Hypereosinophilia Presenting as Eosinophilic Vasculitis and Multiple Peripheral Artery Occlusions without Organ Involvement

We report here a case with hypereosinophilia and peripheral artery occlusion. A 32-yr-old Korean woman presented to us with lower extremity swelling and pain. Angiography revealed that multiple lower extremity arteries were occlusive. The biopsy specimen showed perivascular and periadnexal dense eosinophilic infiltration in dermis and subcutaneous adipose tissue. Laboratory investigations revealed a persistent hypereosinophilia. She was prescribed prednisolone 60 mg daily. Her skin lesion and pain were improved and the eosinophil count was dramatically decreased. After discharge, eosinophil count gradually increased again. Cyanosis and pain of her fingers recurred. She had been treated with cyclophosphamide pulse therapy. Her eosinophilia was decreased, but the cyanosis and tingling sense were progressive. The extremity arterial stenoses were slightly progressed. Skin biopsy showed perivascular eosinophilic infiltration in the dermis and CD40 ligand (CD40L) positive eosinophilic infiltration. The serum TNF-α was markedly increased. These results suggest that CD40L (a member of TNF-α superfamily) could play a role in the inflammatory processes when eosinophil infiltration and activation are observed. We prescribed prednisolone, cyclophosphamide, clopidogrel, cilostazol, beraprost and nifedipine, and she was discharged

CDX1 and CDX2 Expression in Intestinal Metaplasia, Dysplasia and Gastric Cancer

Intestinal metaplasia (IM) has been regarded as a premalignant condition. However, the pathogenesis of IM is not fully understood. The aim of this study was to evaluate the role of CDX1 and CDX2 in the formation of IM and the progression to dysplasia and gastric cancer (GC). A total of 270 subjects included 90 with GC, dysplasia and age- and sex-matched controls. Real-time PCR (RT-PCR) was performed with body specimens for CDX1 and CDX2. The expression of CDX2 was significantly higher in H. pylori positive group than H. pylori negative group (P = 0.045). CDX1 and CDX2 expression increased proportional to the IM grade of the body (P < 0.001). CDX2 expression was significantly higher in incomplete type of IM than in complete type (P = 0.045). The expression of CDX1 in dysplasia group was significantly higher than in the control group (P = 0.001); in addition, CDX1 and CDX2 in cancer group was significantly higher than control group (P < 0.001, and P < 0.001, respectively). Aberrant expression of CDX1 and CDX2 correlated with H. pylori infection and grade of IM in the body. Furthermore, the results suggest that CDX1 and CDX2 play a role in the progression to GC and dysplasia

Construction of 3-D cellular multi-layers with extracellular matrix assembly using magnatic nanoparticles

Construction of 3-dimensional (3-D) engineered tissue is increasingly being investigated for use in drug discovery and regenerative medicine. Here, we developed multi-layered 3-D cellular assembly by using magnetic nanoparticles (MNP) isolated from Magnetospirillum sp. AMB-1 magnetotactic bacteria. Magnetized human dermal fibroblasts (HDFBs) were prepared by treatment with the MNP, induced to form 3-D assembly under a magnetic field. Analyses including LIVE/DEAD assay, transmission electron microscopy revealed that the MNP were internalized via clathrin-mediated endocytosis without cytotoxicity. The magnetized HDFBs could build 3-D structure as a function of seeding density. When the highest seeding density (5 × 105 cells/mm2 was used, the thickness of assembly was 4190 ± 169 μm, with approximately 93±16 cell layers being formed. Immunofluorescence staining confirmed homogeneous distribution of ECM and junction proteins throughout the 3-D assembly. Real-time PCR analysis showed decrease in expression levels of collagen types I and IV but increase in that of connexin 43 in the 3-D assembly compared with the 2-D culture. Finally, we demonstrated that the discernible layers can be formed hierarchically by serial assembly. In conclusion, our study showed that a multi-layered structure can be easily prepared using magnetically-assisted cellular assembly with highlighting cell-cell and cell-ECM communication.OAIID:RECH_ACHV_DSTSH_NO:T201623722RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A002014CITE_RATE:3.929FILENAME:7. (2016.10) Construction of 3-D Cellular Multi-Layers with.pdfDEPT_NM:화학생물공학부EMAIL:[email protected]_YN:YFILEURL:https://srnd.snu.ac.kr/eXrepEIR/fws/file/a5981ae9-bf9b-4b44-bd34-9e96bc984798/linkCONFIRM:

Roles of Arrest-Defective Protein 1225 and Hypoxia-Inducible Factor 1α in Tumor Growth and Metastasis

Background Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A225) acetylates HIF-1??, triggering its degradation, and thus may play a role in decreased expression of VEGFA.Methods We generated ApcMin/+/mARD1A225 transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A225 were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A 225 acetylation of Lys532 in HIF-1??, we injected B16F10-mARD1A225 cell lines stably expressing mutant HIF-1??/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than. 05 were considered statistically significant.Results ApcMin/+/mARD1A225 transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc Min/+ mice (n = 21) (number of intestinal polyps per mouse: Apc Min/+ mice vs ApcMin/+/mARD1A225 transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P &lt;. 001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A225-overexpressing cells than in mice injected with control cells (P &lt;. 01). Moreover, overexpression of mARD1A 225 decreased VEGFA expression and microvessel density in tumor xenografts (P &lt;. 04) and ApcMin/+ intestinal polyps (P =. 001). Mutation of lysine 532 of HIF-1?? in B16F10-mARD1A225 cells prevented HIF-1?? degradation and inhibited the antimetastatic effect of mARD1A225 (P &lt;. 001).Conclusion mARD1A225 may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis

Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models

<p>Abstract</p> <p>Background</p> <p>Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-<it>O</it>-methylhonokiol, a constituent of <it>Magnolia officinalis</it>, on memory deficiency caused by LPS, along with the underlying mechanisms.</p> <p>Methods</p> <p>We investigated whether 4-<it>O</it>-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 μg/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-<it>O</it>-methylhonkiol (0.5, 1 and 2 μM).</p> <p>Results</p> <p>Oral administration of 4-<it>O</it>-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-<it>O</it>-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In <it>in vitro </it>study, we also found that 4-<it>O</it>-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E₂, tumor necrosis factor-α, and interleukin-1β in the LPS-stimulated cultured astrocytes. 4-<it>O</it>-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-<it>O</it>-methylhonokiol inhibited LPS-induced Aβ_1-42generation, β- and γ-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells.</p> <p>Conclusion</p> <p>These results suggest that 4-<it>O</it>-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-<it>O</it>-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD.</p

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p