THE ROLE AND MECHANISM OF THE HOMEOBOX GENE HOXA9 IN THE GROWTH OF EPITHELIAL OVARIAN CANCER

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States. The high lethality of EOCs stems from rapid peritoneal involvement. EOCs frequently colonize peritoneal surfaces that overlie connective and adipose tissues. However, the mechanisms that enable ovarian cancer cells to readily adapt to the peritoneal environment are poorly understood. HOXA9, a homeobox gene that is normally expressed in the developing female reproductive tract, is aberrantly expressed in EOCs and controls the morphologic features of these tumors. The differentiation pattern of a tumor is an important determinant of its clinical behavior and prognosis. The overall goal of this project is to determine the clinical significance of HOXA9 and its mechanisms in the biological behavior of EOC. In this study, I demonstrated that expression of HOXA9 is strongly associated with poor outcomes in EOC patients and in mouse xenograft models of EOC. Whereas HOXA9 promoted EOC growth in vivo, HOXA9 did not stimulate autonomous tumor cell growth in vitro. On the other hand, HOXA9 was found to be associated with increased abundance of cancer-associated fibroblasts (CAFs) in mouse xenograft models of EOCs and with a CAF-like gene signature in human tumors. However, HOXA9 did not induce CAF-like features in EOC cells. Expression of HOXA9 in EOC cells induced normal adipose and bone marrow-derived mesenchymal stem cells (MSCs) as well as normal peritoneal fibroblasts to express markers of CAFs and to stimulate growth of EOC and endothelial cells. These effects of HOXA9 were due in substantial part to its transcriptional activation of TGF-beta2 that acted in a paracrine manner on peritoneal fibroblasts and MSCs to induce CXCL12, IL-6 and VEGF-A expression. These results demonstrate that HOXA9 promotes progression of EOC by ‘educating’ the stroma to become permissive for tumor growth

Putative cell adhesion membrane protein Vstm5 regulates neuronal morphology and migration in the central nervous system

During brain development, dynamic changes in neuronal membranes perform critical roles in neuronal morphogenesis and migration to create functional neural circuits. Among the proteins that induce membrane dynamics, cell adhesion molecules are important in neuronal membrane plasticity. Here, we report that V-set and transmembrane domain-containing protein 5 (Vstm5), a cell-adhesion-like molecule belonging to the Ig superfamily, was found in mouse brain. Knock-down of Vstm5 in cultured hippocampal neurons markedly reduced the complexity of dendritic structures, as well as the number of dendritic filopodia. Vstm5 also regulates neuronal morphology by promoting dendritic protrusions that later develop into dendritic spines. Using electroporationin utero, we found that Vstm5 overexpression delayed neuronal migration and induced multiple branches in leading processes during corticogenesis. These results indicate that Vstm5 is a new cell-adhesion-like molecule and is critically involved in synaptogenesis and corticogenesis by promoting neuronal membrane dynamics.SIGNIFICANCE STATEMENTNeuronal migration and morphogenesis play critical roles in brain development and function. In this study, we demonstrate for the first time that V-set and transmembrane domain-containing protein 5 (Vstm5), a putative cell adhesion membrane protein, modulates both the position and complexity of central neurons by altering their membrane morphology and dynamics. Vstm5 is also one of the target genes responsible for variations in patient responses to treatments for major depressive disorder. Our results provide the first evidence that Vstm5 is a novel factor involved in the modulation of the neuronal membrane and a critical element in normal neural circuit formation during mammalian brain development.</jats:p

Harnessing microRNA-enriched extracellular vesicles for liquid biopsy

Extracellular microRNAs (miRNAs) can be detected in body fluids and hold great potential as cancer biomarkers. Extracellular miRNAs are protected from degradation by binding various proteins and through their packaging into extracellular vesicles (EVs). There is evidence that the diagnostic performance of cancer-associated extracellular miRNAs can be improved by assaying EV-miRNA instead of total cell-free miRNA, but several challenges have hampered the advancement of EV-miRNA in liquid biopsy. Because almost all types of cells release EVs, cancer cell-derived EVs might constitute only a minor fraction of EVs in body fluids of cancer patients with low volume disease. Furthermore, a given cell type can release several subpopulations of EVs that vary in their cargo, and there is evidence that the majority of EVs contain low copy numbers of miRNAs. In this mini-review, we discuss the potential of several candidate EV membrane proteins such as CD147 to define cancer cell-derived EVs, and approaches by which subpopulations of miRNA-rich EVs in body fluids might be identified. By integrating these insights, we discuss strategies by which EVs that are both cancer cell-derived and miRNA-rich could be isolated to enhance the diagnostic performance of extracellular miRNAs

Anti-inflammatory effect and mechanism of action of Lindera erythrocarpa essential oil in lipopolysaccharide-stimulated RAW264.7 cells

The aim of this study was to investigate the chemical constituents of Lindera erythrocarpa essential oil (LEO) by gas chromatography-mass spectrometry and evaluate their inhibitory effect on the expression of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Fifteen compounds, accounting for 63.7 % of the composition of LEO, were identified. The main compounds were nerolidol (18.73 %), caryophyllene (14.41 %), α-humulene (7.73 %), germacrene-D (4.82 %), and α-pinene (4.47 %). LEO significantly inhibited the expression of inducible nitric oxide (NO) synthase and cyclooxygenase-2, and subsequent production of NO and prostaglandin E2. In addition, it reduced the release of pro-inflammatory cytokines in LPS-activated RAW264.7 cells. The molecular mechanism underlying the effect of LEO was associated with inhibition of the phosphorylation of mitogen-activated protein kinase (MAPK). Furthermore, LEO inhibited LPS-induced phosphorylation and degradation of inhibitor of kappa B-α, which is required for the activation of the p50 and p65 nuclear factor (NF)-κB subunits in RAW264.7 cells. Taken together, these data suggest that LEO exerted its anti-inflammatory effect by downregulating LPS-induced production of pro-inflammatory mediators through the inhibition of NF-κB and MAPK signaling in RAW264.7 cells

DIRECT CAROTID WALL SHEAR STRESS IN ACUTE CORONARY SYNDROME PATIENTS DECREASED AFTER ONE MONTH MEDICAL MANAGEMENT

Fuente Fuente, Carlos;Montes Gil, Antonio;Periel Piquer, Montserra

Honeycomb oxide heterostructure: a new platform for Kitaev quantum spin liquid

Kitaev quantum spin liquid, massively quantum entangled states, is so scarce in nature that searching for new candidate systems remains a great challenge. Honeycomb heterostructure could be a promising route to realize and utilize such an exotic quantum phase by providing additional controllability of Hamiltonian and device compatibility, respectively. Here, we provide epitaxial honeycomb oxide thin film Na3Co2SbO6, a candidate of Kitaev quantum spin liquid proposed recently. We found a spin glass and antiferromagnetic ground states depending on Na stoichiometry, signifying not only the importance of Na vacancy control but also strong frustration in Na3Co2SbO6. Despite its classical ground state, the field-dependent magnetic susceptibility shows remarkable scaling collapse with a single critical exponent, which can be interpreted as evidence of quantum criticality. Its electronic ground state and derived spin Hamiltonian from spectroscopies are consistent with the predicted Kitaev model. Our work provides a unique route to the realization and utilization of Kitaev quantum spin liquid

Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury

BACKGROUND AND PURPOSE: The rate of nitric oxide (NO) generation from nitrite is linearly dependent on reductions in oxygen and pH levels. Recently, nitrite-derived NO has been reported to exert a profound protection against liver and heart ischemia-reperfusion injury. In this study, we hypothesized that nitrite would be reduced to NO in the ischemic brain and exert NO-dependent neuroprotective effects. METHODS: Cerebral ischemia-reperfusion injury was induced by intraluminal thread occlusion of middle cerebral artery in the adult male rats. Solutions of sodium nitrite were infused intravenously at the time of reperfusion. Sodium nitrate and carboxy-PTIO (30 minutes before ischemic surgery), a direct NO scavenger, were infused for comparisons. RESULTS: Nitrite reduced infarction volume and enhanced local cerebral blood flow and functional recovery. The effects were observed at concentrations of 48 nmol and 480 nmol, but not at 4800 nmol nitrite and 480 nmol nitrate. The neuroprotective effects of nitrite were inhibited completely by the carboxy-PTIO. The 480 nmol nitrite attenuated dihydroethidium activity, 3-nitrotyrosine formation, and lipid peroxidation in the ischemic brain. CONCLUSIONS: Nitrite exerted profound neuroprotective effects with antioxidant properties in the ischemic brains. These results suggest that nitrite, as a biological storage reserve of NO, may be a novel therapeutic agent in the setting of acute stroke.This study was supported by a Korean Research Foundation grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund, KRF-2005-015-E00182)

Yoga Training Improves Metabolic Parameters in Obese Boys

Yoga has been known to have stimulatory or inhibitory effects on the metabolic parameters and to be uncomplicated therapy for obesity. The purpose of the present study was to test the effect of an 8-week of yoga-asana training on body composition, lipid profile, and insulin resistance (IR) in obese adolescent boys. Twenty volunteers with body mass index (BMI) greater than the 95th percentile were randomly assigned to yoga (age 14.7±0.5 years, n=10) and control groups (age 14.6±1.0 years, n=10). The yoga group performed exercises three times per week at 40~60% of heart-rate reserve (HRR) for 8 weeks. IR was determined with the homeostasis model assessment of insulin resistance (HOMA-IR). After yoga training, body weight, BMI, fat mass (FM), and body fat % (BF %) were significantly decreased, and fat-free mass and basal metabolic rate were significantly increased than baseline values. FM and BF % were significantly improved in the yoga group compared with the control group (p\u3c0.05). Total cholesterol (TC) was significantly decreased in the yoga group (p\u3c0.01). HDL-cholesterol was decreased in both groups (p\u3c0.05). No significant changes were observed between or within groups for triglycerides, LDL-cholesterol, glucose, insulin, and HOMA-IR. Our findings show that an 8-week of yoga training improves body composition and TC levels in obese adolescent boys, suggesting that yoga training may be effective in controlling some metabolic syndrome factors in obese adolescent boys

Snake fang-inspired stamping patch for transdermal delivery of liquid formulations

A flexible microneedle patch that can transdermally deliver liquid-phase therapeutics would enable direct use of existing, approved drugs and vaccines, which are mostly in liquid form, without the need for additional drug solidification, efficacy verification, and subsequent approval. Specialized dissolving or coated microneedle patches that deliver reformulated, solidified therapeutics have made considerable advances; however, microneedles that can deliver liquid drugs and vaccines still remain elusive because of technical limitations. Here, we present a snake fang-inspired microneedle patch that can administer existing liquid formulations to patients in an ultrafast manner (&lt; 15 s). Rear-fanged snakes have an intriguing molar with a groove on the surface, which enables rapid and efficient infusion of venom or saliva into prey. Liquid delivery is based on surface tension and capillary action. The microneedle patch uses multiple open groove architectures that emulate the grooved fangs of rear-fanged snakes: Similar to snake fangs, the microneedles can rapidly and efficiently deliver diverse liquid-phase drugs and vaccines in seconds under capillary action with only gentle thumb pressure, without requiring a complex pumping system. Hydrodynamic simulations show that the snake fang-inspired open groove architectures enable rapid capillary force-driven delivery of liquid formulations with varied surface tensions and viscosities. We demonstrate that administration of ovalbumin and influenza virus with the snake fang-inspired microneedle patch induces robust antibody production and protective immune response in guinea pigs and mice

Genome-wide analysis of DNA methylation patterns in horse

Background: DNA methylation is an epigenetic regulatory mechanism that plays an essential role in mediating biological processes and determining phenotypic plasticity in organisms. Although the horse reference genome and whole transcriptome data are publically available the global DNA methylation data are yet to be known. Results: We report the first genome-wide DNA methylation characteristics data from skeletal muscle, heart, lung, and cerebrum tissues of thoroughbred (TH) and Jeju (JH) horses, an indigenous Korea breed, respectively by methyl-DNA immunoprecipitation sequencing. The analysis of the DNA methylation patterns indicated that the average methylation density was the lowest in the promoter region, while the density in the coding DNA sequence region was the highest. Among repeat elements, a relatively high density of methylation was observed in long interspersed nuclear elements compared to short interspersed nuclear elements or long terminal repeat elements. We also successfully identified differential methylated regions through a comparative analysis of corresponding tissues from TH and JH, indicating that the gene body regions showed a high methylation density. Conclusions: We provide report the first DNA methylation landscape and differentially methylated genomic regions (DMRs) of thoroughbred and Jeju horses, providing comprehensive DMRs maps of the DNA methylome. These data are invaluable resource to better understanding of epigenetics in the horse providing information for the further biological function analyses.open1