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Hepatoid adenocarcinoma of the stomach (HAS) is an extremely rare and unique gastric malignancy. The present study aimed to examine the relevance of the clinicopathological characteristics of HAS with patient prognosis. We retrospectively reviewed clinical data of 34 HAS patients treated at our institution between January 2010 and December 2016, as well as 294 cases reported prior to 2017 in research databases. Among these patients, 45.6% (115/252) had lesions in the gastric antrum and 77.0% (235/305) were male. Elevated levels of serum alpha-fetoprotein (AFP) were detected in most patients (75/93, 80.6%). Vascular invasion (199/286, 69.6%), lymph node metastasis (222/283, 78.4%), and preoperative distant metastasis (121/328, 36.9%) were commonly observed. The 5-year disease-free survival (DFS) and disease-specific survival (DSS) were 20.7% and 29.2%, respectively. DFS and DSS of patients receiving neoadjuvant therapy were significantly higher than those of patients receiving postoperative adjuvant therapy [DFS: P

Hirschsprung disease (HSCR) is a newborn colorectal disease characterized by an absence of ganglia in the distal gut. Hedgehog (Hh) and endothelin signaling serve important roles in gastrointestinal tract formation. Alterations in the signaling pathways disrupt the development of enteric neural crest cells (ENCCs). It is not known whether there is any coordination between these pathways in the pathogenesis of HSCR. In the present study, tissue samples from 35 patients with HSCR, including stenotic aganglionosis gut and normal ganglionic gut, were obtained. The expression of Gli family zinc finger 1 (Gli1) and endothelin receptor type B (EDNRB) was determined using reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting. In addition, the SK-N-SH cell line was used to investigate the association between Hh signaling and the expression of EDNRB. The results revealed aberrant expression of Gli1 in the aganglionic segments, as well as decreased expression of Gli1 in tissues from 7 patients with HSCR exhibited, whereas tissues from 9 patients with HSCR exhibited increased Gli1 expression compared with the expression in the normal tissues. There was a negative association between EDNRB expression and Gli1 expression in the same sample. Knockdown of Gli1 by small interfering RNA and inhibition of Hh signaling by Vismodegib in SK-N-SH cells increased EDNRB expression. By contrast, upregulation of Gli1 expression by plasmids and activation of Hh signaling by Purmorphamine decreased EDNRB expression. Furthermore, premature enteric ganglia were observed in 4 patients with HSCR with decreased Gli1 expression. Thus, the results of the present study suggest that altered Gli1 expression negatively regulates EDNRB expression in patients with HSCR. The increased expression of EDNRB induced by decreased Gli1 expression may represent a novel mechanism in HSCR.

The most common site of gastrointestinal stromal tumors (GISTs) is the stomach, and gastric GISTs (gGISTs) occur most often in elderly patients. However, the clinicopathological features, treatment patterns, and prognosis of elderly patients with gGISTs remain unclear. We retrospectively collected clinicopathological and prognostic data for patients with primary gGISTs who underwent curative-intent resection at 10 medical centers in China from 1998 to 2015. Over the 18 years, 10 medical centers treated 1846 patients with primary gGISTs by curative-intent resection. The median age was 59 (range 18–91) years. The patients were classified into two groups according to age, namely an elderly group (≥ 65 years of age) and a nonelderly group (

The long non-coding RNA MALAT1 has been proved to promote the cell proliferation, drug resistance, invasion, and metastasis of colorectal cancer (CRC) in vitro and in vivo by regulating the expression of various oncogenes and their protein products. Our previous work discovered that the expression of the mRNA-decapping enzymes 1a (DCP1A) is upregulated in CRCs. However, the relationships between MALAT1 and DCP1A in the development of CRC and the underlying mechanisms are still unclear. In this study, we investigated the molecular mechanisms by which MALAT1 and DCP1A may be linked to contribute to the malignancies of CRCs. We found that DCP1A is a direct target molecule of MALAT1. Moreover, by screening the downstream genes of MALAT1, we noticed that microRNA 203(miR203), an oncogene suppressor in numerous cancers, is inversely correlated to both MALAT1 and DCP1A expressions. Following MALAT1 knockdown, we observed overexpression of miR203 accompanied with DCP1A downregulation to a level that reversed the promoted cell proliferation, invasion, and migration in vitro and in vivo, which could be restored by miR203 knockdown or DCP1A overexpression. These results proposed a new molecular mechanism of MALAT-miR203-DCP1A axis which is involved with the development and contributes to the malignancy of colorectal cancers.

// Qian-Na Jin 1 , Jia-Qing Cao 2 , Nan He 3, 4 , Xin Jin 4 , Tao Liu 4 , Xiao-Ming Lu 3, 4 , Kai-Xiong Tao 3 and Guo-Bin Wang 3 1 Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 2 Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China 3 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 4 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Correspondence to: Nan He, email: hero_nan@163.com Keywords: ADAM8; solid tumor; prognosis; survival; meta-analysis Received: March 01, 2017 Accepted: August 29, 2017 Published: January 02, 2018 ABSTRACT A disintegrin and metalloprotease 8 (ADAM8) expression appears to be predictive of prognosis in various solid tumors, though the evidence is not yet conclusive. We therefore performed a meta-analysis to explore the relationship between ADAM8 expression and prognosis in patients with solid tumors. Relevant publications were searched in several widely used databases, and 12 studies (1722 patients) were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between ADAM8 expression and prognosis. Associations between ADAM8 expression and prognosis were observed for 3-year overall survival (OR = 3.09, 95% CI = 2.33 to 4.10, P < 0.00001) and 5-year overall survival (OR = 4.15, 95% CI = 3.14 to 5.48, P < 0.00001). Similar results were observed when disease free survival (DFS) were analyzed, 3-year DFS (OR = 2.47, 95% CI = 1.66 to 3.69, P < 0.00001) and 5-year DFS (OR = 3.30, 95% CI = 2.29 to 4.74, P < 0.00001). In conclusion, elevated ADAM8 expression is associated with poor prognosis in most solid tumors. ADAM8 is a valuable biomarker for prognosis prediction and a promising therapeutic target in human solid tumors.

Background: Based on specific regional evidences, different countries prefer particular types of multimodal treatments against resectable gastric cancer, such as perioperative chemotherapy in Europe, postoperative chemoradiotherapy in USA and postoperative chemotherapy in Asian world. However, irrespective of geographical differences, there is currently lacking of a comprehensive evidence to rank all recommended strategies simultaneously and hierarchically, which could facilitate clinical decision-making and future design of randomized trials. Therefore, we conducted the first systematic review and network meta-analysis on this field. Methods: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO meeting libraries from inception to September 2018. Regarding survival and tolerability, randomized controlled trials featuring comparisons between different preferred multimodal treatments against resectable gastric cancer were eligible. The Cochrane Risk of Bias Tool was applied to assess the methodological quality of included trials. Overall survival was primary endpoint, while recurrence-free survival, hematological and non-hematological adverse events were secondary endpoints. Network calculation was based on random-effects model and the relative ranking of each node was numerically indicated by P-score. Findings: A total of 11 studies were included into our systematic review, corresponding to 7235 patients. The demographic characteristics were comparable and the overall risk of bias was in low level. Regarding overall survival, "PeriCT (FLOT)" (perioperative 5-FU plus leucovorin plus oxaliplatin plus docetaxel chemotherapy) topped the hierarchy (HR 1.00, P-score=0.918), followed by "PostCT (XP)" (postoperative capecitabine plus platinum chemotherapy; HR 1.14, P-score=0.759) and "PostCT (S-1)" (postoperative S-1 monotherapy; HR 1.16, P-score=0.732). Among all subgroup analyses, "PostCT (XP)" became the top regimen for eastern population, D2 lymphadenectomy, less invasion depth and higher TNM stages, "PeriCT (FLOT)" was the optimal node for western population while "PostCT (S-1)" for gastric cases only, severer invasion depth and lower TNM stages. Concerning recurrence-free survival, "PostCRT (XP)" (postoperative capecitabine plus platinum chemoradiotherapy; HR 0.88, P-score=0.940) was the optimal node, slightly better than "PeriCT (FLOT)" (HR 1.00, P-score=0.895). Adverse events for major survival-beneficial regimens seemed to be comparable. Interpretation: Perioperative FLOT chemotherapy could potentially be the best multimodal treatment against resectable gastric cancer than other recommended strategies, including postoperative XELOX (capecitabine plus oxaliplatin) chemotherapy, postoperative S-1 monotherapy or postoperative FL (5-FU plus leucovorin) chemoradiotherapy. Therefore, a global D2-lymphadenectomy randomized controlled trial comparing perioperative FLOT chemotherapy with postoperative XELOX chemotherapy should be carried out. Funding Statement: Scientific Research Training Program for Young Talents (2017); National Natural Science Foundation of China (81572413) Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The protocol of this systematic review and network meta-analysis had been published in PROSPERO (CRD42018109147). The design, conduct and writing of this systematic review and network meta-analysis was strictly in accordance with the requirements from PRISMA Checklist for Network Meta-analysis and Cochrane Handbook 5.1. Each step was conducted by two investigators of our research group. Any discrepancy was judged and solved by the third investigator.

Primers. (DOCX 16 kb)

Figure S1. HDAC1–3 expression correlated B7-H1 expression in clinical gastric specimens. (A) B7-H1 and HDAC1–3 expression in 12 paired gastric cancer (C) and adjacent tissues (A) were determined by western blot. (B) After quantification and normalization, the expression change of HDAC1–3 and B7-H1 between each pair of cancer and adjacent tissue was presented. A, the experiment was repeated three times with similar results. (PDF 105 kb)

Supplementary methods. (DOCX 14 kb)

Background: Failure of first-line systemic therapy is commonly observed among patients with advanced gastric cancer. Although paclitaxel plus ramucirumab has been recommended as the preferred second-line strategy, other regimens also display potentially comparable efficacies. Moreover, there is currently lacking of consensus on the systemic treatment among refractory patients. Unfortunately, despite of several previously published systematic reviews, there is still lacking of a comprehensive and hierarchical evidence that properly compares all eligible literatures simultaneously. Hence, we performed a systematic review as well as network meta-analysis in order to summarize and analyze all potential knowledge on this field. Methods: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO meeting abstract library from inception to August 2018. Regarding survival and tolerability, randomized controlled trials featuring comparisons between different systemic treatments among previously treated patients with advanced gastric cancer were eligible for our systematic review. The quantitative network meta-analyses were additionally performed among second-line unselected patients with fluoropyrimidine-based first-line regimens and refractory unselected cases. Overall survival was the primary endpoint, while progression-free survival, objective response rate, hematological and non-hematological adverse events were selected as secondary endpoints. Hazard ratio (HR) and risk ratio (RR) with their 95% confidence interval were used for time-to-event survival and dichotomous variables respectively. Pairwise and network calculation were based on random-effects model and the relative ranking of each regimen was numerically indicated by P-score. Findings: A total of 36 studies were included into our systematic review. The demographic characteristics were comparable across the studies and the overall risk of bias was in low level. Concerning second-line unselected patients with fluoropyrimidine-based first-line regimens, "PO" (paclitaxel plus olaparib) (HR 1.00 (0.77-1.28), P-score=0.909) and "PRa" (paclitaxel plus ramucirumab) (HR 1.00, P-score=0.907) dominated the overall survival ranking while "PRa" additionally topped the hierarchy for progression-free survival (HR 1.00, P-score=0.983) and objective response rate (RR 1.00, P-score=0.925). Both "PO" and "PRa" displayed acceptable tolerability. As for second-line HER2 positive patients, trastuzumab-based doublets failed to surpass taxane monotherapy in survival efficacies. Among general refractory or third-line only cases, apatinib reigned the hierarchy by significantly and insignificantly surpassing placebo and nivolumab respectively, irrespective of overall and progression-free survival, while showing comparable adverse events as well. Interpretation: In conclusion, paclitaxel plus ramucirumab is the optimal regimen for second-line unselected patients with fluoropyrimidine-based first-line regimens while olaparib-based medications also have the potential to become vital alternatives against advanced gastric cancer, especially among eastern population where paclitaxel plus ramucirumab seems less effective. Paclitaxel monotherapy should be recommended as the preferred second-line regimen among HER2 positive patients who receive standard first-line treatment. Both apatinib and nivolumab could be potentially recommended as refractory regimens due to their significant superiority against placebo, however their mutual efficacies still need to be verified in further global investigations. Funding Statement: Scientific Research Training Program for Young Talents (2017); National Natural Science Foundation of China (81572413). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures were conducted according to Cochrane Handbook 5.1 and PRISMA for Network Meta-analysis (CRD42018104672).

Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is present in both intracellular and extracellular compartments. Although AGR2 is overexpressed in various human cancers and reported to promote aggressive tumor features, little is known regarding AGR2's extracellular functions during tumorigenesis. Here, we demonstrate that secreted AGR2 promotes cell migration and metastasis of colorectal cancer (CRC) in vitro and in vivo. Mechanistically, secreted AGR2 elevated Wnt11 expression, triggering non-canonical Wnt signaling: the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and c-jun amino-terminal kinase (JNK) pathways. Knockdown of Wnt11 or pretreatment with CaMKII and JNK inhibitors reversed the secreted AGR2's migration-promoting effect. Further studies revealed that AGR2 antagonized canonical Wnt/β-catenin signaling via activating CaMKII. Collectively, our study uncovers a critical role of Wnt11-mediated non-canonical Wnt signaling (CaMKII and JNK pathways) in secreted AGR2's promoted migration of CRC cells. These results raise the possibility that secreted AGR2 may be a potential therapeutic target towards inhibiting CRC metastasis.

miRNA‑gene axes have been reported to serve an important role in the carcinogenesis of pancreatic cancer (PC). The aim of the present study was to systematically identity the microRNA signature and hub molecules, as well as hub miRNA‑gene axes, and to explore the potential biomarkers and mechanisms associated with the carcinogenesis of PC. Eleven microRNA profile datasets were obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) and ArrayExpress databases, and a meta‑analysis was performed to identify the differentially expressed miRNAs (DEMs) between tumor tissue and normal tissue. Subsequently, a diagnostic regression model was constructed to identify PC based on The Cancer Genome Atlas (TCGA) miRNA sequence data by using the least absolute shrinkage and selection operator (LASSO) method. In addition, GSE41368 was downloaded, and a weighted gene co‑expression network analysis (WGCNA) was performed to obtain the gene module associated with carcinogenesis by using the TCGAbiolinks and WGCNA packages, respectively. Finally, miRNA‑gene networks were constructed and visualized using Cytoscape software, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses based on the Database for Annotation, Visualization, and Integrated Discovery (DAVID). A total of 14 DEMs were identified, and a 5‑microRNA‑based score generated by the LASSO regression model provided a high accuracy for identifying PC [area under the curve (AUC)=0.918]. In addition, 44 miRNA‑mRNA interactions were constructed, and 4 hub genes were screened on the basis of the above bioinformatic tools and databases. Furthermore, 14 biological process (BP) functions and 6 KEGG pathways were identified according to gene set enrichment analysis (GSEA). In summary, the present study applied integrated bioinformatics approaches to generate a holistic view of PC, thereby providing a basis for further clinical application of the 5‑miRNA signature and the identified hub molecules, as well as the miRNA‑gene axes, which could serve as diagnostic markers and potential treatment targets.

The prognostic value of anterior gradient-2 (AGR2) in tumours remains inconclusive. Here, we systematically reviewed the literature evidence and assessed the association between AGR2 expression and prognosis in solid tumours. The primary outcomes were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS). All analyses were performed by STATA 12.0, with the hazard ratio (HR) or odds ratios (OR), and 95% confidence interval (CI) as the effect size estimate. A total of 20 studies containing 3285 cases were included. Pooled analyses revealed that AGR2 overexpression had an unfavourable impact on OS (HR 1.93, 95% CI 1.32–2.81) and time to tumour progression (TTP) (DFS/RFS/PFS) (HR 1.60 95% CI 1.06–2.40) in solid tumour patients. Subgroup analyses indicated that AGR2 overexpression in breast cancer patients was significantly associated with poor OS (HR 3.02, 95% CI 1.03–8.81) and TTP (HR 1.93, 95% CI 1.17–3.20). Excluding breast cancer, AGR2 overexpression was also found to have a significant correlation with poor OS in the remaining solid tumour patients (HR 1.51, 95% CI 1.04–2.19). Overall, AGR2 might be a potential biomarker to predict prognosis in solid tumour patients.

The interaction between Siglec-10 and its ligand, CD24, selectively represses tissue damage-caused immune responses. However, the nature of Siglec-10 and CD24 in human hepatocellular carcinoma (HCC) is still poorly defined. Hereon, the expression, function, and regulation of CD24 and Siglec-10 in HCC were investigated in the present study.Flow cytometry was performed to examine the expression of Siglec-10 in HCC tissues and adjacent non-tumor tissues of HCC patients. To further determine whether Siglec-10 expression is associated with the clinical characteristics and survival, conventional immunohistochemistry was performed in 96 HCC patients. Additionally, the role of Siglec-10 in the regulation of natural killer (NK) cell dysfunction was evaluated. Finally, CD24 expression in HCC was also assessed.Siglec-10 was expressed most on NK cells in HCC (40.7 ± 4.5%). Compared with surrounding non-tumor tissues, tumor tissues had higher Siglec-10 expression (31.0 ± 1.7% versus 40.7 ± 4.5%, n = 10, P0.05), and the expression was negatively associated with patient survival. Siglec-10(+)CD56(+) NK cells exhibited reduced effector function, as shown by decreased granules and cytokine expressions compared with Siglec-10(-)CD56(+) NK cells. Moreover, the number of CD24(+)CD45(-) cells in HCC tissues was higher than that in adjacent non-tumor tissues (9.4 ± 0.9% versus 3.1 ± 0.9%, n = 15, P0.05).These findings suggest that Siglec-10 is associated with decreased survival and impaired NK cell function in human HCC. This process may function via the CD24-Siglec-10 interaction, which may represent a therapeutic target in HCC patients.

Cancer stem-like cells (CSCs) are a rare tumorigenic population with the ability to self-renew in numerous cancer types. Their existence is considered a pivotal contributor to tumor recurrence. B7-H1 is a ligand of inhibitory inducible co-stimulator (ICOS) that is broadly expressed on various human cancers. ICOS acts as a ligand of programmed death-1 (PD-1) on T cells, induces the immune escape of cancer cells and also acts as a receptor mediating anti-apoptotic effects on cancer cells. However, the expression and function of B7-H1 on CSCs is not yet clear. In the present study, gastric cancer samples were collected and the B7-H1 expression in gastric cancer CSCs was detected. Ki67, a proliferation marker, was found to be expressed at a higher rate in B7-H1+ CSCs compared with the B7-H1− counterparts. SGC-7901 cells, a gastric cancer cell line, were cultured in serum-free medium to form sphere cells that possessed stem cell characteristics and could express B7-H1 with the stimulation of interferon-γ. The proliferative ability of sphere cells was enhanced following B7-H1 activation with recombinant PD-1 in vivo and in vitro. This effect could be eliminated by neutralizing B7-H1. Overall, B7-H1 can act as a stimulating receptor for CSCs, and induce CSC proliferation. Blocking B7-H1 on CSCs may possess therapeutic potential for treating gastric cancer.

Endoscopic minimal invasive cholecystolithotomy (EMIC) is recently popular in China which may offer advantages over laparoscopic cholecystectomy (LC). We try to find out the most favorable treatment for the patients underwent cholecystolithiasis.Databases PubMed, Elsevier, Wiley Online Library, The Cochrane library, CNKI, WanFang Data, and Chongqing VIP were searched for randomized controlled trials (RCTs) and on EMIC vs LC from 2009 to 2013. Odds ratio (OR), risk difference (RD) and weight mean difference (WMD) were calculated with 95% confidence intervals (CI).14 RCTs including 2030 patients were selected. No significant difference was present in operating time between EMIC and LC. EMIC shown significant less blood lost (WMD -23.45; 95% CI -30.34, -16.55; Z=6.66; P0.00001) compared to LC. Shortened exhaust time (WMD -14.11; 95% CI -18.34, -9.88; Z=6.53; P0.00001) and hospital stay (WMD -1.31; 95% CI -1.91, -0.71; Z=4.29; P0.00001) were present in EMIC group. And EMIC shown decreased complication proportion (OR -0.14, 95% CI -0.09 to -0.21; Z=8.53; P0.00001) in comparison with LC. There is no difference present in the recurrence of stones in two procedures but a significantly decreased recurrence rate of gallstones was present in EMIC compared to conventional cholecystolithotomy.Patients treated with EMIC shown faster recovery and less complication which were superior to LC.

// Xiao-Fei Zhang 1 , Ke-ke Li 1 , Lu Gao 3 , Shang-Ze Li 1 , Ke Chen 4 , Jun-Bin Zhang 5 , Di Wang 6 , Rong-Fu Tu 1 , Jin-Xiang Zhang 2 , Kai-Xiong Tao 2 , Guobin Wang 2, * , Xiao-Dong Zhang 1, * 1 College of Life Sciences, Wuhan University, Wuhan 430072, PR China 2 Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China 3 Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China 4 Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China 5 Department of Emergency, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China 6 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China * These authors have contributed equally to this work Correspondence to: Xiao-Dong Zhang, e-mail: zhangxd@whu.edu.cn Keywords: microRNA-191, colorectal cancer, apoptosis, C/EBPβ, tumorigenesis Received: August 28, 2014 Accepted: December 07, 2014 Published: December 27, 2014 ABSTRACT MicroRNA-191 (miR-191), a small non-coding RNA, is involved in disease development and cancer diagnosis and prognosis. However, how miR-191 functions in colorectal cancer remains largely unclear. In this study, we show that miR-191 is highly expressed in colon tumor tissues, and that inhibition of miR-191 leads to decreased cell growth, proliferation and tumorigenicity in a xenograft model. Overexpression of miR-191 in colorectal cancer cell lines alters cell cycle progression and cell resistance to 5-Fu induced cell apoptosis. Mechanistic studies demonstrated that miR-191 directly binds to the 3’UTR of the C/EBPβ mRNA and mediates a decrease in the mRNA and protein expression of C/EBPβ. We further showed that C/EBPβ induces growth arrest in a colorectal cancer cell line and that its expression is negatively correlated with the miR-191 level in patient samples. Our findings suggest that miR-191 may be a potential gene therapy target for the treatment of colorectal cancer.

Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.

To evaluate and compare the value of Modified NIH criteria and AFIP criteria for the risk classification of gastrointestinal stromal tumors (GIST).Clinicopathological and follow-up data of 539 patients diagnosed as primary GIST with or without irregular tyrosine kinase inhibitors in the Nanfang Hospital(n=143), Sun Yat-sen University Cancer Center (n=138), Guangdong Provincial People's Hospital (n=102) and Wuhan Union Hospital (n=156) from January 2012 to December 2015 were retrospectively analyzed. Recurrence risks of these 539 patients were classified by the modified NIH criteria and AFIP criteria. Overall survival and tumor-free survival of patients with different risks were compared by Log-rank test and the accuracy of the two criteria in predicting postoperative recurrence was compared by receiver operating characteristic(ROC) curves.Of 539 GIST patients, 283 were male and 256 were female; the age was (56.5±12.5) years old; tumors of 390 cases (72.4%) located in the stomach; tumor diameter of 178 cases (33.0%) was more than 5 cm; nuclear division number of 164 cases(30.4%) was more than 5/50 high magnification. The mean follow-up time was (37.5±13.6) months. According to the modified NIH criteria, the mean overall survival time of patients with very low, low, intermediate, and high risk was 52.0, 57.0, 56.9 and 53.6 months respectively (P=0.002), and the mean tumor-free survival time was 56.0, 58.1, 58.2 and 51.2 months respectively (P=0.000). According to the AFIP criteria, the mean overall survival time of patients with very low, low, intermediate, and high risk was 54.1, 57.8, 55.5 and 52.0 months respectively(P=0.015), and the mean tumor-free survival time was 57.3, 56.6, 54.9 and 50.4 months respectively(P=0.000). While predicting the risk of postoperative recurrence, the ROC curve of AFIP criteria has a larger area under the curve compared to the curve of the modified NIH criteria(0.689 vs 0.641, P0.05).Compared with the modified NIH criteria, AFIP criteria predicts the risk postoperative recurrence more accurately in GIST patients.

Background Over the past decade, mini-laparoscopic cholecystectomy (MLC) and single-port laparoscopic cholecystectomy (SILC) have been the two main successful mini-invasive surgical interventions for the treatment of cholecystolithiasis since the advent of laparoscopic cholecystectomy (LC). In this study, we conducted a meta-analysis to compare the two treatment alternatives. Methods We searched PubMed, CNKI and the Cochrane library for trials that compared MLC and SILC. Risk difference (RD) and mean difference (MD) were calculated with a 95% confidence interval (CI). Results Four randomized controlled trials (RCTs) and 2 non-randomized comparative studies (nRCSs) involving 2764 patients were identified. A longer operating time (MD -10.49; 95% CI -18.10, −2.88; P = 0.007) and a shorter wound length (MD 3.65; 95% CI 0.51, 6.78; P = 0.02) were found to be associated with SILC compared with MLC. No significant differences were revealed in conversion, hospital stay, pain relief and cosmetic results. Although a lower incidence of complications was observed with MLC (8.2%) compared with SILC (15.9%), but the difference was not statistically significant (RD -0.06; 95% CI -0.12, 0.00; P = 0.07). Conclusions MLC has an advantage over SILC in terms of operating time rather than hospital stay, pain relief, cosmetic results. Though conversion and complication rates were higher with SILC, there existed no statistically differences in the two measures between the two procedures. Whether MLC confers any benefits in terms of conversion or complications still warrants further studies. Electronic supplementary material The online version of this article (doi:10.1186/s12893-017-0287-x) contains supplementary material, which is available to authorized users.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. It is a complicated and often fatal cancer, and is related to a high disease-related mortality. Around 90% of mortalities are caused by the metastasis of CRC. Current treatment statistics shows a less than 5% 5-year survival for patients with metastatic disease. The development and metastasis of CRC involve multiple factors and mechanisms. The Hedgehog (Hh) signaling plays an important role in embryogenesis and somatic development. Abnormal activation of the Hh pathway has been proven to be related to several types of human cancers. The role of Hh signaling in CRC, however, remains controversial. In this review, we will go through previous literature on the Hh signaling and its functions in the formation, proliferation, and metastasis of CRC. We will also discuss the potential of targeting Hh signaling pathway in the treatment, prognosis, and prevention of CRC.

Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options.

Chemotherapy-induced nausea and vomiting (CINV) is one of the commonest side-effects among cancer patients. However, there is lacking of hierarchical evidences comparing different antiemetics against highly emetogenic chemotherapy. Therefore, we conducted a network meta-analysis to investigate their comparative efficacy and tolerability. Randomized controlled trials that compared different antiemetic categories for adult highly emetogenic chemotherapy were included after searching PubMed, Web of Science, Embase and Cochrane Central. Acute-phase no emesis and no nausea were identified as primary endpoints. We made pairwise and hierarchical calculations by random-effects model. Effect sizes were presented by odds ratio and 95% confidential interval. Subgroup analysis was additionally performed. 143 randomized trials were included into pooled analysis, containing 22,776 patients and 18 antiemetic categories. 5-HT3 RA plus corticosteroid plus NK-1 RA plus other (5CNO) displayed best protection against both acute emesis (SUCRA: 99.7%) and nausea (95.6%). 5CNO (99.7%) and 5-HT3 RA plus corticosteroid plus other (5CO, 85.3%) topped subgroup hierarchies for no-naivety and anthracycline plus cyclophosphamide (AC)-based studies. On the other hand, 5-HT3 RA plus dopamine RA plus other (5DO) may be best fit for delayed emesis (92.0%) and nausea (92.7%). Subgroups featuring no-naivety and AC-based trials preferred 5DO (91.9%) and 5CN (88.6%), respectively. In addition, dopamine RA plus other (DO) had the lowest incidence of TRAE in most circumstances, except for AC-based subgroup where corticosteroid plus dopamine RA plus other (CDO) preponderated (69.2%). 5CNO and 5DO should be considered as first-line regimens against highly emetogenic chemotherapy induced acute and delayed CINV, respectively.

// Xiangyu Zeng 1 , Peng Zhang 1 , Hua Xiao 2 , Xiuli Wu 3 , Weizhen Liu 1 , Jun He 3 , Jinbo Gao 1 , Guobin Wang 1 , Xiaoming Shuai 1 and Kaixiong Tao 1 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 2 Department of Gastroduodenal and Pancreatic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China 3 Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China Correspondence to: Kaixiong Tao, email: kaixiongtao@hust.edu.cn Xiaoming Shuai, email: xmshuai@hust.edu.cn Keywords: hepatoid adenocarcinoma; intestines; stomach; feature; prognosis Received: May 10, 2017 Accepted: December 15, 2017 Published: December 21, 2017 ABSTRACT Backgroud: Intestinal hepatoid adenocarcinoma (IHA) is a very rare and unique intestinal malignancy. Due to the lack of case series specifically pertaining to IHA, the clinicopathological features and prognosis of it remain unclear. Results: Of the 42 patients enrolled in this study, 30 (71.4%) were male. Twenty-one cases (50.0%) were located in the colon. Eight cases (19.0%) had accompanying inflammatory bowel disease (IBD). Elevated serum alpha-fetoprotein (AFP) was detected for most patients (25/33, 84.8%). Twenty-five (59.5%) patients received complete resections. Vascular invasion (22/36, 61.1%), lymph node metastasis (28/36, 77.8%) and distant metastasis (21/42, 50.0%) were common. The 1-year progression-free survival (PFS) and disease-specific survival (DSS) of IHA were 26.9% and 30.6%, respectively. Multivariate analysis showed that only pTNM stage was an independent risk factor for PFS and DSS. PFS and DSS in patients with IHA were significantly lower than those with colorectal adenocarcinoma (CA) and hepatoid adenocarcinoma of the stomach (HAS). Conclusions: IHA most commonly occurred in the colon and accompanied by IBD in several cases. pTNM stage was an independent factor for prognosis. The prognosis of IHA was significantly worse than that of CA and HAS. Patients and Methods: Clinical data of IHA from four patients managed at our institution between January 2010 and December 2016, and 38 cases from research databases prior to 2017 were retrospectively studied.

ARID1A, a component of the chromatin remodeling complex SWI/SNF, is an evolutionarily conserved complex that uses the energy of adenosine triphosphate hydrolysis to remodel chromatin structure and functions as a master regulator of gene transcription. Recent genomic studies have revealed that ARID1A is one of the most frequently mutated genes in human cancers. However, therapeutic approaches that selectively target ARID1A-mutant tumors are not yet clinically available. Our previous study showed that ARID1A facilitates chromatin response and cell cycle checkpoint activation after DNA damage. Therefore, an ARID1A deficiency may result in therapeutic vulnerabilities in cell cycle modulators. The goals of our study were to develop a novel screening approach, based on fluorescent ubiquitination-based cell cycle indicators (FUCCI), and to identify chemical agents that can selectively modulate the cell cycle transition in ARID1A-deficient cancer cells. Using this high-throughput assay, we screened 2643 compounds and identified six potential chemical modulators that can selectively modulate the cell cycle in ARID1A-deficient cells; these agents may be useful for developing new therapeutics for ARID1A-mutant tumors. In summary, our study demonstrates that FUCCI cell-based high-content screening is a powerful and effective approach for identifying cell cycle modulators and can be applied to multigenotypic screening for targeted cancer therapeutics.

Processing bodies (P-bodies) are one of the most well understood types of RNA granules, and are associated with a variety of diseases, including cancer. mRNA-decapping enzyme 1a (DCP1a), which may be used as a marker to analyze P-bodies, participates in the removal of the 5'-methylguanosine cap from eukaryotic mRNAs as a cofactor. The aim of the present study was to analyze the association between DCP1a expression and clinical features in colorectal carcinoma (CRC). The levels of DCP1a mRNA expression were detected by reverse transcription-quantitative polymerase chain reaction assay in carcinoma and non-carcinoma tissues from 75 patients, while the protein expression levels were evaluated by immunohistochemistry and western blotting. Additional associations between DCP1a expression and clinical characteristics were analyzed by χ2 test and Cox regression analysis. In the 75 cases, the levels of DCP1a mRNA and protein expression were increased in colorectal carcinoma tissues compared with non-carcinoma tissues. A high expression of DCP1a was significantly associated with lower survival rates in patients with CRC compared with patients with low DCP1a expression (P=0.001). Associations with depth of invasion (P=0.008), lymph node metastasis (P=0.001) and tumor node metastasis stage (P=0.001) were also observed. Additional Cox regression analysis revealed that the DCP1a expression (P=0.012) is an independent factor in survival rate. It was also identified that DCP1a may have high expression in colorectal carcinoma tissues and be associated with poor prognosis. This suggests that DCP1a may be a diagnostic marker or prognostic indicator to assist with patient assessments and therapies.

Globally, gastric cancer is the second leading cause of cancer deaths because of the lack of effective treatments for patients with advanced tumors when curative surgery is not possible. Thus, there is an urgent need to identify molecular targets in gastric cancer that can be used for developing novel therapies and prolonging patient survival. Checkpoint kinase 1 (Chk1) is a crucial regulator of cell cycle transition in DNA damage response (DDR). In our study, we report that Chk1 plays an important role in promoting gastric cancer cell survival and growth, which serves as an effective therapeutic target in gastric cancer. First, Chk1 ablation by small interfering RNA could significantly inhibit cell proliferation and sensitize the effects of ionizing radiation (IR) treatment in both p53 wild type gastric cancer cell line AGS, and p53 mutant cell line MKN1. Secondly, we tested the anticancer effects of Chk1 chemical inhibitor LY2606368, which is a novel Chk1/2 targeted drug undergoing clinical trials in many malignant diseases. We found that LY2606368 can induce DNA damage, and remarkably suppress cancer proliferation and induce apoptosis in AGS and MKN1 cells. Moreover, we identified that LY2606368 can significantly inhibit homologous recombination (HR) mediated DNA repair and thus showed marked synergistic anticancer effect in combination with poly (ADP-ribose) polymerase 1 (PARP1) inhibitor BMN673 in both in vitro studies and in vivo experiments using a gastric cancer PDx model. The synergy between LY2606368 and PARP1 was likely caused by impaired the G2M checkpoint due to LY2606368 treatment, which forced mitotic entry and cell death in the presence of BMN673. In conclusion, we propose that Chk1 is a valued target for gastric cancer treatment, especially Chk1 inhibitor combined with PARP inhibitor may be a more effective therapeutic strategy in gastric cancer.

NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE (DOCX 14Â kb)

Funel plot on MLC vs SILC considering operating time. Figure S2. Sensitivity analysis on MLC vs SILC considering operating time. Figure S3. Funel plot on MLC vs SILC considering conversion. Figure S4. Funel plot on MLC vs SILC considering hospital stay. Figure S5. Sensitivity analysis on MLC vs SILC considering hospital stay. Figure S6. Funel plot on MLC vs SILC considering total complications. Figure S7. Funel plot on MLC vs SILC considering pain. Figure S8. Sensitivity analysis on MLC vs SILC considering pain. (PDF 949Â kb)

The most common cause of gastric cancer is infection with helicobacter pylori (HP), but the associated molecular mechanism is not well understood. In the present study, we found a marked increase in the expression of B7-H1, a member of the B7 co-stimulatory family of molecules that bind to programmed death-1 (PD-1) and play a critical immunoregulatory role in the cell-mediated immune response, in HP-positive gastric cancer tissue. Infection of cultured gastric cancer cells with HP promoted B7-H1 expression and inhibited miR-152 and miR-200b expression. We further demonstrated that these two miRNAs targeted B7-H1 mRNA and suppressed B7-H1 expression in gastric cancer cells. Finally, B7-H1 expression was found to correlate with miR-152 and miR-200b levels in gastric tumor tissues from human patients. Our findings suggest a novel mechanism by which HP infection promotes gastric cancer and also suggest potential targets, i.e., miR-152 and miR-200b, for the prevention and treatment of gastric cancer.

Peritoneal adhesions are fibrous tissues formed after surgery. Both cytokines and transforming growth factors (TGFs) are involved in this process. The objective of this study was to investigate the cross talk between these entities. Peritoneal drainage fluid after surgery from patients and rodent models was examined by enzyme-linked immunosorbent assay and fluorescence-activated cell sorter. Data showed that the concentrations of interferon (IFN)-γ and interleukin (IL)-17 reached their peaks 6-12 hours after surgery, whereas TGF-β1 concentrations showed two postoperative peak time points at 2 and 72-96 hours. By neutralizing IFN-γ, IL-17 6-12 hours, and TGF-β1 72-96 hours after surgery, the degree of adhesion reduced significantly. However, neutralizing TGF-β1 2 hours after surgery did not affect adhesion formation. Furthermore, in vitro studies showed that compared with the fibroblasts that were directly stimulated with TGF-β1, the prestimulation of IL-17 promoted plasminogen activator inhibitor-1 production while inhibiting tissue-type plasminogen activator production. Moreover, additional stimulation with IFN-γ enhanced this effect. Together, these data indicate that IL-17 may promote adhesion formation by increasing the reaction of fibroblasts against TGF-β1. Blocking IL-17 might have a therapeutic potential in preventing adhesion formation after surgery.

It has previously been reported that high mobility group box chromosomal protein 1 (HMGB1) is overexpressed in the majority of gastric adenocarcinoma cell types, and that HMGB1 can be released into the extracellular matrix from stressed or necrotic cancer cells. HMGB1 is considered to promote cell proliferation and invasion in gastric adenocarcinoma cells. Furthermore, in a number of cancer cell types, HMGB1 has been reported to promote autophagy and inhibit anticancer drug‑induced apoptosis, which has been identified as an important mechanism in the development of multidrug resistance (MDR). However, there have been no studies on the effects of HMGB1 on expression of the MDR‑related transporter proteins in gastric adenocarcinoma. In the present study, extracellular HMGB1 increased the expression levels of P-glycoprotein (P-gp) at the pre-transcriptional and post‑transcriptional levels in the human gastric adenocarcinoma cell lines, SGC7901, MKN28 and AGS, as detected by quantitative polymerase chain reaction and western blot assays. MTT and apoptosis assays were also performed and it was demonstrated that extracellular HMGB1 subsequently enhanced resistance to the P‑gp‑related drugs, adriamycin and vincristine. In brief, this study demonstrated that extracellular HMGB1 may promote drug resistance to adriamycin and vincristine by upregulating P‑gp in human gastric adenocarcinoma cells.

To investigate the clinical characteristics, diagnosis and treatment as well as prognostic factors of the giant gastrointestinal stromal tumor (GIST).Clinical data of 235 patients with high risk GIST treated in the Union Hospital, Tongi Medical College, Huazhong University of Science and Technology between January 2005 and July 2015 were retrospectively analyzed. Patients were divided into giant GIST group (diameter equal to or larger than 10 cm, 119 cases) and high risk group (diameter less than 10 cm, 116 cases) according to tumor size. Clinical characteristics and prognosis of two groups were compared and the clinical features of giant GIST were summarized. Multivariate analysis was performed to evaluate the prognostic factors of giant GIST with Cox regression model.Of the 119 patients with giant GIST, which accounted for 50.6%(119/235) of all the high risk patients, there were 63 male and 56 female patients with a median age of 53(20-82) years. Primary giant GIST of 43(36.1%) located in the stomach, of 39(32.8%) in the small intestine, 5(4.2%) in the colon and rectum, and of 32 (26.9%) outside the gastrointestinal tract (mesentery, retroperitoneum, abdominal cavity, etc) and pelvic. Compared to high risk group, age of onset was younger [ratio of ≤50 years, 44.5%(53/119) vs. 31.9%(37/116), P = 0.046] and incidence of outside the gastrointestinal tract was significantly higher [26.9%(32/119) vs. 9.5%(11/116), P=0.000] in giant GIST group. All the giant GIST patients underwent surgical resection, including 115 cases(96.6%) of R0 resection, 3 cases(2.5%) of R1 resection and 1 case(0.9%) of R2 resection, besides, 32 cases(26.9%) underwent expanded resection (namely, underwent lymphadenectomy or combined organ resection simultaneously). Thirty-nine giant GIST cases(32.8%)accepted imatinib 400 mg/d for targeted therapy after operations, which was not significantly different with high risk group (46 cases, 39.6%, P=0.232). Relapse and metastasis occurred in 8 cases in giant GIST group. The 1-, 3-, 5-year overall survival rates of giant GIST group were 94.5%, 89.3%, 79.4% respectively and of high risk group were 99.1%, 92.9%, 85.1% respectively, and no significant difference was found (P=0.788). The 1-, 3-, 5-year recurrence-free survival rates of giant GIST group were 93.6%, 85.1%, 72.8% respectively and of high risk group were 99.1%, 91.7%, 84.2% respectively, and no significant difference was found as well (P=0.932). Multivariate analysis revealed that gender (P=0.047, RR=0.383, 95%CI:0.149-0.987), mitotic count (P=0.001, RR=0.216, 95%CI:0.087-0.538) and targeted therapy(P=0.019, RR=5.719, 95%CI:1.324-24.695) were prognostic risk factors of overall survival (OS), moreover, tumor size (P=0.024, RR=0.368, 95%CI:0.155-0.875) and mitotic count(P=0.007, RR=0.357, 95%CI:0.169-0.755) were prognostic risk factors of RFS.Giant GIST is not unusual in GIST and more likely occurs outside gastrointestinal tract. Complete surgical excision combined with targeted therapy can improve the prognosis significantly. The prognosis of giant GIST and common high risk GIST is similar. Mitotic count is the most important prognostic factor.

To retrospectively analyze the clinicopathology of patients with gastric gastrointestinal stromal tumor(gGIST) who underwent radical excision within 18 years in 10 domestic medical centers in order to understand the status of domestic surgical treatment of gGIST.Clinicopathological data of gGIST patients undergoing radical excision in 10 medical centers from January 1998 to January 2016 were collected, and their operational conditions, postoperative adjuvant therapy, gene detection and survival were analyzed retrospectively.A total of 1 846 cases were recruited in this study, including 246 cases from Guangdong General Hospital, 331 cases from Sun Yat-sen University Cancer Center, 374 cases from Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 342 cases from Nanfang Hospital of Southern Medical University, 265 cases from Fujian Medical University Union Hospital, 148 cases from Fudan University Shanghai Cancer Center, 49 cases from West China Hospital of Sichuan University, 43 cases from Peking University Cancer Hospital and Institute, 28 cases from the 81st Hospital of Pepole's Liberation Army(PLA), 20 cases from Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute. There were 918 male (49.7%) and 928 female patients (50.3%) with median onset age of 59(18 to 95) years old. Fundus(735 cases, 39.8%) and body (781 cases, 42.3%) of stomach were the common sites of lesions. The average size of tumor was (5.3±4.6) cm. There were 1 421 cases with mitotic count ≤5(77.0%). According to the operation procedure, 924 cases (50.1%) underwent laparoscopic surgery, 759 cases (41.1%) laparotomy, 120 cases (6.5%) endoscopic surgery, and 20 cases (1.1%) laparoscopic combined with endoscopic surgery, 6 cases (0.3%) laparoscopic excision surgery through gastric wall and cavity, and 17 cases (0.9%) laparoscopy and then were transferred to laparotomy. Wedge excision were performed in 1 308 cases (70.9%), proximal gastric excision in 226 cases(12.2%), distal gastric excision in 92 cases (5.0%), total gastrectomy in 94 cases (5.1%), and local gastrectomy in 126 cases(6.8%). Multi-visceral excision was performed in 138 cases, and the splenectomy was performed in 83 cases(60.1%)with the highest ratio. According to modified NIH classification, 399 cases(21.6%) were extreme low risk, 580 cases(31.4%) were low risk, 424 cases(23.0%) were moderate risk, 443 cases (24.0%) were high risk. A total of 461 cases received postoperative imatinib adjuvant therapy, accounting for 53.2%(461/867) of patients with moderate and high risk. Among 1 846 cases, 1 402 cases (75.9%) had complete follow-up data and the median follow-up time was 33.6 (0.1 to 158) months. The 5-year survival rates of extreme low risk, low risk, moderate risk and high risk were 100%, 98.5%, 92.5%, and 79.2% with significant difference(P=0.000).Gastric GIST occurs mostly in fundus and body of stomach in China. Wedge excision is the main operational procedure and laparoscopic operation is over 50%. General prognosis of gastric GIST is quite good.

Wee1 is an oncogenic nuclear kinase, which can regulate the cell cycle as a crucial G2M checkpoint. Overexpression of Wee1 can be observed in various cancer types, which may lead to a poor prognosis, but the potential therapeutic value of Wee1 in colorectal cancer has not been fully studied. In the present study, the role of Wee1 in colonic cancer was investigated. Wee1 inhibition by small interfering RNA was demonstrated to significantly restrain cancer cell proliferation and sensitize the p53 mutant colonic cancer cell lines HT29 and SW480 to the effect of treatment with ionizing radiation. The anticancer effect of the Wee1 inhibitor MK1775 was investigated in these two colonic cancer cell lines. MK1775 was demonstrated to induce significant DNA damage, suppress cell viability and induce apoptosis. In addition, MK1775 sensitized HT29 and SW480 cells to the effect of irinotecan. Annexin V/propidium iodide staining demonstrated that combination therapy can induce increased apoptosis compared with MK1775 or irinotecan monotherapy. The results of western blot analysis also indicated increased expression of the DNA damage marker histone H2AX, and apoptosis‑associated protein cleaved caspase 3, in HT29 and SW480 cells. In conclusion, the present study indicated that Wee1 may be a valuable target for treatment of p53 mutant colonic cancer.

Rationale: Gastritis cystica profunda (GCP) is a rare gastric lesion involving cystic dilation of the gastric glands extending into the submucosa. It is usually observed at anastomotic sites in the stomach of patients who have undergone gastric procedures. Bile reflux GCP is rare in patients who have not undergone gastric surgery. Here, we report a rare case of a patient with GCP associated with bile reflux, who had no history of gastric surgery. Patient concerns: A 50-year-old man presented with intermittent abdominal fullness for 2 years, along with nausea. He had never undergone gastric surgery. Endoscopic ultrasonography (EUS) showed a thickened gastric wall and an echo-poor submucosal layer of the gastric fundus. A 3 cm × 2 cm × 1.5 cm lesion was noted. Diagnosis: Bile reflux GCP Interventions: Endoscopic retrograde cholangiopancreatography and endoscopic submucosal dissection (ESD) were performed, and the lesion was removed. Conventional pathological examination revealed GCP with glands hyperplasia and a yellow-brown deposit, which was considered bile. The findings were consistent with a diagnosis of GCP without malignancy. Outcomes: Upper gastrointestinal barium meal revealed postoperative changes at the gastric fundus. Gastroscopy performed at 6 months after surgical resection showed superficial gastritis with bile reflux. Lessons: The findings suggest that GCP etiology varies and that GCP can be caused by bile reflux but without malignancy. Additionally, GCP is not limited to patients who have previously undergone gastric surgery. Moreover, it is difficult to identify. EUS and ESD might be good approaches for the diagnosis and treatment of GCP.

Background The interest in obesity has considerably increased in the scientific community in the last 2 decades. We present a bibliometric analysis to find out the future research hotspot and trends of obesity. Methods Data were based on the Science Citation Index Expanded (SCI-E), from the Institute of Scientific Information Web of Science database and the 5-year impact factor of a journal were issued from the Journal Citation Reports (JCR) in 2017. Articles referring to obesity during 1999 to 2017 were concentrated on the analysis by scientific output characters and the frequency of author keywords used. Results Globally, 50,246 articles meet the inclusion criteria during 1999 to 2017. The cumulative number of publication about obesity followed exponential distribution (R = 0.9974) from 2008. USA was the most productive countries in both independent and international collaborative papers, the countries/regions with the highest average Times Cited scores for independent articles was France and The United Kingdom scored the highest in average Times Cited for international collaborative papers. Collaboration among countries, playing an ever-growing role in contemporary scientific research. The 2 most prolific journals are Obesity Surgery and International Journal of Obesity, responsible for 3.95% of the publication. Conclusion Obesity has been a field of intense research in the last 19 years. By reasonably analyzing the author keywords and the distribution of journals, "bariatric surgery" (especially "sleeve gastrectomy") and "obese complications" (especially "diabetes mellitus," "metabolic syndrome," "depression," and "polycystic ovary syndrome") will undoubtedly maintain the hotspots of obesity research in the next few decades.

Peritoneal metastasis of colorectal cancer is a major clinical issue and results in poor prognosis for patients after surgical resection. Here, we found that abdominal surgery trauma induced high release of high-mobility group box 1 (HMGB1) in the peritoneal cavity of mice. Recombinant HMGB1 injected in the peritoneal cavity recruited abundant myeloid derived suppressor cells (MDSCs) after the surgical trauma. HMGB1 Box-A and gemcitabine reduced the recruitment of MDSCs in the peritoneal cavity after the operation and ameliorated the peritoneal metastasis burden of colon cancer in mouse model. These results showed that abdominal surgery trauma leads to a large amount of HMGB1 released in the peritoneal cavity which recruits numerous MDSCs to promote peritoneal metastasis of colon cancer after curative surgery.

To explore the influence of tumor-associated macrophages(TAMs) on the ability of invasion and metastasis of gastric cancer cells, and its associated mechanism.Immunohistochemistry was used to examine the expression of TAM in 10 samples of normal gastric mucosa and 15 samples of gastric cancer tissues from sample bank of Department of Pathology, Union Hospital. Phorbol 12-myristate 13-acetate(PMA) and macrophage colony stimulating factor (M-CSF) were used to make THP-1 monocytes differentiate into TAMs. AGS gastric cancer cells were divided into two groups: experiment group was cultured with RPMI/1640 condition medium containing 50% TAM and control group was cultured with RPMI/1640 complete medium. The ability of invasion and metastasis of gastric cancer cells was measured by Transwell assays. Real-time PCR and Western blot were applied to detect the expression of MMPs and its inhibitor TIMPs before and after stimulation of TAMs.Immunohistochemistry results showed that CD68(+) cell number in normal gastric mucosa tissue was significantly less than that in gastric cancer tissue [(11.3±0.8)/HP vs. (31.6±1.4)/HP, P0.000 1]. When treated with PMA and M-CSF, THP-1 cells were differentiated into type M2 TAMs with high expression of specific markers CD68, CD163, CD204 and CD206. Transwell test revealed that the number of piercing cells in the experimental group was significantly more than that in control group [(36.8±1.1)/HP vs. (12.8±0.9)/HP, t=17.5, P=0.000). Compared to control group, the expression of MMP-2, MMP-9 mRNA in experimental group respectively increased by 1.61 and 1.87 folds(P=0.017 and P=0.009). Protein level of MMP-2, MMP-9 was up-regulated accordingly. The expression of TIMP-1 and TIMP-3 mRNA was not significantly different between two groups(P=0.120 and P=0.096).TAMs may promote the invasion and metastasis of gastric cancer cells through increasing expression of MMP-9 and MMP-2, which may be one of the mechanisms of gastric cancer development.

Scientific Reports 6: Article number: 22184; Published online: 22 February 2016; Updated: 02 June 2016 Peiwu Yu did not contribute directly to this study and has been removed from the author list. The Acknowledgements section now reads: “We sincerely appreciate Peiwu Yu for providing linguistic support.

Gli1 is a downstream transcriptional factor of Sonic hedgehog pathway in mammalians, and has been recognized as a proliferative indicator of carcinogenesis. However, its actual role in prognosis among solid malignancies remains unclear. Therefore we performed this meta-analysis aiming to discover the correlation between Gli1 positivity and clinical prognosis in patients suffering from diverse carcinomas. A total of 39 studies containing 4496 cases were selected into our quantitative analysis via electronic database search. Original data of 3-year, 5-year, 10-year overall survival and disease-free survival were extracted and calculated using odds ratio and Mantel-Haenszel model. Subgroup analysis was also conducted to clarify the possible confounding factors. P

Elderly patients with colorectal cancer have different clincopathological characteristics from younger patients. Colorectal cancers tend to localize in the proximal colon, from cecum to the splenic flexure in the elderly patients. Changes in the stools, rectal bleeding or black stool, abdominal pain, fatigue, weight loss and anemia are the common symptoms. Analysis showed that age is one of independent risk factors for lower completion rates of colonoscopy. Therefore, the choice of diagnosis methods in elderly patients should be careful. Achieving a clear diagnosis and avoiding complications should be considered at the same time. Most colorectal cancers in elderly are highly and moderately differentiated adenocarcinomas and locally advanced, and have less lymphatic and blood metastasis. The proportion of poorly differentiated adenocarcinoma increases with the increase of age, which should be concerned. Multiple colorectal cancers and colorectal cancer with extra-colorectal malignancy are not rare in the elderly patients. The common extra-colorectal tumors consist of gastric cancer, lung cancer, biliary carcinoma, pancreas cancer and malignancy from blood system. Molecular events, such as mutations of KARS, BRAF, TP53 and deficiency of DNA mismatch repair, are more frequent in elderly colorectal cancer patients. Many factors have impact on treatment decision in elderly patients with colorectal cancer, including age, comorbidities, physiological functions of organs and willingness of patients and their relatives. Although surgery is still the main treatment, the proportion of radical surgery is lower and emergency surgery is higher as compared to younger patients. With the development of minimally invasive surgical techniques and advances in anesthesia and perioperative management, laparoscopic surgery has become widespread in elderly patients with colorectal cancer. In addition, more attention should be paid to adjuvant therapy. Comprehensive individualized treatment plan should be taken to improve outcomes.

// Ji Cheng 1 , Xiaoming Shuai 1 , Jinbo Gao 1 , Ming Cai 1 , Guobin Wang 1 , Kaixiong Tao 1 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence to: Kaixiong Tao, email: kaixiongtaowhuh@126.com Keywords: AMPK, prognosis, cancer, meta-analysis, malignancies Received: May 23, 2016 Accepted: September 20, 2016 Published: October 03, 2016 ABSTRACT Background: AMPK is a well-investigated kinase mediating cellular metabolism and stress responses. However, its indicative role in survival prognosis remains ill-defined. Therefore we performed this meta-analysis in order to clarify the prognostic impact of AMPK expression in human malignancies. Methods: Literatures were retrieved via searching databases of PubMed, Web of Science, Embase and Cochrane Library. Studies comparing the prognostic significance between different AMPK levels among human malignancies were included into the pooled analysis. The statistical procedures were conducted by Review Manager 5.3 and the effect size was displayed by model of odds ratio. Subgroup analyses were additionally implemented to disclose the potential confounding elements. The outcome stability was examined by sensitivity analysis, and both Begg’s test and Egger’s test were utilized to detect the publication bias across the included studies. Results: 21 retrospective cohorts were eventually obtained with a total sample-size of 9987 participants. Patients with higher AMPK expression had better outcomes of 3-year overall survival (P

// Lei Li 1 , Shanshan Wan 2 , Kaixiong Tao 1 , Guobin Wang 1 , Ende Zhao 1 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 2 Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA Correspondence to: Guobin Wang, email: 905083818@qq.com Ende Zhao, email: endezhao@hotmail.com Keywords: KLRG1, senescence, memory T cells, antitumor immunity Received: April 14, 2016 Accepted: August 13, 2016 Published: August 20, 2016 ABSTRACT Killer cell lectin-like receptor subfamily G member 1 (KLRG1) has been found on human memory T lymphocytes. However, the roles of KLRG1 on human T cells especially in tumor microenvironment have not been fully understood. Our results showed KLRG1 expression on T cells significantly increased in tumor microenvironment. KLRG1 + T cells exhibited poor proliferative capacity with decreased effector cytokine production. Meanwhile, KLRG1 + T cells expressed abundant pro-inflammatory cytokines and demonstrated high level of Foxp3 expression. KLRG1 + T cells showed decreased expression of miRNA-101 and higher expression of CtBP2. Our results indicated KLRG1 might contribute to the impaired antitumor immunity of memory T cells in tumor microenvironment. Thus, repressing KLRG1 on human memory T cells might be a novel therapeutics against cancer.

Gli1 is a downstream transcriptional factor of Sonic hedgehog pathway in mammalians, and has been recognized as a proliferative indicator of carcinogenesis. However, its actual role in prognosis among solid malignancies remains unclear. Therefore we performed this meta-analysis aiming to discover the correlation between Gli1 positivity and clinical prognosis in patients suffering from diverse carcinomas. A total of 39 studies containing 4496 cases were selected into our quantitative analysis via electronic database search. Original data of 3-year, 5-year, 10-year overall survival and disease-free survival were extracted and calculated using odds ratio and Mantel-Haenszel model. Subgroup analysis was also conducted to clarify the possible confounding factors. P

The severe cytotoxicity of cancer chemotherapy drugs limits their clinical applications. Various protein-based nanoparticles with good biocompatibility have been developed for chemotherapy drug delivery in hope of reducing drugs' side effects. Sericin, a natural protein from silk, has no immunogenicity and possesses diverse bioactivities that have prompted sericin's application studies. However, the potential of sericin as a multifunctional nanoscale vehicle for cancer therapy have not been fully explored. Here we report the successful fabrication and characterization of folate-conjugated sericin nanoparticles with cancer-targeting capability for pH-responsive release of doxorubicin (these nanoparticles are termed "FA-SND"). DOX is covalently linked to sericin through pH-sensitive hydrazone bonds that render a pH-triggered release property. The hydrophobicity of DOX and the hydrophilicity of sericin promote the self-assembly of sericin-DOX (SND) nanoconjugates. Folate (FA) is then covalently grafted to SND nanoconjugates as a binding unit for actively targeting cancer cells that overexpress folate receptors. Our characterization study shows that FA-SND nanoparticles exhibit negative surface charges that would reduce nonspecific clearance by circulation. These nanoparticles possess good cytotoxicity and hemocompatibiliy. Acidic environment (pH 5.0) triggers effective DOX release from FA-SND, 5-fold higher than does a neutral condition (pH 7.4). Further, FA-SND nanoparticles specifically target folate-receptor-rich KB cells, and endocytosed into lysosomes, an acidic organelle. The acidic microenvironment of lysosomes promotes a rapid release of DOX to nuclei, producing cancer specific chemo-cytotoxicity. Thus, FA-mediated cancer targeting and lysosomal-acidity promoting DOX release, two sequentially-occurring cellular events triggered by the designed components of FA-SND, form the basis for FA-SND to achieve its localized and intracellular chemo-cytotoxicity. Together, this study suggests that these FA-SND nanoparticles may be a potentially effective carrier particularly useful for delivering hydrophobic chemotherapeutic agents for treating cancers with high-level expression of folate receptors.

Maresin 1 (MaR 1) was recently reported to have protective properties in several different animal models of acute inflammation by inhibiting inflammatory response. However, its function in acute liver injury is still unknown. To address this question, we induced liver injury in BALB/c mice with intraperitoneal injection of carbon tetrachloride with or without treatment of MaR 1. Our data showed that MaR 1 attenuated hepatic injury, oxidative stress, and lipid peroxidation induced by carbon tetrachloride, as evidenced by increased thiobarbituric acid reactive substances and reactive oxygen species levels were inhibited by treatment of MaR 1. Furthermore, MaR 1 increased activities of antioxidative mediators in carbon tetrachloride-treated mice liver. MaR 1 decreased indices of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, interleukin-1β, monocyte chemotactic protein 1, myeloperoxidase, cyclooxygenase-2, and inducible nitric oxide synthase. Administration of MaR 1 inhibited activation of nuclear factor kappa B (NF-κb) and mitogen-activated protein kinases (MAPKs) in the liver of CCl4 treated mice. In conclusion, these results suggested the antioxidative, anti-inflammatory properties of MaR 1 in CCl4 induced liver injury. The possible mechanism is partly implicated in its abilities to inhibit ROS generation and activation of NF-κb and MAPK pathway.

The interaction between T cell immunoglobulin- and mucin-domain-containing molecule (Tim-3) expressed on T helper 1 (Th1) cells, and its ligand, galectin-9, negatively regulates Th1-mediated immune responses. However, it is poorly understood if and how the Tim-3/galectin-9 signaling pathway is involved in immune escape in patients with hepatocellular carcinoma (HCC). Here we studied the expression, function, and regulation of the Tim-3/galectin-9 pathway in patients with hepatitis B virus (HBV)-associated HCC. We detected different levels of galectin-9 expression on antigen-presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs in HCC. The highest galectin-9 expression was on KCs in HCC islets, not in the adjacent tissues. Furthermore, Tim-3 expression was increased on CD4+ and CD8+ T cells in HCC as compared to the adjacent tissues, and Tim-3+ T cells were replicative senescent and expressed surface and genetic markers for senescence. Interestingly, tumor-infiltrating T-cell-derived interferon (IFN)-γ stimulated the expression of galectin-9 on APCs in the HCC microenvironment. Immunofluorescence staining revealed a colocalization of Tim-3+ T cells and galectin-9+ KCs in HCC. Functional studies demonstrated that blockade of the Tim-3/galectin-9 signaling pathway importantly increased the functionality of tumor-infiltrating Tim-3+ T cells as shown by increased T-cell proliferation and effector cytokine production. Finally, we show that the numbers of Tim-3+ tumor-infiltrating cells were negatively associated with patient survival. Conclusion: Our work demonstrates that the Tim-3/galectin-9 signaling pathway mediates T-cell senescence in HBV-associated HCC. The data suggest that this pathway could be an immunotherapeutic target in patients with HBV-associated HCC. (HEPATOLOGY 2012)