Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer.

Alteration to the expression and activity of androgen receptor (AR) coregulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR coregulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and colocated with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARV), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial-mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR coregulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also as a suppressor of metastasis-related phenotypes. Cancer Res; 77(13); 3417-30. ©2017 AACR

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Prediction of gene expression regulation by human microRNAs in Plasmodium falciparum

Abstract Background Malaria is a disease annually causing over 400,000 deaths. Deep understanding of molecular and genetic processes underlying its life cycle and pathogenicity is required to efficiently resist it. RNA interference is a mechanism of the gene expression regulation typical for a wide variety of species. Even though the existence of this phenomenon in Plasmodium falciparum has long been rejected, several recent works pose hypotheses and provide direct and indirect evidence of the existence of mechanisms similar to RNA interference in this organism. In particular, the possibility of regulation of P. falciparum gene expression through human microRNAs is of great importance both for fundamental biology and for medicine. In the present work we address the problem of possibility of the existence in the P. falciparum genome of the nucleotide sequences such that mRNAs transcribed from genes containing these sequences could form duplexes with human microRNAs. Using bioinformatics methods we have analysed genomes of 15 P. falciparum isolates for sequences homological to these microRNAs. Results The analysis has demonstrated the existence of a vast number of genes that could potentially be regulated by the human microRNAs in the plasmodial genome. Conclusions Despite the fact that the numbers of homological intervals vary significantly between isolates, the hsa-miR-451a and hsa-miR-223-3p microRNAs are expected to make the most notable contribution to the pathogenesis of P. falciparum malaria. The majority of homological intervals occur in genes encoding cell adhesion proteins

Peculiar features of bone marrow cell proliferation in Djungarian hamsters with genetic disorders under thiotepa effect

The paper aims to examine the proliferation of bone marrow cell pool in Djungarian hamsters and the subsequent restoration of their genetic stability after the action of thiotepa (TT). The study involved 36 animals, of which 16 were in the control group (injected with 0.25 ml of physiological solution), and 20 in the experimental group (0.25 ml of thiotepa at a dose of 1.5 mg per 1 kg of body weight). The maximum number of cells with CA amounting to 30.0% was observed 13 hours after TT injection (p≤0.05 between the control and experimental groups) and rapidly declined to 5.7% over subsequent periods by the 37th hour of the experiment (p≤0.05). The results suggest that the restoration of cell pool genetic stability is largely associated with the cell selection mechanisms, which confers an advantage over cell proliferation without chromosome anomalies

Substructure Development and Damage Initiation in a Carbide-Free Bainitic Steel upon Tensile Test

Carbide-free bainitic (CFB) steels belong to the family of advanced high strength steels (AHSS) that are struggling to become part of the third-generation steels to be marketed for the automotive industry. The combined effects of the bainitic matrix and the retained austenite confers a significant strength with a remarkable ductility to these steels. However, CFB steels usually show much more complex microstructures that also contain MA (Martensite–Austenite) phase and auto-tempered martensite (ATM). These phases may compromise the ductility of CFB steels. The present work analyzes the substructure evolution during tensile tests in the necking zone, and deepens into the void and crack formation mechanisms and their relationship with the local microstructure. The combination of FEG-SEM imaging, EBSD, and X-ray diffraction has been necessary to characterize the substructure development and damage initiation. The bainite matrix has shown great ductility through the generation of high angle grain boundaries and/or large orientation gradients around voids, which are usually found close to the bainite and MA/auto-tempered martensite interfaces or fragmenting the MA phase. Special attention has been paid to the stability of the retained austenite (RA) during the test, which may eventually be transformed into martensite (Transformation Induced Plasticity, or TRIP effect)

Substructure development and damage initiation in a carbide-free bainitic steel upon tensile test

Carbide-free bainitic (CFB) steels belong to the family of advanced high strength steels (AHSS) that are struggling to become part of the third-generation steels to be marketed for the automotive industry. The combined effects of the bainitic matrix and the retained austenite confers a significant strength with a remarkable ductility to these steels. However, CFB steels usually show much more complex microstructures that also contain MA (Martensite–Austenite) phase and auto-tempered martensite (ATM). These phases may compromise the ductility of CFB steels. The present work analyzes the substructure evolution during tensile tests in the necking zone, and deepens into the void and crack formation mechanisms and their relationship with the local microstructure. The combination of FEG-SEM imaging, EBSD, and X-ray diffraction has been necessary to characterize the substructure development and damage initiation. The bainite matrix has shown great ductility through the generation of high angle grain boundaries and/or large orientation gradients around voids, which are usually found close to the bainite and MA/auto-tempered martensite interfaces or fragmenting the MA phase. Special attention has been paid to the stability of the retained austenite (RA) during the test, which may eventually be transformed into martensite (Transformation Induced Plasticity, or TRIP effect)

Substructure development and damage initiation in a carbide-free bainitic steel upon tensile test

Carbide-free bainitic (CFB) steels belong to the family of advanced high strength steels (AHSS) that are struggling to become part of the third-generation steels to be marketed for the automotive industry. The combined effects of the bainitic matrix and the retained austenite confers a significant strength with a remarkable ductility to these steels. However, CFB steels usually show much more complex microstructures that also contain MA (Martensite–Austenite) phase and auto-tempered martensite (ATM). These phases may compromise the ductility of CFB steels. The present work analyzes the substructure evolution during tensile tests in the necking zone, and deepens into the void and crack formation mechanisms and their relationship with the local microstructure. The combination of FEG-SEM imaging, EBSD, and X-ray diffraction has been necessary to characterize the substructure development and damage initiation. The bainite matrix has shown great ductility through the generation of high angle grain boundaries and/or large orientation gradients around voids, which are usually found close to the bainite and MA/auto-tempered martensite interfaces or fragmenting the MA phase. Special attention has been paid to the stability of the retained austenite (RA) during the test, which may eventually be transformed into martensite (Transformation Induced Plasticity, or TRIP effect)

Nanoparticles Produced by Ring-Opening Metathesis Polymerization Using Norbornenyl-poly(ethylene oxide) as a Ligand-Free Generic Platform for Highly Selective In Vivo Tumor Targeting

We described a norbornenyl-poly(ethylene oxide) nanoparticles ligand-free generic platform, made fluorescent with straightforward preparation by ring-opening metathesis polymerization (ROMP). Our method allowed to easily obtain a drug delivery system (DDS) with facilitated functionalization by means of azide-alkyne click chemistry and with a high selectivity for the tumor in vivo, while cellular internalization is obtained without cell targeting strategy. We demonstrated that our nanoparticles are internalized by endocytosis and colocalized with acidic intracellular compartments in two models of aggressive tumoral cell lines with low prognostic and limited therapeutic treatments. Our nanoparticles could be of real interest to limit the toxicity and to increase the clinical benefit of drugs suffering rapid clearance and side effects and an alternative for cancers with poorly efficient therapeutic solutions by associating the drug delivery in the tumor tissue with an acid-sensitive release system

Vorinostat-Polymer Conjugate Nanoparticles for Acid-Responsive Delivery and Passive Tumor Targeting

International audienc

Histone deacetylase inhibitor-polymer conjugate nanoparticles for acid-responsive drug delivery

We report the synthesis of acid responsive polymeric nanoparticles (NPs) consisting of a polymerhistone deacetylase inhibitor conjugate. An innovative aspect of this drug delivery particle lies in the NP conjugation of a histone deacetylase (HDAC) inhibitor, CI-994 (Tacedinaline), introduced with a clickable acid-responsive prodrug during monomer synthesis, prior to polymerization. Another novelty lies in the selected norbornene (NB)-polyethylene oxide (PEO) macromonomer allowing standardization of the polymerization process by Ring-Opening Metathesis Polymerization (ROMP) and functionalization through azide-allcyne click chemistry. Herein we demonstrate that the synthesized polymer gave 300 nm core-shell spherical nanoparticles with low dispersity (0.04), high water dispersability thanks to the PEO shell and well controlled HDAC inhibitor prodrug loading. Bioluminescence Resonance Energy Transfer (BRET) assay in living cells and viability experiments demonstrated efficient cellular internalization without additional chemistry, drug release inside cells with restoration of the HDAC inhibition and induction of apoptosis. Such NPs should minimize drug release in vivo during blood circulation and trigger intracellular delivery after endocytosis, holding promises for improved efficacy of this class of epigenetic inhibitors. This standardized synthesis paves the way for multifunctional nanoparticles synthesis