Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.

Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer

A robust algorithm for optic disc segmentation and fovea detection in retinal fundus images

Accurate optic disc (OD) segmentation and fovea detection in retinal fundus images are crucial for diagnosis in ophthalmology. We propose a robust and broadly applicable algorithm for automated, robust, reliable and consistent fovea detection based on OD segmentation. The OD segmentation is performed with morphological operations and Fuzzy C Means Clustering combined with iterative thresholding on a foreground segmentation. The fovea detection is based on a vessel segmentation via morphological operations and uses the resulting OD segmentation to determine multiple regions of interest. The fovea is determined from the largest, vessel-free candidate region. We have tested the novel method on a total of 190 images from three publicly available databases DRIONS, Drive and HRF. Compared to results of two human experts for DRIONS database, our OD segmentation yielded a dice coefficient of 0.83. Note that missing ground truth and expert variability is an issue. The new scheme achieved an overall success rate of 99.44% for OD detection and an overall success rate of 96.25% for fovea detection, which is superior to state-of-the-art approaches

Le pouvoir des listes au Moyen Âge - I

Les listes constituent une forme d'écriture très présente dans les textes du Moyen Âge, quels que soient leur nature et leur genre. Cette forme syntaxique, graphique et sémantique singulière a été l’objet d’une enquête collective menée dans le cadre d’un projet interdisciplinaire de recherche intitulé « Pouvoir des listes au Moyen Âge » (Polima), qui a bénéficié du soutien de l’ANR. Trois volumes collectifs rassemblent les études de cas issus des ateliers organisés dans le cadre de ce programme. Ils explorent les usages sociaux de cette forme d’écriture dotée de pouvoirs pragmatiques, poétiques et cognitifs. Ce volume propose une approche matérielle de la liste, qui vise à la saisir dans le rapport que son écriture construit avec le support ainsi qu’avec les lieux, démultipliés, de son installation (pages, livres, murs, monuments, reliquaires, objets du quotidien, etc.). Ces singularités documentaires, liées à des procédures ou à des jeux de dénombrement, permettent de rendre compte de l’abondance des listes dans les productions écrites du Moyen Âge et d’interroger ce que les différentes scènes sociales du Moyen Âge font de cet opérateur matériel et cognitif qui produit savoir et agency. Au cours de cette période, les listes et les formes de pensée qu’elles engendrent se transforment sous l’effet de l’apparition de nouveaux enjeux de dénombrement et de catégorisation. À l’arrière-plan des cas étudiés percent ainsi la transformation grégorienne de l’Occident, la formation du savoir scolastique et l’essor des rationalités pratiques

DNA methylation analysis of glioblastomas harboring FGFR3-TACC3 fusions identifies a methylation subclass with better patient survival

FGFR3-TACC3 (F3T3) fusions are seen in 3.1–11.7% of glioblastoma (GBM) cases with better survival [1, 4, 5, 7–9]. We endeavored to characterize methylation profles in detail, using a cohort of 79 F3T3-positive GBMs from 71 patients (seven patients with primary and recurrent tumor resections, Table S1). Compared to gliomas without a docu mented fusion, dimensionality reduction showed that F3T3- positive GBMs nested predominantly to GBM-mesenchymal and RTK-II subclasses (Fig. 1a). Transcriptomic analysis on 9 F3T3-positive and 31 negative patients (Fig. 1b) confrmed a previous fnding of activated mitochondrial activity and altered vascular activity [2, 6]

Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel.

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus- related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis

ABC Transporters, Cholesterol Efflux, and Implications for Cardiovascular Diseases

Most types of cells in the body have no or very limited capacity of catabolizing cholesterol, so cholesterol efflux is essential for cholesterol homeostasis. There are multiple mechanisms responsible for cellular cholesterol efflux. Among them, the active efflux pathways are mediated primarily by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. ABCA1 is essential for cholesterol and phospholipid efflux to apolipoprotein A-I and high density lipoprotein (HDL) biogenesis. ABCG1 promotes cholesterol efflux primarily to HDL particles. Atherosclerotic cardiovascular disease is a chronic inflammatory disease characterized by marked macrophage foam cell accumulation in atherosclerotic plaques and associated pro-inflammatory responses in lesional cells. Findings from both animal and human studies indicate a critical role of disturbed cholesterol homeostasis in pro-inflammatory responses in these cells, particularly in lesional macrophages. ABCA1 and ABCG1 are highly expressed in macrophages, particularly in response to cholesterol accumulation, and are essential in maintenance of cholesterol homeostasis. Functional deficiency of ABCA1 and ABCG1 in macrophage markedly increases atherogenesis, with exacerbated inflammatory responses. ABCA1 and ABCG1 also play a critical role in control of hematopoietic stem and progenitor cell (HSPC) proliferation and extramedullary hematopoiesis. Hematopoietic ABCA1 and ABCG1 deficiencies cause marked HSPC expansion and extramedullary hematopoiesis, particularly in hypercholesterolemia, and lead to marked monocytosis and neutrophilia with exacerbated pro-inflammatory responses. All these contribute to atherosclerosis. In this chapter, we describe these findings and discuss the current understanding of the underlying mechanisms. We also discuss other ABC transporters such as ABCG4, which also promotes cholesterol efflux to HDL and controls megakaryocyte proliferation and platelet biogenesis. By this pathway, ABCG4 also modulates atherogenesis. Therapeutic approaches targeting the pathways and mechanisms described also are discussed.</p