Alterations in genes associated with cytosolic RNA sensing in whole blood are associated with coronary microvascular disease in SLE.

Systemic lupus erythematosus (SLE) patients are 90% women and over three times more likely to die of cardiovascular disease than women in the general population. Chest pain with no obstructive cardiac disease is associated with coronary microvascular disease (CMD), where narrowing of the small blood vessels can lead to ischemia, and frequently reported by SLE patients. Using whole blood RNA samples, we asked whether gene signatures discriminate SLE patients with coronary microvascular dysfunction (CMD) on cardiac MRI (n=4) from those without (n=7) and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD.

α-Ketoglutarate-Dependent KDM6 Histone Demethylases and Interferon-Stimulated Gene Expression in Lupus.

Objective: We aimed to investigate the hypothesis that interferon (IFN)-stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression.

Methods: Monocytes from healthy volunteers and patients with SLE at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation, and gene expression. The histone demethylases KDM6A/B were inhibited using glycogen synthase kinase J4 (GSK-J4).

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.

Metabolic rewiring underlies the effector functions of macrophages, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination.

DOES T STAGE AFFECT PROGNOSIS IN PATIENTS WITH STAGE IV B DIFFERENTIATED THYROID CANCER?

Differentiated thyroid cancer (DTC), the most common subtype of thyroid cancer, has a relatively good prognosis. The 8 edition of the American Joint Committee on Cancer (AJCC) pathologic tumor-node-metastasis (T [primary tumor size], N [regional lymph nodes], M [distant metastasis]) staging system did not take the T stage into consideration in stage IV B DTC patients. We evaluated the prognostic value of the T stage for advanced DTC survival.

County Median Family Income Is an Independent Prognostic Factor for Stage IV Anaplastic Thyroid Cancer.

Background/aim: Advanced anaplastic thyroid cancer (ATC) is a rare, but highly aggressive malignancy, and its prognostic factors need to be further explored. We examined socioeconomic factors' predictive effect for survival performance in stage IV ATC patients.

Materials And Methods: Using the Surveillance, Epidemiology, and End Results database, we collected 1,048 cases with stage IV anaplastic thyroid cancer (ATC) from 2004 to 2015.

PGC-1α Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ.

Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging. Although master regulators of osteoblastic and adipogenic lineages have been identified, little is known about factors that are associated with MAT accumulation and osteoporotic bone loss. Here, we identify peroxisome-proliferator-activated receptor γ coactivator 1-α (PGC-1α) as a critical switch of cell fate decisions whose expression decreases with aging in human and mouse SSCs.

LncRNA MALAT1 regulates smooth muscle cell phenotype switch via activation of autophagy.

Vascular smooth muscle cells (VSMCs), switching from a differentiated to a proliferative phenotype, contribute to various vascular diseases. However, the role of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 MALAT1 in the phenotype switching of VSMCs remains unclear. Here, we report that the knockdown of MALAT1 promotes the transformation of smooth muscle cells from a proliferative phenotype to a differentiated phenotype.

miR-219a-5p inhibits breast cancer cell migration and epithelial-mesenchymal transition by targeting myocardin-related transcription factor A.

Although many miRNAs are reported to be involved in tumor formation and progression, the effect of miR-219a-5p on breast cancer metastasis is not well-known. The aim of this study is to investigate the effect of miR-219a-5p on the migratory ability and epithelial-mesenchymal transition (EMT) of breast cancer cells. First, miR-219a-5p was found to be highly expressed in low-invasive breast cancer MCF-7 cells, but lowly expressed in high-invasive breast cancer MDA-MB-231 cells.

Selective p300 inhibitor C646 inhibited HPV E6-E7 genes, altered glucose metabolism and induced apoptosis in cervical cancer cells.

High risk HPV infection is a causative factor of cervical cancer. The constitutive expression of HPV E6-E7 genes is important for the maintenance of cancer phenotypes. The cellular transcription co-activator p300 plays a crucial role in the regulation of HPV genes thus it was targeted for the inhibition of HPV-associated cervical cancer.

Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone.

Background: Benign human prostate tubule-initiating cells (TIC) and aggressive prostate cancer display common traits, including tolerance of low androgen levels, resistance to apoptosis, and microenvironment interactions that drive epithelial budding and outgrowth. TIC can be distinguished from epithelial and stromal cells that comprise prostate tissue via cell sorting based upon Epcam, CD44, and CD49f antigenic profiles. Fetal prostate epithelial cells (FC) possess a similar antigenic profile to adult TIC and are capable of inducing tubule formation.

Synthesis and Biological Evaluations of Cytotoxic and Antiangiogenic Triterpenoids-Jacaranone Conjugates.

Background: The development of antiangiogenic agents arises as a more effective and selective therapeutic approach for the treatment of cancer. In addition to reduced acute toxicity, the efficacy of chemotherapy could be improved when administered in combination specific antiangiogenic with cytotoxic agents. The conjugation or hybridization of bifunctional molecules is one of the alternative rational design strategies for co-administration of anticancer drugs.

Differential gene expression profiling of functionally and developmentally distinct human prostate epithelial populations.

Background: Human fetal prostate buds appear in the 10th gestational week as solid cords, which branch and form lumens in response to androgen 1. Previous in vivo analysis of prostate epithelia isolated from benign prostatectomy specimens indicated that Epcam⁺ CD44⁻ CD49f(Hi) basal cells possess efficient tubule initiation capability relative to other subpopulations 2. Stromal interactions and branching morphogenesis displayed by adult tubule-initiating cells (TIC) are reminiscent of fetal prostate development.

Modulation of Eg5 activity contributes to mitotic spindle checkpoint activation and Tat-mediated apoptosis in CD4-positive T-lymphocytes.

Tat, the transactivation factor of human immunodeficiency virus type 1 (HIV-1), represents one of the major players mediating the loss of CD4-positive T-lymphocytes in HIV-1-infected patients, primarily due to the ability of Tat to trigger apoptosis. However, the molecular events underlying this process remain elusive. In this study, we provide evidence that Tat interacts with Eg5, a microtubule-associated motor protein, and allosterically modulates the ATPase activity of Eg5 by affecting ADP release from the enzyme's active centre.

Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons.

Leptin acts via neuronal leptin receptors to control energy balance. Hypothalamic pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP)/Neuropeptide Y (NPY)/GABA neurons produce anorexigenic and orexigenic neuropeptides and neurotransmitters, and express the long signaling form of the leptin receptor (LepRb). Despite progress in the understanding of LepRb signaling and function, the sub-cellular localization of LepRb in target neurons has not been determined, primarily due to lack of sensitive anti-LepRb antibodies.

Systematic Analysis of the Functions of Lysine Acetylation in the Regulation of Tat Activity.

The Tat protein of HIV-1 has several well-known properties, such as nucleocytoplasmic trafficking, transactivation of transcription, interaction with tubulin, regulation of mitotic progression, and induction of apoptosis. Previous studies have identified a couple of lysine residues in Tat that are essential for its functions. In order to analyze the functions of all the lysine residues in Tat, we mutated them individually to alanine, glutamine, and arginine.

Over-expression of leptin receptors in hypothalamic POMC neurons increases susceptibility to diet-induced obesity.

Diet-induced obesity (DIO) in rodents is characterized by impaired activation of signal-transducer and activator of transcription 3 (STAT3) by leptin receptors (LepRb) within the hypothalamic arcuate nucleus. This signaling defect likely plays an important role in development of DIO. However, the neuro-chemical identity of the leptin-STAT3 resistant arcuate neurons has not been determined and the underlying mechanisms responsible for development of cellular leptin resistance remain unclear.

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner.

Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility, contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells.

Regulation of Tat acetylation and transactivation activity by the microtubule-associated deacetylase HDAC6.

Reversible acetylation of Tat is critical for its transactivation activity toward HIV-1 transcription. However, the enzymes involved in the acetylation/deacetylation cycles have not been fully characterized. In this study, by yeast two-hybrid assay, we have discovered the histone deacetylase HDAC6 to be a binding partner of Tat.

Tat acetylation regulates its actions on microtubule dynamics and apoptosis in T lymphocytes.

The transactivator protein Tat of human immunodeficiency virus type 1 (HIV-1) is known to suppress microtubule dynamics and thereby trigger apoptosis in T lymphocytes. These actions of Tat constitute one of the major mechanisms for the massive destruction of T lymphocytes associated with the acquired immunodeficiency syndrome. Herein, we show that Tat acetylation at lysine-28 (K28) enhances its interaction with microtubules and increases its activity to promote microtubule assembly, by lowering the critical concentration of tubulin for polymerization into microtubules.

Tumour suppressor CYLD is a negative regulator of the mitotic kinase Aurora-B.

The familial cylindromatosis tumour suppressor CYLD contains three cytoskeleton-associated protein glycine-rich (CAP-Gly) domains and a deubiquitinase domain. The tumour-suppressing function of CYLD has been attributed to its deubiquitinase domain, which removes lysine-63-linked polyubiquitin chains from target proteins, leading to the inhibition of cell survival and proliferation. In this study, we have detected an interaction of CYLD with the mitotic kinase Aurora-B.

CYLD regulates angiogenesis by mediating vascular endothelial cell migration.

Cylindromatosis (CYLD) is a deubiquitinase that was initially identified as a tumor suppressor and has recently been implicated in diverse normal physiologic processes. In this study, we have investigated the involvement of CYLD in angiogenesis, the formation of new blood vessels from preexisting ones. We find that knockdown of CYLD expression significantly impairs angiogenesis in vitro in both matrigel-based tube formation assay and collagen-based 3-dimensional capillary sprouting assay.

Leptin-dependent control of glucose balance and locomotor activity by POMC neurons.

Leptin plays a pivotal role in regulation of energy balance. Via unknown central pathways, leptin also affects peripheral glucose homeostasis and locomotor activity. We hypothesized that, specifically, pro-opiomelanocortin (POMC) neurons mediate those actions.

Validating the mitotic kinesin Eg5 as a therapeutic target in pancreatic cancer cells and tumor xenografts using a specific inhibitor.

Pancreatic cancer is a devastating disease with a high mortality rate. Treatment of this malignancy remains a big challenge in oncology, and none of the currently available chemotherapeutic agents has a remarkable impact on improving patient survival. Consequently, it is important to explore new targets and find effective drugs for the management of this disease.