Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes; however, few have been identified that regulate immune cell differentiation and function. Here, we identified lnc-DC, which was exclusively expressed in human conventional dendritic cells (DCs). Knockdown of lnc-DC impaired DC differentiation from human monocytes in vitro and from mouse bone marrow cells in vivo and reduced capacity of DCs to stimulate T cell activation. lnc-DC mediated these effects by activating the transcription factor STAT3 (signal transducer and activator of transcription 3). lnc-DC bound directly to STAT3 in the cytoplasm, which promoted STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding to and dephosphorylation by SHP1. Our work identifies a lncRNA that regulates DC differentiation and also broadens the known mechanisms of lncRNA action.

The pre-metastatic niche educated by primary tumor-derived elements contributes to cancer metastasis. However, the role of host stromal cells in metastatic niche formation and organ-specific metastatic tropism is not clearly defined. Here, we demonstrate that lung epithelial cells are critical for initiating neutrophil recruitment and lung metastatic niche formation by sensing tumor exosomal RNAs via Toll-like receptor 3 (TLR3). TLR3-deficient mice show reduced lung metastasis in the spontaneous metastatic models. Mechanistically, primary tumor-derived exosomal RNAs, which are enriched in small nuclear RNAs, activate TLR3 in lung epithelial cells, consequently inducing chemokine secretion in the lung and promoting neutrophil recruitment. Identification of metastatic axis of tumor exosomal RNAs and host lung epithelial cell TLR3 activation provides potential targets to control cancer metastasis to the lung.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC‐induced immunosuppression often leads to ineffectiveness of immuno‐promoting therapies. Currently, suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here, we identified one new subset of human CD14+CTLA‐4+ regulatory dendritic cells (CD14+DCs) in HCC patients, representing ∼13% of peripheral blood mononuclear cells. CD14+DCs significantly suppress T‐cell response in vitro through interleukin (IL)‐10 and indoleamine‐2,3‐dioxygenase (IDO). Unexpectedly, CD14+DCs expressed high levels of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and programmed death‐1, and CTLA‐4 was found to be essential to IL‐10 and IDO production. So, we identified a novel human tumor‐induced regulatory DC subset, which suppresses antitumor immune response through CTLA‐4‐dependent IL‐10 and IDO production, thus indicating the important role of nonregulatory T‐cell‐derived CTLA‐4 in tumor‐immune escape or immunosuppression. Conclusions: These data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14+DCs, which may contribute to HCC progression. This adds new insight to the mechanism for HCC‐induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC. (Hepatology 2014;59:567–579)

Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119CD45CD71 phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor β (TGF-β) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.

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As semiconductor devices scale to new dimensions, the materials and designs become more dependent on atomic details. NEMO5 is a nanoelectronics modeling package designed for comprehending the critical multi-scale, multi-physics phenomena through efficient computational approaches and quantitatively modeling new generations of nanoelectronic devices as well as predicting novel device architectures and phenomena. This article seeks to provide updates on the current status of the tool and new functionality, including advances in quantum transport simulations and with materials such as metals, topological insulators, and piezoelectrics.

The ever-improving technology to generate induced pluripotent stem cells (iPSCs) has increased their potential use as novel candidates for disease modeling, drug screening, regenerative medicine and cell therapy. Indeed, iPSCs offer extensive capacity for self-renewal without the ethical concerns faced by embryonic stem cells (ESCs). With respect to potential applications in the immune system, many studies provide evidence to support that there are exclusive advantages to using iPSCs over other systems. Both hematopoietic stem cells and several types of mature immune cells have successfully been reprogrammed to iPSCs and vice versa, paving a path toward our ability to effectively model patient-specific diseases and provide potentially alternative cell sources for transfusion medicine. Despite these potential advances, some limitations regarding the use of iPSCs in the clinic still remain, including the immunogenicity of iPSCs and their derivatives, which is currently under debate in the field. In this review, we mainly focus on discussing the recent progress being made in the latest differentiation methods and clinical implications of iPSCs with respect to the immune system. Additionally, current issues regarding the clinical application of iPSCs are addressed, especially the controversy surrounding immunogenicity, along with various other perspectives.

We introduce Uncertain Natural Language Inference (UNLI), a refinement of Natural Language Inference (NLI) that shifts away from categorical labels, targeting instead the direct prediction of subjective probability assessments. We demonstrate the feasibility of collecting annotations for UNLI by relabeling a portion of the SNLI dataset under a probabilistic scale, where items even with the same categorical label differ in how likely people judge them to be true given a premise. We describe a direct scalar regression modeling approach, and find that existing categorically labeled NLI data can be used in pre-training. Our best models approach human performance, demonstrating models may be capable of more subtle inferences than the categorical bin assignment employed in current NLI tasks.