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Background Oesophageal cancer (EC) ranks high in both morbidity and mortality. A non-invasive and high-sensitivity diagnostic approach is necessary to improve the prognosis of EC patients. Methods A total of 525 serum samples were subjected to lipidomic analysis. We combined serum lipidomics and machine-learning algorithms to select important metabolite features for the detection of oesophageal squamous cell carcinoma (ESCC), the major subtype of EC in developing countries. A diagnostic model using a panel of selected features was developed and evaluated. Integrative analyses of tissue transcriptome and serum lipidome were conducted to reveal the underlying mechanism of lipid dysregulation. Results Our optimised diagnostic model with a panel of 12 lipid biomarkers together with age and gender reaches a sensitivity of 90.7%, 91.3% and 90.7% and an area under receiver-operating characteristic curve of 0.958, 0.966 and 0.818 in detecting ESCC for the training cohort, validation cohort and independent validation cohort, respectively. Integrative analysis revealed matched variation trend of genes encoding key enzymes in lipid metabolism. Conclusions We have identified a panel of 12 lipid biomarkers for diagnostic modelling and potential mechanisms of lipid dysregulation in the serum of ESCC patients. This is a reliable, rapid and non-invasive tumour-diagnostic approach for clinical application.

Lymph node metastasis is one of the most malignant clinical features in patients with esophageal squamous cell carcinoma (ESCC). Understanding the mechanism of lymph node metastasis will provide treatment strategies for patients with ESCC. Long noncoding RNAs (lncRNA) play a critical role in the development and progression of human cancers. However, the role and mechanism of lncRNAs in lymph node metastasis remain largely unknown. Here we show that VEGFC mRNA stability–associated long noncoding RNA (VESTAR) is involved in lymph node metastasis of ESCC. VESTAR was overexpressed in ESCC tissues and was predictive of poor prognosis in patients with ESCC. In ESCC, NXF1 and SRSF3 facilitated nuclear export of VESTAR to the cytoplasm, which was associated with lymph node metastasis. Depletion of VESTAR inhibited ESCC-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, VESTAR directly bound and stabilized VEGFC mRNA. VESTAR also interacted with HuR, a positive regulator of VEGFC mRNA stability, and increased HuR binding to VEGFC mRNA. Our study reveals a novel lncRNA-guided mechanism of lymph node metastasis in ESCC and may provide a potential target for treatment of ESCC lymphatic metastasis. Significance: These findings illustrate the lncRNA-guided regulation of VEGFC mRNA stability via direct RNA–RNA interactions, highlighting a therapeutic target for patients with ESCC with lymphatic metastasis.

Background/aimsThe programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones.MethodsE1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off.ResultsIn total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS (∆LRχ2=5.25; p=0.022), compared with clinicopathological features alone.ConclusionsPD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.

Recent studies have indicated that the presence of ground-glass opacity (GGO) components is associated with favorable survival. The purpose of this study was to reveal the prognostic value of GGO components and differences in prognostic factors for part-solid and solid lesions in invasive stage I NSCLC.The cases of 2010 patients with completely resected invasive pathological stage I NSCLC were reviewed according to the eighth edition of the TNM classification. Patients were categorized into the pure-GGO, part-solid, and solid groups based on consolidation-to-tumor ratio. Cox multivariate proportional hazard analyses were conducted to identify independent prognostic factors in each group.Of the 2010 patients, 146 (7.3%) were in the pure-GGO group, 732 (36.4%) were in the part-solid group, and 1132 (56.3%) were in the solid group. Cox multivariate analyses revealed that GGO absence was a strong independent risk factor for worse recurrence-free survival (p0.001). For the pure-GGO group, there was no recurrence in spite of the invasive stage. For the part-solid group, visceral pleural invasion could not predict recurrence-free survival in general (p = 0.514) or in each tumor size group (for tumors size ≤1 cm, p = 0.664; for tumors size1 to 2 cm, p = 0.456; for tumors size2 to 3 cm, p = 0.900; and for tumors size3 to 4 cm, p = 0.397). For the solid group, adenocarcinoma subtype was not a prognostic factor for recurrence-free survival in general (p = 0.162) or in each tumor size group (for tumors size ≤ 2 cm, p = 0.092; for tumors size2 to 3 cm, p = 0.330; and for tumors size3 to 4 cm, p = 0.885).The presence of GGO components was a strong predictor in patients with invasive pathological stage I NSCLC. Risk factors were distinct in the part-solid and solid groups. There was no prognostic value of visceral pleural invasion in the part-solid group. Adenocarcinoma subtype did not have prognostic value in the solid group.

Gastric cancer (GC) is one of the deadliest cancers, and long noncoding RNAs (LncRNAs) have been reported to be the important regulators during the occurrence and development of GC. The present study identified a novel and functional lncRNA in gastric cancer, named NR038975, which was confirmed to be markedly upregulated in the Gene Expression Profiling Interactive Analysis (GEPIA) dataset and the independent cohort of gastric cancer tissues. We firstly characterized the full-length sequence and subcellular location of NR038975 in gastric cancer cells. Our data demonstrated that upregulated NR038975 expression was significantly related to lymph node metastasis and TNM stage. In addition, knockdown of NR038975 inhibited gastric cancer cell proliferation, migration, invasion and clonogenicity, and vice versa. Mechanistically, RNA pull-down and mass spectrometry assays identified the NR038975 binding proteins, NF90/NF45 complex, and the binding were also confirmed by RNA immunoprecipitation and confocal experiments. We further demonstrated that genetic deficiency of NR038975 abrogated the interaction between NF45 and NF90. Moreover, NF90 increased the stability of NR038975. Thus, NR038975-NF90/NF45 will be an important combinational target of GC. Finally, we detected NR038975 in serum exosomes and serum of gastric cancer patients. Our results indicated that NR038975 was a biomarker for gastric tumorigenesis. The current study demonstrated that NR038975 is a novel lnRNA that is clinically and functionally engaged in the gastric cancer progression and might be a novel diagnostic marker and potential therapeutic target.

Background The epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear. Methods The expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected. TRPM7was knockdown by shRNA in Ovarian cancer cell lines to examine calcium [Ca2+]i, EMT markers and PI3K/AKT markers. Various cellular assays, such as invasion and migration, were performed in vitro, and further confirmed in vivo. Results TRPM7 expression is negatively correlated with E-cadherin, but positively with N-cadherin, Vimentin and Twist expression in ovarian cancer samples. TRPM7 depletion inhibited the migration and invasion in SKOV3 and OVCAR3 cells. In addition, TRPM7 silencing decreased the lung metastasis of SKOV3 tumors and prolonged the survival of tumor-bearing mice. Similar to that of TRPM7 silencing, treatment with MK886, a potent 5-lipoxygenase inhibitor to reduce TRPM7 expression, and/or BAPTA-AM, an intracellular calcium chelator, significantly mitigated the Epidermal growth factor (EGF) or Insulin-like growth factors (IGF)-stimulated migration, invasion, and the EMT in ovarian cancer cells by decreasing the levels of intracellular calcium [Ca2+]i. Furthermore, treatment with LY2904002, a PI3K inhibitor, also inhibited the migration, invasion, and treatment with both LY2904002 and BAPTA-AM further enhanced their inhibition in ovarian cancer cells. Moreover, treatment with BAPTA-AM mitigated the IGF-stimulated migration, invasion, particularly in TRPM7-silenced ovarian cancer cells. Finally, TRPM7 silencing attenuated the PI3K/AKT activation, which was enhanced by BAPTA-AM, MK886 or LY2904002 treatment in ovarian cancer cells. Conclusions TRPM7 silencing inhibited the EMT and metastasis of ovarian cancer by attenuating the calcium-related PI3k/AKT activation. Our findings suggest that TRPM7 may be a therapeutic target for intervention of ovarian cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1061-y) contains supplementary material, which is available to authorized users.

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumour. However, the causes of GBM are not clear, and the prognosis remains poor. The aim of the present study was to elucidate the key coding genes and long non‑coding RNAs (lncRNAs) associated with the survival time of GBM patients by obtaining the RNA expression profiles from the Chinese Glioma Genome Atlas database and conducting weighted gene co‑expression network analysis. Modules associated with overall survival (OS) were identified, and Gene Ontology and pathway enrichment analyses were performed. The hub genes of these modules were validated via survival analysis, while the biological functions of crucial lncRNAs were also analysed in the publicly available data. The results identified a survival‑associated module with 195 key genes. Among them, 33 key genes were demonstrated to be associated with OS, and the majority of these were involved in extracellular matrix‑associated and tyrosine kinase receptor signalling pathways. Furthermore, LOC541471 was identified as an OS‑associated lncRNA, and was reported to be involved in the oxidative phosphorylation of GBM with pleckstrin‑2. These findings may significantly enhance our understanding on the aetiology and underlying molecular events of GBM, while the identified candidate genes may serve as novel prognostic markers and potential therapeutic targets for GBM.

Methylation of components involved in one-carbon metabolism is extremely important in cancer; comprehensive studies on methylation are essential and may provide us with a better understanding of tumorigenesis, and lead to the discovery of potential biomarkers. Here, we present an improved methodology for methylated metabolite profiling and its relative quantification in breast cancer cell lines by isotope dilution mass spectrometry based on 13CD3-methionine metabolic labeling using ultra-high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry (UPLC-HRMS/MS). First, all the methylated metabolites related to methionine were first screened and profiled by introducing 13CD3-methionine as the only medium into breast cancer cell growth cultures for both cellular polar metabolites and lipids. In total, we successfully found 20 labeled methylated metabolites and most of them were identified, some of which have not been reported before. We also developed a relative quantification method for all identified methylated metabolites based on isotope dilution mass spectrometry assays. Finally, the developed method was used for different breast cancer cells and mammary epithelial cells. Most methylated metabolites were disrupted in cancer cells. 1-Methyl-nicotinamide was decreased significantly, while trimethylglycine-glutamic acid-lysine and trimethyl-lysine were increased more than five times. This method offers a new insight into the methylation process, with several key pathways and important new metabolites being identified. Further investigation with biological assays should help to reveal the overall methylation metabolic network.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and the primary cause of cancer-related mortality in China. micoRNA plays a vital role during tumor initiation and malignant progression. miR-4306 has been reported to negatively regulate aggressive cell phenotypes in triple-negative breast cancer (TNBC). Nevertheless, the function of miR-4306 in ESCC was still not clear. In this study, we detected miR-4306 expression by quantitative real-time reverse transcription-PCR (qRT-PCR) and found that miR-4306 expression was downregulated in human ESCC tissue samples and cell lines. Moreover, miR-4306 overexpression could restrain ESCC cell proliferation, migratory and invasive ability and epithelial-mesenchymal transition (EMT), promote cell apoptosis after treatment with or without cisplatin. In contrast, inhibiting the expression of miR-4306 showed the opposing results. Furthermore, we explored the molecular mechanism of effects of miR-4306 and found that miR-4306 inhibited the expression of SIX3 by interaction with SIX3 3'UTR in ESCC cells, and SIX3 overexpression significantly reversed the effect of miR-4306-mediated ESCC cells proliferation. The current study provided evidence of miR-4306 as a tumor suppression gene in ESCC.

Spatially resolved metabolomics offers unprecedented opportunities for elucidating metabolic mechanisms during cancer progression. It facilitated the discovery of aberrant cellular metabolism with clinical application potential. Here, we developed a novel strategy to discover cancer tissue relevant metabolic signatures by high spatially resolved metabolomics combined with a multicellular tumor spheroid (MCTS) in vitro model. Esophageal cancer MCTS were generated using KYSE-30 human esophageal cancer cells to fully mimic the 3D microenvironment under physiological conditions. Then, the spatial features and temporal variation of metabolites and metabolic pathways in MCTS were accurately mapped by using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) with a spatial resolution at ∼12 μm. Metabolites, such as glutamate, tyrosine, inosine and various types of lipids displayed heterogeneous distributions in different microregions inside the MCTS, revealing the metabolic heterogenicity of cancer cells under different proliferative states. Subsequently, through joint analysis of metabolomic data of clinical cancer tissue samples, cancer tissue relevant metabolic signatures in esophageal cancer MCTS were identified, including glutamine metabolism, fatty acid metabolism, de novo synthesis phosphatidylcholine (PC) and phosphatidylethanolamine (PE), etc. In addition, the abnormal expression of the involved metabolic enzymes, i.e., GLS, FASN, CHKA and cPLA2, was further confirmed and showed similar tendencies in esophageal cancer MCTS and cancer tissues. The MALDI-MSI combined with MCTS approach offers molecular insights into cancer metabolism with real-word relevance, which would potentially benefit the biomarker discovery and metabolic mechanism studies.

Brain metastasis (BM) is a major complication of lung adenocarcinoma (LAD). An investigation of the pathogenic mechanisms of BM, as well as the identification of appropriate molecular markers, is necessary. The aim of this study was to determine the expression patterns of microRNAs (miRNAs) in LAD with BM, and to investigate the biological role of these miRNAs during tumorigenesis. miRNA array profiles were used to identify BM-associated miRNAs. These miRNAs were independently validated in 155 LAD patients. Several in vivo and in vitro assays were performed to verify the effects of miRNAs on BM. We identified six miRNAs differentially expressed in patients with BM as compared to patients with BM. Of these, miR-4270 and miR-423-3p were further investigated. miR-4270 and miR-423-3p directly targeted MMP19 and P21, respectively, to influence cell viability, migration, and colony formation in vitro. miR-4270 downregulation and miR-423-3p upregulation was associated with an increased risk of BM in LAD patients. Thus, our results suggested that miR-4270 and miR-423-3p might play an important role in BM pathogenesis in LAD patients, and that these miRNAs might be useful prognostic and clinical treatment targets., Author summary Brain metastasis (BM) is a major complication of lung carcinoma. Here, we aimed to identify the key miRNAs involved in BM lung cancer. We first profiled miRNA expression in 32 tissues from NSCLC patients with BM and 55 tissues from NSCLC patients without BM. We independently validated our results in 68 additional tissues from NSCLC patients. Based on our results, we identified a panel of miRNAs that distinguish BM lung adenocarcinomas from non-BM We report here for the first time that either miR-4270 downregulation or miR-423-3p upregulation significantly increased cell proliferation, colony formation, and migration in vitro. miR-4270 and miR-423-3p increased the risk of BM in mouse models by targeting MMP19 and P21, respectively. Our results suggested that miR-4270 and miR-423-3p might be useful markers of BM in lung adenocarcinoma.

[This corrects the article DOI: 10.1371/journal.pgen.1007888.].

In developing countries, cervical cancer is still the major cause of cancer-related death among women. To better understand the correlation between tumor microenvironment (TME) and prognosis of cervical cancer, we screened 1367 differentially expressed genes (DEGs) of cervical cancer samples in The Cancer Genome Atlas (TCGA) database using Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm-derived immune scores. Then, we extracted 401 tumor immune microenvironment (TIME)-related DEGs that related to patients’ survival outcomes. Protein-protein interaction (PPI) network and functional enrichment analysis revealed that the prognostic genes mainly participated in myeloid leukocyte activation, adaptive immune response regulation, and receptor signaling pathways. A total of 79 key prognostic DEGs were obtained through PPI network. A TF-lncRNA-miRNA-mRNA regulatory network was constructed to explore the potential regulatory mechanism. 4 genes (CCR7, PD-1, ZAP70, and CD28) were validated in another independent cohort of cervical cancer from the Gene Expression Omnibus (GEO) database. Finally, potential drugs for key prognostics DEGs were predicted using DrugBank. In conclusion, we obtained a list of potential prognostic TIME-related genes and potential predicted drugs by integrative bioinformatics approaches. A comprehensive understanding of prognostic genes within the TIME may provide new strategies for cervical cancer treatment.

A feasible and transformable cancer vaccine was designed for personalized immunotherapy of postoperative tumors., Autologous tumor cell–based vaccines (ATVs) are emerging as a transformable approach for personalized immunotherapy, but their therapeutic efficacy remains unsatisfying in patients with cancer. Here, we design a photodynamic therapy (PDT)–motivated ATV (P-ATV) in Fmoc-KCRGDK–phenylboronic acid (FK-PBA) hydrogel, which mobilizes local immune activation to inhibit relapse of postoperative tumors. The FK-PBA targeting overexpressed sialic acid on tumor cells can enable on-demand gelation in residue tumor areas and maintain continuous vaccination in surgical bed. Unlike neoantigen-based vaccine or adoptive cell therapy that takes several months to prepare, P-ATV can be easily manufactured within a few days and efficiently boost neoepitope-specific CD8+ T cells to activate personalized immunotherapy. This simple and powerful approach of engineered ATVs provides an alternative strategy for personalized immunotherapy and is readily transformable to various kinds of cell-based antigens to inhibit the relapse of postoperative tumors.

Targeted molecular therapy is the most effective treatment for cancer. An effective therapeutic target for colorectal cancer (CRC) is urgently needed. However, the mechanisms of CRC remain poorly understood, which has hampered research and development of CRC-targeted therapy. TRIM29 is a ubiquitin E3 ligase that has been reported as an oncogene in several human tumors. In this study, we show that increased levels of TRIM29 were detected in CRC compared with normal tissues and were associated with poor clinical outcome, advanced stage and lymph node metastasis, particularly those with right-sided colorectal cancer (RSCC). Notably, GATA2 (GATA Binding Protein 2) transcriptionally repressed TRIM29 expression. The loss of GATA2 and high expression of TRIM29 occur more frequently in RSCC than in left-sided colorectal cancer (LSCC). Functional assays revealed that TRIM29 promotes the malignant CRC phenotype in vitro and in vivo. Mechanistic analyses indicate that TRIM29 promotes pyruvate kinase (mainly PKM1) degradation via the ubiquitin-proteasome pathway. TRIM29 directly targets PKM1 to reduce PKM1/PKM2 ratio, which results in PKM2-mediated aerobic glycolysis (Warburg effect) acting as the dominant energy source in CRC. Our findings suggest that TRIM29 acts as a tumor promoter in CRC, especially in RSCC, and is a potential therapeutic target for CRC treatment.

Mammary Paget's disease most commonly affects the nipple areolar complex and is frequently associated with an underlying in-situ or invasive breast carcinoma. Pagetoid Bowen's disease of the breast is extremely rare and contains cells which morphologically resemble those of Paget's disease and may also express CK7 on immunohistochemistry. Here, we report two unusual cases of a 42-year-old Chinese woman with a recurrence of high grade ductal carcinoma in-situ presenting as mammary Paget's disease away from the nipple areolar complex, and a 65-year-old Chinese woman with pagetoid Bowen's disease of the breast skin. To our knowledge, there are only two case reports that are similar to the former and one to the latter. Keywords: Mammary Paget's disease, Pagetoid Bowen's disease

Background The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal. Elucidation of the LNM associated genomic alteration and underlying molecular mechanisms may provide clinical therapeutic strategies for ESCC treatment. Methods Joint analysis of ESCC sequencing data were conducted to comprehensively survey SCNAs and identify driver genes which significantly associated with LNM. The roles of miR-548k in lymphangiogensis and lymphatic metastasis were validated both in vitro and in vivo. ESCC tissue and blood samples were analyzed for association between miR-548k expression and patient clinicopathological features and prognosis and diagnosis. Results In the pooled cohort of 314 ESCC patients, we found 76 significant focused regions including 43 amplifications and 33 deletions. Clinical implication analysis revealed a panel of genes associated with LNM with the most frequently amplified gene being MIR548K harbored in the 11q13.3 amplicon. Overexpression of miR-548k remarkably promotes lymphangiogenesis and lymphatic metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-548k modulating the tumor microenvironment by promoting VEGFC secretion and stimulating lymphangiogenesis through ADAMTS1/VEGFC/VEGFR3 pathways, while promoting metastasis by regulating KLF10/EGFR axis. Importantly, we found that serum miR-548k and VEGFC of early stage ESCC patients were significantly higher than that in healthy donators, suggesting a promising application of miR-548k and VEGFC as biomarkers in early diagnosis of ESCC. Conclusions Our study comprehensively characterized SCNAs in ESCC and highlighted the crucial role of miR-548k in promoting lymphatic metastasis, which might be employed as a new diagnostic and prognostic marker for ESCC. Electronic supplementary material The online version of this article (10.1186/s12943-018-0871-4) contains supplementary material, which is available to authorized users.

There is an intimate connection between mitochondrial DNA (mtDNA) methylation and some diseases, such as cancer. MtDNA is almost strictly maternally inherited. However, whether the aberrant mtDNA methylation involved in breast cancer progression and whether mtDNA methylation can be transmitted through maternal line are poorly understood. Here we applied bisulfite sequencing to global mitochondrial DNA and whole genomic DNA methylation array from fifteen members of five three-female-generation families with one breast cancer patient in each family. We found that mtDNA methylation was maternally inherited in D-loop region and eight aberrant mtDNA methylation sites were correlated with breast cancer. Furthermore, conjoint analysis showed that mtDNA methylation sites could be potential biomarkers combined with nuclear DNA methylation sites for breast cancer risk prediction.

// Xixi Zhao 1, * , Jingkun Qu 2, * , Yuxin Hui 3 , Hong Zhang 1 , Yuchen Sun 4 , Xu Liu 2 , Xiaoyao Zhao 1 , Zitong Zhao 1 , Qian Yang 1 , Feidi Wang 1 and Shuqun Zhang 1 1 Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, P.R. China 2 The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China 3 The School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China 4 The Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China * These authors have contributed equally to this work Correspondence to: Shuqun Zhang, email: shuqun_zhang1971@163.com Keywords: breast cancer, c-Met, prognosis, meta-analysis Received: April 05, 2017 Accepted: April 27, 2017 Published: May 24, 2017 ABSTRACT Background: c-Met has been shown to promote organ development and cancer progression in many cancers. However, clinicopathological and prognostic value of c-Met in breast cancer remains elusive. Methods: PubMed and EMBASE databases were searched for eligible studies. Correlation of c-Met overexpression with survival data and clinicopathological features was analyzed by using hazard ratio (HR) or odds ratio (OR) and fixed-effect or random-effect model according to heterogeneity. All statistical tests were two-sided. Results: 32 studies with 8281 patients were analyzed in total. The c-Met overexpression was related to poor OS (overall survival) (HR=1.65 (1.328, 2.051)) of 18 studies with 4751 patients and poor RFS/DFS (relapse/disease free survival) (HR=1.53 (1.20, 1.95)) of 12 studies with 3598 patients. Subgroup analysis according to data source/methods/ethnicity showed c-Met overexpression was related to worse OS and RFS/DFS in Given by author group, all methods group and non-Asian group respectively. Besides, c-Met overexpression was associated with large tumor size, high histologic grade and metastasis. Conclusions: Our results showed that c-Met overexpression was connected with poor survival rates and malignant activities of cancer, including proliferation, migration and invasion, which highlighted the potential of c-Met as significant candidate biomarker to identify patients with breast cancer at high risk of tumor death.

// Hong Zhang 1 , Yafei Zhang 2 , Xixi Zhao 1 , Xingcong Ma 1 , Wanjun Yan 1 , Wen Wang 1 , Zitong Zhao 1 , Qian Yang 1 , Xi Sun 3 , Hui Luan 4 , Xiaoyan Gao 1 and Shuqun Zhang 1 1 Department of Oncology, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China 2 Department of General Surgery, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China 3 Department of Integrated Traditional Chinese and Western Medicine, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China 4 Department of Cardiology, First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China Correspondence to: Shuqun Zhang, email: 15229326653@163.com Keywords: cancer, rs895819, rs6505162, meta-analysis Received: November 30, 2016 Accepted: February 27, 2017 Published: March 22, 2017 ABSTRACT Many studies have been conducted to investigate the association between miR-27 rs895819 A > G and miR-423 rs6505162 C > A and cancer risk; however, the results are not consistent. In order to acquire a more precise assessment of the correlation, we performed this meta-analysis. We searched PubMed, EMBASE and Web of Science databases to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the correlation of these two microRNA polymorphisms with cancer risk. Forty-five eligible studies from thirty-five articles were included in our analysis. The results showed that rs895819 was associated with a decreased cancer risk in Caucasians (AG vs. AA: OR = 0.87, 95% CI = 0.79-0.96; GG+AG vs. AA: OR = 0.89, 95% CI = 0.81-0.98). When grouped by ethnicity, an increased risk was observed in colorectal cancer (G vs. A: OR = 1.19, 95% CI = 1.08-1.32; GG vs. AA: OR = 1.58, 95% CI = 1.28-1.96; GG vs. AG+AA: OR = 1.58, 95% CI = 1.29-1.93), while a decreased risk was found in breast cancer (G vs. A: OR = 0.93, 95% CI = 0.87-0.99; GG+AG vs. AA: OR = 0.91, 95% CI = 0.83-0.99). For rs6505162, a significantly decreased cancer risk was observed in lung cancer under all five genetic models. To summarize, our results indicated that rs895819 was a protective factor for cancer in Caucasians and could increase colorectal cancer risk but decrease breast cancer risk. Moreover, rs6505162 was a protective factor for lung cancer.

Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of effective therapeutic targets to prevent breast cancer metastasis is urgently needed. The function of miR-503-3p has been investigated in other cancers, but its role in breast cancer remains undefined. Here, we found that miR-503-3p was overexpressed in breast cancer tissue and plasma compared with adjacent normal breast tissue and with plasma from healthy individuals. Moreover, we identified miR-503-3p to be an oncogene of breast cancer cell proliferation, migration and invasion. Upregulation of miR-503-3p in breast cancer cells inhibited expression of epithelial–mesenchymal transition (EMT)-related protein SMAD2 and the epithelial marker protein E-cadherin by directly binding to their mRNA 3′ untranslated region, whereas increased expression of mesenchymal marker proteins, including vimentin and N-cadherin. Taken together, our findings support a critical role for miR-503-3p in induction of breast cancer EMT and suggest that plasma miR-503-3p may be a useful diagnostic biomarker for breast cancer.

// Yunwei Ou 1, 2, 3, 4, 7 , Zitong Zhao 2 , Weimin Zhang 2 , Qingnan Wu 2 , Chuanyue Wu 5, 6 , Xuefeng Liu 2 , Ming Fu 2 , Nan Ji 1 , Dan Wang 1 , Jiaji Qiu 1 , Liwei Zhang 1 , Chunjiang Yu 4 , Yongmei Song 2 , Qimin Zhan 2 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China 2 State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 3 Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China 4 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China 5 Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA 6 Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, 518055, China 7 China National Clinical Research Center for Neurological Diseases, Beijing 100050, China Correspondence to: Chunjiang Yu, email: cjyu1955@sina.com Yongmei Song, email: symlh2006@163.com Qimin Zhan, email: zhanqimin@pumc.edu.cn Keywords: EGFR, glioma, Kindlin-2, transcription Received: April 20, 2016 Accepted: August 11, 2016 Published: October 04, 2016 ABSTRACT Kindlin-2 promotes carcinogenesis through regulation of cell-cell and cell-extracellular matrix adhesion. However, the role of Kindlin-2 in glioma has not been elucidated. We investigated Kindlin-2 expression in 188 human glioma tissue samples. High Kindlin-2 expression was correlated with high pathological grade and a worse prognosis. Kindlin-2 promoted glioma cell motility and proliferation both in vitro and in vivo . Importantly, Kindlin-2 activated the EGFR pathway and increased EGFR mRNA levels. In addition to up-regulating Y-box binding protein-1 (YB-1) and β-catenin expression, Kindlin-2 formed a transcriptional complex with YB-1 and β-catenin that bound to the EGFR promoter and enhanced transcription. The β-catenin/YB-1/EGFR pathway was required for Kindlin-2-mediated functions. Our data provide a better understanding of the mechanisms underlying glioma progression, and suggest that Kindlin-2 may be a biomarker and therapeutic target in glioma.

We report a case of pseudotuberculous granulomatous pyelitis in an elderly female patient with hydronephrotic right kidney secondary to obstructing urinary stone. Pseudotuberculous granulomatous pyelitis is a rarely reported entity, characterized by severe granulomatous inflammation limited predominantly to the renal pelvis. It is associated with urinary (pelvicalyceal) obstruction, urolithiasis well as non- Mycobacterial urinary tract infection.

ObjectiveThis study aimed to evaluate the clinicopathologic features of mucinous borderline ovarian tumors (MBOTs), with an emphasis on the risk factors for recurrence.MethodsData of 76 patients with MBOT diagnosed and treated between 2000 and 2007 at a single institution were analyzed in this retrospective study. The clinicopathologic features of different tumor subgroups were analyzed, including pathology, surgical methodology, recurrence, and overall survival.ResultsThe median patient age was 40 years (13–85 years). Forty-six patients with gastrointestinal mucinous borderline tumors (intestinal MBOTs) (73.7%) and 20 patients with endocervical MBOT (26.3%) were identified. Forty radical surgeries and 26 conservative surgeries were performed. There were 74.6% patients (50/67) with stage I disease among the 67 patients who received comprehensive surgical staging.During a median follow-up time of 151 months, 9 recurrences were identified. Median duration from surgery to recurrence was 26.4 months (range, 13–50 months). There was no difference in recurrence rate between intestinal MBOT and endocervical MBOT (14.3% vs 5.0%; P > 0.05). The recurrence rate of stage III tumors was significantly higher than that of stage I (33.3% vs 8%; P < 0.05). The recurrence rate after conservative surgery was higher than that after radical procedures (21.4% vs 6.3%; P < 0.05).ConclusionsThe majority of patients with MBOT had a favorable prognosis. Patients with later-stage disease had a higher recurrence rate.

Background Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC. Methods Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed. Results PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P

Primary cardiac lymphoma (PCL) is a rare neoplasm involving the heart, pericardium or both. Patients with PCL have a median survival of approximately 7 months based on literature. We report a unique case of a 63-year-old woman presenting with worsening exertional dyspnoea and symptoms of superior vena cava obstruction. Investigations revealed a large right atrial (RA) tumour with obstructive features. In the past, PCL was frequently diagnosed at postmortem but with modern imaging and biopsy techniques, this allows early diagnosis and treatment of this rapidly fatal disease. Our patient had a trans-jugular venous biopsy of the RA mass under trans-oesophageal echocardiography guidance. This confirmed the diagnosis of PCL. She subsequently completed seven cycles of chemotherapy and is currently in remission 20 months after diagnosis.

GATA3 is a critical transcription factor in the development of various human systems. The notion that GATA3 expression is required for the differentiation and maintenance of normal breast tissue has been well established. Recently, GATA3 is found to actively participate in the multistep process leading breast cancer pathogenesis, including tumorigenesis, tumor differentiation, epithelial mesenchymal transition, and metastasis through regulation of various target genes. On the other hand, several studies have raised questions and highlighted the role of GATA3-low or GATA3-negative cells during the malignant development of breast cancer. In addition to gene expression, GATA3 mutations provide another dimension of complexity. As one of the most frequently mutated genes in breast cancer, GATA3 mutations may have an effect on DNA-binding ability, protein production, and transactivation activity. Recognition of the multiple function of GATA3 in breast cancer will serve to deepen our understanding of the nature of this disease and develop novel therapeutic approaches.

Helix B surface peptide (HBSP), derived from erythropoietin, displays powerful tissue protection during kidney ischemia reperfusion (IR) injury without erythropoietic side effects. We employed cyclization strategy for the first time, and synthesized thioether-cyclized helix B peptide (CHBP) to improve metabolic stability and renoprotective effect. LC–MS/MS analysis was adopted to examine the stability of CHBP in vitro and in vivo. The renoprotective effect of CHBP in terms of renal function, apoptosis, inflammation, extracellular matrix deposition, and histological injury was also detected in vivo and in vitro. Antibody array and western blot were performed to analyze the signal pathway of involvement by CHBP in the IR model and renal tubular epithelial cells. In this study, thioether-cyclized peptide was significantly stable in vivo and in vitro. One dose of 8nmol/kg CHBP administered intraperitoneally at the onset of reperfusion improved renal protection compared with three doses of 8nmol/kg linear HBSP in a 48h murine IR model. In a one-week model, the one dose CHBP-treated group exhibited remarkably improved renal function over the IR group, and attenuated kidney injury, including reduced inflammation and apoptosis. Interestingly, we found that the phosphorylation of autophagy protein mTORC1 was dramatically reduced upon CHBP treatment. We also demonstrated that CHBP induced autophagy via inhibition of mTORC1 and activation of mTORC2, leading to renoprotective effects on IR. Our results indicate that the novel metabolically stable CHBP is a promising therapeutic medicine for kidney IR injury treatment.

The naked small interfering RNA (siRNA) of caspase-3, a key player in ischemia reperfusion injury, was effective in cold preserved and hemoreperfused kidneys, but not autotransplanted kidneys in our porcine models. Here, chemically modified serum stabilized caspase-3 siRNAs were further evaluated. The left kidney was retrieved and infused by University of Wisconsin solution with/without 0.3 mg caspase-3 or negative siRNA into the renal artery for 24-hour cold storage (CS). After an intravenous injection of 0.9 mg siRNA and right-uninephrectomy, the left kidney was autotransplanted for 2 weeks. The effectiveness of caspase-3 siRNA was confirmed by caspase-3 knockdown in the post-CS and/or post-transplant kidneys with reduced apoptosis and inflammation, while the functional caspase-3 siRNA in vivo was proved by detected caspase-3 mRNA degradation intermediates. HMGB1 protein was also decreased in the post-transplanted kidneys; correlated positively with renal IL-1β mRNA, but negatively with serum IL-10 or IL-4. The minimal off-target effects of caspase-3 siRNA were seen with favorable systemic responses. More importantly, renal function, associated with active caspase-3, HMGB1, apoptosis, inflammation, and tubulointerstitial damage, was improved by caspase-3 siRNA. Taken together, the 2-week autotransplanted kidneys were protected when caspase-3 siRNA administrated locally and systemically, which provides important evidence for future clinical trials.

Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell–driven autoimmune disease caused by impaired central tolerance, are susceptible to developing chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop phenotypes reminiscent of APECED, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the potential link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or depletion of autoreactive CD4 T cells rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or EGFR activity decreases fungal burden. Importantly, fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development.

The presynaptic cytomatrix protein Piccolo, encoded by PCLO, is frequently mutated and amplified in esophageal squamous cell carcinoma (ESCC), but its exact roles in ESCC remain unclear. Here we report that Piccolo expression correlates significantly with clinical stage, patient survival and tumor embolus. Functional studies demonstrate that PCLO knockdown remarkably attenuates ESCC malignancy in vitro and in vivo, and ectopic EGFR expression partially compensates for Piccolo loss. PCLO knockdown promotes ubiquitination and degradation of EGFR, which is associated with the negative regulatory effect of Piccolo on E3 ligase Siah1. An anti-Piccolo monoclonal antibody inhibited tumor proliferation in a mouse model of ESCC. These results demonstrate that Piccolo contributes to tumor aggressiveness in ESCC, likely by stabilizing EGFR and promoting EGFR-dependent signaling. Our results further suggest that Piccolo may represent a novel prognostic biomarker and therapeutic target for patients with ESCC.

IgG4-related disease of the thyroid gland is a recently recognized subtype of thyroiditis, often with rapid progression requiring surgical treatment. It is considered as a spectrum of disease varying from early IgG4-related Hashimoto’s thyroiditis (HT) pattern to late fibrosing HT or Riedel’s thyroiditis patterns. Here, we report a 47-year-old Malay woman presenting with progressively painless neck swelling over 3 years and subclinical hypothyroidism. Computed tomography (CT) scan revealed diffuse thyroid enlargement (up to 13 cm) with retrosternal extension and without regional lymphadenopathy. Fine needle aspiration of the thyroid showed a limited number of follicular epithelial cell groups with widespread Hurthle cell change and scanty background colloid, but no evidence of lymphocytosis. The cytologic features fell into the category of ‘atypia of undetermined significance’. Subsequently, the patient developed hypercapnic respiratory failure secondary to extrinsic upper airway compression by the thyroid mass and underwent emergent total thyroidectomy. Histology of the thyroid showed diffuse dense lymphoplasmacytic infiltrate and fibrosis. Follicular cells exhibited reactive nuclear features and some Hurthle cell change. IgG4+ plasma cells were over 40/high power field while overall IgG4/IgG ratio was above 50%. The overall features suggest the diagnosis of IgG4-related disease of the thyroid gland in the form of IgG4-related HT. Post-surgery, the patient was found to have markedly elevated serum IgG4 concentration but PET/CT did not show significant increased fludeoxyglucose uptake in other areas. Her recovery was complicated by a ventilator-associated pneumonia with empyema, limiting early use of corticosteroids for treatment of IgG4-related disease.

The overall survival remains undesirable in clinical glioma treatment. Inhibition of DNA-PKcs activity by its inhibitors suppresses tumor growth and enhances chemosensitivity of several tumors to chemotherapy. However, whether DNA-PKcs could be a potential target in glioma therapy remains unknown. In this study, we reported that the hyperactivated DNA-PKcs was profoundly correlated with glioma malignancy and observe a significant association between DNA-PKcs activation and survival of the glioma patients. Our data also found that inhibition of DNA-PKcs by its inhibitor KU0060648 sensitized glioma cells to TMZ in vitro. Specifically, we demonstrated that KU0060648 interrupted the formation of DNA-PKcs/AKT complex, leading to suppression of AKT signaling and resultantly enhanced TMZ efficacy. Combination of KU0060648 and TMZ substantially inhibited downstream effectors of AKT. The in vivo results were similar to those obtained in vitro. In conclusion, this study indicated that inhibition of DNA-PKcs activity could suppress glioma malignancies and increase TMZ efficacy, which was mainly through regulation of the of AKT signaling. Therefore, DNA-PKcs/AKT axis may be a promising target for improving current glioma therapy.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly cancers in the world. Currently, clinical therapy of ESCC remains limited and the five-year survival rate is poor. The function of miR-425 has been reported in multiple human cancers. However, the tumorigenic role and clinical significance of miR-425 in ESCC remains unclear. We found that enhanced expression of miR-425 in ESCC cell lines not only promoted cell proliferation and colony formation, but also increased cellular metastasis. Furthermore, we revealed the mechanism that miR-425 inhibited the expression of SMAD2 by targeting the second binding site in the 3′-untranslated region (3′-UTR) in ESCC. This mode of action influenced not only SMAD2 mRNA expression but also protein expression. In addition, we detected the expression of miR-425 in ESCC tissues and plasma. Moreover, we analyzed the relationship between miR-425 expression and SMAD2 mRNA expression. We found that miR-425 was overexpressed in ESCC tissues and the plasma relative to adjacent normal tissues and plasma of healthy individuals. Furthermore, there was a negative correlation between miR-425 expression and SMAD2. Taken together, our results show that miR-425 functions as an oncogene by targeting the 3′-UTR of SMAD2 and indicate the potential utility of plasma miR-425 as a novel biomarker for ESCC diagnosis.

The characterization of CD4+ T-cell subsets reflects the immune status and is important in the maintenance of tumorigenesis and homeostasis. To identify changes in the balance of T helper (Th)1, Th2, Th17 and regulatory T cells (Treg) in individuals with renal cell carcinoma (RCC), the present study investigated a total of 131 patients with RCC and 36 healthy volunteers. The number of CD4+ T-bet+ cells, CD4+ GATA binding protein 3+ cells, CD4+ RAR-related orphan receptor γt+ cells, CD4+ CD25hi CD127lo CD45RA− cells and CD4+ CD25hi CD127lo CD45RA+ cells, defined as Th1, Th2, Th17, activated and naive Treg cells, respectively, were detected in the peripheral blood using flow cytometric analysis. In addition, tumor-infiltrating forkhead box P3 (Foxp3)+ cells were examined using immunohistochemistry. Compared with healthy volunteers, a significant decrease in the peripheral percentages of Th1, activated and naive Treg cells was observed in patients with RCC, while those of the Th2 and Th17 cells were increased. In particular, as the tumor stage and grade progressed, the levels of Th1, activated and naive Treg cells in the peripheral blood decreased; however, the levels of Th2 and Th17 cells increased. Furthermore, the number of tumor-infiltrating Foxp3+ cells increased with increasing tumor stage. These results demonstrated that the balance of Th1 and Th2 cells was skewed towards the Th2 profile and the balance of Th17 and Treg cells was skewed towards the Th17 profile in the peripheral blood of patients with renal cell carcinoma (RCC) and Treg cells were recruited to the tumor sites. Therefore, dysfunctional host anti-tumor immunity was observed in patients with RCC, with a skewed Th1/Th2 and Th17/Treg balance.

Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide(1). Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%)(2,3). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

Soluble fibrinogen-like protein 2 (sfgl2), which is mainly secreted by T cells, is a novel effector of regulatory T cells with immunosuppressive functions. The aim of this study was to investigate serum levels of sfgl2 among renal allograft recipients.From November 2010 to August 2011 we retrospectively divided 47 renal allograft recipients into an acute rejection (n = 19) versus a stable group (n = 28) according to allograft biopsy results, using the Banff 2007 classification. The acute rejection group was subdivided into grade I (n = 8) versus grade II T-cell-mediated (n = 6) or antibody-mediated rejection episodes (n = 5). Peripheral blood samples were collected at the time of biopsy. Fourteen healthy volunteers were included as normal group controls. Serum levels of sfgl2 were analyzed by enzyme-linked immunosorbent assay.Serum levels of sfgl2 were increased among renal allograft recipients suffering from biopsy-proven acute rejection episodes (61.91 ± 45.68 ng/mL), versus those with stable allografts (38.59 ± 19.92 ng/mL, P.05) or healthy volunteers (29.10 ± 18.08 ng/mL, P.05). The sfgl2 level was significantly higher among patients with antibody-mediated (118.48 ± 55.54 ng/mL) than T-cell-mediated acute rejection episodes (41.71 ± 16.44 ng/mL, P.01). Serum sfgl2 levels were remarkably elevated in patients with grade II (51.87 ± 19.13 ng/mL) versus grade I T-cell-mediated rejection (34.10 ± 9.26 ng/mL, P.05).Serum sfgl2 levels were increased among renal allograft recipients with acute rejection episodes to an extent dependent upon the pathological type and severity of the response.

Background Regulatory T cells (Treg) protect kidney against ischemia reperfusion (IR) injury via suppressing innate immunity, but the mechanism has not been fully clarified. Soluble fibrinogen-like protein 2 (sFGL2), a novel effector of Treg, may affect apoptosis and inflammation. This study investigated the role of sFGL2 in renal IR injury in a porcine kidney auto-transplantation model. Materials and methods The left kidney was retrieved from mini pigs and infused by University of Wisconsin solution into the renal artery with the renal artery and vein clamped for 24-h cold storage. After the right nephrectomy, the left kidney was auto-transplanted into the right for 2 weeks. 3 pigs were sacrificed at day 2, 5, 7, 10 and 14 post-transplantation respectively. Collected renal tissues and daily blood samples were stored for further analyses. Results Both serum creatinine and blood urea nitrogen were maximized during day 2 to 5 and followed by a gradual recovery over 2 weeks. The similar pattern were showed in histological damage, myeloperoxidase + cells and apoptosis in the kidney, as well as circulating TNF-α and IFN-γ. Serum sFGL2 presented a fluctuating increase and reached a peak at day 10. The expression of sFGL2 and its receptor FcγRIIB as well as Foxp3 and IL-10 in the kidney was notably increased from day 5 to 10. Conclusion The increased sFGL2 together with FcγRIIB during renal recovery after IR injury suggested that sFGL2 might be a potential renoprotective mediator involved in the renal self-repairing and remodeling in this 2-week porcine auto-transplantation model.

Background: The oncogenesis and developmental mechanisms of glioma must be clarified to control the disease. Results: Migfilin relates to pathological grades, prognosis of glioma, and regulates motility of glioma cells. Conclusion: Migfilin mediates migration and invasion through EGFR-induced PLC-γ and STAT3 pathways. Significance: Migfilin helps us better understand the pathogenesis of glioma, and Migfilin may be a molecular marker in diagnosis and an indicator in prognosis., Migfilin is critical for cell shape and motile regulation. However, its pathological role in glioma is unknown. Using an immunohistochemical staining assay, we demonstrate that there is a significant correlation between expression of Migfilin and pathological tumor grade in 217 clinical glioma samples. High Migfilin expression is associated with poor prognosis for patients with glioma. Investigation of the molecular mechanism shows that Migfilin promotes migration and invasion in glioma cells. Moreover, Migfilin positively modulates the expression and activity of epidermal growth factor receptor, and Migfilin-mediated migration and invasion depend on epidermal growth factor receptor-induced PLC-γ and STAT3-signaling pathways. Our results may provide significant clinical application, including use of Migfilin as a molecular marker in glioma for early diagnosis and as an indicator of prognosis.

The significant improvements in siRNA therapy have been achieved, which have great potential applications in humans. The kidney is a comparatively easy target organ of siRNA therapy due to its unique structural and functional characteristics. Here, we reviewed recent achievements in siRNA design, delivery and application with focuses on kidney diseases, in particular kidney transplant-related injuries. In addition, the strategy for increasing serum stability and immune tolerance of siRNA was also discussed. At last, the future challenges of siRNA therapy including organ/tissue/cell-specific delivery and time-controlled silence, as well as selecting therapeutic targets, were addressed as well.