To determine the expression of components in Toll-like receptors (TLRs)/Nod-like receptors (NLRs)/ infiammasome/caspase-llinterleukin (IL-l)-P pathway, we examined the expression profiles of those genes by analyzing the data from expression sequence tag cDNA cloning and sequencing. We made several important findings: firstly, among 11 tissues examined, vascular tissues and heart express fewer types of TLRs and NLRs than immune and defense tissues including blood, lymph nodes, thymus and trachea; secondly, brain, lymph nodes and thymus do not express proinflammatory cytokines IL-IP and IL-18 constitutively, suggesting that these two cytokines need to be up regulated in the tissues; and thirdly, based on the expression data of three characterized inflammasomes (NALPl, NALP3 and IPAF inflammasome), the examined tissues can be classified into three tiers: the first tier tissues including brain, placenta, blood and thymus express inflammasome(s) in constitutive status; the second tier tissues have inflammasome(s) in nearly-ready expression status (with the requirement of upregulation of one component); the third tier tissues, like heart and bone marrow, require upregulation of at least two components in order to assemble functional inflammasomes. Our original model of three-tier expression of inflammasomes would suggest a new concept oftissue inflammation privilege, and provides an insight to the differences among tissues in initiating acute inflammation in response to stimuli.

Serum and plasma contain abundant biological information that reflect the body's physiological and pathological conditions and are therefore a valuable sample type for disease biomarkers. However, comprehensive profiling of the serological proteome is challenging due to the wide range of protein concentrations in serum. Methods : To address this challenge, we developed a novel in-depth serum proteomics platform capable of analyzing the serum proteome across ~10 orders or magnitude by combining data obtained from Data Independent Acquisition Mass Spectrometry (DIA-MS) and customizable antibody microarrays. Results : Using psoriasis as a proof-of-concept disease model, we screened 50 serum proteomes from healthy controls and psoriasis patients before and after treatment with traditional Chinese medicine (YinXieLing) on our in-depth serum proteomics platform. We identified 106 differentially-expressed proteins in psoriasis patients involved in psoriasis-relevant biological processes, such as blood coagulation, inflammation, apoptosis and angiogenesis signaling pathways. In addition, unbiased clustering and principle component analysis revealed 58 proteins discriminating healthy volunteers from psoriasis patients and 12 proteins distinguishing responders from non-responders to YinXieLing. To further demonstrate the clinical utility of our platform, we performed correlation analyses between serum proteomes and psoriasis activity and found a positive association between the psoriasis area and severity index (PASI) score with three serum proteins (PI3, CCL22, IL-12B). Conclusion : Taken together, these results demonstrate the clinical utility of our in-depth serum proteomics platform to identify specific diagnostic and predictive biomarkers of psoriasis and other immune-mediated diseases.

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PurposeColorectal cancer (CRC) is one of the most common malignant tumors worldwide. This study aimed to explore the prognostic value of lncRNAs in CRC.Material and methodsWe performed gene expression profiling to identify differentially expressed lncRNAs between 51 normal and 646 tumor tissues from The Cancer Genome Atlas database. Cox regression and robust likelihood-based survival models were used to find prognosis-related lncRNAs. A lncRNA signature was developed to predict the overall survival of patients with CRC. In addition, a receiver operating characteristic curve analysis was performed to identify the optimal cutoff with the best Youden index to divide patients into different groups based on risk level.ResultsEighty survival-related lncRNAs were identified and a 15-lncRNA signature was developed on the basis of a risk score to comprehensively predict the overall survival of patients with CRC. The prognostic value of the 15-lncRNA risk score was validated using the internal testing set and total set. The risk indicator was shown to be an independent prognostic factor (hazard ratio =2.92; 95% CI: 1.73–4.94; P<0.001). Notably, all 15 lncRNAs (AC024581.1, FOXD3-AS1, AC012531.1, AC003101.2, LINC01219, AC083967.1, AL590483.1, AC105118.1, AC010789.1, AC067930.5, AC105219.2, LINC01354, LINC02474, LINC02257, and AC079612.1) were newly found to correlate with the prognosis of patients with CRC. Furthermore, the function of 15 lncRNAs was explored through the ceRNA network. These lncRNAs regulated coding genes that were involved in many key cancer pathways.ConclusionA 15-lncRNA expression signature was discovered as a prognostic indicator for patients with CRC, which may act as competing endogenous RNA (ceRNAs) to play a crucial role in the modulation of cancer-related pathways. These findings may allow a better understanding of the prognostic value of lncRNAs.

A model adjusted for reference arm response rates was found to fit clinical trial data significantly better than unadjusted models.

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Xenoantibody production directed at a wide variety of T lymphocyte-dependent and T lymphocyte-independent xenoantigens remains the major immunologic obstacle for successful xenotransplantation. The B lymphocyte subpopulations and their helper factors, involved in T-cellindependent xenoantibody production are only partially understood, and their identification will contribute to the clinical applicability of xenotransplantation. Here we show, using models involving T-celldeficient athymic recipient mice, that rapidly induced, T-cell-independent xenoantibody production is mediated by marginal zone B lymphocytes and requires help from natural killer ( IntroductionSuccessful xenotransplantation may alleviate the ever-increasing need for donor organs, but severe immunologic barriers, of which xenoreactive antibodies represent the most important 1, still hamper (pre)clinical application. Pigs are now generally considered the most suitable organ donors for clinical xenotransplantation, 1 but transplantation of pig organs into nonhuman primates, currently constituting the best validated preclinical model, leads to xenograft rejection within a few hours. This hyperacute rejection is mediated by pre-existing, so-called "natural antibodies," which are directed at a specific Gal␣1,3Gal␤1,4GlcNAc (Gal) oligosaccharide, that is present on (especially endothelial) proteins of most lower animal species, but not of nonhuman primates or man. [2][3][4] Anti-Gal natural antibodies can rapidly activate the complement system of the recipient, leading to hyperacute rejection. 5 Several procedures have been explored in recent years to solve the problem of hyperacute rejection. 6,7 The most appealing ones were the development of genetically modified donor pig strains that either expressed transgenes of human complement regulatory proteins, able to interfere with complement activation, 8 or that lacked the ␣1,3-galactosyltransferase gene to synthesise ␣Gal. 9,10 The latter pig strain seemed particularly attractive, as Gal antigens had been found to be also strongly involved in acute vascular xenograft rejection, a second type of xenograft rejection that develops within a few days in situations where hyperacute rejection is prevented. 7,11 It was hoped, therefore, that elimination of Gal epitopes would prevent both hyperacute rejection and acute vascular rejection.A number of recent reports on the transplantation of ␣1,3-galactosyltransferase-ko pig kidney or heart grafts in nonhuman primates have shown that loss of Gal expression in donor pig organs could indeed prevent hyperacute rejection, but that T-celldependent IgG xenoantibodies were induced against non-Gal xenoantigens, unless a treatment regimen was used that resulted in specific T-cell xenotolerance. [12][13][14] In the latter case, long-term functional renal xenograft survival was obtained, but after a few months, mild focal thrombotic microangiopathy was observed, suggesting that additional modifications to the treatment regimen are needed to permit the development of the kin...

Viral myocarditis (VMC) is a common cardiovascular disease, and microRNAs (miRNAs) have been postulated to be involved in its pathology. Using microarrays, we observed that miRNA-21 and -146b were upregulated in a murine model of VMC. We also found that miRNA-451 was downregulated. In vivo silencing of miRNA-21 and -146b resulted in less-severe VMC. Overexpression of miRNA-451 did not ameliorate the severity of VMC. Further work revealed that inhibition of miRNA-21 and -146b decreased the expression levels of Th17 and RORγt . Overexpression of miRNA-451 had no effect on IL-17 and RORγt expression. Inhibition of miRNA-21 and -146b might ameliorate myocardium inflammation by mediating downregulation of RORγt expression, indicating that these miRNAs are involved in the pathogenesis of murine VMC.