca-Ski cervical cancer cells toward cisplatin.Conclusion: Altogether, upregulation of miR-217 inhibits the aggressiveness phenotypes of cervical carcinoma cell via regulating KRAS gene and increases the sensitivity of cervical cancer cell to cisplatin. Keywords: cervical cancer, cisplatin, miR-217, KRAS

Yong Peng, Mingming Zhang, Zhongzhong Jiang, Yugang Jiang Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China Background: Tripartite motif-containing protein 28 (TRIM28) is a transcriptional corepressor involved in the regulation of several cancers, including glioma. It has been reported that TRIM28 takes part in the process of autophagy. However, its effect on the autophagy and cell proliferation in gliomas has not been elucidated. Here, we report a novel tumor cell proliferation mechanism in which TRIM28-regulated autophagy promotes glioma tumor cell proliferation.Materials and methods: We analyzed the expressions of TRIM28 and LC3 in different WHO grades of gliomas by IHC assays. We then knocked down and overexpressed TRIM28 or knocked down ATG5 in U251 cells and confirmed its roles in autophagy and cell proliferation via cell counting, immunofluorescence, and Western blot.Results: The results showed that TRIM28 and autophagy levels were significantly increased with the progression of tumor grade in glioma. TRIM28 promoted glioblastoma cell proliferation. Knockdown of TRIM28 inhibited autophagy in glioblastoma cells. Meanwhile, TRIM28 promoted glioblastoma cell proliferation by modulating TRIM28.Conclusion: These data demonstrated that TRIM28 activates autophagy and increases cell proliferation in glioma. Keywords: TRIM28, autophagy, glioblastoma, proliferation

Guanghua Jin, Xiaoyun Mao, Zhen Qiao, Bo Chen, Feng Jin Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People’s Republic of China Background: RAP80 is a member of BRCA1-A complex, which plays an important role in regulating the cell cycle checkpoint and DNA damage repair in the nucleus. Method: We investigated RAP80 expression in breast cancer and its paired normal breast tissues to further analyze its role in the biological behavior of breast cancer cells. Results: RAP80 expression in breast cancer (62.3%, 101/162) was significantly lower than that in adjacent normal breast tissues (P

Chaosen Yue,1 Yaoyao Ren,2 Hua Ge,1 Chaojie Liang,1 Yingchen Xu,1 Guangming Li,1 Jixiang Wu1 1Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China Background: Hepatocellular carcinoma (HCC) is an extremely common malignant tumor with worldwide prevalence. The aim of this study was to identify potential prognostic genes and construct a competing endogenous RNA (ceRNA) regulatory network to explore the mechanisms underlying the development of HCC. Methods: Integrated analysis was used to identify potential prognostic genes in HCC with R software based on the GSE14520, GSE17548, GSE19665, GSE29721, GSE60502, and the Cancer Genome Atlas databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway-enrichment analyses were performed to explore the molecular mechanisms of potential prognostic genes. Differentially expressed miRNAs (DEMs) and lncRNAs (DELs) were screened based on the Cancer Genome Atlas database. An lncRNA–miRNA–mRNA ceRNA regulatory network was constructed based on information about interactions derived from the miRcode, TargetScan, miRTarBase, and miRDB databases. Results: A total of 152 potential prognostic genes were screened that were differentially expressed in HCC tissue and significantly associated with overall survival of HCC patients. There were 13 key potential prognostic genes in the ceRNA regulatory network: eleven upregulated genes (CCNB1, CEP55, CHEK1, EZH2, KPNA2, LRRC1, PBK, RRM2, SLC7A11, SUCO, and ZWINT) and two downregulated genes (ACSL1 and CDC37L1) whose expression might be regulated by eight DEMs and 61 DELs. Kaplan–Meier curve analysis showed that nine DELs (AL163952.1, AL359878.1, AP002478.1, C2orf48, C10orf91, CLLU1, CLRN1-AS1, ERVMER61-1, and WARS2-IT1) in the ceRNA regulatory network were significantly associated with HCC-patient prognoses. Conclusion: This study identified potential prognostic genes and constructed an lncRNA–miRNA–mRNA ceRNA regulatory network of HCC, which not only has important clinical significance for early diagnoses but also provides effective targets for HCC treatments and could provide new insights for HCC-interventional strategies. Keywords: hepatocellular carcinoma, prognostic gene, ceRNA

Junfeng Wu,1,* Wei Li,2,* Jinzhuo Ning,1 Weimin Yu,1 Ting Rao,1 Fan Cheng1 1Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; 2Department of Anesthesiology, People’s Hospital of Wuhan University, Wuhan, Hubei, China *These authors contributed equally to this work Background: Rently, the incidence of bladder cancer has been on the rise. Accumulating researches have been conducted to clarify the molecular mechanisms and potential therapeutic targets of bladder cancer. The present study aims to explore the regulatory mechanism of the urothelial carcinoma-associated 1 (UCA1)-miR-582-5p-ATG7 axis in bladder cancer. Methods: Quantitative real-time polymerase chain reaction was used to detect mRNA level. Relative protein expression was detected by western blot. wound healing assay and transwell were used to determine migration and invasion of cells. in addtion, luciferase reporter assay and immunohistochemistry were performed.Results: UCA1 expression was upregulated in bladder cancer tissues and cells, while the depletion of UCA1 by shRNA resulted in the suppression of cell proliferation, invasion, migration, and drug resistance. Further studies demonstrated that UCA1 could directly interact with miR-582-5p, and that there was an inverse correlation between miR-582-5p and UCA1. In addition, we found that ATG7 is a target of miR-582-5p and can be downregulated by either miR-582-5p overexpression or UCA1 knockdown. In particular, the autophagy is reduced when UCA1 shRNA is introduced. Moreover, the in vivo experiment further demonstrated the contribution of UCA1 in bladder cancer including tumor growth, invasion, and migration, and UCA1 knockdown can inhibit the aforementioned activities. Conclusion: These results provided evidence for a novel UCA1 interaction regulatory network in bladder cancer, that is, UCA1-miR-582-5p-ATG7-autophagy axis. Our study provides a new insight into the treatment of bladder cancer. Keywords: lncRNA UCA1, miR-582-5p, bladder cancer, migration and invasion, resistance

Lei Wang, Minyi Xu, Pei Lu, Fangfang Zhou Department of Clinical Laboratory, Shanghai Eighth People’s Hospital, Xuhui Branch of Shanghai Sixth People’s Hospital, Shanghai 200235, People’s Republic of China Background: In recent years, microRNAs (miRNAs) have been reported to be aberrantly expressed in colorectal cancer (CRC). The deregulation of miRNAs is implicated in the formation and progression of CRC, and participates in the regulation of a wide range of biological behaviors. Considering the crucial role of miRNAs in CRC, miRNAs are thought to have significant promise in the diagnosis and therapy of patients with this malignancy. Material and methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-769 expression in CRC tissues and cell lines. MTT assay and flow cytometry analysis were used to determine the effects of miR-769 upregulation in CRC cell proliferation and apoptosis, respectively. The influence of miR-769 overexpression in CRC cell migration and invasion was evaluated through migration and invasion assays. Notably, the possible mechanisms underlying the action of miR-769 in CRC cells were explored. Results: In the present study, miR-769 was frequently found to be poorly expressed in CRC tissues and cell lines. Functional assays showed that recovery of miR-769 expression suppressed CRC cell proliferation, migration, and invasion, increased cell apoptosis in vitro, and inhibited tumor growth in vivo. Cyclin-dependent kinase 1 (CDK1) was the direct target of miR-769 in CRC cells. CDK1 was overexpressed in CRC tissue samples and negatively correlated with miR-769 expression. In addition, CDK1 inhibition imitated the tumor suppressor activity of miR-769 in CRC cells, and restoration of CDK1 expression partially abolished the tumor-suppressing roles of miR-769 in malignant CRC cells. Conclusion: The results of this study demonstrated that miR-769 was downregulated in CRC and directly targeted CDK1 to be implicated in the regulation of CRC cell proliferation, apoptosis, migration and invasion. Thus, the miR-769/CDK1 axis might be an effective thera­peutic target for treating patients with CRC. Keywords: colorectal cancer, microRNA-769, proliferation, apoptosis, metastasis, cyclin-dependent kinase 1

Enrique Pérez-Cárdenas,1 Lucía Taja-Chayeb,1 Catalina Trejo-Becerril,1 José Chanona-Vilchis,2 Alma Chávez-Blanco,1 Guadalupe Domínguez-Gómez,1 Elizabeth Langley,1 Alejandro García-Carrancá,3,4 Alfonso Dueñas-González3,4 1Division of Basic Research, Instituto Nacional de Cancerología, Mexico City, Mexico; 2Department of Pathology, Instituto Nacional de Cancerología, Mexico City, Mexico; 3Unit of Biomedical Research on Cancer, Biomedical Research Institute, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico; 4Unit of Biomedical Research on Cancer, Instituto Nacional de Cancerologia, Mexico City, Mexico Introduction: Metastasis involves the accumulation of genetic and epigenetic alterations leading to activation of prometastatic genes and inactivation of antimetastatic genes. Among epigenetic alterations, DNA hypermethylation and histone hypoacetylation are the focus of intense translational research because their pharmacological inhibition has been shown to produce antineoplastic activity in a variety of experimental models. Aims: This study aimed to evaluate the antimetastatic effect of the DNA-methylation inhibitor, hydralazine, and the histone deacetylase inhibitor, valproic acid. Methods: NIH 3T3-Ras murine cells were treated with hydralazine and valproic acid to evaluate their effects upon cell proliferation, cell motility, chemotaxis, gelatinase activity, and gene expression. Lung metastases were developed by intravenous injection of NIH 3T3-Ras cells in BALB/c nu/nu mice and then treated with the drug combination. Results: Treatment induced a growth-inhibitory effect on NIH 3T3-Ras cells, showed a trend toward increased gelatinase activity of MMP2 and MMP9, and inhibited chemotaxis and cell motility. The combination led to a strong antimetastatic effect in lungs of nude mice. Conclusion: Hydralazine and valproic acid, two repositioned drugs as epigenetic agents, exhibit antimetastatic effects in vitro and in vivo and hold potential for cancer treatment. Keywords: hydralazine, valproic acid, epigenetics, metastasis, ras

Pingting Zhu,1,2,* Zhaoguo Liu,3,* JiaoJiao Zhou,1 Yuanyuan Chen1 1School of Nursing, Yangzhou University, Yangzhou, China; 2Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China; 3Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China *These authors contributed equally to this work Background: Tanshinol is an active constituent of Salvia miltiorrhiza and possess anti-inflammatory, antioxidant, and anti-bacterial activity. Herein, we explored the role of tanshinol on the growth and aggressiveness of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Materials and methods: The proliferation of a panel of HCC cell lines was measured using MTT assay. The expressions of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) were detected by immunofluorescence staining and immunohistochemical assay. The levels of Bcl-2 and Bax were determined using immunoblotting assay. The secretions of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected by ELISA. The migration and invasion abilities of HepG2 cell were determined using wound healing and Transwell invasion assays. The apoptosis of HepG2 cell induced by tanshinol was analyzed by Annexin V/propidium iodide staining. A xenograft model was constructed to investigate the inhibitory effect of tanshinol on HepG2 cell growth in vivo. To further investigate the role of tanshinol on the metastasis of HepG2 cell in vivo, an experimental metastasis assay was performed. Results: Tanshinol inhibited the growth and colony formation of HCC cell in vitro. Tanshinol also induced the apoptosis of HepG2 cell and inhibited the migration and invasion of HepG2 cell. In in vivo experiments, tanshinol suppressed the tumor growth and metastasis of HepG2 cell. Furthermore, the phosphorylation of PI3K and AKT was decreased by tanshinol in vitro and in vivo. Conclusion: Tanshinol exerts its anti-cancer effects via regulating the PI3K-AKT signaling pathway in HCC. Keywords: tanshinol, HCC, migration, invasion, apoptosis

Minggu Zhu,1,* Qicai Wang,2,* Zhaowen Luo,1 Kelong Liu,2 Zhiqiao Zhang1 1Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde District, Guangdong, China; 2Department of General Surgery, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde District, Guangdong, China *These authors contributed equally to this work Background: As a serious challenge for public health, the prognosis of gastric cancer patients is still poor. The current study aimed to develop and validate a prognostic signature to predict the overall survival of gastric cancer patients.Patients and methods: The dataset in the present study was obtained from The Cancer Genome Atlas database. The present study finally included 343 gastric cancer patients with information on long non-coding RNA (lncRNA) expression and overall survival.Results: A prognostic model named Eleven-lncRNA signature was constructed according to the expression values of eleven prognostic lncRNA predictors identified by univariate and multivariate Cox regression model. According to time-dependent receiver operating characteristic curves, the Harrell’s concordance indexes of Eleven-lncRNA signature were 0.764 (95% CI 0.720–0.808), 0.776 (95% CI 0.732–0.820), and 0.807 (95% CI 0.763–0.851) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively in the model group. In the validation group, the Harrell’s concordance indexes of Eleven-lncRNA signature were 0.748 (95% CI 0.704–0.792), 0.794 (95% CI 0.750–0.838), and 0.798 (95% CI 0.754–0.842) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively. The gastric cancer patients (n=343) in the model group could be stratified into low-risk group (n=171) and high-risk group (n=172) according to the median of Eleven-lncRNA signature score. Kaplan–Meier survival curves showed that the mortality rate in the high-risk group was significantly poorer than that in the low-risk group (P

Giandomenico Roviello,1 Rosj Gallicchio,2 Giovanni Bozza,1 Maria Grazia Rodriquenz,1 Michele Aieta,1 Giovanni Storto2 1Division of Medical Oncology, Department of Onco-Hematology, IRCCS CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy; 2Nuclear Medicine Department, IRCCS CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy Background: Radium-223 dichloride is an alpha emitter approved for metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, little data are available on the prognostic factors during radium-223-based therapy.Patients and methods: Patients with histologically confirmed progressive CRPC with two or more bone metastases and symptomatic disease were eligible. Previous therapy with a novel hormonal therapy was allowed. The patients received six intravenous injections of radium-223 every 4 weeks. A visual analog scale (VAS) was adopted to evaluate patients’ basal pain.Results: A total of 25 patients were evaluated. Of these, 6 (24%) reported VAS

Sang Eun Yoon, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Seung Tae Kim Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Aim: Patients in clinical practice are relatively vulnerable compared to those enrolled in clinical trials. We focused on analyzing the pattern of regorafenib use in routine clinical practice, which included initial starting dose and follow-up schedule. We also evaluated the efficacy and safety according to clinical regimen.Methods: We retrospectively reviewed the medical records of 134 Korean heavily pretreated metastatic colorectal cancer (mCRC) patients who had received regorafenib monotherapy as salvage treatment in routine clinical practice between January 2014 and January 2018.Results: Among the 134 mCRC patients, the median age was 55 years (range, 22–80 years), and 51% had previously received four or more chemotherapy treatments. Thirty-eight (28.3%) patients had more than three metastatic lesions. As an initial starting dose, 120mg regorafenib was mostly frequently used (n=65, 48.5%), followed by 80 mg (32.8%) and 160mg (18.7%). The first follow-up after regorafenib initiation was most frequently at 28 days (45.5%), followed by 14 days (29.9%), 7 days (13.4%), and 21 days (11.2%). There was no significant difference in response rate according to initial dose of regorafenib (80 mg vs 120 mg vs 160 mg, 4.5% vs 1.5% vs 4.0%, P=0.596) or disease control rate (80 mg vs 120 mg vs 160 mg, 38.6% vs 29.2% vs 31.6%, P=0.299). Progression-free survival did not differ according to initial dose (80 mg vs 120 mg vs 160 mg, 2.8 months [95% CI 2.1–3.5] vs 2.2 months [95% CI 1.7–2.8] vs 1.9 months [95% CI 1.3–2.4], P=0.076). Grade 3/4 adverse events occurred in 17 (12.7%) patients and were not related to initial dose of regorafenib (P=0.126).Conclusion: Here, we present efficacy and safety data according to different initial doses of regorafenib in clinical practice. These data may provide useful information when using regorafenib for refractory mCRC in clinical practice. Keywords: regorafenib, colorectal cancer, initial dose

Ze Tang, Hongfei Cai, Rui Wang, Youbin Cui Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China Background: CD300A, a type I transmembrane glycoprotein receptor, plays an important role in immune response. Recent studies have reported that CD300A is involved in the development of hematological malignancies. Purpose: The objective of this study was to investigate the role of CD300A in the progression of non-small-cell lung cancer (NSCLC) and explore the associated mechanism. Materials and methods: Gene Expression Profiling Interactive Analysis (GEPIA) was used to analyze the expression of CD300A in NSCLC and its prognostic value. NSCLC cell lines A549 and H1650 were transfected with siRNA-CD300A or pcDNA3.1-CD300A vector to down- or up-regulate the expression of CD300A. Cell Counting Kit 8, colony formation and Transwell assays were used to assess the effects of CD300A on cell proliferation and migration capacities. Flow cytometry was performed to examine rate of apoptosis, and the protein levels of associated proteins was detected using Western blot assay. Results: From GEPIA analysis, we observed that expression of CD300A mRNA was downregulated in NSCLC and positively correlated with the overall survival of NSCLC patients. Overexpression of CD300A significantly suppressed cell growth and migration capacities of A549 and H1650 cells and induced cell apoptosis via regulating apoptosis-related proteins. Moreover, decreasing level of CD300A promoted cell growth and migration and blocked apoptosis of NSCLC cells. Furthermore, upregulation of CD300A led to significant decrease in expression level of Wnt3 and β-catenin, the pivotal components in Wnt/β-catenin signaling pathway, and an increase in expression of E-cad, a key protein in tumor metastasis, in A549 and H1650 cells; while depletion of CD300A up-regulated the Wnt/β-catenin signaling pathway. In conclusion, the present study highlighted an anti-oncogenic role of CD300A in the progression of NSCLC via inhibiting Wnt/β-catenin pathway, suggesting that CD300A might be a potential target for the treatment of NSCLC. Conclusion: CD300A plays an anti-oncogenic role in the progression of NSCLC through inhibiting the Wnt/β-catenin pathway, suggesting that CD300A might be a potential target for the treatment of NSCLC. Keywords: non-small-cell lung cancer, CD300A, prognosis, progression

Ying Ye,1,* Yanan Song,1,* Juhua Zhuang,1 Guoyu Wang,1 Jing Ni,1 Suiliang Zhang,2 Wei Xia1 1Department of Nuclear Medicine, The Seventh People’s Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Oncology Department, The Seventh People’s Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Involvement of microRNAs in tumor development and their potential as prognostic biomarkers had been well acknowledged. However, the expression, clinical significance, and functional mechanisms of microRNA (miR)-302a-3p in hepatocellular carcinoma (HCC) have not been reported. Patients and methods: Real-time quantitative polymerase chain reaction was used to evaluate the expression of miR-302a-3p in 111 HCC tissues and adjacent normal liver tissues. Its association with clinicopathological characteristics was analyzed by the chi-square test. The Kaplan–Meier univariate survival analysis and multivariate Cox regression analysis were used to identify the clinical significance of miR-302a-3p in the overall survival (OS) of HCC patients. Transfection of miR-302a-3p mimics into HepG2 and Huh7 HCC cell lines was conducted to reveal its underlying mechanism in regulating HCC progression. Results: miR-302a-3p expression was significantly decreased in HCC tissues compared with that in paired adjacent normal liver tissues (P=0.005). miR-302a-3p expression was correlated with tumor number (P=0.003), tumor size (P

Yiping Zhang,1,2 Furong Huang,3 Qingyu Luo,3 Xiaowei Wu,3 Zhihua Liu,3 Hongyan Chen,3 Yinghui Huang1 1Cancer Institute, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China; 2China National Center for Biotechnology Development, Beijing, China; 3The State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing,China Purpose: Carboplatin is a first-line treatment for ovarian cancer. However, most patients develop resistance and undergo disease recurrence. This study aims to explore the relationship between the expression of X-linked inhibitor of apoptosis protein (XIAP) and carboplatin sensitivity in ovarian cancer.Patients and methods: We examined the expression of XIAP in ovarian cancer by immunochemistry. Next, we investigated the role of XIAP in regulating carboplatin sensitivity in ovarian cancer ES2 and 3AO cells through Cell Counting Kit-8 cell viability assay and fluorescein isothiocyanate-Annexin V/propidium iodide apoptosis assay. Expression of apoptotic effectors was measured by Western blot.Results: The immunochemistry results showed that high XIAP expression levels inversely correlated with carboplatin response (P=0.03) and progression-free survival (P=0.0068) in patients with ovarian cancer. Knockdown of XIAP repressed the cell viabilities in the carboplatin-treated cells and increased carboplatin-induced caspase activation. In summary, our data show that XIAP mediates carboplatin sensitivity of ovarian cancer.Conclusion: In summary, our data show that XIAP mediates carboplatin sensitivity of ovarian cancer and XIAP may be a novel target for the treatment of carboplatin-resistant ovarian cancer. Keywords: XIAP, carboplatin, chemosensitivity, ovarian cancer

Peng Chen,1,* Fuchao Chen,2,* Jiexin Lei,3 Benhong Zhou1 1Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of China; 2Department of Pharmacy, Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, People’s Republic of China; 3Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of China *These authors contributed equally to this work Background: Osimertinib is an EGFR-TKI that is selective for both EGFR-TKI-sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer (NSCLC). The purpose of this study was conducting a meta-analysis to evaluate the clinical efficacy and safety of osimertinib in the treatment for NSCLC. Methods: Using “osimertinib” as a keyword combined with “non-small-cell lung cancer” and “randomized controlled trial” as medical subject headings, the following electronic databases were searched: PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure. After data extraction and quality assessment of the included randomized controlled trials, the RevMan 5.3 software and R meta package were applied for meta-analysis of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Ten studies met our criteria and were included in the meta-analysis, with a total of 3,260 participants. The meta-analysis showed that osimertinib therapy was superior to the control therapy alone in ORR (combined RR=1.53, 95% CI: 0.87–2.71, P=0.14), DCR (combined RR=1.07, 95% CI: 0.79–1.44, P=0.66), PFS (combined RR=0.32, 95% CI: 0.24–0.44, P

Yang Liu,1 Shao-Cheng Lyu,2 Xian-Qiang Wang,3 Yan-Bin Wang1 1Department of Hepatobiliary, PLA General Hospital of China, Beijing 100853, People’s Republic of China; 2Department of Hepatobiliary, Beijing Chaoyang Hospital, Beijing 100020, People’s Republic of China; 3Department of Pediatric Surgery, PLA General Hospital of China, Beijing 100853, People’s Republic of China Objective: This study aimed to investigate the application of preoperative three-dimensional model design in radioactive particle implantation for advanced pancreatic cancer, and accordingly analyze the effect of particle implantation in the treatment of advanced pancreatic cancer.Methods: The clinical data of 63 patients with advanced pancreatic cancer treated with particle implantation from January 2009 to June 2015 in the General Hospital of Chinese PLA were retrospectively analyzed. The implantation design was conducted using the FitMe three-dimensional model reconstruction software for all patients before the operation to explore the significance of preoperative three-dimensional model design in guiding operation. These data were compared with the general data, postoperative recovery, and follow-ups of patients with advanced pancreatic cancer, who underwent conservative treatment at the same time period, in order to explore the effect of particle implantation in the treatment of advanced pancreatic cancer.Results: In the 63 patients with advanced pancreatic cancer who underwent particle implantation, the average number of implanted particles was 53.4±18.7. Gastroparesis occurred in 17 patients and pancreatic fistula occurred in 13 patients after the operation, and no perioperative death occurred.Follow-up results: In the particle group, the relief rate of abdominal pain was 90.9%, the 1-month, 6-month, 1-year, and 2-year survival rates were 100%, 58.7%, 22.4%, and 9%, respectively, and median survival time was 10.4±0.7 months, which were significantly higher than patients in the control group (P

Long noncoding RNA (lncRNA) Sox2 overlapping transcript (SOX2OT) has been reported to be upregulated in various types of cancers, including non-small-cell lung cancer (NSCLC). However, the biological role and underlying mechanism of SOX2OT activity in NSCLC remain largely unknown. This study aims to investigate the function and possible molecular mechanisms of SOX2OT in NSCLC.Quantitative real-time polymerase chain reaction was used to detect SOX2OT expression, and cellular proliferation, migration, and invasion were measured using cell counting kit-8, wound healing, and Transwell invasion assays, respectively. Western blotting was used to determine protein expression. Starbase 2.0 and luciferase reporter assay were utilized to identify the molecular target of SOX2OT.Here, we discovered that SOX2OT was markedly upregulated in NSCLC tissues and cell lines. Knockdown of SOX2OT inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in NSCLC cells. Moreover, we explored the regulatory mechanism of SOX2OT and found that SOX2OT directly bound microRNA 132 (miR-132) in NSCLC cells. Importantly, miR-132 inhibition partially reversed the SOX2OT knockdown-mediated inhibitory effect on cell proliferation, migration, invasion, and EMT process. We also found that SOX2OT could regulate zinc finger E-box-binding homeobox 2 (a target of miR-132) expression, which played crucial roles in tumor cell proliferation and invasion.These findings indicated that SOX2OT was a noncoding oncogene that exerted important regulatory functions in NSCLC via sponging miR-132 and might represent a novel strategy for overcoming this disease.

Chen Qiu,1– 3,* Xin Zhang,3,4,* Bin Huang,3,4 Shuai Wang,3,4 Wenjing Zhou,3,4 Chao Li,3,4 Xingang Li,3,4 Jian Wang,3– 5 Ning Yang3,4,6 1Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, People’s Republic of China; 4Shandong Key Laboratory of Brain Function Remodeling, Jinan, People’s Republic of China; 5K. G. Jebsen Brain Tumor Research Center, Department of Biomedicine, University of Bergen, Bergen, Norway; 6Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning Yang Email yangning@sdu.edu.cnIntroduction: Disulfiram (DSF), a drug used in the treatment of alcoholism since 1948, has been shown to have antitumor properties in various tumor types possibly due to the induction of a type cell death, ferroptosis, and the sensitization of cells to chemo- and radiotherapy. In this study, we explored the antitumor properties of DSF in glioblastoma (GBM) and investigated the underlying molecular mechanisms.Methods: GBM cell lines U251 and LN229 were treated with DSF to assess cytotoxicity and activity of the molecule in vitro. Response of cells to treatment was examined using cell viability, flow cytometry, LDH release assay, immunofluorescence and Western blot analysis.Results: DSF inhibited cell growth of GBM U251 and LN229 cell lines in vitro in a concentration-dependent manner. Flow cytometry demonstrated that DSF caused G0-G1 growth arrest. DSF treatment led to increased ROS and lipid peroxidation levels relative to controls indicating the involvement of ferroptosis. Furthermore, DSF triggered lysosomal membrane permeabilization (LMP), a critical mechanism promoting cell death, in a ROS-dependent manner. Finally, DSF enhanced radiosensitivity of U251 and LN229 cells.Discussion: Our findings indicated that DSF induced ferroptosis and LMP and enhanced the radiosensitivity of GBM cells. Therefore, DSF might have efficient antitumor activity in the treatment of human GBM.Keywords: disulfiram, ferroptosis, lysosomal membrane permeabilization, ROS, glioblastoma