A lack of association between genetic polymorphisms in beta-defensins and susceptibility of psoriasis in Taiwanese: A case–control study

AbstractBackgroundGenetic predisposition of the inflammatory-host response may affect the development of psoriasis. Previous studies have shown that copy number variations (CNVs) of β-defensin genes (DEFB) are associated with the susceptibility of psoriasis in Caucasian populations.ObjectivesThis study aimed to assess the role of the CNVs of the DEFB4 gene and functional variants in the DEFB1 gene in Taiwanese patients with psoriasis.MethodsIn total, 196 patients with psoriasis and 196 control individuals were analyzed for the presence of the DEFB4 CNVs using the paralogue ratio test, and also for the DEFB1 polymorphisms rs11362, rs1800972, and rs1799946, using a polymerase chain reaction.ResultsNone of the polymorphisms were found to be associated with psoriasis. The distribution of DEFB4 genomic CNVs did not significantly differ between the control group and psoriasis group. The frequencies of patients who carried a greater than the median (≥ 5) number of copies did not significantly differ in patients with psoriasis and controls. The multivariate analysis similarly revealed that the DEFB4 CNVs were not associated with psoriasis (odds ratio = 1.03, 95% confidence interval = 0.89–1.19, p = 0.720). No significant difference was detected in the genotype and allele distribution for any of the individual DEFB1 polymorphisms between the cases and the controls. Finally, the overall haplotype frequency profiles derived from the three polymorphisms did not significantly differ between the cases and the controls.ConclusionOur results do not suggest that these genetic variants of the β-defensin genes contribute to the genetic background of psoriasis in Taiwanese patients

HPV infection and p53 inactivation in pterygium

PurposeOur recent report indicated that tumor suppressor gene (p53) mutations and protein aberrant expression were detected in pterygium. Inactivation of p53 by Human papillomavirus (HPV) 16/18 E6 plays a crucial role in cervical tumorigenesis. In this study, we further speculate that p53 inactivation may be linked with HPV infection in pterygium pathogenesis. To investigate the involvement of HPV 16/18 E6 in p53 inactivation in pterygium, the association between HPV 16 or HPV 18 infection, the HPV E6 oncoprotein, and p53 protein expression was analyzed in this study.MethodsHPV 16/18 infection was detected by nested-polymerase chain reaction (nested-PCR), the p53 mutation was detected by direct sequencing, and the p53 and the HPV 16/18 E6 proteins were studied using immunohistochemistry on 129 pterygial specimens and 20 normal conjunctivas.ResultsThe HPV 16/18 was detected in 24% of the pterygium tissues (31 of 129) but not in the normal conjunctiva, and the HPV16/18 E6 oncoprotein was detected in 48.3% of HPV 16/18 DNA-positive pterygium tissues (15 of 31). In addition, p53 protein negative expression in pterygium was correlated with HPV16/18 E6 oncoprotein expression but not with a p53 mutation.ConclusionsHPV 16/18 E6 contributes to HPV-mediated pterygium pathogenesis as it is partly involved in p53 inactivation and is expressed in HPV DNA-positive pterygium

Identification of Postoperative Prognostic MicroRNA Predictors in Hepatocellular Carcinoma

Comparison of microRNA (miRNA) expression profiles in the noncancerous liver tissues adjacent to hepatocelluar carcinomas (HCCs) was a strategy to identify postoperative prognostic predictors in this study. Expression profiles of 270 miRNAs were determined in the paraneoplastic liver tissues of 12 HCC patients with known postoperative prognosis. A panel of candidate miRNA predictors was identified. The prognostic predictive value of these candidate miRNAs was then verified in 216 postoperative HCC patients. Univariate analysis identified 8 and 3 miRNA predictors for recurrence-free (RFS) and overall (OS) survivals, respectively. Multivariate analysis revealed high expression levels of miR-155 (HR, 2.002 [1.324–3.027]; P = .001), miR-15a (HR, 0.478 [0.248–0.920]; P = .027), miR-432 (HR, 1.816 [1.203–2.740]; P = .015), miR-486-3p (HR, 0.543 [0.330–0.893]; P = .016), miR-15b (HR, 1.074 [1.002–1.152]; P = .043) and miR-30b (HR, 1.102 [1.025–1.185]; P = .009) were significantly associated with RFS. When clinicopathological predictors were included, multivariate analysis revealed that tumor number and miR-432, miR-486-3p, and miR-30b expression levels remained significant as independent predictors for RFS. Additionally, expression knockdown of miR-155 in J7 and Mahlavu hepatoma cells resulted in decreased cell growth and enhanced cell death in xenograft tumors, suggesting an oncogenic effect of miR-155. In conclusion, significant prognostic miRNA predictors were identified through examination of miRNA expression levels in paraneoplastic liver tissues. Functional analysis of a miRNA predictor, miR-155, suggested that the prognostic miRNA predictors identified under this strategy could serve as potential molecular targets for anticancer therapy

HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation

SummaryAcute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance. HDAC8 deficiency or inhibition using HDAC8-selective inhibitors (HDAC8i) effectively restores p53 acetylation and activity. Importantly, HDAC8 inhibition induces apoptosis in inv(16)+ AML CD34+ cells, while sparing the normal hematopoietic stem cells. Furthermore, in vivo HDAC8i administration profoundly diminishes AML propagation and abrogates leukemia-initiating capacity of both murine and patient-derived LSCs. This study elucidates an HDAC8-mediated p53-inactivating mechanism promoting LSC activity and highlights HDAC8 inhibition as a promising approach to selectively target inv(16)+ LSCs

Functional characterization of cellulases identified from the cow rumen fungus Neocallimastix patriciarum W5 by transcriptomic and secretomic analyses

<p>Abstract</p> <p>Background</p> <p><it>Neocallimastix patriciarum</it> is one of the common anaerobic fungi in the digestive tracts of ruminants that can actively digest cellulosic materials, and its cellulases have great potential for hydrolyzing cellulosic feedstocks. Due to the difficulty in culture and lack of a genome database, it is not easy to gain a global understanding of the glycosyl hydrolases (<it>GHs</it>) produced by this anaerobic fungus.</p> <p>Results</p> <p>We have developed an efficient platform that uses a combination of transcriptomic and proteomic approaches to <it>N. patriciarum </it>to accelerate gene identification, enzyme classification and application in rice straw degradation. By conducting complementary studies of transcriptome (Roche 454 GS and Illumina GA IIx) and secretome (ESI-Trap LC-MS/MS), we identified 219 putative <it>GH </it>contigs and classified them into 25 <it>GH</it> families. The secretome analysis identified four major enzymes involved in rice straw degradation: β-glucosidase, endo-1,4-β-xylanase, xylanase B and Cel48A exoglucanase. From the sequences of assembled contigs, we cloned 19 putative cellulase genes, including the <it>GH1</it>, <it>GH3</it>, <it>GH5</it>, <it>GH6</it>, <it>GH9</it>, <it>GH18</it>, <it>GH43 </it>and <it>GH48 </it>gene families, which were highly expressed in <it>N. patriciarum </it>cultures grown on different feedstocks.</p> <p>Conclusions</p> <p>These <it>GH </it>genes were expressed in Pichia pastoris and/or Saccharomyces cerevisiae for functional characterization. At least five novel cellulases displayed cellulytic activity for glucose production. One β-glucosidase (W5-16143) and one exocellulase (W5-CAT26) showed strong activities and could potentially be developed into commercial enzymes.</p

Task-Dependent Differences in Operant Behaviors of Rats With Acute Exposure to High Ambient Temperature: A Potential Role of Hippocampal Dopamine Reuptake Transporters

Behavioral or cognitive functions are known to be influenced by thermal stress from the change in ambient temperature (Ta). However, little is known about how increased Ta (i.e., when the weather becomes warm or hot) may affect operant conditioned behavior and the neural substrates involved. The present study thus investigated the effects of high Ta on operant behaviors maintained on a fixed-ratio 1 (FR1) and a differential reinforcement for low-rate responding 10 s (DRL 10-s) schedule of reinforcement. The rats were randomly assigned to three groups receiving acute exposure to Ta of 23°C, 28°C, and 35°C, respectively, for evaluating the effects of high Ta exposure on four behavioral tests. Behavioral responses in an elevated T-maze and locomotor activity were not affected by Ta treatment. Regarding operant tests, while the total responses of FR1 behavior were decreased only under 35°C when compared with the control group of 23°C, those of DRL 10-s behavior were significantly reduced in both groups of 28°C and 35°C. Distinct patterns of inter-response time (IRT) distribution of DRL behavior appeared among the three groups; between-group differences of behavioral changes produced by high Ta exposure were confirmed by quantitative analyses of IRT data. Western blot assays of dopamine (DA) D1 and D2 receptor, DA transporter (DAT) and brain-derived neurotrophic factor (BDNF) were conducted for the sample tissues collected in six brain areas from all the subjects after acute high Ta exposure. Significant Ta-related effects were only revealed in the dorsal hippocampus (dHIP). In which, the DAT levels were increased in a Ta-dependent fashion that was associated with operant behavior changes under high Ta exposure. And, there as an increased level of D1 receptors in the 28°C group. In summary, these data indicate that the performance of operant behavior affected by the present high Ta exposure is task-dependent, and these changes of operant behaviors cannot be attributed to gross motor function or anxiety being affected. The regulation of dHIP DAT may be involved in this operant behavioral change under high Ta exposure

Glyoxalase-I Is a Novel Prognosis Factor Associated with Gastric Cancer Progression

Glyoxalase I (GLO1), a methylglyoxal detoxification enzyme, is implicated in the progression of human malignancies. The role of GLO1 in gastric cancer development or progression is currently unclear. The expression of GLO1 was determined in primary gastric cancer specimens using quantitative polymerase chain reaction, immunohistochemistry (IHC), and western blotting analyses. GLO1 expression was higher in gastric cancer tissues, compared with that in adjacent noncancerous tissues. Elevated expression of GLO1 was significantly associated with gastric wall invasion, lymph node metastasis, and pathological stage, suggesting a novel role of GLO1 in gastric cancer development and progression. The 5-year survival rate of the lower GLO1 expression groups was significantly greater than that of the higher expression groups (log rank P = 0.0373) in IHC experiments. Over-expression of GLO1 in gastric cancer cell lines increases cell proliferation, migration and invasiveness. Conversely, down-regulation of GLO1 with shRNA led to a marked reduction in the migration and invasion abilities. Our data strongly suggest that high expression of GLO1 in gastric cancer enhances the metastasis ability of tumor cells in vitro and in vivo, and support its efficacy as a potential marker for the detection and prognosis of gastric cancer

Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia

Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR–ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR–ABL, which led to inhibition of the RAN–exportin-5–RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR–ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML

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 \u3c 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