Hepatitis B virus (HBV) infection substantially increases the risk of chronic liver disease and hepatocellular carcinoma in humans. RNA interference (RNAi) of virus-specific genes has emerged as a potential antiviral mechanism. Here we show that RNAi can be applied to inhibit production of HBV replicative intermediates in cell culture and in immunocompetent and immunodeficient mice transfected with an HBV plasmid. Cotransfection with plasmids expressing short hairpin RNAs (shRNAs) homologous to HBV mRNAs induced an RNAi response. Northern and Southern analyses of mouse liver RNA and DNA showed substantially reduced levels of HBV RNAs and replicated HBV genomes upon RNAi treatment. Secreted HBV surface antigen (HBsAg) was reduced by 94.2% in cell culture and 84.5% in mouse serum, whereas immunohistochemical detection of HBV core antigen (HBcAg) revealed >99% reduction in stained hepatocytes upon RNAi treatment. Thus, RNAi effectively inhibited replication initiation in cultured cells and mammalian liver, showing that such an approach could be useful in the treatment of viral diseases.

Inhibition of hepatitis B virus in mice by RNA interference

The IL-33/ST2 axis: Role in health and disease.

Mesenchymal Stromal Cells (MSCs) are potential cellular candidates for several immunotherapy purposes. Their multilineage potential and immunomodulatory properties make them interesting tools for the treatment of various immunological diseases. However, depending on the local microenvironment, diverse biological functions of MSCs can be modulated. Indeed, during infections such as obtained following TLR-agonist engagement (called as TLR priming), the phenotype, multilineage potential, hematopoietic support and immunomodulatory capacity of MSCs can present critical changes, which could further affect their therapeutic potential. Thus, for appropriate clinical application of MSCs, it is important to well know and understand these effects in particular during infectious episodes and to find the suitable experimental settings to study that. Pre-stimulation of MSCs with a specific TLR ligand may serve as an effective priming step to modulate one of its function to achieve a desired therapeutic issue.

/pdf/mesenchymal-stromal-cells-and-toll-like-receptor-priming-a-477qdsnir6.pdf

Mesenchymal Stromal Cells and Toll-Like Receptor Priming: A Critical Review.

BACKGROUND
Colorectal cancer is the third most diagnosed cancer in adults in the United States. Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality.


METHODS
We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions.


RESULTS
The clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3). Sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3). A total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3). Specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7).


CONCLUSIONS
In an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. (Funded by Guardant Health; ECLIPSE ClinicalTrials.gov number, NCT04136002.).

A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening.

Toll-like receptors as a key regulator of mesenchymal stem cell function: An up-to-date review

The roles of carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21-1) and neuron-specific enolase (NSE) in metastases occurrence and poor diagnosis in specific histological classifications of lung cancer need further exploring. In this study, we investigated relationship between elevated levels of three biomarkers of CEA, CYFRA21-1 and NSE (individually and in combination) and metastasis, survival status and prognosis in lung cancer patients. Eight hundred and sixty eight lung cancer patients including adenocarcinoma (ADC, N = 445), squamous cell carcinoma (SCC, N = 215), small cell lung cancer (SCLC, N = 159) and other types (N = 49) were categorized into negative, moderate and high groups according to serum levels of biomarkers, and were then categorized into negative, single, double and triple groups according to any positive combination of three biomarkers. The cutoff values of three biomarkers for groupings were developed on the training group (N = 432) and verified in a validation group (N = 436). Clinical and laboratory characteristics were then assessed for correlation with occurrence of metastasis, survival status and prognosis between the two groups. Further correlation analyses were also conducted by different subtypes (ADC, SCC and SCLC) and tumor stages (I + II, III and IV) of lung cancers. The consistent results between training and validation group confirmed the rationality of grouping methods. CYFRA21-1 levels had stronger association with metastases and survival status than CEA and NSE in all lung cancer patients. When stratified by subtypes, these significances only existed in ADC patients for CYFRA21-1. Cox regression analyses showed that CYFRA21-1 and NSE were independent prognostic factors for lung cancer patients. However, only CYFRA21-1 was an independent prognostic factor in ADC and SCLC patients subtypes. Cox-regression results also indicated that CYFRA21-1 could act as independent prognostic factor in different stages (I + II, III and IV) of lung cancer. CYFRA21-1 was more important in metastasis occurrence and in predicting poor prognosis in lung cancer patients than CEA, NSE and positive numbers of biomarkers.

/pdf/the-important-role-of-circulating-cyfra21-1-in-metastasis-3licwkbcuo.pdf

The important role of circulating CYFRA21-1 in metastasis diagnosis and prognostic value compared with carcinoembryonic antigen and neuron-specific enolase in lung cancer patients.

Mesenchymal stem cells (MSCs) have been applied to cell-based therapy due to their multiple differentiation ability, the low expression of co-stimulatory molecules and immunosuppressive properties. Despite their immunomodulatory role, the issue of the survival and permanence of MSCs at the site of injury has not yet been fully resolved. Therefore, in order to improve the therapeutic potential of MSCs, it is important to study the mechanisms mediating the relative instability of MSCs in clinical trials. The Toll-like receptors (TLRs) are an important component of innate and adaptive immune responses. In this study, we demonstrate that the activation of two TLRs, namely TLR3 and TLR4, in human umbilical cord-derived MSCs (UCMSCs) induces the expression of inflammatory markers. In addition, as shown by our results, TLR3 upregulated the expression of stem cell markers, while TLR4 downregulated their expression. The upregulation in the expression of the inflammatory markers did not alter the immune status of the UCMSCs or mediate the immune attack of the MSCs by allogeneic immune cells. We found that the activation of TLR3 inhibited the differentiation of UCMSCs into osteocytes, while that of TLR4 increased this differentiation to a certain extent. Taken together, the results of this study provide a new role for TLR3 and TLR4 as regulators of the biological functions of UCMSCs.

/pdf/the-role-of-toll-like-receptor-3-and-4-in-regulating-the-1jokq0elfk.pdf

The role of Toll-like receptor 3 and 4 in regulating the function of mesenchymal stem cells isolated from umbilical cord.

Mesenchymal stem cells (MSCs) are considered the best candidate in stem cells therapy due to their multipotent differentiation ability, low expression of co-stimulatory molecules (CD80, CD86, CD34 and HLA-II) and immunosuppression effects on in vivo immune responses. MSCs were now widely used in clinical trials but received no encourage results. The major problem was the fate of engrafted MSCs in vivo could not be defined. Some studies indicated that MSCs could induce immune response and result in the damage and rejection of MSCs. As toll like receptors (TLRs) are important in inducing of immune responses, in this study we study the role of TLR7 in mediating the immune status of MSCs isolated from umbilical cord. Our results indicated that TLR7 agonist Imiquimod could increase the proliferation of PBMC isolated from healthy human volunteers and release of lactate dehydrogenase (LDH) in supernatant from PBMC-UCMSCs co-culture system. Flow cytometry and quantitative PCR also confirmed the regulated expression of surface co-stimulatory molecules and pro-inflammatory genes (IL-6, IL-8, IL-12, TGF-β and TNF-α). And the down-regulation expression of stem cell markers also confirmed the loss of stemness of UCMSCs. We also found that the osteo-differentiation ability of UCMSCs was enhanced in the presence of Imiquimod. To our knowledge, this is the first report that activation of TLR7 pathway increases the immunogenicity of UCMSCs. Extensive researches have now been conducted to study whether the change of immune status will be help in tumor rejection based on the tumor-tropism of MSCs.

/pdf/the-tlr7-agonist-imiquimod-promote-the-immunogenicity-of-1kold26nca.pdf

The TLR7 agonist Imiquimod promote the immunogenicity of msenchymal stem cells

Purpose: To investigate the association of IL-17F rs763780T>C with cancer risk. Materials and Methods: We searched the Cochrane Central Library, PubMed, MEDLINE, EMBASE, CNKI (China National Knowledge Infrastructure) and WangFang databases until May 2014 for a meta-analysis conducted using RevMan 5.2 software. Results: A total of ten papers were included into this meta analysis, involving 3, 336 cases and 4, 217 healthy people. There were no significant differences on association of IL-17F rs763780T>C polymorphism with cancer risk except in the CC vs TT genetic model. Although the the risk in the gastric cancer group is higher than that in control group, there were no significant differences on the association of IL-17F rs763780T>C polymorphism with other cancers. Conclusions: Our meta analysis reveal the IL-17A rs763780T>C gene polymorphism is involved in risk of gastric cancer but not other tumor types.

http://koreascience.or.kr:80/article/JAKO201435053629063.pdf

Meta Analysis of Association of the IL-17F rs763780T>C Gene Polymorphism with Cancer Risk

Background: Preliminary studies indicate a relative link between the expression of heterogeneous nuclear ribonucleoproteins (hnRNPs) and cancer. Overexpression of hnRNP B1 correlated with the eventual development of lung cancer. Here we describe inhibition of HnRNP B1 replication in human lung cell line A549 by siRNAs targeted to various regions of hnRNP B1 sequences. Methods: Small interfering RNA technique was used to interfer the expression of hnRNPB1 in Lung Cell Line A549 in vitro; the RT-PCR and Western blot technique were used to detect the quantity of hnRNPB1 mRNA and its protein; flow cytometry was used to detect the apoptosis; then the cells were transfected to nude mice. Results: We demonstrated that plasmidderived siRNAs could inhibit hnRNP B1 mRNA and protein expression, and the siRNA expressed from activated plasmid in A549 cells could suppress the cell proliferation by increasing the G1 cells. Our experiment also found that siRNA could induce apoptosis. Conclusions: These results demonstrated the effectiveness of siRNA in lung cancer cells, which indicated a possible clinical therapy method for lung cancer development.

/pdf/the-expression-inhibition-of-hnrnp-b1-in-lung-cell-line-a549-3cqfl1fvkx.pdf

The Expression Inhibition of HnRNP B1 in Lung Cell Line A549 by Small Interfering RNA

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