HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via Induction.

The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in downregulation.

Precision medicine and lymphoma.

Purpose Of Review: The treatment of the germinal center lymphomas, diffuse large B cell (DLBCL) and follicular lymphoma, has changed little beyond the introduction of immunochemotherapies. However, there exists a substantial group of patients within both diseases for which improvements in care will involve appropriate tailoring of treatment.

Recent Findings: DLBCL consists of two major subtypes with striking differences in their clinical outcomes paralleling their underlying genetic heterogeneity.

Catalog of Differentially Expressed Long Non-Coding RNA following Activation of Human and Mouse Innate Immune Response.

Despite increasing evidence to indicate that long non-coding RNAs (lncRNAs) are novel regulators of immunity, there has been no systematic attempt to identify and characterize the lncRNAs whose expression is changed following the induction of the innate immune response. To address this issue, we have employed next-generation sequencing data to determine the changes in the lncRNA profile in four human (monocytes, macrophages, epithelium, and chondrocytes) and four mouse cell types (RAW 264.7 macrophages, bone marrow-derived macrophages, peritoneal macrophages, and splenic dendritic cells) following exposure to the pro-inflammatory mediators, lipopolysaccharides (LPS), or interleukin-1β.

Transcriptional profiling identifies differential expression of long non-coding RNAs in Jo-1 associated and inclusion body myositis.

Myositis is characterised by muscle inflammation and weakness. Although generally thought to be driven by a systemic autoimmune response, increasing evidence suggests that intrinsic changes in the muscle might also contribute to the pathogenesis. Long non-coding RNAs (lncRNAs) are a family of novel genes that regulate gene transcription and translation.

Follicular lymphoma, a B cell malignancy addicted to epigenetic mutations.

While follicular lymphoma (FL) is exquisitely responsive to immuno-chemotherapy, many patients follow a relapsing remitting clinical course driven in part by a common precursor cell (CPC) population. Advances in next generation sequencing have provided valuable insights into the genetic landscape of FL and its clonal evolution in response to therapy, implicating perturbations of epigenetic regulators as a hallmark of the disease. Recurrent mutations of histone modifiers KMT2D, CREBBP, EP300, EZH2, ARIDIA, and linker histones are likely early events arising in the CPC pool, rendering epigenetic based therapies conceptually attractive for treatment of indolent and transformed FL.

Knockdown of Nuclear-Located Enhancer RNAs and Long ncRNAs Using Locked Nucleic Acid GapmeRs.

The human genome is widely transcribed outside of protein-coding genes, producing thousands of noncoding RNAs from different subfamilies including enhancer RNAs. Functional studies to determine the role of individual genes are challenging with noncoding RNAs appearing to be more difficult to knockdown than mRNAs. One factor that may have hindered progress is that the majority of noncoding RNAs are thought to be located within the nucleus, where the efficiency of traditional RNA interference techniques is debatable.

Reduced Expression of Histone Methyltransferases KMT2C and KMT2D Correlates with Improved Outcome in Pancreatic Ductal Adenocarcinoma.

Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.

Long Intergenic Noncoding RNAs Mediate the Human Chondrocyte Inflammatory Response and Are Differentially Expressed in Osteoarthritis Cartilage.

Objective: To identify long noncoding RNAs (lncRNAs), including long intergenic noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes, associated with the inflammatory response in human primary osteoarthritis (OA) chondrocytes and to explore their expression and function in OA.

Methods: OA cartilage was obtained from patients with hip or knee OA following joint replacement surgery. Non-OA cartilage was obtained from postmortem donors and patients with fracture of the neck of the femur.

Divergent signalling pathways regulate lipopolysaccharide-induced eRNA expression in human monocytic THP1 cells.

Recent studies have indicated that non-coding RNAs transcribed from enhancer regions are important regulators of enhancer function and gene expression. In this report, we have characterised the expression of six enhancer RNAs (eRNAs) induced in human monocytic THP1 cells following activation of the innate immune response by lipopolysaccharide (LPS). Specifically, we have demonstrated that LPS-induced expression of individual eRNAs is mediated through divergent intracellular signalling pathways that includes NF-κB and the mitogen activated protein kinases, extracellular regulated kinase-1/2 and p38.

Long non-coding RNAs in the regulation of the immune response.

It is increasingly clear that long non-coding RNAs (lncRNAs) regulate a variety biological responses, and that they do so by a diverse range of mechanisms. In the field of immunology, recent publications have shown widespread changes in the expression of lncRNAs during the activation of the innate immune response and T cell development, differentiation, and activation. These lncRNAs control important aspects of immunity such as production of inflammatory mediators, differentiation, and cell migration through regulating protein-protein interactions or via their ability to basepair with RNA and DNA.

Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.

Early reports indicate that long non-coding RNAs (lncRNAs) are novel regulators of biological responses. However, their role in the human innate immune response, which provides the initial defence against infection, is largely unexplored. To address this issue, here we characterize the long non-coding RNA transcriptome in primary human monocytes using RNA sequencing.