Transcriptional network involving ERG and AR orchestrates Distal-less homeobox-1 mediated prostate cancer progression

Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, ~96% of TMPRSS2-ERG fusion-positive and ~70% of androgen receptor (AR)-positive patients show elevated DLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation of DLX1 in ERG-positive background. However, in ERG-negative context, AR/AR-V7 and FOXA1 suffice to upregulate DLX1. Notably, inhibiting ERG/AR-mediated DLX1 transcription using BET inhibitor (BETi) or/and anti-androgen drugs reduce its expression and downstream oncogenic effects. Conclusively, this study establishes DLX1 as a direct-target of ERG/AR with an oncogenic role and demonstrates the clinical significance of BETi and anti-androgens for DLX1-positive patients

Carlinoside reduces hepatic bilirubin accumulation by stimulating bilirubin-UGT activity through Nrf2 gene expression

Accu mulati on of biliru bin, prima rily because of its insol ubilit y, has bee n found to be associa ted with liver disea ses includ ing jaundice . Free bilir ubin is insol uble; its glucuro nidation by bilirubin -UGT enz yme (UGT1 A1) makes it soluble and elimina tes it throu gh urine and fae ces. Taki ng CCl 4 induced ra t liver dysfun ction m odel, we demonst rated that supp ression of UGT1A 1 activity in ra t liv er increa sed ser um biliru bin level wh ich could be reve rsed by carl inoside (Cln), a flavone glyc oside. Alth ough Cln is a flavone compou nd, it escaped self-glucu ronid ation in the intestin e and readily absorbe d. Kineti c stud y of mic rosoma l UGT1A 1 from HepG 2 cells sugg ested that Cln enhan ced enz yme activity by increa sing V max with out alterin g K m. This altered V max was foun d to be due to UGT1A 1 ove rexpre ssion by Cln wh ich wa s obser ved in both HepG 2 and rat prima ry hepa tocytes . Sin ce Nrf2 is the transc ription factor of UG T1A1, we exam ined whethe r Cln effe ct on UG T1A1 overexp ression is media ted th rough Nrf2. In Nrf2 knock -out cells, Cln cou ld not eleva te UG T1A1 activity indica ting Nrf2 to be its target. Cln signific antly increas ed Nrf2 ge ne expr ession in HepG2 cells wh ich was subse quently locali zed in nuclear region . Resu lts from Ch IP assa y show ed that Cln mar kedly augm ented Nrf2 bindi ng to UGT1A 1 prom oter that con sequentl y enhan ced report er act ivity. Our findings therefor e show that Cln upreg ulated Nr f2 gene expr ession, incr eased its nu clear tran slocation and stimula ted UGT1A 1 prom oter act ivity. Tota l outc ome of these even ts brought about a signific ant increase of biliru bin glucur onida tion. Cln ther efore could be a wor thy choice to int ervene hype rbilir ubinemi a due to liv er dysfunc tion

Fingerprint classification using a fuzzy multilayer perceptron

A fuzzy multilayer perceptron is used for the classification of fingerprint patterns. The input vector consists of texturebased features along with some directional features. The output vector is defined in terms of membership values to the three classes, viz.Whorl, Left Loop and Right Loop. Perturbation is produced randomly at pixel locations to generate noisy patterns. This helps to demonstrate the ability of the model in handling distorted fingerprint images. A study is made on the effect of reducing the number of input features while increasing the size of the network on its recognition performance

Histological and immunohistochemical appearance of osteochondral defect filled with non-mulberry silk scaffolds (<i>Am</i>) without growth factors <i>in vivo</i>.

<p>(A) AB/SR staining; (B) Birefringence of AB/SR section; (C) immunostaining with type I collagen and (D) immunostaining with type II collagen. Black asterisks denote the scaffold within the defects. Scale bars represented 50 µm.</p

Schematic representation of fabrication of 3D scaffolds of <i>B. mori</i> and <i>A. mylitta</i>.

<p>Cut pieces of <i>B. mori</i> silk cocoons were alkaline hydrolyzed, degummed fibers dissolved and dialyzed to yield silk fibroin solution. The mature 5^th instar larvae of <i>A. mylitta</i> were dissected to isolate silk glands and dialyzed to obtain gland silk fibroin solutions. The solutions were used to fabricate 3D scaffolds.</p

Histological and immunohistochemical appearance of osteochondral defect filled with mulberry silk scaffolds (<i>Bm</i>) treated with growth factors <i>in vivo</i>.

<p>(A) AB/SR staining; (B) Birefringence of AB/SR section; (C) immunostaining with type I collagen and (D) immunostaining with type II collagen. Black asterisks denote the scaffold within the defects. Scale bars represented 50 µm.</p

Histological and immunohistochemical appearance of osteochondral defect filled with non-mulberry silk scaffolds (<i>Am</i>) treated with growth factors <i>in vivo</i>.

<p>(A) AB/SR staining; (B) Birefringence of AB/SR section; (C) immunostaining with type I collagen and (D) immunostaining with type II collagen. Black asterisks denote the scaffold within the defects. Scale bars represented 50 µm.</p

Confocal images of hBMSCs seeded on 3D silk fibroin scaffolds and cultured in chondroinductive and osteoinductive media.

<p>Non-mulberry <i>A. mylitta</i> silk constructs: (A) 4 weeks after chondrogenic culture and (C) 8 weeks after osteogenic culture. Mulberry <i>B. mori</i> silk constructs: (B) 4 weeks after chondrogenic culture; (D) 8 weeks after osteogenic culture condition. Yellow arrows indicate attachment of viable cells onto all available areas of the scaffold. Scale bars represent 300 µm.</p