Cell division cycle associated 8: A novel diagnostic and prognostic biomarker for hepatocellular carcinoma.

The cell division cycle associated 8 (CDCA8) is a crucial component of the chromosome passenger complex (CPC). It has been implicated in the regulation of cell dynamic localization during mitosis. However, its role in hepatocellular carcinoma (HCC) is not clearly known. In this study, data of 374 patients with HCC were retrieved from the Cancer Genome Atlas (TCGA) database. Pan analysis of Gene Expression Profiling Interactive Analysis (GEPIA) database was performed to profile the mRNA expression of CDCA8 in HCC. Then, the Kaplan-Meier plotter database was analysed to determine the prognostic value of CDCA8 in HCC. In addition, samples of tumour and adjacent normal tissues were collected from 88 HCC patients to perform immunohistochemistry (IHC), reverse transcription-quantitative polymerase chain reaction (qRT-PCR) and Western blotting. The results obtained from bioinformatic analyses were validated through CCK-8 assay, EdU assay, colony formation assay, cell cycle assays and Western blotting experiments. Analysis of the Kaplan-Meier plotter database showed that high expression of CDCA8 may lead to poor overall survival (OS, p = 4.06e-05) in patients with HCC. For the 88 patients with HCC, we found that stages and grades appeared to be strongly linked with CDCA8 expression. Furthermore, the high expression of CDCA8 was found to be correlated with poor OS (p = 0.0054) and progression-free survival (PFS, p = 0.0009). In vitro experiments revealed that inhibition of CDCA8 slowed cell proliferation and blocked the cell cycle at the G0/G1 phase. In vivo experiments demonstrated that inhibition of CDCA8 inhibited tumour growth. Finally, blockade of CDCA8 reduced the expression levels of cyclin A2, cyclin D1, CDK4, CDK6, Ki67 and PCNA. And, there is an interaction between CDCA8 and E2F1. In conclusion, this research demonstrates that CDCA8 may serve as a biomarker for early diagnosis and prognosis prediction of HCC patients. In addition, CDCA8 could be an effective therapeutic target in HCC.

Expression and prognostic analyses of the insulin-like growth factor 2 mRNA binding protein family in human pancreatic cancer.

BACKGROUND: Despite advances in early diagnosis and treatment, cancer remains the leading cause of mortality worldwide. The insulin-like growth factor 2 mRNA binding protein (IGF2BP) family has been reported to be involved in a variety of human malignant tumours. However, little is known about their expression and prognostic value in human pancreatic cancer. Therefore, we performed a detailed cancer versus normal differential analysis. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to analyse the mRNA expression levels of the IGF2BP family in various cancers, including pancreatic cancer. Then, the LinkedOmics and GEPIA databases were used to assess the relation between the expression levels of IGF2BPs and overall survival (OS). Then, univariate and multivariate Cox regression analyses were performed, and subgroups based on grade and stage were analysed. The signalling pathways associated with IGF2BP2 and IGF2BP3 were then investigated via gene set enrichment analysis (GSEA). RESULTS: IGF2BP2 and IGF2BP3 were associated with each subset of OS based on grade and stage. Further clinical correlation analysis of IGF2BP2 and IGF2BP3 confirmed that IGF2BP2 and IGF2BP3 are fundamental factors in promoting pancreatic cancer progression. CONCLUSION: IGF2BP2 and IGF2BP3 are key factors in promoting the progression of pancreatic cancer and are closely related to overall survival.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.

The use of fluorescence laparoscopy in the resection of splenic tissue replantation in the right lobe of the liver: A case report and literature review.

BACKGROUND: Ectopic replantation and regeneration of splenic tissue fragments following splenic trauma or splenectomy is known as replantation of splenic tissue. It typically takes place in the abdominal cavity, however, splenic tissue replantation in the liver is extremely rare and difficult to diagnose. It is often misdiagnosed as a liver tumor and removed. CASE PRESENTATION: We present the case of a patient with a history of traumatic splenectomy 15 years prior to the replantation of splenic tissue in the liver. A 4 cm mass in the liver was found during the most recent physical examination, and a computed tomography scan indicated the possibility of a malignant tumor. The tumor was then removed using fluorescence laparoscopy. CONCLUSION: There is a possibility of intrahepatic replantation of splenic tissue in patients who have had a splenectomy in the past, have recently discovered an intrahepatic space-occupying lesion, and do not have any high-risk factors for liver cancer. Unnecessary surgery can be avoided if 99mTc-labeled red blood cells imaging using mass puncture or radionuclide examination provides a clear preoperative diagnosis. Globally, there are no reports of the use of fluorescence laparoscopy in resecting replanted splenic tissue in the liver. Specifically, in the current case, there was no indocyanine green uptake in the mass, and only a small amount was found in the normally functioning liver tissue surrounding the tumor.

Exosomal miR-222 from adriamycin-resistant MCF-7 breast cancer cells promote macrophages M2 polarization via PTEN/Akt to induce tumor progression.

Exosome-mediated intercellular communication is considered to be an effective mode for malignant cells to transform biological behaviors in stromal cells. However, the mechanisms by which exosomes modulate macrophages within tumor microenvironment remain largely unclear. In this study, we found that both adriamycin-resistant breast cancer (BCa) cells and the corresponding exosomes (A/exo) were capable of inducing macrophages M2 polarization, which promoted the mobility, proliferation, migration and invasion of BCa cells. Since exosomes deliver microRNAs to affect cellular functions in recipient cells, we confirmed that miR-222 was significantly enriched in A/exo and could be successfully transferred to macrophages. Increased miR-222 level was also detected in exosomes derived from plasma and tissues of chemoresistant patients. Moreover, exosomal miR-222 from A/exo polarized M2 macrophages by targeting PTEN and activating Akt signaling pathway, which promoted BCa cells progression in a feed back loop. Co-culture of adriamycin-resistant BCa cells with macrophages in which miR-222 was upregulated or treated with A/exo facilitated tumor growth in vivo. Collectively, our data demonstrated that chemoresistant BCa cells could remodel macrophages within tumor microenvironment by secreting exosomal miR-222, which directly targeted PTEN and caused Akt cascade activation and macrophages M2 polarization. Our findings may provide a foundation for a promising strategy of BCa treatment by targeting exosomes or exosomal miR-222.

Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats.

Ligustrazine, an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort, has been clinically applied to treat the cerebrovascular diseases. Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD). Memory deficits can be caused by Hhcy via pathologies of AD-like tau and amyloid-ß (Aß) in the hippocampus. Here, we investigated whether homocysteine (Hcy) can induce AD-like pathologies and the effects of ligustrazine on these pathologies. The Hcy rat model was constructed by 14-day Hcy injection via vena caudalis, and rats were treated with daily intragastric administration of ligustrazine at the same time. We found that the pathologies of tau and Aß were induced by Hcy in the hippocampus, while the Hcy-induced tau hyperphosphorylation and Aß accumulation could be markedly attenuated by simultaneous ligustrazine treatment. Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced AD-like pathologies.

Serine protease HtrA1 expression in human hepatocellular carcinoma.

BACKGROUND: HtrA1, a serine protease, is down-regulated in various human solid tumors. Overexpression of HtrA1 in human cancer cells inhibits cell growth and proliferation in vitro and in vivo, suggesting its possible role as a tumor suppressor. METHODS: Immunohistochemistry was used to determine the expression of HtrA1 in 50 hepatocellular carcinoma specimens and adjacent liver tissues. The correlation between the expression of HtrA1 and the clinico-pathologic data were analyzed. RESULTS: The levels of HtrA1 were lower in tumor tissues than in their adjacent liver tissues. Moreover, an inverse relationship was found between HtrA1 expression and the differentiation of hepatocellular carcinoma. Loss of HtrA1 was more frequently found in tumors in Edmondson grade III-IV, especially in those with venous invasion, compared to tumors in Edmondson grade I-II. Most importantly, patients with higher HtrA1 expression had a better survival rate. CONCLUSION: All these data suggest an important role of HtrA1 in hepatocellular carcinoma development and progression, which may be a new target for its treatment.

[Specific immune against pancreatic cancer induced by dendritic cells pulsed with mutant K-ras peptide].

OBJECTIVE: To investigate whether dendritic cells (DCs) pulsed with mutant K-ras peptide (12-Val) can induce efficiently specific anti-tumor immune response against pancreatic cancer. METHODS: Immature DCs were isolated from the peripheral blood of a volunteer and were pulsed with synthesized mutant K-ras peptide (YKLVVVGAV). When the DCs were matured the expression rate of Kras antigen epitope on the DC's surface was detected by mono antibody (K-ras-12-Val). Autogeneic and homologous T cells were mixed with the mutant K-ras peptide-pulsed DCs. Human pancreatic cancer cells of the line Patu8988 were mixed with cytotoxic T lymphocytes (CTLs) cultured for 5 days, and the killing effects of the CTLs on the cells was assessed by MTT method. Patu8988 cells were injected subcutaneously into nude mice, cancer cells were obtained from the tumor masses and injected subcutaneously into other nude mice to establish mice models of pancreatic cancer. Then 32 mice with pancreatic cancer were randomly divided into 4 equal groups: control group, K-ras specific CTL intra-tumor injection group, CTL caudal vein injection group, and IL-2 activated non-specific CTL intra-tumor injection group. The tumor size was measure regularly. Immunohistochemistry was used to detect the pathological analysis of the transplanted tumors. RESULTS: The mutational epitope (K-ras-12-Val) induced by mutant peptide could be found on the DCs'surface efficiently. After co-incubation with the mature DCs pulsed with tumor antigen the autogeneic T cells were activated, the CD8 T cells accounted for (44.8 +/- 2.1)%. Without damage the normal tissue cells, the killing rate of activated K-ras specific CTLs to the tumor cell when the ratios of CTL: Patu8988 cells were 10:1, 20:1, and 50:1 were (21.2 +/- 1.9)%, (32.4 +/- 2.1)%, and (45.7 +/- 5.3)% respectively, all while the killing efficiency significantly superior to those of the non-specific activated T lymphocyte (all P < 0.05). Eight days after CTL injection into the nude mice the tumor size of the intratumor injection group was (68 +/- 13) mm3, significantly smaller than those of the control group and IL-2 activated non-specific CTL intra-tumor injection group [(87 +/- 14) mm3 and (79 +/- 19) mm3, both P < 0.05]. The survival rates of the nude mice of the K-ras specific CTL intra-tumor injection group, CTL caudal vein injection group, and IL-2 activated non-specific CTL intra-tumor injection group were all significantly higher than that of the control group (all P < 0.05), and the survival rate of the K-ras specific CTL intra-tumor injection group was significantly higher than that of the IL-2 activated non-specific CTL intra-tumor injection group (P < 0.05). Immunohistochemical staining confirmed that K-ras specific CTL had the ability to move toward tumor. CONCLUSION: DCs pulsed with mutant K-ras peptide (12-Val) induces specific anti-tumor immune response in pancreatic cancer efficiently.

Association of a common genetic variant in RNASEL and prostate cancer susceptibility.

The RNASEL gene (2', 5'-oligoisoadenylate synthetase-dependent) encodes a ribonuclease that plays a significant role in the apoptotic and antiviral activities of interferons. Various studies have used polymorphisms in the RNASEL gene to evaluate prostate cancer risk but studies that show an association between RNASEL Arg462Gln (1385G>A, R462Q, rs486907) polymorphism and prostate cancer risk are somewhat inconclusive. To assess the impact of RNASEL Arg462Gln polymorphism on prostate cancer risk, we conducted a meta-analysis of all available studies including 11,522 patients and 10,976 control subjects. The overall results indicated no positive association between the variant and prostate cancer risk. However, in a subgroup analysis by ethnicity, obvious associations were observed in Hispanic Caucasians for allelic contrast (OR = 1.18, 95% CI = 1.00 - 1.39, Pheterogeneity = 0.010), homozygote comparison (OR = 1.50, 95% CI = 1.02 - 2.20, Pheterogeneity = 0.001), and the recessive genetic model (OR = 1.44, 95% CI = 1.01 - 2.05, Pheterogeneity = 0.002) ; and in African descendants for homozygote comparison (OR = 2.59, 95% CI = 1.29 - 5.19, Pheterogeneity = 0.194) and the recessive genetic model (OR = 2.61, 95% CI = 1.30 - 5.23, Pheterogeneity = 0.195). In conclusion, the RNASEL Arg462Gln polymorphism may contribute to the risk of developing prostate cancer in African descendants and Hispanic Caucasians. Further larger and well-designed studies are warranted to evaluate this association in detail.

MYO9B gene polymorphisms are associated with the risk of inflammatory bowel diseases.

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.