STAT1: A Novel Target of miR-150 and miR-223 Is Involved in the Proliferation of HTLV-I–Transformed and ATL Cells

AbstractWe have previously reported on the deregulation of cellular microRNAs involved in hematopoiesis and inflammation in human T-cell lymphotropic virus type 1 (HTLV-I)–transformed cells. In this study, we demonstrate that miR-150 and miR-223 specifically target the signal transducer and activator of transcription 1 (STAT1) 3′ untranslated region, reducing STAT1 expression and dampening STAT1-dependent signaling in human T cells. The effects of miR-150 and miR-223 on endogenous STAT1 were confirmed using inducible cell lines. Our studies also showed that miR-150 expression is upregulated by interleukin-2 signaling in adult T cell leukemia/lymphoma (ATL) cells. HTLV-I–transformed and ATL-derived cells have reduced levels of miR150 and miR223 expression, which coincide with increased STAT1 expression and STAT1-dependent signaling. Knockdown of STAT1 by short hairpin RNA demonstrated that the constitutive activation of STAT1 is required for the continuous proliferation of HTLV-I–transformed cells. Our studies further demonstrate that increased expression of STAT1 in ATL cells is associated with higher levels of major histocompatibility complex class I expression. Previous studies have demonstrated that the pressure exerted by natural killer (NK) cells in vivo can edit leukemic tumor cells by forcing an increased expression of major histocompatibility complex class I to escape immune clearance. STAT1-expressing tumor cells produce more aggressive tumors because they cannot be eliminated by NK cells. Our results suggest that therapeutic approaches using combined targeting of STAT1 and MHC class I may be an effective approach to activate NK cell–mediated clearance of ATL tumor cells

Jean-Noël Jeanneney, Clemenceau. Dernières nouvelles du Tigre

« Il y a des gens qui rétrécissent par manque d’admiration », nous rappelle Jean-Noël Jeanneney, en citant ces mots attribués à Victor Hugo. Ce ne fut pas le cas de Clemenceau, pas plus que de ceux qui, aujourd’hui, s’intéressent à cette figure marquante de la vie politique française. Car son souvenir et par lui sa défense, voire son modèle, restent d’une actualité toujours stimulante où l’admiration prend une place qu’elle n’a pas toujours eue. Sur ce personnage central de la Troisième Répub..

Jean-Michel Guieu, Gagner la paix (1914-1929)

Le 11 novembre 1918, les Alliés, vainqueurs de la guerre, réagissent avec liesse à l’annonce de l’Armistice. La population légitimement enjouée célèbre alors la fin du premier conflit mondial. Mais la paix se substitue-t-elle pour autant à la guerre ? Rien n’est moins sûr et les années qui suivent vont montrer précisément les difficultés de sa mise en place. Clemenceau, clairvoyant bien qu’heureux de se voir fêté en « Père la Victoire », ne dit pas autre chose : « Nous avons gagné la guerre, ..

Hyperspectral images segmentation: a proposal

Hyper-Spectral Imaging (HIS) also known as chemical or spectroscopic imaging is an emerging technique that combines imaging and spectroscopy to capture both spectral and spatial information from an object. Hyperspectral images are made up of contiguous wavebands in a given spectral band. These images provide information on the chemical make-up profile of objects, thus allowing the differentiation of objects of the same colour but which possess make-up profile. Yet, whatever the application field, most of the methods devoted to HIS processing conduct data analysis without taking into account spatial information.Pixels are processed individually, as an array of spectral data without any spatial structure. Standard classification approaches are thus widely used (k-means, fuzzy-c-means hierarchical classification...). Linear modelling methods such as Partial Least Square analysis (PLS) or non linear approaches like support vector machine (SVM) are also used at different scales (remote sensing or laboratory applications). However, with the development of high resolution sensors, coupled exploitation of spectral and spatial information to process complex images, would appear to be a very relevant approach. However, few methods are proposed in the litterature. The most recent approaches can be broadly classified in two main categories. The first ones are related to a direct extension of individual pixel classification methods using just the spectral dimension (k-means, fuzzy-c-means or FCM, Support Vector Machine or SVM). Spatial dimension is integrated as an additionnal classification parameter (Markov fields with local homogeneity constrainst [5], Support Vector Machine or SVM with spectral and spatial kernels combination [2], geometrically guided fuzzy C-means [3]...). The second ones combine the two fields related to each dimension (spectral and spatial), namely chemometric and image analysis. Various strategies have been attempted. The first one is to rely on chemometrics methods (Principal Component Analysis or PCA, Independant Component Analysis or ICA, Curvilinear Component Analysis...) to reduce the spectral dimension and then to apply standard images processing technics on the resulting score images i.e. data projection on a subspace. Another approach is to extend the definition of basic image processing operators to this new dimensionality (morphological operators for example [1, 4]). However, the approaches mentioned above tend to favour only one description either directly or indirectly (spectral or spatial). The purpose of this paper is to propose a hyperspectral processing approach that strikes a better balance in the treatment of both kinds of information....Cet article présente une stratégie de segmentation d’images hyperspectrales liant de façon symétrique et conjointe les aspects spectraux et spatiaux. Pour cela, nous proposons de construire des variables latentes permettant de définir un sous-espace représentant au mieux la topologie de l’image. Dans cet article, nous limiterons cette notion de topologie à la seule appartenance aux régions. Pour ce faire, nous utilisons d’une part les notions de l’analyse discriminante (variance intra, inter) et les propriétés des algorithmes de segmentation en région liées à celles-ci. Le principe générique théorique est exposé puis décliné sous la forme d’un exemple d’implémentation optimisé utilisant un algorithme de segmentation en région type split and merge. Les résultats obtenus sur une image de synthèse puis réelle sont exposés et commentés

Hyperspectral image segmentation: the butterfly approach

International audienceFew methods are proposed in the litterature for coupling the spectral and the spatial dimension available on hyperspectral images. This paper proposes a generic segmentation scheme named butterfly based on an iterative process and a cross analysis of spectral and spatial information. Indeed, spatial and spatial structures are extracted in spatial and spectral space respectively both taking into account the other one. To apply this layout on hyperspectral imgages, we focus particulary on spatial and spectral structures i.e. topologic concepts and latent variable for the spatial and the spectral space respectively. Moreover, a cooperation scheme with these structures is proposed. Finally, results obtained on real hyperspectral images using this specific implementation of the butterfly approach are presented and discussed

Measurements of mechanical thermal noise and energy dissipation in optical dielectric coatings

In recent years an increasing number of devices and experiments are shown to be limited by mechanical thermal noise. In particular sub-Hertz laser frequency stabilization and gravitational wave detectors, that are able to measure fluctuations of 1E-18 m/rtHz or less, are being limited by thermal noise in the dielectric coatings deposited on mirrors. In this paper we present a new measurement of thermal noise in low absorption dielectric coatings deposited on micro-cantilevers and we compare it with the results obtained from the mechanical loss measurements. The coating thermal noise is measured on the widest range of frequencies with the highest signal to noise ratio ever achieved. In addition we present a novel technique to deduce the coating mechanical losses from the measurement of the mechanical quality factor which does not rely on the knowledge of the coating and substrate Young moduli. The dielectric coatings are deposited by ion beam sputtering. The results presented here give a frequency independent loss angle of (4.70 $\pm$ 0.2)x1E-4 with a Young's modulus of 118 GPa for annealed tantala from 10 Hz to 20 kHz. For as-deposited silica, a weak frequency dependence (~ f^{-0.025}) is observed in this frequency range, with a Young's modulus of 70 GPa and an internal damping of (6.0 $\pm$ 0.3)x1E-4 at 16 kHz, but this value decreases by one order of magnitude after annealing and the frequency dependence disappears.Comment: Accepted for publication in Phys. Rev.

Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases

Background: Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods: Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results: We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients' samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions: These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current "wait and see approach" in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits

Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background HTLV-I is associated with the development of an aggressive form of lymphocytic leukemia known as adult T-cell leukemia/lymphoma (ATLL). A major obstacle for effective treatment of ATLL resides in the genetic diversity of tumor cells and their ability to acquire resistance to chemotherapy regimens. As a result, most patients relapse and current therapeutic approaches still have limited long-term survival benefits. Hence, the development of novel approaches is greatly needed. Methods In this study, we found that a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), PJ-34, is very effective in activating S/G2M cell cycle checkpoints, resulting in permanent cell cycle arrest and reactivation of p53 transcription functions and caspase-3-dependent apoptosis of HTLV-I-transformed and patient-derived ATLL tumor cells. We also found that HTLV-I-transformed MT-2 cells are resistant to PJ-34 therapy associated with reduced cleaved caspase-3 activation and increased expression of RelA/p65. Conclusion Since PJ-34 has been tested in clinical trials for the treatment of solid tumors, our results suggest that some ATLL patients may be good candidates to benefit from PJ-34 therapy

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348