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Long noncoding RNAs (lncRNAs) are known to regulate gene expression; however, in many cases, the mechanism of this regulation is unknown. One novel lncRNA relevant to inflammation and arachidonic acid (AA) metabolism is the p50-associated COX-2 extragenic RNA (PACER). We focused our research on the regulation of PACER in lung cancer. While the function of PACER is not entirely understood, PACER is known to play a role in inflammation-associated conditions. Our data suggest that PACER is critically involved in COX-2 transcription and dysregulation in lung cancer cells. Our analysis of The Cancer Genome Atlas (TCGA) expression data revealed that PACER expression is significantly higher in lung adenocarcinomas than normal lung tissues. Additionally, we discovered that elevated PACER expression strongly correlates with COX-2 expression in lung adenocarcinoma patients. Specific siRNA-mediated knockdown of PACER decreases COX-2 expression indicating a direct relationship. Additionally, we show that PACER expression is induced upon treatment with proinflammatory cytokines to mimic inflammation. Treatment with prostaglandin E2 (PGE2) induces both PACER and COX-2 expression, suggesting a PGE2-mediated feedback loop. Inhibition of COX-2 with celecoxib decreased PACER expression, confirming this self-regulatory process. Significant overlap between the COX-2 promotor and the PACER promotor led us to investigate their transcriptional regulatory mechanisms. Treatment with pharmacologic inhibitors of NF-κB or AP-1 showed a modest effect on both PACER and COX-2 expression but did not eliminate expression. These data suggest that the regulation of expression of both PACER and COX-2 is complex and intricately linked.

Background: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood. Materials and Methods: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing. Results: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast (n = 67), non-small cell lung (n = 25), colorectal (n = 18), gastroesophageal (n = 17), pancreatic (n = 11), and uterine (n = 11). The PPV of ERBB2 CNG in determining HER2 positivity by standard IHC/FISH definitions was 88% for tissue NGS (n = 57) and 80% for ctDNA (n = 47). The PPV among breast cancer patients for tissue NGS was 97% (n = 35) and ctDNA was 93% (n = 39). However, for non-breast cancer cases, the PPV of ERBB2 amplification by tissue NGS dropped to 76% (n = 22) and by ctDNA to 44% (n = 7). Conclusions: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer.

GZ17-6.02 is undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in renal carcinoma cells and to determine whether it interacted with axitinib to enhance tumor cell killing. GZ17-6.02 interacted in an arithmetically greater than additive fashion with axitinib to kill kidney cancer cells. GZ17-6.02 and axitinib cooperated to inactivate ERBB2, c-MET, c-KIT, c-SRC, the AMPK, STAT3, STAT5 and eIF2α and to activate PERK, ULK1 and ATG13. The drugs interacted to increase the expression of FAS-L and to decrease the levels of MCL1, BCL-XL, and HDACs 1-3. The drugs as single agents inactivated the Hippo pathway. GZ17-6.02 and axitinib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, eIF2α, toxic BH3 domain proteins or CD95/FADD significantly reduced drug combination lethality. GZ17-6.02 and axitinib increased the expression of BAK, BIM, Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs increased phosphorylation of ULK1 S757 and ATG13 S318 and decreased the phosphorylation of mTORC1 and mTORC2, effects blocked by knock down of AMPKα. Knock down of Beclin1 or ATG5 prevented the drug combination reducing expression of HDACs 1-3 and from enhancing the expression of MHCA. Knock down of HDACs 1-3 enhanced MHCA expression. We conclude that GZ17-6.02 and axitinib interact to kill requiring ER stress signaling, autophagy and death receptor signaling. Autophagic degradation of HDACs played a key role in enhancing MHCA expression and of a potential improved response to checkpoint inhibitory immunotherapy.

Background: We assessed the relationship between preoperative prognostic nutritional index (PNI) and short- and long-term outcomes among gastric cancer patients because the clinical significance of PNI in these patients remains controversial. Materials and Methods: We retrospectively reviewed the medical records of 434 consecutive patients who underwent curative laparoscopic gastrectomy for gastric cancer. Results: Patients with postoperative complications had a significantly poorer overall survival (OS) than those without. On multivariate analyses, postoperative complications were independently associated with PNI value and operative procedure type. In the low PNI group (n = 118), those with postoperative complications experienced significantly poorer OS than those without complications. Among the low PNI group with pTNM stage I and II disease, those with postoperative complications experienced significantly worse OS than those without complications. However, among the high PNI group and patients with stage II and III disease in the low PNI group, OS was similar with respect to postoperative complications. Conclusions: The present study confirmed that long-term prognosis was unaffected by postoperative complications in well-nourished gastric cancer patients. In addition, preoperative nutritional status and postoperative complications, may be crucial in determining the prognosis of gastric cancer, especially in early-stage cancer.

Photodynamic therapy (PDT) is a promising primary treatment option for colorectal cancer (CRC), however CRC is accelerated by resilient CRC stem-like cells, which decrease its efficacy. In recent years, researchers have shown an emerging interest in the anticancer stem cell effects of cannabidiol (CBD). This study developed a targeted nanobioconjugate for specific ZnPcS4 photosensitizer intracellular accumulation within in vitro cultured human CRC cells (CaCo-2) for enhanced PDT primary treatment, as well as limited its secondary spread by combining this treatment with CBD. The final nanobioconjugate (FNBC) was successfully synthesized and characterized using various methods. The cytotoxicity of the FNBC and CBD were tested on CRC cells using laser irradiation at 673 nm with a fluency of 10 J/cm2. 24 h post treatment, morphological changes were assessed via microscopy, cell viability was measured using Annexin V-FITC and cellular nuclear DNA was visualized under fluorescent microscopy, following Hoechst staining. FNBC and CBD combinative treatment induced the most significant photodamage, leaving a staggering 6%*** viable cells. Overall, through active targeting of CRC cells using the FNBC, the enhanced PDT primary treatment of CRC was achieved, and the combinative treatment with CBD noted significant limitations on its secondary spread.

Bladder cancer remains one of the most common forms of cancer and yet there are limited small molecule targeted therapies. Here, we present a computational platform to identify new potential targets for bladder cancer therapy. Our method initially exploited a set of known driver genes for bladder cancer combined with predicted bladder cancer genes from mutationally enriched protein domain families. We enriched this initial set of genes using protein network data to identify a comprehensive set of 323 putative bladder cancer targets. Pathway and cancer hallmarks analyses highlighted putative mechanisms in agreement with those previously reported for this cancer and revealed protein network modules highly enriched in potential drivers likely to be good targets for targeted therapies. 21 of our potential drug targets are targeted by FDA approved drugs for other diseases — some of them are known drivers or are already being targeted for bladder cancer (FGFR3, ERBB3, HDAC3, EGFR). A further 4 potential drug targets were identified by inheriting drug mappings across our in-house CATH domain functional families (FunFams). Our FunFam data also allowed us to identify drug targets in families that are less prone to side effects i.e., where structurally similar protein domain relatives are less dispersed across the human protein network. We provide information on our novel potential cancer driver genes, together with information on pathways, network modules and hallmarks associated with the predicted and known bladder cancer drivers and we highlight those drivers we predict to be likely drug targets.

High-risk neuroblastoma (NB) remains an extremely difficult subgroup to cure and is associated with MYCN amplification. Serine hydroxymethyltransferase 2 (SHMT2) regulates serine metabolism in a myc-dependent manner; it is upregulated in several cancers and is associated with tumor aggressiveness. Akt-2, an important regulator of MYCN via the PI3K/Akt pathway, induces metastatic potential in NB. The association between SHMT2 and PI3K/Akt in hepatocyte regeneration has been well established but its mechanistic interaction in cancer has yet to be clearly elucidated. Herein, we evaluated the exact role of SHMT2 on the PI3K/Akt pathway, in addition to NB tumorigenesis and metastatic potential in vitro. SHMT2 gene expression and overall survival (OS) were assessed. Two human NB cell lines were examined. SHMT2 silencing and overexpression were performed. The downstream effects were analyzed with immunoblotting, RT-qPCR and functional assays were performed. We found SHMT2 gene expression is associated with decreased OS and MYCN amplification. SHMT2 protein and mRNA expression are increased in MYCN-amplified cells. SHMT2 expression has a direct interaction with Akt-2 and MYCN. Induction of SHMT2 increased cellular proliferation, colony formation and cellular migration and SHMT2 expression was increased in metastatic NB cells. We conclude that SHMT2 regulates N-Myc via phosphorylation of Akt-2 and plays an important role in NB tumorigenesis by contributing to cell growth, migration, colony formation and metastasis in vitro.

G-1, a GPER1 agonist, was shown to inhibit the growth of castration-resistant mouse xenografts but not their parental androgen-dependent tumors. It is currently unknown how the androgen receptor (AR) represses GPER1 expression. Here, we found that two GPER1 mRNA variants (GPER1v2 and GPER1v4) were transcriptionally repressed, not via transcript destabilization, by the androgen-activated AR. Although no AR binding was found in all active promoters near GPER1, data from promoter assays suggested that both variants' promoters were inhibited by androgen treatment. Site-directed mutagenesis on Sp1/Sp3 binding sites revealed their role in supporting the basal expression of GPER1. Knockdown of Sp1 and Sp3 together but not separately repressed GPER1 expression whereas overexpression of both Sp1 and Sp3 together was required to alleviate AR repression of GPER1. Based on the chromatin immunoprecipitation data, Sp3 was found to bind to the promoters prior to the binding of Sp1 and RNA polymerase II. However, the binding of all three transcription factors was inhibited by DHT treatment. Concordantly, DHT treatment induced nuclear interactions between AR and Sp1 or Sp3. Taken together, these results indicate that AR represses transcription of GPER1 by binding to Sp1 and Sp3 independently to prevent their transactivation of the GPER1 promoters.

Background: Tumor mutational burden (TMB) is a potential biomarker to predict tumor response to immuno-oncology agents in patients with metastatic non-small cell lung cancer (NSCLC). Materials and Methods: A multi-site cohort study evaluated patients diagnosed with stage IV NSCLC between 2012 and 2019 who had received comprehensive genomic profiling (CGP) and any NSCLC-related treatment at 9 U.S. cancer centers. Baseline characteristics and clinical outcomes were compared between patients with TMB 10 showed a significant association towards longer overall survival (OS) (HR: 0.43, 95% CI: 0.21–0.88, p = 0.02) and progression-free survival (PFS) (HR: 0.43, 95% CI: 0.21–0.85, p = 0.02) in patients treated with first-line immunotherapy and tested by Foundation Medicine or Caris at treatment initiation. Conclusions: TMB levels greater than or equal to 10 mut/Mb, when tested by Foundation Medicine or Caris at treatment initiation, were significantly associated with improved OS and PFS among patients treated with first-line immunotherapy-containing regimens. Additional prospective research is warranted to validate this biomarker along with PD-L1 expression.

Glutathione is an antioxidant that has an important role in chemotherapeutic drug resistance in cancer. Cysteine is synthesized from cystine and is transported into the cell via the xCT antiporter. Another pathway for synthesizing cysteine involves intracellular methionine. We determined whether targeting the xCT represents a promising strategy for the treatment of endometrial cancer and identified factors that predict efficacy of this treatment strategy. In uterine serous carcinoma (USC) cell lines, the combination of cisplatin and the xCT inhibitor, sulfasalazine, significantly inhibited cell growth compared with single-agent cisplatin or sulfasalazine. Sulfasalazine treatment significantly decreased intracellular glutathione levels and induced apoptosis when combined with cisplatin in USC cell lines. On the one hand, the effectiveness of combined cisplatin and sulfasalazine was not evident in endometrioid carcinoma. USC cell lines exhibited increased expression of xCT and decreased expression of cystathionine gamma lyase (CGL), which is an enzyme involved in the synthesis of cysteine from methionine. On the other hand, endometrioid carcinoma cell lines exhibited increased CGL expression or decreased xCT expression. These findings suggest that using a glutathione synthesis pathway-based approach for selecting subjects for sulfasalazine treatment may be an effective strategy for circumventing glutathione-related chemotherapeutic drug resistance in endometrial carcinoma.

Linoleic acid (LA) has been shown to cause inflammation and promote development of colorectal cancer (CRC). Moreover, many literatures show that LA is associated with cancer metastasis. Metastatic cancer cells have high stemness, suggesting that LA might affect the stemness of cancer cells. In this study, we examined the effect of LA on the hedgehog system, which affects cancer stemness. In CT26 cells, LA treatment induced the expression of sonic hedgehog (Shh); the signal transduction factor, and glioma-associated oncogene homolog (Gli) 2, whereas the expression of SRY-box transcription factor (Sox) 17 was suppressed. Furthermore, LA reduced GLI2 ubiquitination, resulting in an increase in the N-terminal fragment of GLI2, known as suppressive GLI2, produced by cleavage of GLI2. LA-induced cleaved GLI2 was also detected in Colo320 and HT29 human CRC cells. Knocking down Gli2 abrogated the LA-mediated suppression of Sox17 expression. These results suggest that LA promotes tumor cell stemness by increasing of suppressive GLI2 fragments via GLI2 modification. In mouse liver metastasis models, LA enhanced metastasis with production of the suppressive GLI2 fragments in CT26 and HT29 cells, whereas knockdown of GLI2 abrogated LA-induced metastatic activity. In human CRCs, the cases with liver metastasis showed the suppressive GLI2 fragments. This study provides mechanistic insights into LA-induced stemness in colon cancer cells. This finding suggests that dietary intake of LA might increase the stemness of cancer cells and enhance metastatic activity of the cancer.

Clinical evidence supports the combination of cabozantinib with an immune checkpoint inhibitor for the treatment of metastatic clear cell renal cell carcinoma (mccRCC) and suggests a synergistic antitumour activity of this combination. Nevertheless, the biological basis of this synergy is not fully characterized. We studied the mechanisms underpinning the potential synergism of cabozantinib combined with a PD1 inhibitor in mccRCC and delved into cabozantinib monotherapy properties supporting its role to partner these combinations. To model physiological drug action, we used a machine learning-based technology known as Therapeutic Performance Mapping Systems, applying two approaches: Artificial Neural Networks and Sampling Methods. We found that the combined therapy was predicted to exert a wide therapeutic action in the tumour and the microenvironment. Cabozantinib may enhance the effects of PD1 inhibitors on immunosurveillance by modulating the innate and adaptive immune system, through the inhibition of VEGF-VEGFR and Gas6-AXL/TYRO3/MER (TAM) axes, while the PD1 inhibitors may boost the antiangiogenic and pro–apoptotic effects of cabozantinib by modulating angiogenesis and T-cell cytotoxicity. Cabozantinib alone was predicted to restore cellular adhesion and hamper tumour proliferation and invasion. These data provide a biological rationale and further support for cabozantinib plus PD1 inhibitor combination and may guide future nonclinical and clinical research.

GZ17-6.02 is presently undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in estrogen receptor positive breast cancer cells and to determine whether it interacted with palbociclib to enhance tumor cell killing. GZ17-6.02 interacted in an additive fashion with palbociclib to kill ER+ breast cancer cells. GZ17-6.02 and palbociclib cooperated to inactivate mTOR and AKT and to activate ULK1 and PERK. The drugs interacted to increase the expression of FAS-L and BAX, and to decrease the levels of MCL1, the estrogen receptor, and HDACs 1–3. Palbociclib activated ERBB3, an effect blocked by GZ17-6.02. GZ17-6.02 and palbociclib interacted to increase the expression of multiple toxic BH3 domain proteins and to reduce MCL1 and BCL-XL expression. Knock down of FAS-L reduced the lethality of [GZ17-6.02 + palbociclib]. GZ17-6.02 and palbociclib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, BAG3, eIF2α, toxic BH3 domain proteins or CD95 significantly reduced drug combination lethality. GZ17-6.02 and palbociclib increased the expression of Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs also increased the phosphorylation of the AMPK and ATG13, effects blocked by knock down of ATM. Knock down of ATM or the AMPK, or expression of activated mTOR significantly reduced the abilities of GZ17-6.02 and palbociclib to enhance autophagosome formation and autophagic flux.

Several distinct metastasis-associated glycosylation changes have been shown to promote cancer cell invasion and metastasis, the main cause of death of cancer patients. However, it is unclear whether their presence reflects cell- or tissue-specific variations for metastasis, or species needed to drive different phases of the metastatic cascade. To address this issue from a different perspective, we investigated here whether different cancer cell lines share any glycotopes that are common and important for their invasive phenotype. By using lectin microarray glycan profiling and an established myoma tissue-based 3D invasion assay, we identified a single glycotope recognized by Helix Pomatia agglutinin (HPA), whose expression level in different cancer cells correlated significantly with their invasive potential. Lectin pull-down assay and LC-MS/MS analysis in highly- (A431 and SW-48) and poorly invasive (HepG2 and RCC4) cancer cells revealed ~85 glycoproteins of which several metastasis-promoting members of the integrin family of cell adhesion receptors, the epidermal growth factor receptor (EGFR) and the matrix metalloproteinase-14 (MMP-14) were among the abundant ones. Moreover, we showed that the level of the GalNAc glycotope in MMP-14, EGFR, αV-, β1- and β4 integrin in highly and poorly invasive cancer cells correlated positively with their invasive potential. Collectively, our findings suggest that altered glycosylation of several metastasis-associated glycoproteins with terminal GalNAc drives the highly invasive cancer cell phenotype.

// Dong-Qin Wang 1 , Ying-Lian Gao 2 , Jin-Xing Liu 1 , Chun-Hou Zheng 1 and Xiang-Zhen Kong 1 1 School of Information Science and Engineering, Qufu Normal University, Rizhao, China 2 Library of Qufu Normal University, Qufu Normal University, Rizhao, China Correspondence to: Jin-Xing Liu, email: sdcavell@126.com Chun-Hou Zheng, email: zhengch99@126.com Keywords: L 2,1 -norm, L 1 -norm, integrative penalized matrix decomposition, paired drug-pathway associations, drug discovery Received: January 23, 2017 Accepted: May 01, 2017 Published: May 29, 2017 ABSTRACT The traditional methods of drug discovery follow the “one drug-one target” approach, which ignores the cellular and physiological environment of the action mechanism of drugs. However, pathway-based drug discovery methods can overcome this limitation. This kind of method, such as the Integrative Penalized Matrix Decomposition (iPaD) method, identifies the drug-pathway associations by taking the lasso-type penalty on the regularization term. Moreover, instead of imposing the L 1 -norm regularization, the L 2,1 -Integrative Penalized Matrix Decomposition (L 2,1 -iPaD) method imposes the L 2,1 -norm penalty on the regularization term. In this paper, based on the iPaD and L 2,1 -iPaD methods, we propose a novel method named L 1 L 2,1 -iPaD (L 1 L 2,1 -Integrative Penalized Matrix Decomposition), which takes the sum of the L 1 -norm and L 2,1 -norm penalties on the regularization term. Besides, we perform permutation test to assess the significance of the identified drug-pathway association pairs and compute the P-values. Compared with the existing methods, our method can identify more drug-pathway association pairs which have been validated in the CancerResource database. In order to identify drug-pathway associations which are not validated in the CancerResource database, we retrieve published papers to prove these associations. The results on two real datasets prove that our method can achieve better enrichment for identified association pairs than the iPaD and L 2,1 -iPaD methods.

Background: Anthracycline (ANT) is often used for breast cancer treatment but its clinical use is limited by cardiotoxicity (CTX). CECCY trial demonstrated that the β-blocker carvedilol (CVD) could attenuate myocardial injury secondary to ANT. Mieloperoxydase (MPO) is a biomarker of oxidative stress and galectin-3 (Gal-3) is a biomarker of fibrosis and cardiac remodeling. We evaluated the correlation between MPO and Gal-3 behavior with CTX. Materials and Methods: A post hoc analysis was performed in the patients who were included in the CECCY trial. A total of 192 women had her blood samples stored during the study at –80°C until the time of assay in a single batch. Stored blood samples were obtained at baseline, 3 and 6 months after randomization. We excluded samples from 18 patients because of hemolysis. MPO and Gal-3 were measured using Luminex xMAP technology through MILLIPLEX MAP KIT (Merck Laboratories). Results: 26 patients (14.9%) had a decrease of at least 10% in LVEF at 6 months after the initiation of chemotherapy. Among these, there was no significant difference in the MPO and Gal-3 when compared to the group without drop in LVEF (p = 0.85 for both MPO and Gal-3). Blood levels of MPO [baseline: 13.2 (7.9, 24.8), 3 months: 17.7 (11.1, 31.1), 6 months: 19.2 (11.1, 37.8) ng/mL] and Gal-3 [baseline: 6.3 (5.2, 9.6), 3 months: 12.3 (9.8, 16.0), 6 months: 10.3 (8.2, 13.1) ng/mL] increased after ANT chemotherapy, and the longitudinal changes were similar between the placebo and CVD groups (p for interaction: 0.28 and 0.32, respectively). In an exploratory analysis, as there is no normal cutoff value established for Gal-3 and MPO in the literature, the MPO and Gal-3 results were splited in two groups: above and below median. In the placebo group, women with high (above median) baseline MPO blood levels demonstrated a greater increase in TnI blood levels than those with low baseline MPO blood levels (p = 0.041). Compared with placebo, CVD significantly reduced TnI blood levels in women with high MPO blood levels (p < 0.001), but did not reduce the TnI levels in women with low baseline MPO blood levels (p = 0.97; p for interaction = 0.009). There was no significant interaction between CVD treatment and baseline Gal-3 blood levels (p for interaction = 0.99). Conclusions: In this subanalysis of the CECCY trial, MPO and Gal-3 biomarkers did not predict the development of CTX. However, MPO blood levels above median was associated with more severe myocardial injury and identified women who were most likely to benefit from carvedilol for primary prevention (NCT01724450).

// Qiao Li 1, * , Lina Quan 1, * , Jiankun Lyu 1 , Zenghui He 1 , Xia Wang 1 , Jiajia Meng 1 , Zhenjiang Zhao 1 , Lili Zhu 1 , Xiaofeng Liu 1 , Honglin Li 1 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China * These Authors contributed equally to this work Correspondence to: Lili Zhu, email: zhulfl@ecust.edu.cn Xiaofeng Liu, email: xxffliu@gmail.com Honglin Li, email: hlli@ecust.edu.cn Keywords: immunotherapy, human programmed death 1, peptide inhibitor, protein-protein interactions (PPIs), de novo peptide design Received: June 06, 2016 Accepted: July 29, 2016 Published: August 12, 2016 ABSTRACT Blocking the interaction of human programmed death 1 (hPD-1) and its ligand hPD-L1 has been a promising immunotherapy in cancer treatment. In this paper, using a computational de novo peptide design method, we designed several hPD-1 binding peptides. The most potent peptide Ar5Y_4 showed a KD value of 1.38 ± 0.39 μM, comparable to the binding affinity of the cognate hPD-L1. A Surface Plasmon Resonance (SPR) competitive binding assay result indicated that Ar5Y_4 could inhibit the interaction of hPD-1/hPD-L1. Moreover, Ar5Y_4 could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Peptides described in this paper provide promising biologic candidates for cancer immunotherapy or diagnostics.

This paper aims to systematically review the major findings from meta-analyses comparing different treatment options for hepatocellular carcinoma (HCC). A total of 153 relevant papers were searched via the PubMed, EMBASE, and Cochrane library databases. They were classified according to the mainstay treatment modalities (i.e., liver transplantation, surgical resection, radiofrequency ablation, transarterial embolization or chemoembolization, sorafenib, and others). The primary outcome data, such as overall survival, diseases-free survival or recurrence-free survival, progression-free survival, and safety, were summarized. The recommendations and uncertainties regarding the treatment of HCC were also proposed.

// Jian-Yong Wang 1 , Ling-Ling Chen 1 and Xiong-Hui Zhou 1 1 College of Informatics, Huazhong Agricultural University, Wuhan 430070, P.R. China Correspondence to: Xiong-Hui Zhou, email: zhouxionghui@mail.hzau.edu.cn Keywords: DirGenerank, ovarian cancer, prognosis, biomarker, drug target Received: March 17, 2017 Accepted: April 26, 2017 Published: May 25, 2017 ABSTRACT Identifying the prognostic genes in cancer is essential not only for the treatment of cancer patients, but also for drug discovery. However, it’s still a big challenge to select the prognostic genes that can distinguish the risk of cancer patients across various data sets because of tumor heterogeneity. In this situation, the selected genes whose expression levels are statistically related to prognostic risks may be passengers. In this paper, based on gene expression data and prognostic data of ovarian cancer patients, we used conditional mutual information to construct gene dependency network in which the nodes (genes) with more out-degrees have more chances to be the modulators of cancer prognosis. After that, we proposed DirGenerank (Generank in direct netowrk) algorithm, which concerns both the gene dependency network and genes’ correlations to prognostic risks, to identify the gene signature that can predict the prognostic risks of ovarian cancer patients. Using ovarian cancer data set from TCGA (The Cancer Genome Atlas) as training data set, 40 genes with the highest importance were selected as prognostic signature. Survival analysis of these patients divided by the prognostic signature in testing data set and four independent data sets showed the signature can distinguish the prognostic risks of cancer patients significantly. Enrichment analysis of the signature with curated cancer genes and the drugs selected by CMAP showed the genes in the signature may be drug targets for therapy. In summary, we have proposed a useful pipeline to identify prognostic genes of cancer patients.

// Chenyan Yue 1 , Yan Li 1 , Yamin Wang 1 , Yan Liu 2 , Linsheng Cao 1 , Xu Zhu 3 , Kathryn Martin 3 , Huaqing Wang 1 and Zhijie An 1 1 The Department of National Immunization Programme, Chinese Center for Disease Control and Prevention, Beijing, 100050, China 2 Hangzhou Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310021, China 3 China Office of United Nations Children’s Fund, Beijing, 100600, China Correspondence to: Zhijie An, email: anzj@chinacdc.cn Keywords: varicella vaccine, vaccination, coverage, children, GDP Received: October 20, 2016 Accepted: April 05, 2017 Published: April 21, 2017 ABSTRACT Background: Vaccine is the most effective way to protect susceptible children from varicella. Few published literature or reports on varicella vaccination of Chinese children exist. Thus, in order to obtain specific information on varicella vaccination of this population, we conducted this survey. Methodology: We first used purposive sampling methods to select 6 provinces 10 counties from eastern, middle and western parts of China with high quality of Immunization Information Management System (IIMS), and then randomly select children from population in the IIMS, then we checked vaccination certificate on-site. Principal Findings: Based on the varicella vaccination information collected from 481 children's vaccination certificates from all ten selected counties in China, overall coverage of the first dose of varicella vaccine was 73.6%. There is a positive linear correlation between per capita GDP and vaccine coverage at county level (r=0.929, P < 0.01). The cumulative vaccine coverage among children at 1 year, 2 years and ≥3 years old were 67.6%, 71.9% and 73.6% respectively ( X 2 =4.53, P =0.10). The age of vaccination was mainly concentrated in 12-17 months. Conclusions: The coverage rate of the first dose of varicella vaccine in selected areas was lower than that recommended by WHO position paper. The coverage rate was relatively low in areas of low social-economic status. The cumulative coverage had no significant statistical difference among different age group. Most children received varicella vaccine before 3 years old. We suggest introducing the varicella vaccine into routine immunization program, to ensure universal high coverage among children in China. We also suggest that varicella vaccination information should be checked before entering school, in order to control and prevent varicella outbreaks in schools.

// Li-Chun Zheng 1, 2, * , Xiao-Qing Wang 2, * , Kun Lu 3, * , Xiao-Ling Deng 3 , Cheng-Wei Zhang 4 , Hong Luo 2 , Xu-Dong Xu 2 , Xiao-Man Chen 2 , Lu Yan 5 , Yi-Qing Wang 2 and Song-Lin Shi 3 1 Medical College of Xiamen University, Jinshan Community Health Service Center, Xiamen Traditional Chinese Medical Hospital, Xiamen 361000, P.R. China 2 Xiamen Heart Center, Medical College of Xiamen University, Xiamen 361000, P.R. China 3 Department of Basic Medicine, Medical College of Xiamen University, Cancer Research Center of Xiamen University, Xiamen 361102, P.R. China 4 Department of Cardiology, Affiliated Dongnan Hospital of Xiamen University, Zhangzhou 363000, P.R. China 5 Department of Basic Medicine, Medical College of Xiamen University, Xiamen 361102, P.R. China * These authors have contributed equally to this work Correspondence to: Yi-Qing Wang, email: wang_gina@163.com Song-Lin Shi, email: shisonglin@xmu.edu.cn Keywords: ephrin-B2, proliferation, migration, human umbilical vein endothelial cell, proteomic analysis Received: December 09, 2016 Accepted: April 03, 2017 Published: April 20, 2017 ABSTRACT Tumor growth and metastasis are angiogenesis dependent. Angiogenic growth involves endothelial cell proliferation, migration, and invasion. Ephrin-B2 is a ligand for Eph receptor tyrosine kinases and is an important mediator in vascular endothelial growth factor-mediated angiogenesis. However, research offer controversial information regarding effects of ephrin-B2 on vascular endothelial cells. In this paper, proteome analyses showed that ephrin-B2/Fc significantly activates multiple signaling pathways related to cell proliferation, survival, and migration and suppresses apoptosis and cell death. Cytological experiments further confirm that ephrin-B2/Fc stimulates endothelial cell proliferation, triggers dose-dependent migration, and suppresses cell apoptosis. Results demonstrate that soluble dose-dependent ephrinB2 can promote proliferation and migration and inhibit apoptosis of human umbilical vein endothelial cells. These results also suggest that ephrinB2 prevents ischemic disease and can potentially be a new therapeutic target for treating angiogenesis-related diseases and tumors.

Arginine starvation has the potential to selectively treat both primary tumor and (micro) metastatic tissue with very low side effects. Arginine deiminase (ADI; EC 3.5.3.6), an arginine-degrading enzyme, has been studied as a potential anti-tumor drug for the treatment of arginine-auxotrophic tumors. Though ADI-PEG20 (pegylated ADI by PEG 20,000) already passed the phase I/II clinical trials [1], it is just used as adjuvant therapy because of its low efficiency and less targeting. Then, this paper discussed the efficiency of arginine starvation mediated by ADI expressed in cytoplasm for liver cancers. In order to guarantee the tumor targeting, human telomerase reverse transcriptase (hTERT) promoter was used to drive the expression of ADI in vivo. To access the anti-tumor efficiency of ADI, p53 gene was used as the positive control. Thus, ADI displayed obvious cytotoxicity to BEL7402 and HUH7 cell lines in cytoplasm. The apoptosis rates rose from 15% to nearly 60% after changing the expression vectors from pcDNA4 plasmid to adenovirus. Compared with p53-adenovirus, ADI-adenovirus showed the higher oncolytic activity in the intratumoral injection model of mice. Tumor disappeared after the treatment of ADI-adenovirus for two weeks, and the mice pulled through all. Therefore, ADI is an ideal anti-tumor gene for caner targeting therapy with the help of hTERT promoter.

// Lei Cai 1, 2, * , Theodoros Michelakos 1, * , Cristina R. Ferrone 1 , Liyuan Zhang 1 , Vikram Deshpande 3 , Qi Shen 3 , Albert DeLeo 4 , Teppei Yamada 1 , Gong Zhang 1 , Soldano Ferrone 1, 5 and Xinhui Wang 1 1 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Hepatobiliary, Southwest Hospital, Third Military Medical University, Chongqing, China 3 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 4 University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA 5 Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA * Lei Cai and Theodoros Michelakos contributed equally to this paper Correspondence to: Xinhui Wang, email: XWANG30@mgh.harvard.edu Keywords: folate receptor alpha, pancreatic ductal adenocarcinoma, predictor of survival, smoking, alcohol consumption Received: January 28, 2017 Accepted: March 01, 2017 Published: April 05, 2017 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognosis among malignancies. Thus, the identification of markers useful in developing innovative diagnostic and therapeutic methods is an imperative need. Folate receptor alpha (FRα) has been associated with prognosis in several cancers and has served as a target of novel anti-tumor therapies. However, FRα expression in PDAC and its correlation with the clinical course of the disease has not been thoroughly investigated. In this study, we analyzed FRα expression in 140 PDAC specimens and 7 PDAC cell lines in order to define the significance of FRα expression in PDAC and its potential role as a target for immunotherapy. Immunohistochemical analysis demonstrated that FRα expression intensity was low, intermediate and high in 22(16%), 73(52%) and 45(32%) PDACs, respectively. The staining was located in both membrane and cytoplasm in most cases (123, 88%). Lower FRα expression was associated with cigarette smoking (p

// Heui Chang Lee 1, 2 , Bongyong Song 3 , Jin Sung Kim 4 , James J. Jung 5 , H. Harold Li 6 , Sasa Mutic 6 and Justin C. Park 6 1 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA 2 J Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA 3 Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA 4 Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 5 Department of Radiation Oncology, University of Florida, Gainesville, Florida, USA 6 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA Correspondence to: Jin Sung Kim, email: jinsung@yuhs.ac Keywords: SART, weighted least squares, image reconstruction, GPU, IGRT Received: October 19, 2016 Accepted: March 20, 2017 Published: April 24, 2017 ABSTRACT Compared to analytical reconstruction by Feldkamp-Davis-Kress (FDK), simultaneous algebraic reconstruction technique (SART) offers a higher degree of flexibility in input measurements and often produces superior quality images. Due to the iterative nature of the algorithm, however, SART requires intense computations which have prevented its use in clinical practice. In this paper, we developed a fast-converging SART-type algorithm and showed its clinical feasibility in CBCT reconstructions. Inspired by the quasi-orthogonal nature of the x-ray projections in CBCT, we implement a simple yet much faster algorithm by computing Barzilai and Borwein step size at each iteration. We applied this variable step-size (VS)-SART algorithm to numerical and physical phantoms as well as cancer patients for reconstruction. By connecting the SART algebraic problem to the statistical weighted least squares problem, we enhanced the reconstruction speed significantly (i.e., less number of iterations). We further accelerated the reconstruction speed of algorithms by using the parallel computing power of GPU.

// Lin Yang 1, * , Hong Chen 1, * , Miao Zhao 1 and Peng Peng 1 1 Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China * These authors contributed equally to this work Correspondence to: Hong Chen, email: njchenhong66@163.com Keywords: VDBP, 25(OH)D, colorectal cancer, prognosis, overall survival Received: January 04, 2017 Accepted: March 13, 2017 Published: March 27, 2017 ABSTRACT Numerous studies have suggested that there was a significantly positive association between circulating total 25-hydroxyvitamin D (25(OH)D) and survival in colorectal cancer patients. Moreover, plasma vitamin D was also found significantly associated with the concentration of vitamin D binding protein (VDBP). However, there was no paper to clarify the prognostic value of VDBP, free and bioavailable 25(OH)D in colorectal carcinogenesis. The aim of this study was to comprehensively assess the prognostic value of VDBP, total, free and bioavailable 25(OH)D in stage I-III colorectal cancer patients. A total of 206 colorectal cancer patients were enrolled in this prospective study. Preoperative plasma total 25(OH)D and VDBP concentrations were measured by direct enzyme-linked immunosorbent assay, and albumin concentration was measured by Beckman automatic biochemical analyzer. Free and bioavailable 25(OH)D concentrations were calculated based on the concentrations of plasma VDBP, total 25(OH) D and albumin. X-title program was used to determine the optimal cut-off values of VDBP, total, free and bioavailable 25(OH)D. Results showed that elevated free and bioavailable 25(OH)D were significantly associated with better 5-year overall survival (OS) by univariate analysis. By multivariate cox analysis, we also found that the high level of free 25(OH)D (HR = 0.442, 95%CI = 0.238–0.819, P < 0.010) could be identified as an independent factor for better OS. In conclusion, our study suggested that higher levels of free and bioavailable 25(OH)D were associated with better OS in stage I-III colorectal cancer patients. Moreover, free 25(OH)D could be considered as an independent prognostic biomarker for OS.

// Dingding Zhang 1, * , Xiaoxin Guo 1, * , Jinliang Hu 2, 3, * , Guangqun Zeng 4 , Maomin Huang 1, 5 , Dandan Qi 1 , Bo Gong 1 1 Sichuan Provincial Key Laboratory for Disease Gene Study, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China 2 Institute of Health Policy and Hospital Management, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, 610072, China 3 School of Public Health, Sichuan University, Chengdu, Sichuan, 610041, China 4 Department of Clinical Laboratory, People’s Hospital of Pengzhou, Pengzhou, Sichuan, 611930, China 5 Department of Immunology, Zunyi Medical College, Zunyi, Guizhou, 563000, China * These authors contributed equally to this study Correspondence to: Bo Gong, email: gongbo2007@hotmail.com Keywords: gastric cancer, meta-analysis, hOGG1 rs1052133, association Received: January 10, 2017 Accepted: March 04, 2017 Published: March 11, 2017 ABSTRACT Purpose: To conduct a comprehensive evaluation of the association of the human8-oxoguanine glycosylase 1 ( hOGG1 ) gene polymorphism rs1052133 with gastric cancer (GC) through a systematic review and meta-analysis of genetic association study. Results: A total of 15 articles from published papers were included in our analysis. The meta-analyses for hOGG1 rs1052133, composed of 4024GC patients and 6022controls, showed low heterogeneity for the included populations in all the genetic models, except for the Caucasian population under allelic genetic model, the Asian population under addictive model and Caucasian population under dominant model. The analyses of all the genetic models in overall pooled populations did not identify any significant association between GC and hOGG1 rs1052133 (Allelic model: C vs. G , p = 0.746; Addictive model: CC vs. GG, p = 0.888; Recessive model: CC +GC vs. GG, p = 0.628; Dominant model: CC vs. GG+GC, p = 0.147), even though stratified analyses were conducted in different ethnicities under each genetic model. Materials and Methods: All case-control association studies on hOGG1 and GC reported up to December 15, 2016 in PubMed, Embase, Web of Science, and the Chinese Biomedical Database were retrieved. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphism (SNP) using fixed- and random- effects models according to between-study heterogeneity. Publication bias analyses were conducted using Begg test. Conclusions: This meta-analysis showed there was no association between hOGG1 rs1052133 and GC. Given the limited sample size, further investigations including more ethnic groups are required to validate the association.

// Qing Xie 1, * , Shuai Wang 2, * , Yue Zhao 1 , Zhenchao Zhang 2 , Chuan Qin 1 , Xianjun Yang 1 1 Tumor Signaling and Transduction Lab, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang City, Henan Province, 453003, PR China 2 Department of Human Parasitology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang City, Henan Province, 453003, PR China * These authors have contributed equally to this work Correspondence to: Qing Xie, email: hnxxqingxie@126.com Keywords: BCSCs, miR-519d, cisplatin, resistance, MCL-1 Received: December 28, 2016 Accepted: January 25, 2017 Published: February 28, 2017 ABSTRACT Cancer stem cells are considered as the cell population which is responsible for chemoresistance and treatment failure in breast cancer patients. Therefore, it is urgent to explore the mechanism by which cancer stem cells survive under the treatment of chemotherapeutic drugs such as cisplatin. In this paper, we demonstrated significant decrease of miR-519d in breast cancer stem cells by quantitative RT-PCR analysis. Furthermore, we found the enforced expression of miR-519d in T-47D-cancer stem cells significantly increased their sensitivity to cisplatin through the apoptosis pathway. In addition, the gene of MCL-1, which is a member of pro-apoptotic Bcl-2 family, was found to be the target of miR-519d in T-47D-cancer stem cells. Our date demonstrated that enforced miR-519d expression enhanced the cisplatin-induced apoptosis through the MCL-1 dependent mitochondria pathway in breast cancer stem cells. Taken together, the present study suggests that miR-519d reduces chemoresistance in breast cancer stem cells, and understanding of miR-519d may be helpful for increasing the efficacy of chemotherapy.

// Youhong Liu 1, 2, * , Yijun Liu 1, 2, * , Bowen Yuan 1, 2 , Linglong Yin 1, 2 , Yuchong Peng 1, 2 , Xiaohui Yu 1, 2 , Weibing Zhou 3 , Zhicheng Gong 4 , Jianye Liu 5, 6 , Leye He 5, 6 , Xiong Li 1, 2, 6 1 Center for Molecular Medicine, Xiangya Hospital, Central South University, China 2 Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, China 3 Department of Oncology, Xiangya Hospital, Central South University, China 4 Department of Pharmacy, Xiangya Hospital, Central South University, China 5 Department of Urology, The Third Xiangya Hospital, Central South University, China 6 Research Institute of Prostate Diseases, Central South University, China * These authors equally contributed to this paper Correspondence to: Xiong Li, email: lixiongxiangya@csu.edu.cn Keywords: PSA, FOXM1, gene transcription, androgen receptor, prostate cancer Received: November 11, 2016 Accepted: January 09, 2017 Published: February 09, 2017 ABSTRACT Androgen/AR is the primary contributor to prostate cancer (PCa) progression by regulating Prostate Specific Antigen (PSA) gene transcription. The disease inevitably evolves to androgen-independent (AI) status. Other mechanisms by which PSA is regulated and develops to AI have not yet been fully determined. FOXM1 is a cell proliferation-specific transcription factor highly expressed in PCa cells compared to non-malignant prostate epithelial cells, suggesting that the aberrant overexpression of FOXM1 contributes to PCa development. In addition to regulating AR gene transcription and cell cycle-regulatory genes, FOXM1 selectively regulates the gene transcription of KLK2 and PSA, typical androgen responsive genes. Screening the potential FOXM1-binding sites by ChIP-PCR, we found that FOXM1 directly binds to the FHK binding motifs in the PSA promoter/enhancer regions. AI C4-2 cells have more FOXM1 binding sites than androgen dependent LNCaP cells. The depletion of FOXM1 by small molecular inhibitors significantly improves the suppression of PSA gene transcription by the anti-AR agent Cadosax. This is the first report showing that FOXM1 promotes PCa progression by regulating PSA gene transcription, particularly in AI PCa cells. The combination of anti-AR agents and FOXM1 inhibitors has the potential to greatly improve therapy for late-stage PCa patients by suppressing PSA levels.

// Heleen H. Van Acker 1 , Ottavio Beretta 2 , Sebastien Anguille 1, 3 , Lien De Caluwe 1, 4 , Angela Papagna 2 , Johan M. Van den Bergh 1 , Yannick Willemen 1 , Herman Goossens 1 , Zwi N. Berneman 1, 3 , Viggo F. Van Tendeloo 1 , Evelien L. Smits 1, 3, 5 , Maria Foti 2, * , Eva Lion 1, 3, * 1 Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Faculty of Medicine and Health Sciences, Antwerp, Belgium 2 School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy 3 Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium 4 Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium 5 Center for Oncological Research (CORE), University of Antwerp, Faculty of Medicine and Health Sciences, Antwerp, Belgium * Share senior authorship Correspondence to: Heleen H. Van Acker, email: heleen.vanacker@uantwerp.be Keywords: CCL4-CCR5 signaling, dendritic cell vaccination, γδ T cells, immune cell recruitment, NK cells Received: April 25, 2016 Accepted: January 03, 2017 Published: January 13, 2017 ABSTRACT Success of dendritic cell (DC) therapy in treating malignancies is depending on the DC capacity to attract immune effector cells, considering their reciprocal crosstalk is partially regulated by cell-contact-dependent mechanisms. Although critical for therapeutic efficacy, immune cell recruitment is a largely overlooked aspect regarding optimization of DC vaccination. In this paper we have made a head-to-head comparison of interleukin (IL)-15-cultured DCs and conventional IL-4-cultured DCs with regard to their proficiency in the recruitment of (innate) immune effector cells. Here, we demonstrate that IL-4 DCs are suboptimal in attracting effector lymphocytes, while IL15 DCs provide a favorable chemokine milieu for recruiting CD8 + T cells, natural killer (NK) cells and gamma delta (γδ) T cells. Gene expression analysis revealed that IL-15 DCs exhibit a high expression of chemokines involved in antitumor immune effector cell attraction, while IL-4 DCs display a more immunoregulatory profile characterized by the expression of Th2 and regulatory T cell-attracting chemokines. This is confirmed by functional data indicating an enhanced recruitment of granzyme B + effector lymphocytes by IL-15 DCs, as compared to IL-4 DCs, and subsequent superior killing of tumor cells by the migrated lymphocytes. Elevated CCL4 gene expression in IL-15 DCs and lowered CCR5 expression on both migrated γδ T cells and NK cells, led to validation of increased CCL4 secretion by IL15 DCs. Moreover, neutralization of CCR5 prior to migration resulted in an important inhibition of γδ T cell and NK cell recruitment by IL-15 DCs. These findings further underscore the strong immunotherapeutic potential of IL-15 DCs.

// Artur Kadurin 1, 2, 3, 4 , Alexander Aliper 2 , Andrey Kazennov 2, 7 , Polina Mamoshina 2, 5 , Quentin Vanhaelen 2 , Kuzma Khrabrov 1 , Alex Zhavoronkov 2, 6, 7 1 Search Department, Mail.Ru Group Ltd., Moscow, Russia 2 Pharmaceutical Artificial Intelligence Department, Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, Baltimore, Maryland, USA 3 Big Data and Text Analysis Laboratory, Kazan Federal University, Kazan, Republic of Tatarstan, Russia 4 St. Petersburg Department of V.A. Steklov Institute of Mathematics of the Russian Academy of Sciences, Petersburg, Russia 5 Department of Computer Science, University of Oxford, Oxford, UK 6 The Biogerontology Research Foundation, Trevissome Park, Truro TR4 8UN, UK 7 Moscow Institute of Physics and Technology, Dolgoprudny, Russia Correspondence to: Alex Zhavoronkov, email: alex@insilicomedicine.com Keywords: generative adversarian networks, adversarial autoencoder, deep learning, drug discovery, artificial intelligence Received: June 14, 2016 Accepted: November 24, 2016 Published: December 22, 2016 ABSTRACT Recent advances in deep learning and specifically in generative adversarial networks have demonstrated surprising results in generating new images and videos upon request even using natural language as input. In this paper we present the first application of generative adversarial autoencoders (AAE) for generating novel molecular fingerprints with a defined set of parameters. We developed a 7-layer AAE architecture with the latent middle layer serving as a discriminator. As an input and output the AAE uses a vector of binary fingerprints and concentration of the molecule. In the latent layer we also introduced a neuron responsible for growth inhibition percentage, which when negative indicates the reduction in the number of tumor cells after the treatment. To train the AAE we used the NCI-60 cell line assay data for 6252 compounds profiled on MCF-7 cell line. The output of the AAE was used to screen 72 million compounds in PubChem and select candidate molecules with potential anti-cancer properties. This approach is a proof of concept of an artificially-intelligent drug discovery engine, where AAEs are used to generate new molecular fingerprints with the desired molecular properties.

// Tong Tong 1 , Zhong Yang 2 , John W. Chen 3 , Jianming Zhu 4 , Zhenwei Yao 2 1 Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Radiology, Fudan University Huashan Hospital, Shanghai, China 3 Institute for Innovation in Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 4 Department of Radiation Oncology, The University of North Carolina, Chapel Hill, NC, USA Correspondence to: Zhenwei Yao, e-mail: aocnhnr@126.com John W. Chen, e-mail: jwchen@mgh.harvard.edu Keywords: clinical paper, magnetic resonance imaging, magnetic resonance spectroscopy, glioma, differential diagnosis Received: May 18, 2015 Accepted: August 07, 2015 Published: August 20, 2015 ABSTRACT Purpose: To determine whether the changes of [Cho/NAA] ratio in patients with glioma, measured by dynamic 1 H-MRS can be used to differentiate between high-grade and low-grade gliomas. Materials and Methods: This prospective study was approved by the institutional ethics committee. Written informed consent was obtained. Forty-nine patients with biopsy-proven glioma and 20 normal control subjects were recruited in this study. The maximum [Cho/NAA] ratios, acquired at 0 min, and at 6 min, were calculated and assessed from volume of interests (VOI) in the tumor areas and in the surrounding normal tissue for each patient. Absolute difference in the [Cho/NAA] ratios, from MRS acquired at 0 and 6 min, in high-grade glioma, low-grade glioma, and control subjects were compared. Results: The maximum [Cho/NAA] ratio acquired from the tumor area at the 0 min is 6.08 ± 2.02, which was significantly different ( p = .017) from that acquired after 6 min, 4.87 ± 2.13. The [Cho/NAA] ratio from the surrounding normal tissue area did not change significantly from spectra acquired at different times (0 min, 6 min). Absolute difference in [Cho/NAA] ratios acquired at 0 and 6 min time points were significantly higher ( P < 0.001) in high-grade glioma (= 3.86 ± 3.31) than in low-grade glioma (= 0.81 ± 0.90), and control subjects (0.061 ± 0.026, P = 0.000), while there was no significantly difference in low-grade glioma and control subjects. Conclusions: Dynamic 1 H-MRS can be useful for differential diagnosis between high-grade and low-grade gliomas as well as insight into the heterogeneity within the tumor.

// Jiliang Qiu 1,* , Weiqun Lu 1,* , Nanrong Yu 1 , Guohua Yang 1 , Yi Li 2 , Zhiliang Huang 1 , Jianchang Li 1 , Kefei Li 1 , Houwei Xu 1 , Shicai Chen 1 , Xiang Zeng 1 and Haiying Liu 1 1 Department of Abdominal Oncosurgery, Cancer Center of Guangzhou Medical University, Guangzhou, China 2 Department of Surgery, the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China * These authors have contributed equally to this paper Correspondence to: Haiying Liu, email: // Keywords : hepatocellular carcinoma, hepatic resection, Habib TM 4X, clamp-crush, complication Received : July 13, 2016 Accepted : December 01, 2016 Published : December 11, 2016 Abstract Long term outcome of ablation-assisted hepatic resection is unclear for hepatocellular carcinoma (HCC) patients. This study was scheduled to compare the outcome of Habib 4X ablation assisted resection (Habib group) with clamp-crush resection (CC group) for HCC. In this study, we retrospectively enrolled 81 patients from the Habib group and 103 patients from the CC group. Oncologic outcomes were analyzed using a propensity score matching (PSM) method. Compared with the CC group, the Habib group had higher levels of γ-glutamyltransferase ( P =0.044) and albumin ( P =0.001), larger tumor sizes ( P =0.007), shorter operation times ( P =0.001), less blood loss ( P =0.005), and less blood transfusions ( P =0.038). There were no significant differences in complications ( P =0.310), recurrence-free survival rates (RFS, P =0.112), or overall survival rates (OS, P =0.203) between the two groups. For the 67 patient pairs selected from the PSM analysis, the Habib group had better RFS and OS ( P =0.033 and P =0.014, respectively). A Cox proportional hazards analysis revealed that Habib-assisted resection was an independent factor for RFS and OS ( P =0.008 and P =0.016, respectively). Furthermore, for the 42 patients with central and large tumors, the Habib group had better RFS and OS than the CC group ( P =0.035 and P =0.038, respectively). However, the differences of RFS and OS ( P =0.117 and P =0.126, respectively) were not significant among 92 patients with peripheral or small tumors. Hence, Habib TM 4X-assisted resection is safe and provides better survival for HCC patients, particularly those with central and large tumors.

// Wei Zhang 1 , Zhifen Zhang 1 1 Department of Gynecology, Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People’s Hospital, 310006, Hangzhou, China Correspondence to: Zhifen Zhang, email: zhangzhifen624@qq.com Keywords: ERCC2, XRCC2, ovarian cancer, meta-analysis, single nucleotide polymorphism Received: October 07, 2016 Accepted: October 29, 2016 Published: November 15, 2016 ABSTRACT Recent studies explored XRCC2 rs3218536 and ERCC2 rs13181 polymorphisms and ovarian cancer (OC) risk. However, the association between these two single nucleotide polymorphisms and OC risk remains conflicting. Thus, we conducted a comprehensive systematic review and meta-analysis to investigate the association. We searched the databases of PubMed, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. 15 case-control studies published in 11 papers including 4,757 cases and 8,431 controls were included in this meta-analysis. No associations were obtained between XRCC2 rs3218536 and ERCC2 rs13181 polymorphisms and OC risk. Stratification analyses of Hardy–Weinberg equilibrium status indicated that rs3218536 polymorphism was associated with the decreased risk of OC when in analysis of combined HWE positive studies. In conclusion, this meta-analysis indicates that XRCC2 rs3218536 and ERCC2 rs13181 polymorphisms may not be associated with the risk of OC.

// Shayahati Bieerkehazhi 1, 2, * , Zhenghu Chen 3, 4, * , Yanling Zhao 4 , Yang Yu 4 , Huiyuan Zhang 4 , Sanjeev A. Vasudevan 5 , Sarah E. Woodfield 5 , Ling Tao 4 , Joanna S. Yi 4 , Jodi A. Muscal 4 , Jonathan C. Pang 4, 6 , Shan Guan 4 , Hong Zhang 2 , Jed G. Nuchtern 5 , Hui Li 7 , Huiwu Li 8 , Jianhua Yang 4 1 Department of Labour Hygiene and Sanitary Science, College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China 2 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 3 Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China 4 Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA 5 Division of Pediatric Surgery, Texas Children’s Hospital Department of Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA 6 Department of Biosciences, Weiss School of Natural Sciences, Rice University, Houston, Texas 77005, USA 7 Central Laboratory of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China 8 Cancer Prevention and Research Institute, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China * These authors have contributed equally to this work and should be considered co-first authors Correspondence to: Huiwu Li, email: huiwuli1234@163.com Jianhua Yang, email: jianhuay@bcm.edu Keywords: neuroblastoma, bosutinib, SKI-606, Bosulif, chemotherapy Received: October 29, 2016 Accepted: November 12, 2016 Published: November 26, 2016 ABSTRACT Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro . In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.

// Xianling Zeng 1 , Yafei Zhang 2 , Ting Yue 1 , Taohong Zhang 1 , Junxia Wang 1 , Yan Xue 1 , Ruifang An 1 1 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Shaanxi 710061, China 2 Department of General Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Shaanxi 710004, China Correspondence to: Ruifang An, email: anruifangxj@163.com Keywords: X-ray repair cross complementing 1, polymorphism, cervical cancer, meta-analysis Received: September 23, 2016 Accepted: November 21, 2016 Published: November 26, 2016 ABSTRACT The present meta-analysis was intended to explore the relationship between the X-ray repair cross complementing 1 (XRCC1) polymorphisms (Arg194Trp, Arg280His and Arg399Gln) and cervical cancer risk. Several electronic databases were searched systematically and bibliographies of relevant papers were identified carefully. Then, a meta-analysis was performed based on eligible studies in various genetic models. Pooled odds ratios (OR) with 95% confidence intervals (95% CI) were employed to evaluate the strength of associations between the XRCC1 polymorphisms and cervical cancer risk. Additionally, heterogeneity analysis and sensitivity analysis were done if necessary. Totally, 11 articles involving 2092 cases and 2803 controls were included. Taken together, there was no obvious association between the Arg194Trp or Arg280His polymorphism and cervical cancer risk. Considering the great heterogeneity, subgroup analysis was done, but the pooled result remained stable. Nevertheless, the association between the Arg399Gln polymorphism and cervical cancer risk showed distinct statistic significance in the allele model, dominant model, homozygous model and heterozygous model. In view of the exiting heterogeneity, we did subgroup analysis stratified by ethnicity, resulting in the fact that the Arg399Gln polymorphism was related to the decreased risk of cervical cancer. The Begg’s test and Egger’s test were used to find no publication bias. To conclude, the current meta-analysis indicated that the XRCC1 Arg399Gln polymorphism decreased the risk of cervical cancer, while the Arg194Trp and Arg280His polymorphisms were not associated with cervical caner risk. Certainly, a well-designed large-scale multicenter study is warranted to confirm the finding.

// Zhi-Rui Zhou 1,2,3,* , Qing Han 3,* , Shi-Xiong Liang 3,4 , Xiao-Dong He 4 , Nu-Yun Cao 5 and Ying-Jie Zi 3 1 Department of Radiation Oncology, Fudan University, Shanghai Cancer Center, Shanghai, P.R.China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R.China 3 Department of Radiation Oncology, Cancer Hospital of Guangxi Medical University, Nanning, P.R.China 4 Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R.China 5 College of Mathematics and Information Science, Guangxi University, Nanning, P.R.China * These authors have contributed equally to this paper Correspondence to: Shi-Xiong Liang, email: // Keywords : intensity modulated radiotherapy; normal tissue complication probability; radiation-induced lung injury; breast cancer Received : September 16, 2016 Accepted : October 24, 2016 Published : October 28, 2016 Abstract To investigate the relationship between dosimetric factors, including Lyman normal-tissue complication (NTCP) parameters and radiation-induced lung injury (RILI), in postoperative breast cancer patients treated by intensity modulated radiotherapy (IMRT). 109 breast cancer patients who received IMRT between January 2012 and December 2013 were prospectively enrolled. A maximum likelihood analysis yielded the best estimates for Lyman NTCP parameters. Ten patients were diagnosed with RILI (primarily Grade 1 or Grade 2 RILI); the rate of RILI was 9.17% (10/109). Multivariate analysis demonstrated that ipsilateral lung V 20 was an independent predictor ( P =0.001) of RILI. Setting V 20 =29.03% as the cut-off value, the prediction of RILI achieved high accuracy (94.5%), with a sensitivity of 80% and specificity of 96%. The NTCP model parameters for 109 patients were m=0.437, n =0.912, and TD 50 (1)=17.211 Gy. The sensitivity of the modified Lyman NTCP model to predict the RILI was 90% (9/10), the specificity was 69.7% (69/99), and the accuracy was 71.6% (78/109). The RILI rate of the NTCP 9.62% in patients with breast cancer was 23.08% (9/39), ( P =0.001). In conclusion, V 20 is an independent predictive factor for RILI in patients with breast cancer treated by IMRT; V 20 =29.03% could be a useful dosimetric parameter to predict the risk of RILI. The Lyman NTCP model parameters of the new value (m=0.437, n =0.912, TD50 (1) =17.211 Gy) can be used as an effective biological index to evaluate the risk of RILI.

Various intravesical therapies have been introduced into clinical practices for controlling non-muscle invasive bladder cancer (NMIBC). However, evidence with respect to the efficacy and safety of those intravesical therapies is very limited. Hence, we present a network meta-analysis in order to address this limitation in the current literature. The primary outcomes were the risk of tumor recurrence (TR), tumor progression (TP) and disease-specific mortality (DM). Secondary outcomes included the risk of fever, cystitis and haematuria. Conventional pair-wise and network meta-analysis were both performed for each endpoint. The surface under the cumulative ranking curve (SUCRA) was incorporated in our analysis for ranking the corresponding intravesical instillation interventions. In total, 23 randomized clinical trials (RCTs) were finally included in our study after irrelevant papers were screened out. Results of network meta-analysis suggested that Epirubicin (EPI) was less preferable than Bacille Calmette Guerin (BCG), BCG+EPI, BCG+ Isoniazid (INH), BCG+ Mytomicin C (MMC), Gemcitabine (GEM) and MMC with respect to TR. As suggested by the corresponding ranking probabilities and SUCRA, incorporating EPI or MMC into BCG may enhance the efficacy of BCG monotherapy.

// Qingzhou Guan 1 , Rou Chen 1 , Haidan Yan 1 , Hao Cai 1 , You Guo 1, 2 , Mengyao Li 1 , Xiangyu Li 1 , Mengsha Tong 1 , Lu Ao 1 , Hongdong Li 1 , Guini Hong 1 , Zheng Guo 1 1 Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, 350001, China 2 Department of Preventive Medicine, School of Basic Medicine Sciences, Gannan Medical University, Ganzhou, 341000, China Correspondence to: Zheng Guo, email: guoz@ems.hrbmu.edu.cn Guini Hong, email: hongguini08@gmail.com Keywords: gene expression profiling, multiple platforms, differentially expressed genes, heterogeneity of cancer, individual level Received: February 23, 2016 Accepted: August 09, 2016 Published: September 13, 2016 ABSTRACT The highly stable within-sample relative expression orderings (REOs) of gene pairs in a particular type of human normal tissue are widely reversed in the cancer condition. Based on this finding, we have recently proposed an algorithm named RankComp to detect differentially expressed genes (DEGs) for individual disease samples measured by a particular platform. In this paper, with 461 normal lung tissue samples separately measured by four commonly used platforms, we demonstrated that tens of millions of gene pairs with significantly stable REOs in normal lung tissue can be consistently detected in samples measured by different platforms. However, about 20% of stable REOs commonly detected by two different platforms (e.g., Affymetrix and Illumina platforms) showed inconsistent REO patterns due to the differences in probe design principles. Based on the significantly stable REOs (FDR

// Xiaolong Qi 1,* , Yanna Liu 1,* , Wei Wang 2,* , Danxian Cai 1 , Wende Li 3 , Jialiang Hui 1 , Chuan Liu 1 , Yanxia Zhao 4 and Guoxin Li 1 1 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China 2 Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China 3 Guangdong Laboratory Animal Monitoring Institute, Guangzhou, China 4 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China * These authors contributed equally to this work Correspondence to: Xiaolong Qi, email: // Guoxin Li, email: // Yanxia Zhao, email: // Keywords : advanced gastric cancer, management, surgery, chemotherapy, meta-analysis Received : June 30, 2016 Accepted : August 26, 2016 Published : September 17, 2016 Abstract This study aims to provide an overview of different treatment for advanced gastric cancer. In the present study, we systematically reviewed the major findings from relevant meta-analyses. A total of 54 relevant papers were searched via the PubMed, Web of Science, and Google scholar databases. They were classified according to the mainstay treatment modalities such as surgery, chemotherapy and others. Primary outcomes including overall survival, response rate, disease-free survival, recurrence-free survival, progression-free survival, time-to-progression, time-to failure, recurrence and safety were summarized. The recommendations and uncertainties regarding the treatment of advanced gastric cancer were also proposed. It was suggested that laparoscopic gastrectomy was a safe and technical alternative to open gastrectomy. Besides, neoadjuvant chemotherapy and adjuvant chemotherapy were thought to benefit the survival over surgery alone. And it was demonstrated in the study that targeted therapy like anti-angiogenic and anti-HER2 agents but anti-EGFR agent might have a significant survival benefit.

// Nadia Lobello 1, * , Flavia Biamonte 1, * , Maria Elena Pisanu 2, 3 , Maria Concetta Faniello 1 , Žiga Jakopin 4 , Emanuela Chiarella 5 , Emilia Dora Giovannone 5, 6 , Rita Mancini 2, 3 , Gennaro Ciliberto 7 , Giovanni Cuda 1, * , Francesco Costanzo 1, * 1 Centro di Ricerca di Biochimica e Biologia Molecolare Avanzata, Dipartimento di Medicina Sperimentale e Clinica, Universita degli Studi “Magna Graecia”, Catanzaro, Italy 2 Dipartimento di Medicina Clinica e Molecolare, Sapienza Universita di Roma, Italy 3 Laboratorio di Biologia Cellulare e Molecolare, Dipartimento di Chirurgia “P. Valdoni”, Sapienza Universita di Roma, Italy 4 Faculty of Pharmacy, University of Ljubljana, Slovenia 5 Dipartimento di Medicina Sperimentale e Clinica, Universita degli Studi “Magna Graecia”, Catanzaro, Italy 6 Centro Interdipartimentale di Servizi e Ricerca, Universita degli Studi “Magna Graecia”, Catanzaro, Italy 7 Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, Napoli, Italy * These authors contributed equally to this work Correspondence to: Gennaro Ciliberto, email: g.ciliberto@istitutotumori.na.it Keywords: ferritin heavy chain, ovarian cancer, cancer stem cells, EMT, miRNAs Received: February 28, 2016 Accepted: August 09, 2016 Published: August 22, 2016 ABSTRACT Objectives: Ferritin is the major intracellular iron storage protein essential for maintaining the cellular redox status. In recent years ferritin heavy chain (FHC) has been shown to be involved also in the control of cancer cell growth. Analysis of public microarray databases in ovarian cancer revealed a correlation between low FHC expression levels and shorter survival. To better understand the role of FHC in cancer, we have silenced the FHC gene in SKOV3 cells. Results: FHC-KO significantly enhanced cell viability and induced a more aggressive behaviour. FHC-silenced cells showed increased ability to form 3D spheroids and enhanced expression of NANOG, OCT4, ALDH and Vimentin. These features were accompanied by augmented expression of SCD1, a major lipid metabolism enzyme. FHC apparently orchestrates part of these changes by regulating a network of miRNAs. Methods: FHC-silenced and control shScr SKOV3 cells were monitored for changes in proliferation, migration, ability to propagate as 3D spheroids and for the expression of stem cell and epithelial-to-mesenchymal-transition (EMT) markers. The expression of three miRNAs relevant to spheroid formation or EMT was assessed by q-PCR. Conclusions: In this paper we uncover a new function of FHC in the control of cancer stem cells.

// Nicolle M. Linnerth-Petrik 1 , Lisa A. Santry 1 , Roger Moorehead 2 , Manfred Jucker 3 , Sarah K. Wootton 1, * , Jim Petrik 2, * 1 Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada 2 Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada 3 Center of Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany * These authors have contributed equally to this work Correspondence to: Jim Petrik, email: jpetrik@uoguelph.ca Keywords: ovarian cancer, Akt isoforms, Akt inhibitors, tumor development Received: March 21, 2016 Accepted: July 27, 2016 Published: August 11, 2016 ABSTRACT Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells ( Figure 1 ). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo . Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer.

// Ming-Jie Wang 1,* , Xiao-Liang Xu 2,* , Guo-Liang Yao 3,* , Qiang Yu 4 , Chun-Fu Zhu 4 , Zhi-Jun Kong 4 , Hui Zhao 5 , Li-Ming Tang 4 and Xi-Hu Qin 4 1 Department of Orthopedics, Affiliated Hospital of Nanjing Medical University, Changzhou Second People’s Hospital, Changzhou, China 2 Liver Surgery of Jiangsu Province People’s Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 3 Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 4 Department of General Surgery, Affiliated Hospital of Nanjing Medical University, Changzhou Second People’s Hospital, Changzhou, China 5 Department of General Surgery, Wuxi Third People’s Hospital, Wuxi, China * These authors have contributed equally to this study Correspondence to: Zhi-Jun Kong, email: // Hui Zhao, email: // Xi-Hu Qin, email: // Keywords : inflammatory bowel disease; Crohn’s disease; ulcerative colitis; MYO9B; polymorphism; Immunology and Microbiology Section; Immune response; Immunity Received : March 25, 2016 Accepted : July 19, 2016 Published : August 19, 2016 Abstract Myosin IXB ( MYO9B ) gene polymorphisms have been extensively investigated in terms of their associations with inflammatory bowel disease (IBD), with contradictory results. The aim of this meta-analysis was to evaluate associations between MY09B gene polymorphisms and the risk of IBD, Crohn’s disease (CD) and ulcerative colitis (UC). Eligible studies from PubMed, Embase, and CNKI databases were identified. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Ten studies published in eight papers reporting 8,975 cases and 9,482 controls were included in this meta-analysis. Five MY09B gene polymorphisms were evaluated: rs1545620, rs962917, rs1457092, rs2305764, and rs2305767. Our data suggested that the rs1545620 polymorphism was associated with a decreased risk of IBD. A similar result was found for rs2305767 and UC. The rs962917 single nucleotide polymorphism (SNP) increased the risk of IBD, CD and UC. Moreover, rs1457092 increased the risk of IBD and UC. Rs2305764 was also associated with an increased risk of IBD. Furthermore, stratification analyses indicated that rs1545620 decreased the risk of IBD, while rs962917 increased the risk of IBD, CD and UC in Caucasian populations. To sum up, our data indicate that these five SNPs in MY09B are significantly associated with the risk of IBD.

// Ting Lan 1 , Ji Pang 1 , Yan Wu 1 , Miaolin Zhu 1 , Xiaoyuan Yao 4 , Min Wu 1 , Hai Qian 1 , Zhenyu Zhang 2 , Jizong Gao 3 , Yongchang Chen 1 1 Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China 2 Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital of Capital Medical University, Beijing, China 3 R&D Department, BioRegen Biomedical (Changzhou) Co., Ltd., Changzhou, China 4 Basic Medical Department, Changchun Medical College, Changchun City, Jilin Province, China Correspondence to: Yongchang Chen, email: ycchen54@ujs.edu.cn Keywords: cross-linked hyaluronic acid gel (CHAG), inhibition, migration, growth, cancer cell Received: April 09, 2016 Accepted: August 24, 2016 Published: August 31, 2016 ABSTRACT Cross-linked hyaluronic acid gel (CHAG) has been used to prevent postoperative adhesion of abdominal tumorectomy. However, its effect on tumor cells is still unknown. This paper was designed to investigate the effect of CHAG on metastasis and growth of tumor cells. Migration and invasion assays, Western blotting, pull down assay, siRNA interference, and nude mice implantation tumor model were applied in this study. The results of in vitro experiments with gastric cancer cell line AGS and hepatic cancer cell line HepG2 showed that CHAG inhibited the migration and invasion activities, the MAPK and PI3K/Akt mediated signaling, the activation of small G proteins Rac1 and RhoA, and the expression of MMPs and PCNA initiated by EGF, through blocking the activation of EGFR. CHAG also had inhibitory effect on activation of other membrane receptors, including integrin and VEGFR. When the expression of hyaluronic acid receptors (CD44 or RHAMM) was interfered, the above inhibitory effects of CHAG still existed. In vivo experimental results showed that CHAG suppressed colonization, growth and metastasis of gastric cancer cell line SGC-7901 in peritoneal cavity of nude mice. In conclusion, CHAG had inhibitory effect on tumor cells, through covering cell surface and blocking the interaction between extracellular stimulative factors and their receptors.

Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of humanin that is important for humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.

// Giada Poli 1, * , Giulia Cantini 1, * , Roberta Armignacco 1, * , Rossella Fucci 1 , Raffaella Santi 2 , Letizia Canu 1 , Gabriella Nesi 2 , Massimo Mannelli 1 , Michaela Luconi 1 1 Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence Italy 2 Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence Italy * These authors contributed equally to this work Correspondence to: Michaela Luconi, email: michaela.luconi@unifi.it Keywords: metformin, H295R, IGF-1R, apoptosis, tumor proliferation Received: March 24, 2016 Accepted: June 09, 2016 Published: July 06, 2016 ABSTRACT Adrenocortical carcinoma (ACC) is a rare heterogeneous malignancy with poor prognosis. Since radical surgery is the only available treatment, more specific and effective drugs are urgently required. The anti-diabetic drug metformin has been associated with a decreased cancer prevalence and mortality in several solid tumors, prompting its possible use for ACC treatment. This paper evaluates the in vitro and in vivo anti-cancer effects of metformin using the ACC cell model H295R. Metformin treatment significantly reduces cell viability and proliferation in a dose- and time-dependent manner and associates with a significant inhibition of ERK1/2 and mTOR phosphorylation/activation, as well as with stimulation of AMPK activity. Metformin also triggers the apoptotic pathway, shown by the decreased expression of Bcl-2 and HSP27, HSP60 and HSP70, and enhanced membrane exposure of annexin V, resulting in activation of caspase-3 apoptotic effector. Metformin interferes with the proliferative autocrine loop of IGF2/IGF-1R, which supports adrenal cancer growth. Finally, in the ACC xenograft mouse model, obtained by subcutaneous injection of H295R cells, metformin intraperitoneal administration inhibits tumor growth, confirmed by the significant reduction of Ki67%. Our data suggest that metformin inhibits H295R cell growth both in vitro and in vivo . Further preclinical studies are necessary to validate the potential anti-cancer effect of metformin in patients affected by ACC.

// Santasree Banerjee 1,2 , Qian Wu 1 , Yuyi Ying 1 , Yanni Li 1 , Matsuyuki Shirota 3 , Dante Neculai 1 and Chen Li 1 1 Department of Cell Biology and Medical Genetics, School of Medicine, Zhejiang University, Hangzhou, China 2 BGI-Shenzhen, Shenzhen, China 3 Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai, Japan Correspondence to: Chen Li, email: // Keywords : genodermatoses, missense mutations, coiled-coil heterodimer, in silico analysis, Pathology Section Received : March 30, 2016 Accepted : May 17, 2016 Published : July 13, 2016 Abstract The K1 and K10 associated genodermatoses are characterized by clinical symptoms of mild to severe redness, blistering and hypertrophy of the skin. In this paper, we set out to computationally investigate the structural and functional effects of missense mutations on the 2B domain of K1/K10 heterodimer and its consequences in disease phenotype. We modeled the structure of the K1/K10 heterodimer based on crystal structures for the human homolog K5/K14 heterodimer, and identified that the missense mutations exert their effects on stability and assembly competence of the heterodimer by altering physico-chemical properties, interatomic interactions, and inter-residue atomic contacts. Comparative structural analysis between all the missense mutations and SNPs showed that the location and physico-chemical properties of the substituted amino acid are significantly correlated with phenotypic variations. In particular, we find evidence that a particular SNP ( K10 , p.E443K) is a pathogenic nsSNP which disrupts formation of the hydrophobic core and destabilizes the heterodimer through the loss of interatomic interactions. Our study is the first comprehensive report analyzing the mutations located on 2B domain of K1/K10 heterodimeric coiled-coil complex.

// Jia Sun 1, * , Jintao Chen 1, * , Juan Cao 1 , Tianxiang Li 1 , Shaoxia Zhuang 1 , Xiufeng Jiang 1 1 Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, Jiangsu, China * These authors have contributed equally to this paper Correspondence to: Xiufeng Jiang, email: xiufengjiangg@sina.com Keywords: lung injury, mesenchymal stem cell, angiogenesis, microRNA, Wnt/β-catenin Received: June 03, 2016 Accepted: July 04, 2016 Published: July 18, 2016 ABSTRACT Considerable attentions have been focused on the treatment of lung injury using mesenchymal stem cells that can replenish damaged tissues including the blood vessels. In human lung-derived mesenchymal stem cells (hL-MSC), we investigated the potential role of an IL-1β-stimulated miR-433 pathway in angiogenesis in vitro . The expressions of miR-433 and its target genes were examined in cells treated with IL-1β. The angiogenic activity of hL-MSC was studied by cell migration and tube formation assays in which miR-433 levels were manipulated. The reporter assay and chromatin immunoprecipitation (ChIP) were also performed to analyze the underlying regulations. We found that the expression of miR-433 was enhanced in hL-MSC by IL-1β in a NF-κB dependent manner via a NF-κB binding site at its promoter region. The effects of IL-1β on promoting angiogenic activities in hL-MSC can be mimicked by the overexpression of miR-433 and were blocked by anti-miR-433. Mechanistically, our data suggested that miR-433 directly targets the 3’-UTR of Dickkopf Wnt signaling pathway inhibitor 1 (DKK1) mRNA and decreases its expression. Consistently, the expression of β-catenin, the major mediator of canonical Wnt pathway that is capable of inducing endothelial differentiation and angiogenesis, was upregulated by IL-1β through miR-433. Thus, increasing miR-433 expression by IL-1β in mesenchymal stem cells could stimulate their capacity of vascular remodeling for efficient repair processes, which may be utilized as a therapeutic target in patients suffering from severe lung injury.

// Ying Zhang 1, * , Hu Wang 2, * , Chao Bi 1 , Yinping Xiao 1 , Zhaoyong Liu 2 1 Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China 2 Department of Orthopaedics, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong Province, China * These authors have contributed equally to this work Correspondence to: Zhaoyong Liu, email: langtian07@hotmail.com Key words: CDX2, Helicobacter pylori, gastric cardia cancer, cell proliferation Received: August 30, 2015 Accepted: June 12, 2016 Published: July 1, 2016 ABSTRACT Background : Gastric cardia cancer (GCC) is located in the distal stomach, and strongly correlates with atrophic gastritis and Helicobacter pylori (H.pylori) infection. Caudal-related homeobox transcription factor 2 (CDX2) is homeobox gene encoding an intestine-specific transcription factor usually expressed in the intestinal epithelium cells. However, in several recent published papers, CDX2 was found to be aberrantly expressed in gastric, thyroid and ovarian cancer. Results: Higher expression of CDX2 was found in GCC tissues in comparison with non-malignant cardia mucosa (p

// Wei Yu 1 , Yiming Ma 1 , Sharmila Shankar 1, 2 , Rakesh K. Srivastava 1, 3 1 Kansas City VA Medical Center, Kansas City, MO 66128, USA 2 Department of Pathology, University of Missouri-School of Medicine, Kansas City, MO 64108, USA 3 Department of Pharmaceutical Sciences, University of Missouri-School of Medicine, Kansas City, MO 64108, USA Correspondence to: Rakesh K. Srivastava, email: rsrivastava.lab@gmail.com Sharmila Shankar, email: sharmila.shankar@va.gov Keywords: pancreatic cancer, SATB2, cancer stem cell, stem cell, pluripotency Received: May 01, 2016 Accepted: July 10, 2016 Published: July 27, 2016 ABSTRACT SATB2 (special AT-rich binding protein-2), a transcription factor and chromatin modulator, regulates the expression of genes required for maintaining pluripotency and self-renewal. The molecular mechanisms by which human pancreatic normal ductal epithelial cells are transformed to cancer cells are not well understood. The main goal of the paper is to examine the molecular mechanisms by which SATB2 regulates transformation of human pancreatic normal ductal epithelial (HPNE) cells, and assess whether transformed HPNE cells gained the phenotypes of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in pancreatic CSCs, primary tissues and cell lines, but not in HPNE cells. SATB2 induces cellular transformation, stemness and epithelial to mesenchymal transition in HPNE cells, and inhibition of its expression suppresses these activities. Overexpression of SATB2 in HPNE cells resulted in induction of stem cell markers (CD44, CD24 and CD133), and transcription factors (Oct4, Sox2 and Nanog). SATB2 can directly bind to promoters of Bcl-2, Bsp, Nanog, c-Myc, XIAP, Klf4 and Hoxa2, suggesting the role of SATB2 in pluripotency, cell survival and proliferation. SATB2-overexpressing HPNE cells (HPNE/SATB2) formed tumors in Balb C nude mice, whereas HPNE/Empty vector cells did not form any tumor. Since SATB2 is highly expressed in human pancreatic cancer tissues and cell lines, but not in HPNE cells and normal pancreatic tissue, it can drive pancreatic cancer growth and metastasis. Our findings suggest that SATB2 can induce dedifferentiation by inducing stemness and may have a role in pancreatic carcinogenesis, and can be used as a diagnostic biomarker.

// Zhen Wang 1, * , Bin Yu 1, * , Baoming Wang 1 , Jingyi Yan 1 , Xiao Feng 1 , Zixuan Wang 1 , Lizheng Wang 1 , Haihong Zhang 1 , Hui Wu 1 , Jiaxin Wu 1 , Wei Kong 1, 2 , Xianghui Yu 1, 2 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, China 2 Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, Jilin University, Changchun, 130012, China * These authors contributed equally to this work Correspondence to: Xianghui Yu, email: xianghui@jlu.edu.cn Wei Kong, email: weikong@jlu.edu.cn Keywords: oncolytic adenovirus, gene therapy, capsid protein IX, TRAIL Received: January 17, 2016 Accepted: June 04, 2016 Published: June 15, 2016 ABSTRACT Oncolytic adenovirus (Ad)-vectored gene therapy is a promising strategy for cancer treatment. However, the lack of cancer cell selectivity or tumor tissue specificity of Ads limits their clinical application by intravenous (IV) injection. In this paper, a novel recombinant Ad5 vector was constructed carrying the capsid protein IX modified by the tumor necrosis factor related apoptosis-inducing ligand (TRAIL), which targets tumor cells bearing high levels of its receptor far above those of normal cells. Specific association of the Ad virion with TRAIL was achieved using synthetic leucine zipper-like dimerization domains (zippers). Analysis of the chemical properties of the modified recombinant Ad (rAd5pz-zTRAIL-RFP) showed that the TRAIL protein was present on the surface of purified virus particles, and it could induce apoptosis of infected cancer cells prior to expression of foreign genes. We also constructed a novel modified recombinant oncolytic Ad (rAd5pz-zTRAIL-RFP-SΔ24E1a) which showed significantly enhanced anti-tumor effects both in vitro and in vivo by linkage of TRAIL to the viral capsid. Moreover, rAd5pz-zTRAIL-RFP-SΔ24E1a showed significantly improved tumor tissue targeting and reduced liver tropism when IV injected in vivo . Thus, we successfully obtained new oncolytic Ad5 gene therapy vectors with enhanced targeting and efficacy, providing a platform for further clinical application of Ad vectors for cancer treatment.