Explore the vast range of titles available.

Altered expression levels of the long noncoding RNA (lncRNA) nuclear‐enriched abundant transcript 1 (NEAT1) have been reported in different types of cancer. More than half of the NEAT1 studies in cancer have been published within the last 2 years. In this review, we discuss very recent developments and insights into NEAT1 contribution to carcinogenesis. Summarizing the literature, it becomes obvious that NEAT1 is a lncRNA highly de‐/upregulated in a variety of cancer entities, in which it primarily acts as a competing endogenous RNA (ceRNA) which sponges tumor‐suppressive microRNA (miRNA). The sponged miRNA lose their ability to degrade, silence, or hamper translation of their downstream—mostly oncogenic—target transcripts, ultimately promoting carcinogenesis. This role of NEAT1 function in tumorigenesis suggests it may be a prognostic biomarker as well as potential therapeutic target, pending the completion of further studies into the underlying mechanisms. Nuclear‐enriched abundant transcript 1 (NEAT1) acts as ceRNA in cancer. In contrast to low NEAT1 expression in normal tissue, high expression levels of NEAT1 in cancer sponge tumor‐suppressive microRNAs (miRNAs) leading to reduced binding of these miRNAs to oncogenic mRNAs. As a result, high numbers of oncogenic mRNAs are translated to oncogenic proteins and carcinogenesis is promoted.

The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments.

Long non-coding RNAs (lncRNAs) are involved in a variety of biological and cellular processes as well as in physiologic and pathophysiologic events. This review summarizes recent literature about the role of the lncRNA nuclear enriched abundant transcript 1 (NEAT1) in non-cancerous diseases with a special focus on viral infections and neurodegenerative diseases. In contrast to its role as competing endogenous RNA (ceRNA) in carcinogenesis, NEAT1’s function in non-cancerous diseases predominantly focuses on paraspeckle-mediated effects on gene expression. This involves processes such as nuclear retention of mRNAs or sequestration of paraspeckle proteins from specific promoters, resulting in transcriptional induction or repression of genes involved in regulating the immune system or neurodegenerative processes. NEAT1 expression is aberrantly—mostly upregulated—in non-cancerous pathological conditions, indicating that it could serve as potential prognostic biomarker. Additional studies are needed to elucidate NEAT1’s capability to be a therapeutic target for non-cancerous diseases.

Pancreatic beta (β) cell dysfunction results in compromised insulin release and, thus, failed regulation of blood glucose levels. This forms the backbone of the development of diabetes mellitus (DM), a disease that affects a significant portion of the global adult population. Physiological calcium (Ca2+) signaling has been found to be vital for the proper insulin-releasing function of β-cells. Calcium dysregulation events can have a dramatic effect on the proper functioning of the pancreatic β-cells. The current review discusses the role of calcium signaling in health and disease in pancreatic β-cells and provides an in-depth look into the potential role of alterations in β-cell Ca2+ homeostasis and signaling in the development of diabetes and highlights recent work that introduced the current theories on the connection between calcium and the onset of diabetes.

Immunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects. In this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI≥25). 40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, χ2), and lower likelihood of brain metastases (p = 0.012, χ2). No differences were found between both groups with respect to gender (p = 0.324, χ2), T-stage (p = 0.197, χ2), or the occurrence of side effects (p = 0.646, χ2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank). The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.

At least 40% of human cancers are associated with aberrant ERK pathway activity (ERKp). Inhibitors targeting various effectors within the ERKp have been developed and explored for over two decades. Conversely, a substantial body of evidence suggests that both normal human cells and, notably to a greater extent, cancer cells exhibit susceptibility to hyperactivation of ERKp. However, this vulnerability of cancer cells remains relatively unexplored. In this review, we reexamine the evidence on the selective lethality of highly elevated ERKp activity in human cancer cells of varying backgrounds. We synthesize the insights proposed for harnessing this vulnerability of ERK-associated cancers for therapeutical approaches and contextualize these insights within established pharmacological cancer-targeting models. Moreover, we compile the intriguing preclinical findings of ERK pathway agonism in diverse cancer models. Lastly, we present a conceptual framework for target discovery regarding ERKp agonism, emphasizing the utilization of mutual exclusivity among oncogenes to develop novel targeted therapies for precision oncology.

Platelet-to-Lymphocyte Ratio (PLR) is an easily applicable blood test. An elevated PLR has been associated with poor prognosis in patients with different oncologic disorder. As platelets play a key role in atherosclerosis and atherothrombosis, we investigated PLR and its association with critical limb ischemia (CLI) and other vascular endpoints in peripheral arterial occlusive disease (PAOD) patients. We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. PLR was calculated and the cohort was categorized into tertiles according to the PLR. An optimal cut-off value for the continuous PLR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI significantly increased with an increase in PLR. As an optimal cut-off value, a PLR of 150 was identified. Two groups were categorized, one containing 1228 patients (PLR≤150) and a second group with 893 patients (PLR>150). CLI was more frequent in PLR>150 patients (410(45.9%)) compared to PLR≤150 patients (270(22.0%)) (p<0.001), as was prior myocardial infarction (51(5.7%) vs. 42(3.5%), p = 0.02). Regarding inflammatory parameters, C-reactive protein (median 7.0 mg/l (3.0-24.25) vs. median 5.0 mg/l (2.0-10.0)) and fibrinogen (median 457 mg/dl (359.0-583.0) vs. 372 mg/dl (317.25-455.75)) also significantly differed in the two patient groups (both p<0.001). Finally, a PLR>150 was associated with an OR of 1.9 (95%CI 1.7-2.1) for CLI even after adjustment for other well-established vascular risk factors. An increased PLR is significantly associated with patients at high risk for CLI and other cardiovascular endpoints. The PLR is a broadly available and cheap marker, which could be used to highlight patients at high risk for vascular endpoints.

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8 +  T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8 + T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8 + T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokine high RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8 + T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

Analysis of RNA isolated from fixed and paraffin-embedded tissues is widely used in biomedical research and molecular pathological diagnostics. We have performed a comprehensive and systematic investigation of the impact of factors in the pre-analytical workflow, such as different fixatives, fixation time, RNA extraction method and storage of tissues in paraffin blocks, on several downstream reactions including complementary DNA (cDNA) synthesis, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and microarray hybridization. We compared the effects of routine formalin fixation with the non-crosslinking, alcohol-based Tissue Tek Xpress Molecular Fixative (TTXMF, Sakura Finetek), and cryopreservation as gold standard for molecular analyses. Formalin fixation introduced major changes into microarray gene expression data and led to marked gene-to-gene variations in delta-ct values of qRT-PCR. We found that qRT-PCR efficiency and gene-to-gene variations were mainly attributed to differences in the efficiency of cDNA synthesis as the most sensitive step. These differences could not be reliably detected by quality assessment of total RNA isolated from formalin-fixed tissues by electrophoresis or spectrophotometry. Although RNA from TTXMF fixed samples was as fragmented as RNA from formalin fixed samples, much higher cDNA yield and lower ct-values were obtained in qRT-PCR underlining the negative impact of crosslinking by formalin. In order to better estimate the impact of pre-analytical procedures such as fixation on the reliability of downstream analysis, we applied a qRT-PCR-based assay using amplicons of different length and an assay measuring the efficiency of cDNA generation. Together these two assays allowed better quality assessment of RNA extracted from fixed and paraffin-embedded tissues and should be used to supplement quality scores derived from automated electrophoresis. A better standardization of the pre-analytical workflow, application of additional quality controls and detailed sample information would markedly improve the comparability and reliability of molecular studies based on formalin-fixed and paraffin-embedded tissue samples.

ObjectiveTo investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target.DesignFLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases.ResultsFLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis.ConclusionsBased on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.