Time-trends and treatment gaps in the antithrombotic management of patients with atrial fibrillation after percutaneous coronary intervention: Insights from the CHUM AF-STENT Registry.

BACKGROUND: The management of atrial fibrillation and flutter (AF) patients undergoing percutaneous coronary intervention (PCI) has undergone a rapid recent evolution. In 2016, the Canadian Cardiovascular Society (CCS) published expert recommendations to help guide clinicians in balancing bleeding and thrombotic risks in these patients. HYPOTHESIS: Antithrombotic regimen prescriptions for AF patients undergoing PCI evolved after the publication of the 2016 CCS AF guidelines. METHODS: A prospective cohort of AF patients undergoing PCI with placement of a coronary stent from a single tertiary academic center was analyzed for the recommended antithrombotic regimen at discharge. Prescribing behavior was compared between three time periods (Cohort A [2010-2011]; Cohort B [2014-2015]; Cohort C [2017]) using the χ2 test. In addition, antithrombotic management in Cohorts B and C were compared to guideline-recommended therapy. RESULTS: A total of 459 patients with AF undergoing PCI were identified. Clinical and procedural characteristics were similar between cohorts, with the exception of an increase in drug-eluting stent (DES) use over time (P < .01). Overall, the rate of oral anticoagulation (OAC) increased over time (P < .01), associated with an increase in nonvitamin K OAC prescription (P < .01) and a concomitant decrease in vitamin K antagonist prescription (P < .01). Despite this, the overall rate of anticoagulation remains below what would be predicted with perfect guideline compliance (75% vs 94%, P < .01). CONCLUSION: There has been a dramatic shift in clinical practice for AF patients requiring PCI, with increases in prescription of OAC even in the context of an increase in the use of DES. However, room for further practice optimization still exists

Fill in Fabrics: Body-Aware Self-Supervised Inpainting for Image-Based Virtual Try-On

Previous virtual try-on methods usually focus on aligning a clothing item with a person, limiting their ability to exploit the complex pose, shape and skin color of the person, as well as the overall structure of the clothing, which is vital to photo-realistic virtual try-on. To address this potential weakness, we propose a fill in fabrics (FIFA) model, a self-supervised conditional generative adversarial network based framework comprised of a Fabricator and a unified virtual try-on pipeline with a Segmenter, Warper and Fuser. The Fabricator aims to reconstruct the clothing image when provided with a masked clothing as input, and learns the overall structure of the clothing by filling in fabrics. A virtual try-on pipeline is then trained by transferring the learned representations from the Fabricator to Warper in an effort to warp and refine the target clothing. We also propose to use a multi-scale structural constraint to enforce global context at multiple scales while warping the target clothing to better fit the pose and shape of the person. Extensive experiments demonstrate that our FIFA model achieves state-of-the-art results on the standard VITON dataset for virtual try-on of clothing items, and is shown to be effective at handling complex poses and retaining the texture and embroidery of the clothing

A Synthetic Interaction Screen Identifies Factors Selectively Required for Proliferation and TERT Transcription in p53-Deficient Human Cancer Cells

Numerous genetic and epigenetic alterations render cancer cells selectively dependent on specific genes and regulatory pathways, and represent potential vulnerabilities that can be therapeutically exploited. Here we describe an RNA interference (RNAi)-based synthetic interaction screen to identify genes preferentially required for proliferation of p53-deficient (p53-) human cancer cells. We find that compared to p53-competent (p53+) human cancer cell lines, diverse p53- human cancer cell lines are preferentially sensitive to loss of the transcription factor ETV1 and the DNA damage kinase ATR. In p53- cells, RNAi-mediated knockdown of ETV1 or ATR results in decreased expression of the telomerase catalytic subunit TERT leading to growth arrest, which can be reversed by ectopic TERT expression. Chromatin immunoprecipitation analysis reveals that ETV1 binds to a region downstream of the TERT transcriptional start-site in p53- but not p53+ cells. We find that the role of ATR is to phosphorylate and thereby stabilize ETV1. Our collective results identify a regulatory pathway involving ETV1, ATR, and TERT that is preferentially important for proliferation of diverse p53- cancer cells

The Human Gonadotropin Releasing Hormone Type I Receptor Is a Functional Intracellular GPCR Expressed on the Nuclear Membrane

The mammalian type I gonadotropin releasing hormone receptor (GnRH-R) is a structurally unique G protein-coupled receptor (GPCR) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression (PME). Compared to its murine counterparts, the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum (ER) leading to a further reduction in PME. The decrease in PME and concomitant increase in intracellular localization of the mammalian GnRH-RI led us to characterize the spatial distribution of the human and mouse GnRH receptors in two human cell lines, HEK 293 and HTR-8/SVneo. In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane. A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence (NLS) in the first intracellular loop of GnRH-RI. Surprisingly, however, neither the deletion of the NLS nor the addition of the Xenopus GnRH-R cytoplasmic tail sequences to the human receptor altered its spatial distribution. Finally, we demonstrate that GnRH treatment of nuclei isolated from HEK 293 cells expressing exogenous GnRH-RI triggers a significant increase in the acetylation and phosphorylation of histone H3, thereby revealing that the nuclear-localized receptor is functional. Based on our findings, we conclude that the mammalian GnRH-RI is an intracellular GPCR that is expressed on the nuclear membrane. This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor

Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK

Direct pharmacological targeting of the anti-apoptotic B-cell lymphoma-2 (BCL-2) family is an attractive therapeutic strategy for treating cancer. Obatoclax is a pan-BCL-2 family inhibitor currently in clinical development. Here we show that, although obatoclax can induce mitochondrial apoptosis dependent on BCL-2 associated x protein/BCL-2 antagonist killer (BAX/BAK) consistent with its on-target pharmacodynamics, simultaneous silencing of both BAX and BAK did not abolish acute toxicity or loss of clonogenicity. This is despite complete inhibition of apoptosis. Obatoclax dramatically reduced viability without inducing loss of plasma membrane integrity. This was associated with rapid processing of light chain-3 (LC3) and reduction of S6 kinase phosphorylation, consistent with autophagy. Dramatic ultrastructural vacuolation, not typical of autophagy, was also induced. Silencing of beclin-1 failed to prevent LC3 processing, whereas knockout of autophagy-related (Atg)7 abolished LC3 processing but failed to prevent obatoclax-induced loss of clonogenicity or ultrastructural changes. siRNA silencing of Atg7 in BAX/BAK knockout mouse embryonic fibroblasts did not prevent obatoclax-induced loss of viability. Cells selected for obatoclax resistance evaded apoptosis independent of changes in BCL-2 family expression and displayed reduced LC3 processing. In summary, obatoclax exhibits BAX- and BAK-dependent and -independent mechanisms of toxicity and activation of autophagy. Mechanisms other than autophagy and apoptosis are blocked in obatoclax resistant cells and contribute significantly to obatoclax's anticancer efficacy

Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites

Le magmatisme de la région de Kwyjibo, Province\ud du Grenville (Canada) : intérêt pour les\ud minéralisations de type fer-oxydes associées

The granitic plutons located north of the Kwyjibo property in Quebec’s Grenville Province are of\ud Mesoproterozoic age and belong to the granitic Canatiche Complex . The rocks in these plutons are calc-alkalic, K-rich,\ud and meta- to peraluminous. They belong to the magnetite series and their trace element characteristics link them to\ud intraplate granites. They were emplaced in an anorogenic, subvolcanic environment, but they subsequently underwent\ud significant ductile deformation. The magnetite, copper, and fluorite showings on the Kwyjibo property are polyphased\ud and premetamorphic; their formation began with the emplacement of hydraulic, magnetite-bearing breccias, followed by\ud impregnations and veins of chalcopyrite, pyrite, and fluorite, and ended with a late phase of mineralization, during\ud which uraninite, rare earths, and hematite were emplaced along brittle structures. The plutons belong to two families:\ud biotite-amphibole granites and leucogranites. The biotite-amphibole granites are rich in iron and represent a potential\ud heat and metal source for the first, iron oxide phase of mineralization. The leucogranites show a primary enrichment in\ud REE (rare-earth elements), F, and U, carried mainly in Y-, U-, and REE-bearing niobotitanates. They are metamict and\ud underwent a postmagmatic alteration that remobilized the uranium and the rare earths. The leucogranites could also be\ud a source of rare earths and uranium for the latest mineralizing events

Overexpression of Myocilin in the Drosophila Eye Activates the Unfolded Protein Response: Implications for Glaucoma

Glaucoma is the world's second leading cause of bilateral blindness with progressive loss of vision due to retinal ganglion cell death. Myocilin has been associated with congenital glaucoma and 2-4% of primary open angle glaucoma (POAG) cases, but the pathogenic mechanisms remain largely unknown. Among several hypotheses, activation of the unfolded protein response (UPR) has emerged as a possible disease mechanism.We used a transgenic Drosophila model to analyze whole-genome transcriptional profiles in flies that express human wild-type or mutant MYOC in their eyes. The transgenic flies display ocular fluid discharge, reflecting ocular hypertension, and a progressive decline in their behavioral responses to light. Transcriptional analysis shows that genes associated with the UPR, ubiquitination, and proteolysis, as well as metabolism of reactive oxygen species and photoreceptor activity undergo altered transcriptional regulation. Following up on the results from these transcriptional analyses, we used immunoblots to demonstrate the formation of MYOC aggregates and showed that the formation of such aggregates leads to induction of the UPR, as evident from activation of the fluorescent UPR marker, xbp1-EGFP. CONCLUSIONS / SIGNIFICANCE: Our results show that aggregation of MYOC in the endoplasmic reticulum activates the UPR, an evolutionarily conserved stress pathway that culminates in apoptosis. We infer from the Drosophila model that MYOC-associated ocular hypertension in the human eye may result from aggregation of MYOC and induction of the UPR in trabecular meshwork cells. This process could occur at a late age with wild-type MYOC, but might be accelerated by MYOC mutants to account for juvenile onset glaucoma

Ligand-Induced Tyrosine Phosphorylation of Cysteinyl Leukotriene Receptor 1 Triggers Internalization and Signaling in Intestinal Epithelial Cells

Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinity LTD(4) receptor CysLT(1)R exhibits tumor-promoting properties by triggering cell proliferation, survival, and migration in intestinal epithelial cells. In addition, increased expression and nuclear localization of CysLT(1)R correlates with a poorer prognosis for patients with colon cancer

The synthetic inhibitor of Fibroblast Growth Factor Receptor PD166866 controls negatively the growth of tumor cells in culture

<p>Abstract</p> <p>Background</p> <p>Many experimental data evidence that over-expression of various growth factors cause disorders in cell proliferation. The role of the Fibroblast Growth Factors (FGF) in growth control is indisputable: in particular, FGF1 and its tyrosine kinase receptor (FGFR1) act through a very complex network of mechanisms and pathways. In this work we have evaluated the antiproliferative activity effect of PD166866, a synthetic molecule inhibiting the tyrosin kinase action of FGFR1.</p> <p>Methods</p> <p>Cells were routinely grown in Dulbecco Modified Eagle's medium supplemented with newborn serum and a penicillin-streptomycin mixture.</p> <p>Cell viability was evaluated by Mosmann assay and by trypan blue staining. DNA damage was assessed by <it>in situ </it>fluorescent staining with Terminal Deoxynucleotidyl Transferase dUTP nick end labeling (TUNEL assay).</p> <p>Assessment of oxidative stress at membrane level was measured by quantitative analysis of the intra-cellular formation of malonyl-dialdheyde (MDA) deriving from the decomposition of poly-unsaturated fatty acids.</p> <p>The expression of Poly-ADP-Ribose-Polymerase (PARP), consequent to DNA fragmentation, was evidenced by immuno-histochemistry utilizing an antibody directed against an N-terminal fragment of the enzyme.</p> <p>Results</p> <p>The bioactivity of the drug was investigated on Hela cells. Cytoxicity was assessed by the Mosmann assay and by vital staining with trypan blue. The target of the molecule is most likely the cell membrane as shown by the significant increase of the intracellular concentration of malonyl-dihaldheyde. The increase of this compound, as a consequence of the treatment with PD166866, is suggestive of membrane lipoperoxidation. The TUNEL assay gave a qualitative, though clear, indication of DNA damage. Furthermore we demonstrate intracellular accumulation of poly-ADP-ribose polymerase I. This enzyme is a sensor of nicks on the DNA strands and this supports the idea that treatment with the drug induces cell death.</p> <p>Conclusions</p> <p>Data presented in this work show that PD166866 has clear antiproliferative effects. The negative control of cell proliferation may be exerted through the activation of the apoptotic pathway. The results of experiments addressing this specific point, such as: evaluation of DNA damage, lipoperoxidation of the cell membrane and increase of expression of PARP, an enzyme directly involved in DNA repair. Results suggest that cells exposed to PD16866 undergo apoptosis. However, concomitant modes of cell death cannot be ruled out. The possible use of this drug for therapeutic purposes is discussed.</p