In-vivo high resolution imaging of optic nerve head drusen using spectral-domain Optical Coherence Tomography

<p>Abstract</p> <p>Background</p> <p>Optic nerve head drusen (ONHD) are white calcareous deposits, seen either superficially on the optic nerve head or buried within it. Diagnosis of ONHD is made by one or more ways: clinical exam, autofluorescence, ultrasound of the optic nerve, CT scan and/or visual field examination. The present study describes features of ONHD based on another diagnostic modality, the spectral-domain OCT (Spectralis).</p> <p>Methods</p> <p>This is a retrospective case series of 5 patients with bilateral ONHD with a best-corrected visual acuity of 20/20 and no other posterior segment pathology. All the patients underwent fundus photography, fundus autofluorescence, B-scan ultrasonography, Spectralis OCT and Humphrey 30-2 threshold visual fields.</p> <p>Results</p> <p>All 5 patients had surface ONHD which were autofluorescent and echodense on B-scan ultrasonography. Spectralis OCT findings in the corresponding areas include 'scattered spots with high reflectivity' casting a shadow underneath. The reflectivity can be distinctly differentiated from the blood vessels on the optic nerve. Two patients had an arcuate scotoma on the Humphrey visual fields. No correlation was found between the changes on Spectralis OCT with that of visual field.</p> <p>Conclusions</p> <p>Spectralis OCT is another useful ancillary investigation in the diagnosis of ONHD and we describe the features in the present study.</p

Metabolism of ticagrelor in patients with acute coronary syndromes.

© The Author(s) 2018Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.Peer reviewedFinal Published versio

Bromocriptine treatment associated with recovery from peripartum cardiomyopathy in siblings: two case reports

<p>Abstract</p> <p>Introduction</p> <p>Peripartum cardiomyopathy is a rare form of cardiomyopathy, with heterogeneous presentation occurring in women between one-month antepartum and six months postpartum. It carries a poor prognosis and a high risk of mortality.</p> <p>Case presentation</p> <p>We report the development of peripartum cardiomyopathy in two sisters, 27- and 35-year-old African women, one of whom presented with a large left ventricular thrombus. Subsequently, both patients were treated with bromocriptine, heparin and standard therapy for heart failure (angiotensin converting enzyme inhibitors, beta-blockers and diuretics). During follow-up, the left ventricular thrombus observed in one patient degraded. Neither patient experienced a thrombotic event, and both experienced continuous improvements in cardiac function and New York Heart Association stage.</p> <p>Conclusion</p> <p>The development of peripartum cardiomyopathy in two sisters indicates that there may be a genetic basis for this type of cardiomyopathy, and that women with a positive family history for peripartum cardiomyopathy may have an increased risk of developing the disease. This is also the first report of a patient experiencing degradation of a large left ventricular thrombus under standard therapy for heart failure with bromocriptine. It suggests that the use of bromocriptine in association with adequate anti-coagulation and heart failure therapy may be beneficial and safe.</p

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

© 2017 The Authors. Published by Nature Publishing Group. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/cddis.2017.176Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs. Here, we report the in vitro and in vivo activity of DS in combination with copper (Cu) against CD34(+)/CD38(+) leukemia stem-like cells sorted from KG1α and Kasumi-1 AML cell lines, as well as primary CD34(+) AML samples. DS plus Cu (DS/Cu) displayed marked inhibition of proliferation, induction of apoptosis, and suppression of colony formation in cultured AML cells while sparing the normal counterparts. DS/Cu also significantly inhibited the growth of human CD34(+)/CD38(+) leukemic cell-derived xenografts in NOD/SCID mice. Mechanistically, DS/Cu-induced cytotoxicity was closely associated with activation of the stress-related ROS-JNK pathway as well as simultaneous inactivation of the pro-survival Nrf2 and nuclear factor-κB pathways. In summary, our findings indicate that DS/Cu selectively targets leukemia stem-like cells both in vitro and in vivo, thus suggesting a promising LSC-targeted activity of this repurposed agent for treatment of relapsed and refractory AML

Nox4 Mediates Renal Cell Carcinoma Cell Invasion through Hypoxia-Induced Interleukin 6- and 8- Production

Inflammatory cytokines are detected in the plasma of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. However, the primary cell type involved in producing inflammatory cytokines and the biological significance in RCC remain unknown. Inflammation is associated with oxidative stress, upregulation of hypoxia inducible factor 1-alpha, and production of pro-inflammatory gene products. Solid tumors are often heterogeneous in oxygen tension together suggesting that hypoxia may play a role in inflammatory processes in RCC. Epithelial cells have been implicated in cytokine release, although the stimuli to release and molecular mechanisms by which they are released remain unclear. AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status and a role for AMPK in the regulation of cell inflammatory processes has recently been demonstrated.We have identified for the first time that interleukin-6 and interleukin-8 (IL-6 and IL-8) are secreted solely from RCC cells exposed to hypoxia. Furthermore, we demonstrate that the NADPH oxidase isoform, Nox4, play a key role in hypoxia-induced IL-6 and IL-8 production in RCC. Finally, we have characterized that enhanced levels of IL-6 and IL-8 result in RCC cell invasion and that activation of AMPK reduces Nox4 expression, IL-6 and IL-8 production, and RCC cell invasion.Together, our data identify novel mechanisms by which AMPK and Nox4 may be linked to inflammation-induced RCC metastasis and that pharmacological activation of AMPK and/or antioxidants targeting Nox4 may represent a relevant therapeutic intervention to reduce IL-6- and IL-8-induced inflammation and cell invasion in RCC

Active nuclear import and cytoplasmic retention of activation-induced deaminase

The enzyme activation-induced deaminase (AID) triggers antibody diversification in B cells by catalyzing deamination and consequently mutation of immunoglobulin genes. To minimize off-target deamination, AID is restrained by several regulatory mechanisms including nuclear exclusion, thought to be mediated exclusively by active nuclear export. Here we identify two other mechanisms involved in controlling AID subcellular localization. AID is unable to passively diffuse into the nucleus, despite its small size, and its nuclear entry requires active import mediated by a conformational nuclear localization signal. We also identify in its C terminus a determinant for AID cytoplasmic retention, which hampers diffusion to the nucleus, competes with nuclear import and is crucial for maintaining the predominantly cytoplasmic localization of AID in steady-state conditions. Blocking nuclear import alters the balance between these processes in favor of cytoplasmic retention, resulting in reduced isotype class switching.This work was supported by the Canadian Institutes of Health Research (MOP 84543) and a Canada Research Chair (to J.M.D.). A.O. was supported by a fellowship from the Canadian Institutes of Health Research Cancer Training Program at the IRCM. V.A.C. was supported in part by a Michel Saucier fellowship from the Louis-Pasteur Canadian Fund through the University of Montreal