Anti-MRC1 monoclonal antibody, clone MR5D3 [FITC]

Organ allografts deficient in interferon-gamma (Ifng) or major histocompatibility complex (MHC) class I products develop accelerated necrosis when rejection develops, depending on perforin and granzymes. Thus Ifng-induced donor class I products deliver inhibitory signals to host inflammatory cells. We used microarrays to investigate whether Ifng-induced donor class I products also control inflammation patterns in mouse kidney allografts. Compared to wild-type (WT) allografts, many transcripts were increased in both Ifng-deficient allografts (Ifng-suppressed transcripts [GSTs]) and class I-deficient allografts (class I-suppressed transcripts [CISTs]), with 73% overlap between GSTs and CISTs. Some GSTs and CISTs reflected increased necrosis, including known injury-induced transcripts. However, many GSTs and CISTs were independent of perforin, granzymes and necrosis, and were associated with alternative macrophage activation (AMA) (e.g. arginase I [Arg1], macrophage elastase [Mmp12] and macrophage mannose receptor 1 [Mrc1]). AMA transcripts were induced despite absence of host interleukin (IL)4 and IL13 receptors. The AMA inducer may be activins, whose genes (inhibin A [InhbA] and inhibin B [InhbB]) were increased in all allografts with AMA. We conclude that in allograft rejection, Ifng acts via donor Ifng receptors (Ifngr) to induce donor class Ia and Ib products, which engage host inflammatory cells to limit perforin-granzyme-mediated damage and prevent AMA associated with inhibition of activin expression. Thus, Ifng may control T helper type 2 (Th2) cell inflammation by induction of class I products.

Background Muscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice. Methods This study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways. Results In the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC. Conclusions In summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.