The results highlight the importance of a complete excision to obtain the cure of patients. The efficacy of chemotherapy is controversial, however it was able to control the disease in 4 patients in ST II. The value of the Wienecke score system in predicting patients' outcome was confirmed. p53 mutation was more frequent in malignant tumors and represented the sentinel of the Li-Fraumeni syndrome.
Switched and IgM memory B cells execute different and noninterchangeable functions.We studied memory B cells in children of different ages, in peripheral blood and spleen and compared them with those of children born asplenic or unable to build germinal centers. We show that, whereas switched memory B cells are mostly generated in the germinal centers at all ages, IgM memory B cells can be distinct in three types with different developmental history. Innate IgM memory B cells, the largest pool in infants, are generated in the spleen by a germinal center-independent mechanism. With age, if the spleen is present and germinal centers are functional, innate IgM memory B cells are remodelled and accumulate somatic mutations. The third type of IgM memory B cell is a by-product of the germinal center reaction. Our data suggest that the B-cell memory developmental program is implemented during the first 5-6 years of life. Keywords:Antibodies r B cells r B cell development r Immunoglobulins r Innate immunity Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Rita Carsetti e-mail: rita.carsetti@opbg.net * These authors contributed equally to this work.The copyright line for this article was changed on 9th February 2018 after original online publication.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 328Alaitz Aranburu et al. Eur. J. Immunol. 2017. 47: 327-344 IntroductionImmunological memory is the ability of the immune system to recognize and neutralize a previously encountered pathogen, thereby preventing re-infection and disease. Memory is acquired by the immune system through experience. Infants lack immunological memory and have a high risk of infections. The rate of infection and mortality is highest in infants and declines after the age of 5. The decline of child mortality in the last century has been one of the most significant achievements in medical history and is largely due to the introduction of vaccination and use of antibiotics. The first response to infection or vaccination generates the elements of memory: long-lived plasma cells and memory B cells [1][2][3][4]. Long-lived plasma cells continuously secrete specific antibodies (Abs) that upon re-infection will exert the first protection. Memory B cells rapidly react to the renewed challenge and produce Abs when and where these are most needed, i.e. when the pathogen again tries to invade the organism and at the site of its entry.In the adult, 50% of the B cells in the peripheral blood (PB) are memory B cells [5]. Phenotypically memory B cells can be identified by the expression of the CD27 marker. B cells that express CD27 carry somatic mutations in their immunoglobulin (Ig) genes [6]. These are permanent genetic imprints left by the mechanism of Somatic Hyper Mutation (SHM). Somatic mutations are triggered by activation events and results from the combined action of the activation-induced deaminase AID, the uracil-DNA glycosylase UNG and several DNA...
BackgroundEmbryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts.MethodsEmbryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo.ResultsHere we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21Cip1. It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin, MCK and MHC. These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo.ConclusionsThese results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS.
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