Systematic review of the prevalence of psychiatric illness and sleep disturbance as co-morbidities of HIV infection in the UK.

Psychiatric illness and sleeping disorders are important co-morbidities of human immunodeficiency virus (HIV) infection, which impact both the individual and antiretroviral therapy (ART) selection. This systematic review aimed to assess the prevalence of psychiatric illness and sleep disturbance in people living with HIV (PLHIV) in the UK. Systematic searches for publications reporting epidemiological data for psychiatric co-morbidities and sleep disturbance with HIV were conducted in Embase, MEDLINE, Cochrane Library, eight key conferences (2013-2015), and by hand-searching references of included publications. Data were extracted from publications (2000 onwards) reporting the UK prevalence of depression, anxiety, suicide ideation, or sleep disturbance as a co-morbidity of HIV infection. Comparative UK general population data were obtained from the 2007 Adult Psychiatric Morbidity in England household survey, the 2012 Health Survey for England, and 'PatientBase' (epidemiological database). Sixteen publications met the inclusion criteria. Amongst PLHIV in the UK, the prevalence of depression varied from 17-47%, compared with a reported 2-5% prevalence for the UK general population. A similar disparity was observed in the prevalence of anxiety (22-49% PLHIV versus 4-5% general population), depression or anxiety (50-58% PLHIV versus 27% general population), difficulty sleeping (61% PLHIV versus 10% population), and suicide ideation (31% PLHIV versus 1% general population). This systematic review of UK data demonstrates that rates of psychiatric illness and sleep disturbance are substantially higher amongst PLHIV than in the general population. These data underline the importance of fully considering sleep and psychiatric issues prior to selection and prescription of antiretroviral drugs, as well as the need for ongoing psychiatric and psychological support for PLHIV on ART.

In vitro transformation of mesenchymal stem cells induces gradual genomic hypomethylation.

Genome-wide DNA hypomethylation was one of the first epigenetic alterations described in cancer cells. However, the cause of this hypomethylation is still poorly understood. We have previously developed a line of primary mesenchymal stem cells (MSC, the putative origin of various types of sarcoma) in which five oncogenic steps toward a fully transformed state are sequentially introduced including: human telomerase, inactivation of p53 and pRb tumor suppressor genes and activation of the oncogenes c-Myc and H-Ras. We hypothesized that DNA hypomethyation would occur during stepwise transformation of MSC and could be a model to investigate the mechanism of global hypomethylation in cancer. Here we show, firstly, that satellite-2 and long interspersed nuclear element 1 repetitive elements became hypomethylated (54 and 30% reduction, respectively) on the introduction of oncogenic H-Ras after the final step of transformation. Secondly, we observed hypomethylation only after 4 weeks in culture following the introduction of H-Ras, suggesting a gradual loss of methylation. Finally, using an inducible estrogen receptor-Ras fusion construct, we were able to transform MSC's in the absence of detectable hypomethylation, suggesting that it was not a requirement for transformation. These studies show that DNA hypomethylation can occur late during stepwise transformation, although in vitro transformation could also take place in the absence of hypomethylation. These data support the hypothesis that DNA hypomethylation occurs via a gradual mechanism and is not a requirement for transformation.

Genome-wide hypomethylation in cancer may be a passive consequence of transformation.

Epigenetics describes the study of stable, reversible alterations to the genome that affect gene expression and genome function, the most studied mechanisms are DNA methylation and histone modifications. Over recent years there has been rapid progress to elucidate the nature and role of the mechanisms involved in promoter hypermethylation during carcinogenesis, however, the mechanism behind one of the earliest epigenetic observations in cancer, genome-wide hypomethylation, remains unclear. Current evidence is divided between the hypotheses that hypomethylation is either an important early cancer-causing aberration or that it is a passive inconsequential side effect of carcinogenesis. With recent discoveries of gene-body methylation, fast cyclic methylation of hormone dependent genes and candidate proteins involved in DNA demethylation elucidation of the role of hypomethylation and the mechanism behind it appears ever closer. With the burgeoning use of DNA methyltransferase inhibitors as a cancer therapy there is an increased need to understand the mechanisms and importance of genome-wide hypomethylation in cancer. This review will discuss the timing and potential causes of genomic hypomethylation during carcinogenesis and will propose a way forward to understand the underlying mechanisms.

Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets.

Since the sequencing of the human genome, recent efforts in cancer drug target discovery have focused more on the identification of novel functions of known genes and the development of more appropriate tumor models. In the present study, we investigated in vitro transformed human adult mesenchymal stem cells (MSC) to identify novel candidate cancer drug targets by analyzing the transcriptional profile of known enzymes compared with non-transformed MSC. The identified enzymes were compared with published cancer gene expression data sets. Surprisingly, the majority of up-regulated enzymes are already known cancer drug targets or act within known druggable pathways. Only three enzymes (RNASEH2A, ADARB1, and PPAP2C) are potentially novel targets that are up-regulated in transformed MSC and expressed in numerous carcinomas and sarcomas. We confirmed the overexpression of RNASEH2A, PPAP2C, and ADARB1 in transformed MSC, transformed fibroblasts, and cancer cell lines MCF7, SK-LMS1, MG63, and U2OS. In functional assays, we show that small interfering RNA knockdown of RNASEH2A inhibits anchorage-independent growth but does not alter in vitro proliferation of cancer cell lines, normal MSC, or normal fibroblasts. Knockdown of PPAP2C impaired anchorage-dependent in vitro growth of cancer cell lines and impaired the in vitro growth of primary MSC but not differentiated human fibroblasts. We show that the knockdown of PPAP2C decreases cell proliferation by delaying entry into S phase of the cell cycle and is transcriptionally regulated by p53. These in vitro data validate PPAP2C and RNASEH2A as putative cancer targets and endorse this in silico approach for identifying novel candidates.