Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS.

The rapid and reversible modification of tubulin subunits by PHS1-mediated phosphorylation enables dynamic remodeling of the plant microtubule cytoskeleton in response to external stimuli. Suppression of the potent tubulin kinase activity by the juxtaposed phosphatase domain tightly controls this stress-activated microtubule regulator.

The World Health Organization classification was used to conduct an analysis of geographic, age, sex, and lesion primarily biopsied/resected distribution of 2260 lymphoid neoplasms diagnosed during 2001-2006 throughout Japan. B-cell neoplasms accounted for 65% of all lymphoid neoplasms, T/natural killer (T/NK)-cell neoplasms for 25% and Hodgkin lymphoma for 7%. The most common type was diffuse large B-cell lymphoma (DLBCL, 33%), followed by follicular lymphoma (18%), and adult T-cell leukemia/lymphoma (ATLL, 10%). The high rate of 18% for follicular lymphoma was similar to that in Western countries (11-33%). T/NK-cell neoplasms accounted for a higher percentage of lymphoid neoplasms in Kyushu (30%) and Okinawa (38%) compared with other areas of Japan (18-20%). Among T/NK-cell neoplasms, ATLL was the most common type in Okinawa (54%) and Kyushu (59%). Extranodal NK/T cell lymphoma was the second most common type of T/NK-cell neoplasms in Okinawa (15%). This epidemiological study shows that the distribution patterns of malignant lymphoma differ especially in Kyushu and Okinawa, the endemic area of human T-cell leukemia/lymphoma virus type 1.

The circadian clock provides adaptive advantages to an organism, resulting in increased fitness and survival. The phosphorylation events that regulate circadian-dependent signaling and the processes which post-translationally respond to clock-gated signals are largely unknown. To better elucidate post-translational events tied to the circadian system we carried out a survey of circadianregulated protein phosphorylation events in Arabidopsis seedlings. A large-scale mass spectrometry-based quantitative phosphoproteomics approach employing TiO2-based phosphopeptide enrichment techniques identified and quantified 1586 phosphopeptides on 1080 protein groups. A total of 102 phosphopeptides displayed significant changes in abundance, enabling the identification of specific patterns of response to circadian rhythms. Our approach was sensitive enough to quantitate oscillations in the phosphorylation of low abundance clock proteins (EARLY FLOWERING4; ELF4 and PSEUDORESPONSE REGULATOR3; PRR3) as well as other transcription factors and kinases. During constant light, extensive cyclic changes in phosphorylation status occurred in critical regulators, implicating direct or indirect regulation by the circadian system. These included proteins influencing transcriptional regulation, translation, metabolism, stress and phytohormones-mediated responses. We validated our analysis using the elf4 -211 allele, in which an S45L transition removes the phosphorylation herein identified. We show that removal of this phosphorylatable site diminishes interaction with EARLY FLOWERING3 (ELF3), a key partner in a tripartite evening complex required for circadian cycling. elf4 -211 lengthens period, which increases with increasing temperature, relative to the wild type, resulting in a more stable temperature compensation of circadian period over a wider temperature range. Molecular

CD10 and MUM1 are representative B cell differentiation markers. Follicular lymphoma (FL) is usually positive for CD10 and negative for MUM1. In this study, however, we compared 22 FLs with peculiar phenotype CD10 ؊ MUM1 ؉ with 119 typical CD10 ؉ MUM1 ؊ FLs. All CD10 ؊ MUM1 ؉ FL patients exhibited follicular structure with follicular dendritic meshwork, and a high rate of somatic hypermutation and ongoing mutation, similar to typical FL. However, CD10 ؊ MUM1 ؉ FLs were encountered frequently in the elderly compared with CD10 ؉ MUM1 ؊ typical FLs (67.0 versus 58.7 years, P < .01), showed high grade (grade 3A or 3B) morphology (91% versus 17%, P < .001), diffuse proliferation (59% vs 19%, P < .001), and lacked BCL2/IGH translocation (5% versus 92.5%, P < .001), which is the most characteristic aberration in FL, and 88% showed BCL6 gene abnormalities (translocation or amplification IntroductionFollicular lymphoma (FL) is the most prevalent form of low-grade B-cell lymphoma in adults. 1 Typically, FL cells express CD10, BCL2, and BCL6. CD10 is a marker for germinal center (GC) B cells, and thus its expression suggests that GC B cells are a normal counterpart of FL. 2 However, some reports, including our previous study, described the existence of CD10 Ϫ FL, especially in high-grade (grade 3) FL. [3][4][5][6] However, it is not clear whether CD10 negativity is just aberrant loss or whether it is meaningful, reflecting a specific differentiation stage and affecting clinical features. MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) is a lymphoid-specific member of the interferon regulatory factor family of transcription factors, 7-9 and it is a reliable marker of "late-stage GC" or "post-GC" B cells. 8 In this study, we clinicopathologically compared CD10 Ϫ MUM ϩ and "classical" CD10 ϩ MUM1 Ϫ FLs. Materials and methods Biologic materialTissue specimens were obtained from human lymph nodes filed at the Department of Pathology at Fukuoka University and Kurume University. The 147 FL patients have already been reported in our previous publication. 5 Paraffin-embedded tissues were available in almost all patients, while frozen tissues and cell suspensions were available in some patients. Histopathological diagnoses and grading were based on the new WHO classification and carried out by 4 pathologists (Y.G., K.K., M.K., and K.O.). 1 Clinical information was obtained by reviewing the tumor registry records and/or patients' medical charts. This study was approved by the Kurume University institutional review board (Kurume, Japan), and patients provided informed consent in accordance with the Declaration of Helsinki. ImmunohistochemistryParaffin sections from each sample were immunostained with monoclonal antibodies against CD10 (Novocastra, Newcastle, United Kingdom), Bcl2 (DAKO, Glostrup, Denmark), MUM1 (DAKO), CD21 (DAKO), CD138 (Novocastra), and Bcl6 (Novocastra) following the method described previously. 5 The following 2 categories were defined: negative (Ͻ 30% positively-stained tumor cells) and ...