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Sorigue M, Sancho JM, Ribera JM

Open questions in watchful waiting for follicular lymphoma.

Br. J. Haematol. 8 Jul 2016, . Epub 8 Jul 2016More information
Manils J, Eduard C, Viña-Vilaseca A, López-Cano M, Díez-Villanueva A, Gómez D, Marruecos L, Ferran M, Benito C, Perrino FW, Vavouri T, Maria de Anta J, Ciruela F, Soler C

The exonuclease TREX2 shapes psoriatic phenotype.

J. Invest. Dermatol. 27 Jun 2016, . Epub 27 Jun 2016
TREX2 is a keratinocyte-specific 3'-deoxyribonuclease that participates in the maintenance of skin homeostasis following DNA damage. Here, we show that this exonuclease is strongly upregulated in human psoriasis, a hyperproliferative and inflammatory skin disease. Similarly, the imiquimod (IMQ)- and IL23-induced mouse psoriasis was associated with a substantial upregulation of TREX2, which was recruited into fragmented chromatin in keratinocytes that were undergoing impaired proliferation, differentiation and cell death, indicating an important role in DNA processing. Using Trex2 knockout mice, we have found that TREX2 deficiency attenuated IMQ-induced psoriasis-like skin inflammation and enhanced IMQ-induced parakeratosis. Also, IL23-induced ear swelling was diminished in Trex2 knockout mice in comparison with wt mice. Transcriptome analysis identified multiple genes that were deregulated by TREX2 loss following treatment with IMQ. Specifically, immune response genes and pathways normally associated with inflammation were down-regulated, whereas those related to skin differentiation and chromatin biology showed increased expression. Interestingly, TREX2 deficiency led to decreased IMQ-induced keratinocyte death via both cell autonomous and non-cell autonomous mechanisms. Hence, our data indicate that TREX2 acts as a critical factor in the pathogenesis of psoriasis by promoting keratinocyte apoptosis and enucleation and thereby influencing skin immune responses.z.
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Pfeilstöcker M, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Levis A, Luebbert M, Maciejewski J, Machherndl-Spandl S, Magalhaes SM, Miyazaki Y, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, Van de Loosdrecht AA, Germing U, Haase D, Greenberg PL

Time-dependent changes in mortality and transformation risk in MDS.

Blood 22 Jun 2016, . Epub 22 Jun 2016
In myelodysplastic syndromes (MDS) evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study we describe changes in risk over time, the consequences for basal prognostic scores and their potential clinical implications. Major MDS prognostic risk scoring systems (IPSS, IPSS-R, WPSS, LR-PSS) and their constituent individual predictors were analyzed in 7,212 primary untreated MDS patients from the IWG-PM database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. In higher risk MDS, hazards regarding mortality and AML transformation diminished over time from diagnosis, whereas they remained stable in lower risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and essentially equivalent after five years. This fact led to loss of prognostic power of different scoring systems considered - more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management the differing development of risks suggested a reasonable division into lower and higher risk MDS based on the IPSS-R at a cut-off of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower risk patients at diagnosis remain "constant lower risk", while "initially high risk" patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making.
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Socié G, Schrezenmeier H, Muus P, Lisukov I, Röth A, Kulasekararaj A, Lee JW, Araten D, Hill A, Brodsky R, Urbano-Ispizua A, Szer J, Wilson A, Hillmen P

Changing prognosis in Paroxysmal Nocturnal Haemoglobinuria disease subcategories; an analysis of International PNH Registry.

Intern Med J 15 Jun 2016, . Epub 15 Jun 2016
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease. Although much progress has been made in the understanding of the pathophysiology of the disease, far less is known with respect to the clinical outcomes of the patients with PNH. Few retrospective studies provide survival estimates and even fewer have explored the clinical heterogeneity of the disease. Haemolytic and aplastic anaemia forms have been recognised as main disease categories with the haemolytic form being associated with worst prognosis by the largest studied cohort some years ago.
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Cantarino N, Musulen E, Valero V, Peinado MA, Perucho M, Moreno V, Forcales SV, Douet J, Buschbeck M

Downregulation of the Deiminase PADI2 is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis.

Mol. Cancer Res. 8 Jun 2016, . Epub 8 Jun 2016
Peptidyl arginine deiminases (PADIs) are a family of enzymes that catalyze the poorly understood post-translational modification converting arginine residues into citrullines. In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or immunohistochemistry (IHC) for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases of active ulcerative colitis. The data indicate that PADI2 is the dominantly expressed PADI enzyme in colon mucosa and is up-regulated during differentiation. PADI2 expression is low or absent in colorectal cancer. Frequently this occurs already at the stage of low-grade dysplasia. Mucosal PADI2 expression is also low in ulcerative colitis. The expression level of PADI2 in tumor and adjacent mucosa correlates with differential survival: low levels associate with poor prognosis.
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