Search

Supplementary Table 8. Sequence of primers for real-time PCR. Supplementary Table 9. Sequence of primers for CHIP real-time PCR.

Supplementary Table 5. Proteins in the two distict bands specific to GClnc1 identified by Liquid Chromatography-Mass Spectrometry.

Supplementary Table 4. RNA-seq analysis in BGC823 cells after GClnc1 shRNA and control shRNA transfection.

Supplementary Table 6. A, ChIP-Seq Library Statistics. B, ChIP-Seq Library Peak Calls. C, WDR5 and KAT2A peaks within 2kb of RefSeq gene promoters where read coverage were significant decreased in BGC823 GC cells after transduction of GClnc1 shRNA virus,compared with transduction of control shRNA virus. D, the differentiated expression genes in BGC823 cells after downregulation of GClnc1. E, Intersection of ChIP-Seq and RNA seq data. Supplementary Table 7. The association between GClnc1 with target genes in the coexpression network analysis.

Supplementary Methods

Supplementary Figure 1, related to Figure 1. Clinical relevance of lncRNA candidate BC041951 in gastric cancer. Supplementary Figure 2, related to Figure 2. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) in gastric cancer cells and gastric cancer patients with high and low GClnc1 expression. Supplementary Figure 3, related to Figure 3. GClnc1 is an oncogenic lncRNA in gastric cancer. Supplementary Figure 4, related to Figure 4. GClnc1 interacts with WDR5 and KAT2A epigenetic modification complex. Supplementary Figure 5, related to Figure 5. GClnc1 coordinates the localization of WDR5 and KAT2A genome-wide. Supplementary Figure 6, related to Figure 6. GClnc1 promotes gastric cancer progression via SOD2. Supplementary Figure 7, related to Figure 7. GClnc1 is a molecular link among WDR5/KAT2A and SOD2.

Fig. S1. RNF6 genomic amplification is prevalent in colorectal cancer and correlated with shortened patient survival. Fig. S2. RNF6 is clinically relevant in colorectal cancer. Fig. S3. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) in RNF6-higher/lower expression CRC cells and patients, and RNF6 is an oncogenic gene. FigureS4. RNF6 upregulates pSTAT3 via downregulating SHP-1 expression. Figure S5. RNF6 Interacts with SHP-1 and enhances ubiquitylation and degradation of SHP-1. Figure S6. Effectiveness of pSTAT3 inhibitors in treating RNF6-amplified tumors.

Supplementary Material and Methods clean

Fig. S1. RNF6 genomic amplification is prevalent in colorectal cancer and correlated with shortened patient survival. Fig. S2. RNF6 is clinically relevant in colorectal cancer. Fig. S3. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) in RNF6-higher/lower expression CRC cells and patients, and RNF6 is an oncogenic gene. FigureS4. RNF6 upregulates pSTAT3 via downregulating SHP-1 expression. Figure S5. RNF6 Interacts with SHP-1 and enhances ubiquitylation and degradation of SHP-1. Figure S6. Effectiveness of pSTAT3 inhibitors in treating RNF6-amplified tumors.

Table S1.Expression of human ubiquitin ligase genes in 246 CRC patients of TCGAdatabase.TableS2.Clinial information of 62 cases CRC patients (fresh tissues).Table S3.Clinial information of 78 cases CRC patients (paraffin tissues).Table S4.Clinial information of 97 cases CRC patients (paraffin tissues).Table S5.RNA sequence data. TableS 6. Primer sequences

Objective: The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer. We aimed to explore the mechanical, biological, and clinical role of RNF6 in colorectal cancer initiation and progression.Design: The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real-time PCR, Western blot, and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and in vitro. Role of RNF6 in modulating SHP-1 expression was examined by coimmunoprecipitation and confocal microscopy, respectively.Results: The copy number of RNF6 was significantly amplified in colorectal cancer, and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with patients with colorectal cancer with poor prognosis. The gene set enrichment analysis (GSEA) revealed cell proliferation, and invasion-related genes were enriched in RNF6 high-expressed colorectal cancer cells as well as in patients from TCGA dataset. Downregulation of RNF6 impaired the colorectal cancer cell proliferation and invasion in vitro and in vivo. RNF6 may activate the JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1.Conclusions: Genomic amplification drives RNF6 overexpression in colorectal cancer. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors. Clin Cancer Res; 24(6); 1473–85. ©2017 AACR.

A pair of new oxindole alkaloids, named macrophyllines C (1) and D (2), together with two known oxindole alkaloids isorhynchophylline (3) and corynoxine (4) were isolated from Uncaria macrophylla. Their structures were elucidated based on detailed spectroscopic analysis and by comparison with literature data. In addition, all the isolates were tested for their anti-HIV activities and cytotoxicities in C8166 cells and compounds 2-4 showed weak anti-HIV activities with EC50 values of 11.31 ± 3.29 μM, 18.77 ± 6.14 μM and 30.02 ± 3.73 μM, respectively.

Patients with liver fibrosis who have pain in the liver region may have changed nerve factors. The expression of neurokines and hepatic nerves in liver fibrosis, however, was little understood. In order to better understand how liver fibrosis develops, we plan to look into the hepatic nerve and neurokine changes and how they relate to hepatic stellate cells (HSCs).The expression of neurokines in liver samples from 55 chronic hepatitis B patients and the carbon tetrachloride (CClThe levels of mRNA for neurokines such as BDNF, GFAP, and growth-associated protein (GAP43) are significantly increased in both human and animal liver fibrosis. As liver fibrosis advances, we found that Nissl bodies and α-SMA may co-localize, suggesting a connection between hepatic nerves and HSCs. Human fibrotic serum may increase neurkines, notably BDNF, in SH-SY5Y cells. We also found that BDNF increased pro-inflammatory cytokines and fibrogenic markers in hHSCs.Patients with hepatic fibrosis had significantly higher levels of BDNF, GFAP, GAP43, and nerve fibers. HSC and nerve fibers interact, and nerves also create neurogenic substances that promote liver fibrosis and HSC activation.

ObjectiveMicrobiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC.Design18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1.ResultsWe have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function.ConclusionF. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.

The development of male and female gametophytes is a prerequisite for successful propagation of angiosperms. The small GTPases RAN play fundamental roles in numerous cellular processes. Although RAN GTPases have been characterized in plants, their roles in cellular processes are far from understood. We report here that RAN GTPases in Arabidopsis are critical for gametophytic development. RAN1 loss-of-function showed no defects in gametophytic development likely due to redundancy. However, the expression of a dominant negative or constitutively active RAN1 resulted in gametophytic lethality. Genetic interference of RAN GTPases caused the arrest of pollen mitosis I and of mitosis of functional megaspores, implying a key role of properly regulated RAN activity in mitosis during gametophytic development.

Marine-derived fungi are well known as rich sources of bioactive natural products. Growing evidences indicated that indole alkaloids, isolated from a variety of marine-derived fungi, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities, and therefore, indole alkaloids have potential to be pharmaceutical lead compounds. Systemic compilation of the relevant literature. In this review, we demonstrated a comprehensive overview of 431 new indole alkaloids from 21 genera of marine-derived fungi with an emphasis on their structures and bioactivities, covering literatures published during 1982–2019. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s42995-020-00072-w) contains supplementary material, which is available to authorized users.

Euphopias A-C (1-3), three rearranged jatrophane-type diterpenoids with tricyclo[8.3.0.02,7]tridecane (1 and 2) and tetracyclo[11.3.0.02,10.03,7]hexadecane (3) cores, were isolated from Euphorbia helioscopia. Comprehensive spectroscopic analyses, quantum-chemical calculations, and X-ray diffractions were used to identify their structures. Compounds 1-3 could significantly inhibit NLRP3 inflammasome activation and block NLRP3 inflammasome-induced pyroptosis. Additionally, a mechanistic study revealed that 2 could ameliorate mitochondria damage, thereby interrupting NLRP3 inflammasome activation.

Background Splicing factor SRSF3 is an oncogene and overexpressed in various kinds of cancers, however, the function and mechanism involved in colorectal cancer (CRC) remained unclear. The aim of this study was to explore the relationship between SRSF3 and carcinogenesis and progression of CRC. Methods The expression of SRSF3 in CRC tissues was detected by immunohistochemistry. The proliferation and invasion rate was analyzed by CCK-8 assay, colony formation assay, transwell invasion assay and xenograft experiment. The expression of selected genes was detected by western blot or real time PCR. Results SRSF3 is overexpressed in CRC tissues and its high expression was associated with CRC differentiation, lymph node invasion and AJCC stage. Upregulation of SRSF3 was also associated with shorter overall survival. Knockdown of SRSF3 in CRC cells activated ArhGAP30/Ace-p53 and decreased cell proliferation, migration and survival; while ectopic expression of SRSF3 attenuated ArhGAP30/Ace-p53 and increases cell proliferation, migration and survival. Targeting SRSF3 in xenograft tumors suppressed tumor progression in vivo. Conclusions Taken together, our data identify SRSF3 as a regulator for ArhGAP30/Ace-p53 in CRC, and highlight potential prognostic and therapeutic significance of SRSF3 in CRC.

We aimed to develop an HCC classification model based on the integrated gene expression and methylation data of methylation-driven genes. Genome, methylome, transcriptome, proteomics and clinical data of 369 HCC patients from The Cancer Genome Atlas Network were retrieved and analyzed. Consensus clustering of the integrated gene expression and methylation data from methylation-driven genes identified 4 HCC subclasses with significant prognosis difference. HS1 was well differentiated with a favorable prognosis. HS2 had high serum α-fetoprotein level that was correlated with its poor outcome. High percentage of CTNNB1 mutations corresponded with its activation in WNT signaling pathway. HS3 was well differentiated with low serum α-fetoprotein level and enriched in metabolism signatures, but was barely involved in immune signatures. HS3 also had high percentage of CTNNB1 mutations and therefore enriched in WNT activation signature. HS4 was poorly differentiated with the worst prognosis and enriched in immune-related signatures, but was barely involved in metabolism signatures. Subsequently, a prediction model was developed. The prediction model had high sensitivity and specificity in distributing potential HCC samples into groups identical with the training cohort. In conclusion, this work sheds light on HCC patient prognostication and prediction of response to targeted therapy.

Background Chemotherapy resistance is the major cause of recurrence in patients with colorectal cancer (CRC). A previous study found that Fusobacterium (F.) nucleatum promoted CRC chemoresistance. Additionally, metformin rescued F. nucleatum-induced tumorigenicity of CRC. Here, we aimed to investigate whether metformin could revert F. nucleatum-induced chemoresistance and explore the mechanism. Methods The role of metformin in F. nucleatum-infected CRC cells was confirmed using cell counting kit 8 assays and CRC xenograft mice. Stemness was identified by tumorsphere formation. Bioinformatic analyses were used to explore the regulatory molecules involved in metformin and F. nucleatum-mediated regulation of the sonic hedgehog pathway. Results We found that metformin abrogated F. nucleatum-promoted CRC resistance to chemotherapy. Furthermore, metformin attenuated F. nucleatum-stimulated stemness by inhibiting sonic hedgehog signaling. Mechanistically, metformin diminished sonic hedgehog signaling proteins by targeting the MYC/miR-361-5p cascade to reverse F. nucleatum-induced stemness, thereby rescuing F. nucleatum-triggered chemoresistance in CRC. Conclusions Metformin acts on F. nucleatum-infected CRC via the MYC/miR-361-5p/sonic hedgehog pathway cascade, subsequently reversing stemness and abolishing F. nucleatum-triggered chemoresistance. Our results identified metformin intervention as a potential clinical treatment for patients with chemoresistant CRC with high amounts of F. nucleatum.

A pair of new oxindole alkaloids, named macrophyllines C (

Tree ring data is of significance for reconstructing climate and predicting environmental dynamics. In order to accurately measure spacing and other parameters of年轮信息对重建气候和预测环境的动态变化有重要意义。为准确测量梭梭年轮间距等各项参数,研究基于GIS对扫描后的梭梭圆盘PS图像赋予坐标系统,通过ENVI图像分类软件结合GIS测量工具,完成梭梭年轮间距测量;利用WinDENDRO年轮分析系统验证测量结果的准确性。结果表明: 两种方法测量结果差异不显著(

Neutron and gamma ray pulse signal discrimination technology is an essential part of many modern scientific fields, such as biology, geology, radiation imaging, and nuclear medicine. Neutrons are always accompanied by gamma rays due to their unique penetration characteristic; thus, the development of n- $$\gamma$$ discrimination methods is especially crucial. In the present study, a novel n- $$\gamma$$ discrimination method is proposed that implements a pulse-coupled neural network for n- $$\gamma$$ discrimination. In addition, experiments were conducted on the pulse signals detected by an EJ299-33 plastic scintillator, which is especially suitable for n- $$\gamma$$ discrimination. The proposed method was compared to three other discrimination methods, including the back-propagation neural network (BPNN), the fractal spectrum method, and the charge comparison method, with respect to two aspects: (i) the figure of merit ( $${{FoM}}$$ ) and (ii) discrimination time. The experimental results showed that the pulse-coupled neural network (PCNN) has a 26.49% improvement in $${{FoM}}$$ -value compared to the charge comparison method, a 72.80% improvement compared to the BPNN, a 66.24% improvement compared to the fractal spectrum method, and the second-fastest discrimination time of 2.22 s. In conclusion, the PCNN treats the input signal as a whole for analysis and processing, imparting it with an excellent anti-noise effect and the ability to process the dynamic information contained in a pulse signal.

Activation of hedgehog (Hh) signaling contributes to the progression of Barrett’s esophagus (BE), which increases the risk of esophageal adenocarcinoma. Recent clinical studies revealed that proton-pump inhibitors (PPIs) but not H2 receptor antagonists (H2RAs) were associated with a decreased risk of esophageal adenocarcinoma. We would like to know whether PPIs interfere with BE progression during BE treatment. Here, we explored the role of omeprazole on Hh signaling and expression of two crucial biomarkers of BE, SOX9 and CDX2. We demonstrated that bile acids elevated expression of Hh pathway target genes, such as GLI1 and PTCH1, and induced SOX9 and CDX2 up-regulation in both CP-A and CP-B cells. Omeprazole, but not famotidine, down-regulated these genes induced by bile acids. In addition, omeprazole-induced down-regulation of SOX9 and CDX2 was mediated by Hh signaling. To explore the mechanisms by which omeprazole inhibits Hh signaling, we performed luciferase assay but did not find any effects of omeprazole on the activity of GLI1 promoter, the critical transcription factor of Hh signaling. Therefore, we used miRNA sequencing and a bioinformatics tool in our study to identify the differently expressed miRNAs in BE organoids treated with or without omeprazole, and we identified miR-2116-3p was involved in omeprazole-mediated inhibition of Hh signaling and subsequent down-regulation of SOX9 and CDX2. Collectively, our data indicate omeprazole inhibits Hh signaling and subsequent SOX9 and CDX2 expression via up-regulating miR-2116-3p. We have demonstrated a novel acid-independent mechanism of omeprazole that might yield valuable insight into clinical management of BE progression, irrespective of acid reflux symptoms.

The chemokine ligand C-X-C motif chemokine ligand 11 (CXCL11) is involved in the progression of various cancers, but its biological roles in colorectal cancer (CRC) remain confused. Therefore, the prognostic value and underlying mechanism of CXCL11 in CRC were preliminarily evaluated. Three independent datasets were used for mRNA-related analysis: one dataset from the Cancer Genome Atlas (TCGA, n = 451) and two single-cell RNA sequencing (scRNA-seq) datasets from Gene Expression Omnibus (GEO): GSE146771 and GSE132465. In addition, a colon adenocarcinoma (COAD) patient cohort (the Yijishan Hospital cohort, YJSHC, n = 108) was utilized for analysis of cell infiltration by immunohistochemistry. We determined the distribution of CXCL11 in tumor tissue across all TCGA cancers and found that CXCL11 expression was significantly upregulated in both COAD and rectal adenocarcinoma (READ). However, the upregulation of CXCL11 mRNA was associated with a better prognosis in COAD, but not in READ. Within the YJSHC, the patients with a high abundance of intratumoral CXCL11+ cells had prolonged survival (p = 0.001). Furthermore, we found that the high CXCL11 expression group had a higher proportion of antitumor immune cells, and a lower proportion of protumor immune cells. Additionally, we discovered the changes of gene expression and enriched immune pathway network mediated by CXCL11. Interestingly, both cytotoxic genes (IFNG, GZMA, GZMB, GZMK, GZMM, and PRF1) and immunosuppressive molecules, including PD-L1, were positively correlated with CXCL11 expression. CXCL11, which promoted antitumor immunity to benefit survival, was identified as an independent prognostic biomarker in patients with COAD.

Background The effect of metformin on gut microbiota has been reported, but whether metformin can suppress colorectal cancer (CRC) by affecting gut microbiota composition and rescue F. nucleatum-induced tumourigenicity remains unclear. Methods To identify microbiota associated with both CRC occurrence and metformin treatment, first, we reanalyzed the gut microbiome of our previous data on two human cohorts of normal and CRC individuals. Subsequently, we summarized microbiota altered by metformin from published literatures. Several taxa, including Fusobacterium, were associated with both CRC occurrence and metformin treatment. We investigated the effect of metformin on APCMin/+ mice given with or without F. nucleatum. 16S rRNA gene sequencing was performed. Findings We summarized 131 genera altered by metformin from 18 published literatures. Five genera reported to be changed by metformin, including Bacteroides, Streptococcus, Achromobacter, Alistipes and Fusobacterium, were associated with CRC in both of our human cohorts. Metformin relieved the symptoms caused by F. nucleatum administration in APCMin/+ mice, and showed promise in suppressing intestinal tumour formation and rescuing F. nucleatum-induced tumourigenicity. Administration of F. nucleatum and/or metformin had effect on gut microbiome structure, composition and functions of APCMin/+ mice. Interpretation This study pioneers in predicting critical CRC-associated taxa contributing to the antitumour effect of metformin, and correlating gut microbiome with the antitumour effect of metformin in experimental animals. We presented a basis for future investigations into metformin's potential effect on suppressing F. nucleatum-induced tumor formation in vivo. Funding This work was supported by grants from the National Natural Science Foundation of China (31701250).

Euphopias A-C (

To investigate the effects of combined infusion of mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) on lung injury after hematopoietic stem cell transplantation (HSCT).The experiment was divided into normal control group, irradiation group, bone marrow cell transplantation group (BMT group), BMT+EPC group, BMT+MSC group and BMT+EPC+MSC group. The model of HSCT was established, on the 30th day after transplantation, the mice were sacrificed. Then lung tissue was taken for testing. The mRNA expression levels of VEGF, IL-18, IL-12b were detected by RT-PCR, and protein expression level of NLRP3 was detected by Western blot. The expression of MPO and CD146 was observed by immunohistochemistry assay.The expression level of VEGF gene in BMT+EPC+MSC group was significantly higher than that in other groups (P＜0.01). The expression level of IL-18 and IL-12b gene was the highest in BMT group and the lowest in BMT+EPC+MSC group, and the difference was statistically significant (P＜0.05). HSCT could increase the expression of NLRP3 protein, and the BMT+EPC+MSC could significantly reduce the level of NLRP3 protein in lung cells, tending to normal. Compared with normal tissues, the BMT+EPC+MSC could improve the lung tissue structure more effectively, the expression of MPO positive cells was lower, and the expression of VEGF positive cells was higher.The combined infusion of MSC and EPC can promote capillary regeneration, alleviate inflammation and promote lung repair after HSCT, which is superior to single EPC or MSC infusion.间充质干细胞和内皮祖细胞联合输注对造血干细胞移植后损伤肺的影响.探索骨髓间充质干细胞（mesenchymal stem cell，MSC)和内皮祖细胞（endothelial progenitor cell，EPC）联合输注对造血干细胞移植（hematopoietic stem cell transplantation，HSCT）后损伤肺的影响.实验分为正常对照（normal）、单纯照射（TBI）、骨髓细胞移植（BMT）、骨髓移植联合EPC输注（BMT+EPC）、骨髓移植联合MSC输注（BMT+MSC）、骨髓移植联合EPC和MSC输注（BMT+EPC+MSC）共6组，建立HSCT模型，于移植后d 30脱颈处死，取肺组织，待测。RT-PCR检测VEGF，IL-18，IL-12b的mRNA表达水平，Western blot法检测NLRP3蛋白表达水平，HE染色观察肺组织病理学形态，免疫组织化学观察MPO，CD146VEGF基因在BMT+EPC+MSC组的表达水平明显高于其他各组（P＜0.01），而BMT+EPC、BMT+MSC和BMT组基因表达水平相近，且均高于正常对照组（P＜0.05）。IL-18，IL-12b基因的表达水平在BMT组最高，BMT+EPC+MSC组最低，与对照组之间比较差异有统计学意义（P＜0.05）。HSCT能引起NLRP3蛋白表达增高，BMT+EPC+MSC组可明显降低肺细胞NLRP3蛋白水平，趋于正常。与正常组织相比，BMT+EPC+MSC组能更有效地改善肺组织结构，MPO联合输注MSC和EPC能促进HSCT后损伤肺的毛细血管新生，减轻炎症反应，促进肺的修复，优于单一的治疗方法.

Respiratory viruses, including influenza virus, respiratory syncytial virus, coronavirus, etc., have seriously threatened the human health. For example, the outbreak of severe acute respiratory syndrome coronavirus, SARS, affected a large number of countries around the world. Marine organisms, which could produce secondary metabolites with novel structures and abundant biological activities, are an important source for seeking effective drugs against respiratory viruses. This report reviews marine natural products with activities against respiratory viruses, the emphasis of which was put on structures and antiviral activities of these natural products. This review has described 167 marinederived secondary metabolites with activities against respiratory viruses published from 1981 to 2019. Altogether 102 references are cited in this review article.

Objective Fusobacterium nucleatum (F. nucleatum) has been reported to be enriched in patients with inflammatory bowel disease (IBD). This study aimed to explore the role of F. nucleatum in IBD and its pathogenic mechanism. Methods Several bacteria that have been reported to be associated with IBD or colorectal cancer were measured in the fecal samples of 91 patients with IBD and 43 healthy individuals. Mice with dextran sulfate sodium (DSS)-induced colitis and a Caco-2 cell line were used to explore the pathogenicity of F. nucleatum. Barrier damage was evaluated by a transmission electron microscope, the permeability of fluorescein isothiocyanate-dextran, transepithelial electrical resistance and immunofluorescence. Protein levels of the cell-cell junction and activation of the STAT3 signaling pathway were detected by immunohistochemistry and immunoblot. Cytokine secretion and T-cell differentiation were measured by quantitative real-time polymerase chain reaction and flow cytometry. Results F. nucleatum was significantly enriched in the feces of patients with IBD and its abundance correlated with disease activity. Administration of F. nucleatum markedly exacerbated colitis in a DSS mouse model. Mechanistically, F. nucleatum damaged epithelial integrity and increased permeability by regulating the expression and distribution of tight junction proteins zonula occludens-1 and occludin. Moreover, F. nucleatum promoted the secretion of cytokines (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1β, IL-6, and IL-17), activated the STAT3 signaling pathway, and induced CD4+ T cell proliferation and Th1 and Th17 subset differentiations. Conclusion F. nucleatum can damage the intestinal barrier and induce aberrant inflammation, which exacerbates colitis.

BACKGROUND PD-L1 expression on tumor-infiltrating lymphocytes (TILs) has recently been reported as a biomarker for colorectal cancer (CRC). However, the prognostic and clinical significance of PD-L1 on TILs in CRC remains controversial. We performed this meta-analysis to evaluate the association between the PD-L1 expression on TILs and clinicopathological features and prognosis of CRC patients. METHODS A comprehensive literature search for relevant studies published up to Feb 2020 was performed using Medline, Embase, and Web of Science. Odds ratio (OR) with 95% CI was selected to appraise the correlation between PD-L1 expression on TILs with prognostic and clinicopathological characteristics of CRC patients. Begg's and Egger's test were used to assess publication bias. The statistical analysis was conducted using Stata software. RESULTS A total of 19 studies including 5,213 CRC cases were included in this meta-analysis. The pooled results showed that PD-L1 overexpression on TILs was relevant to longer OS (OR = 1.36, 95% CI = 1.19 - 1.55, p < 0.01) and longer DFS/RFS (OR = 1.22, 95% CI = 1.03 - 1.44, p = 0.02). Moreover, CRC patients with high expression of PD-L1 on TILS was associated with lower T stage (OR = 2.30, 95% CI = 1.85 - 2.87, p < 0.01), less lymph node in-vasion (OR = 1.48, 95% CI = 1.03 - 2.13, p = 0.03), less distant metastasis (OR = 2.56, 95% CI = 1.81 - 3.64, p < 0.01), earlier TNM stage (OR = 1.93, 95% CI = 1.34 - 2.66, p < 0.01), later tumor grade (OR = 0.38, 95% CI = 0.23 - 0.62, p < 0.01) and high MSI status (OR = 0.36, 95% CI = 0.25 - 0.52, p < 0.01). But it is not related to tumor size, tumor differentiation, MMR status, BRAF mutant, and KRAS mutant. CONCLUSIONS This meta-analysis revealed that PD-L1 expression on TILs can serve as a significant biomarker for positive prognosis and clinicopathological features of CRC. Our results may provide some useful information when using PD-L1 expression to predict the survival of CRC patients and to select the beneficial CRC patients from PD-1/PD-L1 antibody treatment.

Members of the fungal genus Myrothecium produce structurally unique secondary metabolites, a considerable number of which display promising biological and pharmacological properties. So far, 174 secondary metabolites have been discovered in this genus. This report reviews biologically active secondary metabolites from the fungi Myrothecium spp. with an emphasis on their structures, synthesis, and biological activities.

Although several prognostic signatures have been developed for gastric cancer (GC), the utility of these tools is limited in clinical practice due to lack of validation with large and multiple independent cohorts, or lack of a statistical test to determine the robustness of the predictive models. Here, a prognostic signature was constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression model and a training dataset with 300 GC patients. The signature was verified in three independent datasets with a total of 658 tumors across multiplatforms. A nomogram based on the signature was built to predict disease-free survival (DFS). Based on the LASSO model, we created a GeneExpressScore signature (GESGC ) classifier comprised of eight mRNA. With this classifier patients could be divided into two subgroups with distinctive prognoses [hazard ratio (HR) = 4.00, 95% confidence interval (CI) = 2.41-6.66, P

Objective: The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer. We aimed to explore the mechanical, biological, and clinical role of RNF6 in colorectal cancer initiation and progression. Design: The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real-time PCR, Western blot, and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and in vitro. Role of RNF6 in modulating SHP-1 expression was examined by coimmunoprecipitation and confocal microscopy, respectively. Results: The copy number of RNF6 was significantly amplified in colorectal cancer, and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with patients with colorectal cancer with poor prognosis. The gene set enrichment analysis (GSEA) revealed cell proliferation, and invasion-related genes were enriched in RNF6 high-expressed colorectal cancer cells as well as in patients from TCGA dataset. Downregulation of RNF6 impaired the colorectal cancer cell proliferation and invasion in vitro and in vivo. RNF6 may activate the JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1. Conclusions: Genomic amplification drives RNF6 overexpression in colorectal cancer. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors. Clin Cancer Res; 24(6); 1473–85. ©2017 AACR.

A concise and efficient protocol for the regioselective synthesis of dual 1,4-dihydropyridines with several substituted patterns has been developed from a cascade cyclization of enaminones and aldehydes in different media (EtOH/CH3CN). The one-pot cascade reaction involves at least five reactive sites and generates multiple C–C and C–N bonds. The established protocol explores the chemistry of enaminones by employing their three reactive sites. The method has several advantages including mild conditions, operational simplicity, and high bond-forming efficiency. It may offer promise in a variety of biochemical applications.

Long noncoding RNAs (lncRNAs) contribute to many steps in carcinogenesis and often serve as biomarkers or therapeutic targets for tumor diagnosis and therapy. Although the role of lncRNAs in tumor formation is becoming clear, whether lncRNAs mediate gut microbiota-induced colorectal cancer (CRC) is largely unknown. Enterotoxigenic Bacteroides fragilis (ETBF) is a well-known tumor-inducing bacterium in the human gut; however, its tumorigenic effect remains to be explored. In the present study, we revealed the mechanism by which a lncRNA participates in gut bacteria-induced carcinogenesis: Bacteroides fragilis-associated lncRNA1 (BFAL1) in CRC tissues mediates ETBF carcinogenesis. BFAL1 was highly expressed in CRC tissues compared with that in adjacent normal tissues. In vitro, BFAL1 was upregulated in ETBF-treated CRC cells. Mechanistically, ETBF promoted tumor growth via BFAL1 by activating the Ras homolog, which is the MTORC1 binding/mammalian target of the rapamycin (RHEB/mTOR) pathway. Furthermore, BFAL1 regulated RHEB expression by competitively sponging microRNAs miR-155-5p and miR-200a-3p. Clinically, both high expression of BFAL1 and high abundance of ETBF in CRC tissues predicted poor outcomes for patients with CRC. Thus, BFAL1 is a mediator of ETBF-induced carcinogenesis and may be a potential therapeutic target for ETBF-induced CRC.

One-third of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis. The prognosis of these patients is poor. To identify potential prognostic biomarkers and therapeutic targets for ccRCC, we re-evaluated published long non-coding RNA (lncRNA) expression profiling data from the Gene Expression Omnibus and ArrayExpress database. We found that five lncRNAs were differentially expressed in ccRCC and adjacent tissues. These lncRNAs were assessed in an independent cohort of 71 paired patient samples using real-time PCR. Differences in expression of three of the lncRNAs (ENSG00000177133, TCL6, and ENSG00000244020) were validated in this analysis. Kaplan-Meier analysis indicated that low expression of ENSG00000177133 and TCL6 was associated with a poor prognosis. Univariate and multivariate regression analyses demonstrated that TCL6 but not ENSG00000177133 expression was an independent predictor of ccRCC aggressiveness and had hazard ratios predictive of clinical outcome. TCL6 expression was negatively correlated with pTNM stage. Overexpression of TCL6 in 786-O and Caki-1 ccRCC cells decreased proliferation and increased apoptosis compared to controls. Our results indicate that lncRNA expression is altered in ccRCC and that decreased TCL6 expression may be an independent adverse prognostic factor in ccRCC patients.

Nine new diterpenoids, Rubellacrns A − I (1–9), including five isopimaranes (1–4, 9), four pimaranes (5–8), together with five known isopimarane analogues (10–14), were isolated from Callicarpa rubella. The structures of these compounds were unambiguously established by HR-ESIMS and NMR spectroscopic data, the absolute configurations of compounds 5 and 9 were determined by ECD. All the isolated compounds were tested for their anti-inflammatory effects and compounds 2 and 11–14 showed NLRP3-inflammasome inhibitory activity with IC50 values ranging from 7.02 to 14.38 μM.

Citrinin dimeric derivatives are bioactive polyketides previously reported from Penicillium, Aspergillus and Monascus fungi species. Due to the large distance between the stereogenic centers of the two monomer units, it was difficult to determine the absolute configuration of the whole molecule (1). In previous work, the absolute configuration of 1 was just proposed by biogenetic considerations. To address this problem, the experimental VCD of 1 was compared with the corresponding DFT calculations for two diastereomers (1a and 1b). Also, the experimental ECD and NMR spectra of 1 were combined for analysis with the corresponding theoretical predictions for different diastereomers. Additionally, compound 1 showed promising anti-Vibrio activity against pathogenic Vibrio spp. with MIC values ranging from 0.4 to 0.8 μM.

// Ya-Nan Yu 1, 2, * , Ta-Chung Yu 1, * , Hui-Jun Zhao 1 , Tian-Tian Sun 1 , Hui-Min Chen 1 , Hao-Yan Chen 1 , Hui-Fang An 3 , Yu-Rong Weng 1 , Jun Yu 4 , Min Li 5 , Wen-Xin Qin 6 , Xiong Ma 1 , Nan Shen 7 , Jie Hong 1 , Jing-Yuan Fang 1 1 State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China 2 Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China 3 Shanghai Majorbio Bio-pharm Biotechnology Co. Ltd., Shanghai, China 4 Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong 5 Department of Clinical Laboratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 6 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China 7 Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China Correspondence to: Jing-Yuan Fang, e-mail: jingyuanfang@sjtu.edu.cn Jie Hong, e-mail: jiehong97@gmail.com Keywords: colorectal tumorigenesis, intestinal microbiota, Fusobacterium nucleatum, berberine, tumor-immune cytokine Received: May 20, 2015 Accepted: August 31, 2015 Published: September 12, 2015 ABSTRACT Background: Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated. Methods: 454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting. Results: The levels of opportunistic pathogens, such as Fusobacterium , Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) ( P < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. nucleatum -mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p -STAT3, p -STAT5 and p -ERK1/2 in mice, compared with mice fed with F. nucleatum alone. Conclusions: F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum -induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways.

In this paper, we apply outer synchronization to identify unknown parameters existing in the node dynamics between two interacted networks. According to the coupling and interacted matrices, we design the corresponding adaptive control schemes and updating laws to achieve the outer synchronization. By the Lyapunov functional theory, we derive two theorems of the appearance of outer synchronization. Finally we provide numerical simulations to demonstrate the validity of our theoretical results and show the process of outer synchronization and the identification of unknown parameters.

Objectives Proton pump inhibitors (PPIs) have been used for treatment of Barrett's esophagus (BE) for many years. However, the connection between PPIs and esophageal adenocarcinoma (EAC) in patients with BE has still been controversial. The current systematic review and meta-analysis was designed to evaluate the association between PPIs and the risk of EAC or high-grade dysplasia (HGD) in patients with BE. Methods A systematic literature search of studies reporting the association between PPIs and the risk of EAC and/or HGD in patients with BE was conducted in PubMed, Embase, Web of Science and the Cochrane Library. Next, literature was screened using previously established criteria and relevant data were extracted from included studies. Finally, the software program Review Manage 5.2 was applied to aggregate data and analyze the results. Results Nine observational studies, comprising five cohort and four case-control studies (including a total of 5712 patients with BE), were identified. Upon meta-analysis, PPIs were found to have no association with the risk of EAC and/or HGD in patients with BE (unadjusted OR 0.43, 95% CI 0.17–1.08). Analysis for duration response relationship revealed no significant trend toward protection against EAC or HGD with PPIs usage for >2~3 years (one study using 7-year cutoff) when compared to usage for shorter time periods (PPIs usage >2~3 years vs.