Exosomes, which are nanosized endocytic vesicles that are secreted by most cells, contain an abundant cargo of different RNA species that can modulate the behavior of recipient cells and may be used as circulating biomarkers for diseases. Here, we develop a web-accessible database (http://www.exoRBase.org), exoRBase, which is a repository of circular RNA (circRNA), long non-coding RNA (lncRNA) and messenger RNA (mRNA) derived from RNA-seq data analyses of human blood exosomes. Experimental validations from the published literature are also included. exoRBase features the integration and visualization of RNA expression profiles based on normalized RNA-seq data spanning both normal individuals and patients with different diseases. exoRBase aims to collect and characterize all long RNA species in human blood exosomes. The first release of exoRBase contains 58 330 circRNAs, 15 501 lncRNAs and 18 333 mRNAs. The annotation, expression level and possible original tissues are provided. exoRBase will aid researchers in identifying molecular signatures in blood exosomes and will trigger new exosomal biomarker discovery and functional implication for human diseases.

BaCKgRoUND aND aIMS: Cancer-associated fibroblasts (CAFs) are key players in multicellular, stromal-dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor-associated neutrophils (TANs) during different stages of HCC pathogenesis. appRoaCH aND ReSUltS: In the HCC-TME, CAFderived cardiotrophin-like cytokine factor 1 (CLCF1) increased chemokine (C-X-C motif ) ligand 6 (CXCL6) and TGFβ secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGFβ secreted by HCC cells activated extracellular signal-regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1-mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up-regulation of the CLCF1−CXCL6/TGFβ axis exhibited a marked correlation with increased cancer stem cells, "N2"-polarized TANs, tumor stage, and poor prognosis. CoNClUSIoNS:This study reveals a cytokine-mediated cellular crosstalk and clinical network involving the CLCF1− CXCL6/TGFβ axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC. (Hepatology 2021;73:1717-1735. M ore than 80% of HCCs are characterized by extensive liver fibrosis caused by the activation, proliferation, and accumulation of fibroblasts. (1) A hallmark feature of the tumor microenvironment (TME) of HCC is the mass of cancer-associated fibroblasts (CAFs), which has been extensively reported to influence HCC progression. (1)

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Cytokines are small proteins that have an essential role in the immune and inflammatory responses. The repertoire of cytokines is becoming diverse and expanding. Here we report the identification and characterization of a novel cytokine designated as chemokine-like factor 1 (CKLF1). The full-length cDNA of CKLF1 is 530 bp long and a single open reading frame encoding 99 amino acid residues. CKLF1 bears no significant similarity to any other known cytokine in its amino acid sequence. Expression of CKLF1 can be partly inhibited by interleukin 10 in PHA-stimulated U937 cells. Recombinant CKLF1 is a potent chemoattractant for neutrophils, monocytes and lymphocytes; moreover, it can stimulate the proliferation of murine skeletal muscle cells. These results suggest that CKLF1 might have important roles in inflammation and in the regeneration of skeletal muscle.

Programmed Cell Death-1 (PD-1)3 is responsible for T cell exhaustion during chronic viral infections and is expressed on a variety of immune cells following activation. Despite its importance, the mechanisms that regulate PD-1 in cell types other than CD8 T cells are poorly defined. Here, the molecular mechanism(s) for inducing PD-1 expression in CD4 T cells, macrophages, and B cells was explored. In CD4 T cells, PD-1 induction following TCR stimulation required NFAT, as the Calcineurin/NFAT pathway inhibitor cyclosporine A (CsA) was able to block PD-1 induction in a manner similar to that seen in CD8 T cells. By contrast, LPS but not PMA and Ionomycin stimulation was able to induce PD-1 expression in macrophages in a manner insensitive to CsA-mediated inhibition. B cells could use both pathways, although the levels of PD-1 expression were highest with PMA and Ionomycin. NF-κB binding site located upstream of the gene in Conserved Region-C was required for NF-κB dependent PD-1 gene activation in macrophages. Chromatin immunoprecipitation showed NF-κB p65 binding to this region following stimulation of macrophages with LPS. PD-1 induction was associated with histone modifications characteristic of accessible chromatin; however, in contrast to CD8 T cells, Conserved Region B in macrophages did not lose CpG methylation upon stimulation and PD-1 expression. The linkage of TLR / NF-κB signaling to the induction of PD-1 suggest the possibility of an opportunistic advantage to microbial infections in manipulating immune inhibitory responses.