SUMMARYWe characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigeneticallyinduced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

The relationship among neuroinflammation, blood-brain barrier (BBB) dysfunction, and progressive HIV-1 infection as they affect the onset and development of neuroAIDS is incompletely understood. IntroductionHuman immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) commonly results in behavioral, motor, and cognitive impairments. [1][2][3] Although disease severity and progression has slowed, in part, as a result of antiretroviral therapy, 76% to 83% of brain autopsies continue to show observable neuropathological abnormalities. [4][5][6] Disease pathology ranges from mild brain atrophy and gliosis to robust viral replication, multinucleated giant cell formation, astrogliosis and microgliosis, myelin pallor, and neuronal loss. 7,8 These pathological findings are collectively termed HIV-1 encephalitis (HIVE). HIVE is a common correlate to the later stages of behavioral, motor, neuropsychiatric, and neurologic consequences of disease termed HIV-1-associated dementia (HAD) (for recent reviews, see McArthur 1 ; Grant et al 2 ; Ghafouri 3 ). HIVE is fueled by viral infection and immune activation of brain mononuclear phagocytes (MPs: blood-derived perivascular macrophages and microglia). 9 Such MP-and virus-associated neuroinflammation promotes monocyte trafficking across the bloodbrain barrier (BBB), MP infiltration into the CNS, and neurodegeneration. [10][11][12] Thus, dysfunction of the BBB is one critical feature of HIV-1 neuropathogenesis.Brain microvascular endothelial cells, a major component of BBB function and integrity, are connected by tight junctions (TJs) that limit paracellular flux and restrict permeability. 13 Indeed, under normal physiologic conditions, the brain endothelium functions as an interface between the blood and the brain parenchyma, strictly regulating influx of ions, molecules, and leukocytes into the CNS. Nonetheless, in disease, a variety of environmental, toxic, degenerative, and microbial insults could cause BBB breakdown. 12,14 Such a breakdown occurs during progressive HIV-1 infection 12,[15][16][17] and was documented in laboratory, animal models, human clinical observations, and autopsy studies. 10,[16][17][18][19][20] Underlying mechanisms of BBB dysfunction and how it affects ongoing disease are incompletely understood. 1,12,14 Dysfunction of the BBB enhances penetration of cell-free virus, ingress of activated HIV-1-infected monocytes across the BBB, accumulation of MP in the CNS, and spread of the virus to neighboring microglia and astrocytes. 15,21 Thus, BBB breech is commonly associated with accelerated disease and the development of behavioral and cognitive deficits that are signatures of HAD. 1,16 Based on these observations, the elucidation of the signaling pathways mediating BBB compromise can prove important for understanding disease mechanisms and development of new therapies.Signal transducers and activators of transcription (STATs) proteins are latent cytoplasmic transcription factors that are phosphorylated by Janus kinases (JAKs) in...

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How neuroinflammatory activities affect signaling pathways leading to blood-brain barrier (BBB) injury during HIV/AIDS are currently unknown. Our previous work demonstrated that HIV-1 exposure activates pro-inflammatory genes in human brain microvascular endothelial cells (HBMEC) and showed that these genes are linked to the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Here, we report that HIV-1 gp120 protein activated STAT1 and induced interleukin (IL)-6 and IL-8 secretion in HBMEC. IL-6, IL-8, and gp120 increased monocyte adhesion and migration across in vitro BBB models. The STAT1 inhibitor, fludarabine, prevented gp120-induced IL-6 and IL-8 secretion. Inhibitors of STAT1, mitogen activated protein kinase kinase (MEK) (PD98059), and phosphatidyl inositol 3 kinase (PI3K) (LY294002), blocked gp120-induced STAT1 activation and significantly diminished IL-8-, IL-6-, and gp120-induced monocyte adhesion and migration across in vitro BBB models. These data support the notion that STAT1 plays an important role in gp120-induced inflammation and BBB dysfunction associated with viral infection. Results also suggest crosstalk between STAT1, MEK, and PI3K pathways in gp120-induced BBB dysfunction. Inhibition of STAT1 activation could provide a unique therapeutic strategy to decrease neuroinflammation and BBB dysfunction in HIV/AIDS.

Aims/IntroductionThe incidence and prevalence of type 2 diabetes mellitus (T2DM) and related macrovascular complications in Korea were estimated using the Health Insurance Review and Assessment (HIRA) database from 2007–2011, which covers the claim data of 97.0% of the Korean population.Materials and MethodsT2DM, coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral artery disease (PAD) were defined according to ICD-10 codes. We used the Healthcare Common Procedure Coding System codes provided by HIRA to identify associated procedures or surgeries. When calculating incidence, we excluded cases with preexisting T2DM within two years before the index year. A Poisson distribution was assumed when calculating 95% confidence intervals for prevalence and incidence rates.ResultsThe prevalence of T2DM in Korean adults aged 20–89 years was 6.1–6.9% and the annual incidence rates of T2DM ranged from 9.5–9.8/1,000 person-year (PY) during the study period. The incidence rates of T2DM in men and women aged 20–49 years showed decreasing patterns from 2009 to 2011 (P<0.001); by contrast, the incidence in subjects aged 70–79 years showed increased patterns from 2009 to 2011 (P<0.001). The incidence rates of CAD and CVD in patients newly diagnosed with T2DM were 18.84/1,000 PY and 11.32/1,000 PY, respectively, in the year of diagnosis. Among newly diagnosed individuals with T2DM who were undergoing treatment for PAD, 14.6% underwent angioplasty for CAD during the same period.ConclusionsOur study measured the national incidences of T2DM, CAD, CVD, and PAD, which are of great concern for public health. We also confirmed the relatively higher risk of CAD and CVD newly detected T2DM patients compared to the general population in Korea.