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Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent small B-cell neoplasm that may transform into a clinically aggressive disease, namely Richter syndrome, usually as diffuse large B-cell lymphoma. Besides, CLL/SLL encompasses an increased risk of developing other secondary cancers, including a variety of T-cell lymphomas, often of the anaplastic large-cell type or with a cytotoxic phenotype. Here, we report a small series of patients with composite lymphomas consisting of CLL/SLL and angioimmunoblastic T-cell lymphoma (AITL), a hitherto unrecognized association. The 3 patients (1 male/2 females, 68 to 83 y) presented with high-grade-type symptoms. One patient was clinically suspicious for Richter syndrome, in the others CLL/SLL and AITL were concomitant de novo diagnoses. CLL/SLL and AITL were admixed in the same lymph nodes (3/3 cases) and in the bone marrow (1/2 cases). In all cases, the AITL comprised prominent clear cells with a strong T follicular helper immunophenotype and similar mutations consisting of TET2 or DNMT3A alterations, IDH2 R172K/M, and RHOA G17V. The 3 patients received chemotherapy. One died of early AITL relapse. The other 2 remained in complete remission of AITL, 1 died with recurrent CLL, and 1 of acute myeloid leukemia. These observations expand the spectrum of T-cell lymphoma entities that occur in association with CLL/SLL, adding AITL to the rare variants of aggressive neoplasms manifesting as Richter syndrome. Given that disturbances of T-cell homeostasis in CLL/SLL affect not only cytotoxic but also helper T-cell subsets, these may contribute to the emergence of neoplasms of T follicular helper derivation.

Nodal peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with cytotoxic phenotype is overall rare, with most reports coming from Asia. Given its elusive pathobiology, we undertook a clinicopathological and molecular study of 54 Western patients diagnosed with PTCL, NOS expressing cytotoxic molecules, within a lymph node. More commonly males (M/F-2,6/1) with median age of 60 years were affected. Besides lymphadenopathy, 87% of patients had ≥1 involved extranodal site. High-stage disease (III-IV), International Prognostic Index2, B symptoms, LDH level, and cytopenia(s) were observed in 92, 63, 67, 78, and 66% of cases, respectively. Ten patients had a history of B-cell malignancies, one each of myeloid neoplasm, breast or prostate cancer, and 4 others had underlying immune disorders. Most patients (70%) died, mostly of disease, with a median overall survival of 12.7 months. Immunophenotypically, the neoplastic lymphocytes were T-cell receptor (TCR) αβ + (47%), TCR-silent (44%) or TCRγδ+ (10%), commonly CD8 + (45%) or CD4-CD8- (32%). All except one had an activated cytotoxic profile, and 95% were subclassified into PTCL-TBX21 subtype based on CXCR3, TBX21, and GATA3 expression pattern. Seven patients (13%) disclosed EBER + tumor cells. Targeted DNA deep-sequencing (33 cases) and multiplex ligation-dependent reverse transcription-polymerase chain reaction assay (43 cases) identified frequent mutations in epigenetic modifiers (73%), including TET2 (61%) and DNMT3A (39%), recurrent alterations affecting the TCR (36%) and JAK/STAT (24%) signaling pathways and TP53 mutations (18%). Fusion transcripts involving VAV1 were identified in 6/43 patients (14%). Patients with nodal cytotoxic PTCL, NOS have an aggressive behavior and frequently present in a background of impaired immunity, although the association with Epstein-Barr virus is rare. The recurrent alterations in genes involved in DNA methylation together with genes related to cytokine or TCR signaling, suggest that co-operation of epigenetic modulation with cell-signaling pathways plays a critical role in the pathogeny of these lymphomas.

Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786.

Simple Summary Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary T-cell lymphoma of the digestive tract that is characterized by an aggressive clinical course. The aim of this study was to analyze the clinicopathological characteristics and genomic profile of Asian MEITL. In this study, nine cases of Japanese MEITL were analyzed by targeted Next Generation Sequencing and immunohistochemistry and were integrated with previously reported whole-genome copy number microarray-based assay data. All cases showed alterations of the tumor suppressor gene SETD2 and mutations in one or more genes of the JAK/STAT pathway. Therefore, we concluded that the combination of epigenetic deregulation and cell signaling activation may represent a major oncogenic event in the pathogenesis of Asian MEITL, similar to Western MEITL. Abstract Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary T-cell lymphoma of the digestive tract derived from intraepithelial lymphocytes and characterized by an aggressive clinical course. In this study, nine cases of Japanese MEITL were analyzed by targeted Next Generation Sequencing (NGS) and immunohistochemistry and were integrated with previously reported whole-genome copy number microarray-based assay data. The highlight of our findings is that all cases showed alterations of the tumor suppressor gene SETD2 by mutations and/or loss of the corresponding 3p21 locus. We also demonstrated that all cases showed mutations in one or more genes of JAK/STAT pathway. Therefore, the combination of epigenetic deregulation and cell signaling activation represent major oncogenic events in the pathogenesis of MEITL in Asian MEITL, similar to Western MEITL.

Peripheral T-cell lymphoma comprises a heterogeneous group of mature non-Hodgkin lymphomas. Their diagnosis is challenging, with up to 30% of cases remaining unclassifiable and referred to as "not otherwise specified". We developed a reverse transcriptase-multiplex ligation-dependent probe amplification gene expression profiling assay to differentiate the main T-cell lymphoma entities and to study the heterogeneity of the "not specified" category. The test evaluates the expression of 20 genes, including 17 markers relevant to T-cell immunology and lymphoma biopathology, one Epstein-Barr virus-related transcript, and variants of RHOA (G17V) and IDH2 (R172K/T). By unsupervised hierarchical clustering, our assay accurately identified 21 of 21 ALK-positive anaplastic large cell lymphomas, 16 of 16 extranodal natural killer (NK)/T-cell lymphomas, 6 of 6 hepatosplenic T-cell lymphomas, and 13 of 13 adult T-cell leukemia/lymphomas. ALK-negative anaplastic lymphomas (n=34) segregated into one cytotoxic cluster (n=10) and one non-cytotoxic cluster expressing Th2 markers (n=24) and enriched in DUSP22-rearranged cases. The 63 T FH -derived lymphomas divided into two subgroups according to a predominant T FH (n=50) or an enrichment in Th2 (n=13) signatures. We next developed a support vector machine predictor which attributed a molecular class to 27 of 77 not specified T-cell lymphomas: 17 T FH , five cytotoxic ALK-negative anaplastic and five NK/T-cell lymphomas. Among the remaining cases, we identified two cell-of-origin subgroups corresponding to cytotoxic/Th1 (n=19) and Th2 (n=24) signatures. A reproducibility test on 40 cases yielded a 90% concordance between three independent laboratories. This study demonstrates the applicability of a simple gene expression assay for the classification of peripheral T-cell lymphomas. Its applicability to routinely-fixed samples makes it an attractive adjunct in diagnostic practice.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary T-cell lymphoma of the digestive tract derived from intraepithelial lymphocytes and characterized by an aggressive clinical course. In this study, nine cases of Japanese MEITL were analyzed by targeted Next Generation Sequencing (NGS) and immunohistochemistry and were integrated with previously reported whole-genome copy number microarray-based assay data. The highlight of our findings is that all cases showed alterations of the tumor suppressor gene SETD2 by mutations and/or loss of the corresponding 3p21 locus. We also demonstrated that all cases showed mutations in one or more genes of JAK/STAT pathway. Therefore, the combination of epigenetic deregulation and cell signaling activation represent major oncogenic events in the pathogenesis of MEITL in Asian MEITL, similar to Western MEITL.

The mechanisms underlying cellular and organismal phenotypes due to copy number alterations (CNA) are not fully understood. Aneuploidy is a major source of gene dosage imbalance due to CNA and viable human trisomies are model disorders of altered gene expression. To understand the cellular impact of gene dosage imbalance, we studied gene and allele specific expression (ASE) of 9668 single-cell fibroblasts in trisomies T21, T18, T13 and T8. To limit the bias of interindividual noise, all comparisons between euploid and trisomic single-cells were performed on an isogenic setting for all trisomies studied. Initially we examined 928 single cells with deep RNA-Seq. For T21 we used fibroblasts from one pair of monozygotic twins discordant for T21 and from mosaic T21. For T18, T13 and T8 we analyzed single cells from mosaic individuals. Single-cell analyses revealed inconsistencies concerning the overexpression of some genes observed in differential trisomic vs euploid bulk RNAseq while this imbalance was not detectable in trisomic vs. euploid single cells. Moreover, ASE profiling of all single cells uncovered a substantial monoallelic pattern of expression in the trisomic fraction of the genome. By classifying genes according to the level of mono and bi-allelic transcription, we have observed that, for genes with monoallelic and low-to-average expression, the altered gene dosage is mainly due to the higher fraction of cells simultaneously expressing these genes in the trisomic samples. These results were confirmed in a further experiment of 8740 single fibroblasts from the monozygotic twins discordant for T21 samples. We conclude that gene dosage imbalance is of bidimensional nature: over time (simultaneous expression of all alleles resulting in increased accumulation of RNA of copy altered genes in each single cell) as previously stated, and over space (increased fraction of cells simultaneously expressing copy altered genes). These results strongly suggest that each class of genes contributes to the phenotypic variability of trisomies according to its temporal and spatial behavior and propose an improved model to understand the effects of copy number alterations.

The majority of aneuploid fetuses are spontaneously miscarried. Nevertheless, some aneuploid individuals survive despite the strong genetic insult. Here, we investigate if the survival probability of aneuploid fetuses is affected by the genome-wide burden of slightly deleterious variants. We analyzed two cohorts of live-born Down syndrome individuals (388 genotyped samples and 16 fibroblast transcriptomes) and observed a deficit of slightly deleterious variants on Chromosome 21 and decreased transcriptome-wide variation in the expression level of highly constrained genes. We interpret these results as signatures of embryonic selection, and propose a genetic handicap model whereby an individual bearing an extremely severe deleterious variant (such as aneuploidy) could escape embryonic lethality if the genome-wide burden of slightly deleterious variants is sufficiently low. This approach can be used to study the composition and effect of the numerous slightly deleterious variants in humans and model organisms.

Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. In this “Data in Brief” paper, we sum up the whole genome analysis by mRNA sequencing of normal and DS induced pluripotent stem cells that was recently published by Hibaoui et al. in EMBO molecular medicine.

The fission fragment yield distribution has been measured in the $^{239}\mathrm{Pu}\left({n}_{\mathrm{th}},f\right)$ reaction in the mass region of $A=126$ to 150 using the Lohengrin recoil-mass spectrometer. Three independent experimental campaigns were performed, allowing a significant reduction of the uncertainties compared to evaluated nuclear data libraries. The long-standing discrepancy of around 10% for the relative yield of $A=134$ reported in JEF-2.2 and JEFF-3.1.1 data libraries is finally solved. Moreover, the measured mass distribution in thermal neutron-induced fission does not show any significant dip around the shell closure ($A=136$) as seen in heavy-ion fission data of $^{208}\mathrm{Pb}$($^{18}\mathrm{O}$, $f$) and $^{238}\mathrm{U}$($^{18}\mathrm{O}$, $f$) reactions. Lastly, comparisons between our experimental data and the predictions from Monte Carlo codes (gef and fifrelin) are presented and discussed.

The oscillation results published by the Double Chooz Collaboration in 2011 and 2012 rely on background models substantiated by reactor-on data. In this analysis, we present a background-model-independent measurement of the mixing angle θ13 by including 7.53 days of reactor-off data. A global fit of the observed antineutrino rates for different reactor power conditions is performed, yielding a measurement of both θ13 and the total background rate. The results on the mixing angle are improved significantly by including the reactor-off data in the fit, as it provides a direct measurement of the total background rate. This reactor rate modulation analysis considers antineutrino candidates with neutron captures on both Gd and H, whose combination yields sin2(2θ13)=0.102±0.028(stat.)±0.033(syst.). The results presented in this study are fully consistent with the ones already published by Double Chooz, achieving a competitive precision. They provide, for the first time, a determination of θ13 that does not depend on a background model.

Introduction: AITL, one of the most common peripheral T-cell Lymphoma portends a poor prognosis. AITL is characterized by neoplastic T cells with a follicular helper immunophenotype, frequent mutations in epigenetic regulators TET2, IDH2, DNMT3A and in RHOA, and a prominent tumor microenvironment that could contribute to lymphomagenesis. Aiming to target this microenvironment and given the promising activity of lenalinomide (Len) in a relapsed setting (PMID: 23731832), we postulated that AITL patients (pts) might benefit from a treatment with Len combined with a classical CHOP regimen. This multicenter, open label, phase 2 trial (NCT01553786) investigates this treatment in previously untreated elderly pts. Patients and methods: Patients older than 59 years were treated with 8 cycles of Len + CHOP 21 (Len 25 mg/day (d), d1 to 14) and received intrathecal methotrexate prophylaxis. Thromboprophylaxis with low molecular weight heparin was mandatory. PET CTs at diagnosis and at the end of treatment were centrally reviewed. The primary objective was to evaluate the complete metabolic response rate according to the Lugano 2014 Classification. Secondary endpoints were safety, progression-free (PFS) and overall survival (OS). Mutations in TET2, IDH2, DNMT3A, RHOA, CD28, PLCG1, STAT3 and STAT5B were analyzed by deep sequencing (1000X) using DNA extracted from formalin-fixed paraffin-embedded tumor samples by PGM technology and were correlated to clinical parameters. Results: Between November 2011 and March 2017, 80 pts were enrolled, and 78 were evaluable. Central pathology review confirmed the diagnosis of AITL in 72 cases (92%). Median age was 69 (59-80), 52 % were female, 68% had a performance status of 0 to 1, 94% an Ann Arbor stage ≥III, 82% IPI≥3. Forty-five patients (58 %) completed the 8 planned cycles (mean number of cycles delivered, 5.9). Of the 624 planned treatment cycles, 458 (72 %) were completed. Treatment was stopped in 8 pts because of progressive disease, and in 15 because of adverse events. Toxicity was within the range expected of R-CHOP therapy with 70% grade 4 neutropenia and 31 % thrombocytopenia. Deep vein thrombosis occurred in 8 pts. Four secondary primary malignancies were reported. Five patients died from toxicity (4 from infection). Len dose reductions or interruptions were applied in 37 (5%) and 59 (9%) cycles, respectively, related to toxic effects. The median dose of Len per patient was 2275 mg (IQR 95-2825)-i.e. 81% of the planned dose of 2800 mg. Doxorubicin and cyclophosphamide were administrated at 98% and 97% of the planned dose. Complete metabolic response was observed in 34 patients (43.6%) (90%CI = [34.0%; 53.5%]), partial metabolic response in 3 (3.8%), no metabolic response in 2 (2.6%) and progressive metabolic disease in 16 (20.5%), the other being not evaluated because of progression (N=20) or death (N=3). With a median follow-up duration of 31.5 months (95%CI = [23.0; 43.7]) at the time of the cut-off, 2-year PFS is 42.3% (95%CI = [30.9%; 53.2%]) and 2-year OS is 60.1% (95%CI = [47.4%; 70.7%]). IPI was strongly associated with the survival (figure 1A). Mutational status was successfully determined in 64 pts with confirmed AITL diagnosis. TET2 mutations were detected in 49 cases (77%), with 28 (43%) pts bearing ≥2 TET2 mutations. RHOAG17V mutations in 34 pts (53%), DNMT3A mutations in 20 (31%) pts, including 6 with the DNMT3AR882X variant and IDH2 mutations in 14 (22%). CD28, PLCCG1 and STAT mutations were detected in less than 10% of pts (figure 1B). TET2 mutations correlated to age>65 years (p=0.006) and IPI 3-5 (p=0.007). Interestingly, DNMT3A mutations were associated with a decreased response rate (p=0.003), a shorter PFS (p=0.04) and a trend toward a shorter OS (0.08). It is noteworthy that none of the 6 pts with the DNMT3AR882X mutant had response, suggesting that the resistance to anthracycline reported in DNMT3AR882X mutated acute myeloid leukemia (PMID: 27841873) could also occur in DNMT3AR882X mutated AITL. No correlation between other detected mutations and outcome was observed (table 1C). Conclusion A combination of 25 mg of Len for 14 days with CHOP cycles gives acceptable toxicity in AITL elderly pts. However, response rate and outcome appear similar to previous studies. We also confirmed in a prospective study the frequency of mutations in epigenetic regulators and RHOA in AITL and clarified their prognostic impact. Figure Figure. Disclosures Bachy: Gilead Sciences: Honoraria; Sandoz: Consultancy; Janssen: Honoraria; Roche: Research Funding; Takeda: Research Funding; Amgen: Honoraria; Celgene: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria. Casasnovas:Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; MSD: Honoraria. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Gaulard:Celgene: Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Haioun:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Transcription activation of some yeast genes correlates with their repositioning to the nuclear pore complex (NPC). The NPC-bound Mlp1 and Mlp2 proteins have been shown to associate with the GAL1 gene promoter and to maintain Ulp1, a key SUMO protease, at the NPC. Here, we show that the release of Ulp1 from the NPC increases the kinetics of GAL1 derepression, whereas artificial NPC anchoring of Ulp1 in the Δmlp1/2 strain restores normal GAL1 regulation. Moreover, artificial tethering of the Ulp1 catalytic domain to the GAL1 locus enhances the derepression kinetics. Our results also indicate that Ulp1 modulates the sumoylation state of Tup1 and Ssn6, two regulators of glucose-repressed genes, and that a loss of Ssn6 sumoylation correlates with an increase in GAL1 derepression kinetics. Altogether, our data highlight a role for the NPC-associated SUMO protease Ulp1 in regulating the sumoylation of gene-bound transcription regulators, positively affecting transcription kinetics in the context of the NPC.

Originally designed as a new nuclear reactor monitoring device, the Nucifer detector has successfully detected its first neutrinos. We provide the second shortest baseline measurement of the reactor neutrino flux. The detection of electron antineutrinos emitted in the decay chains of the fission products, combined with reactor core simulations, provides an new tool to assess both the thermal power and the fissile content of the whole nuclear core and could be used by the Inter- national Agency for Atomic Energy (IAEA) to enhance the Safeguards of civil nuclear reactors. Deployed at only 7.2m away from the compact Osiris research reactor core (70MW) operating at the Saclay research centre of the French Alternative Energies and Atomic Energy Commission (CEA), the experiment also exhibits a well-suited configuration to search for a new short baseline oscillation. We report the first results of the Nucifer experiment, describing the performances of the 0.85m3 detector remotely operating at a shallow depth equivalent to 12m of water and under intense background radiation conditions. Based on 145 (106) days of data with reactor ON (OFF), leading to the detection of an estimated 40760 electron antineutrinos, the mean number of detected antineutrinos is 281 +- 7(stat) +- 18(syst) electron antineutrinos/day, in agreement with the prediction 277(23) electron antineutrinos/day. Due the the large background no conclusive results on the existence of light sterile neutrinos could be derived, however. As a first societal application we quantify how antineutrinos could be used for the Plutonium Management and Disposition Agreement., 22 pages, 16 figures - Version 4

Using the Double Chooz detector, designed to measure the neutrino mixing angle $\theta_{13}$, the products of $\mu^-$ capture on $^{12}$C, $^{13}$C, $^{14}$N and $^{16}$O have been measured. Over a period of 489.5 days, $2.3\times10^6$ stopping cosmic $\mu^-$ have been collected, of which $1.8\times10^5$ captured on carbon, nitrogen, or oxygen nuclei in the inner detector scintillator or acrylic vessels. The resulting isotopes were tagged using prompt neutron emission (when applicable), the subsequent beta decays, and, in some cases, $\beta$-delayed neutrons. The most precise measurement of the rate of $^{12}\mathrm C(\mu^-,\nu)^{12}\mathrm B$ to date is reported: $6.57^{+0.11}_{-0.21}\times10^{3}\,\mathrm s^{-1}$, or $(17.35^{+0.35}_{-0.59})\%$ of nuclear captures. By tagging excited states emitting gammas, the ground state transition rate to $^{12}$B has been determined to be $5.68^{+0.14}_{-0.23}\times10^3\,\mathrm s^{-1}$. The heretofore unobserved reactions $^{12}\mathrm C(\mu^-,\nu\alpha)^{8}\mathrm{Li}$, $^{13}\mathrm C(\mu^-,\nu\mathrm n\alpha)^{8}\mathrm{Li}$, and $^{13}\mathrm C(\mu^-,\nu\mathrm n)^{12}\mathrm B$ are measured. Further, a population of $\beta$n decays following stopping muons is identified with $5.5\sigma$ significance. Statistics limit our ability to identify these decays definitively. Assuming negligible production of $^{8}$He, the reaction $^{13}\mathrm C(\mu^-,\nu\alpha)^{9}\mathrm{Li}$ is found to be present at the $2.7\sigma$ level. Limits are set on a variety of other processes.

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

Down syndrome caused by trisomy 21 is a collection of phenotypes with variable expressivity and penetrance. The significant advances in exploring the human genome now provide the tools to better understand the contribution of trisomy 21 in the different manifestations of Down syndrome, and the functional links between the genome variability and the phenotypic variability.

MicroRNAs (miRNAs) are regulatory noncoding RNAs that affect the production of a significant fraction of human mRNAs via post-transcriptional regulation. Interindividual variation of the miRNA expression levels is likely to influence the expression of miRNA target genes and may therefore contribute to phenotypic differences in humans, including susceptibility to common disorders. The extent to which miRNA levels are genetically controlled is largely unknown. In this report, we assayed the expression levels of miRNAs in primary fibroblasts from 180 European newborns of the GenCord project and performed association analysis to identify eQTLs (expression quantitative traits loci). We detected robust expression for 121 miRNAs out of 365 interrogated. We have identified significant cis- (10%) and trans- (11%) eQTLs. Furthermore, we detected one genomic locus (rs1522653) that influences the expression levels of five miRNAs, thus unraveling a novel mechanism for coregulation of miRNA expression.

Introduction Les carcinomes basocellulaires (BCC) sont les cancers cutanes les plus frequents chez l’homme. Leur determinisme est lie a l’activation de la voie hedgehog, qui est actuellement la cible d’inhibiteurs specifiques. Neanmoins, l’implication de mutations dans des genes lies a d’autres voies physiopathologiques n’a pas ete exploree de facon systematique et exhaustive. Celles-ci pourraient intervenir dans l’agressivite tumorale et/ou la differentiation en sous-types histologiques particuliers. La recherche de variants de sequences dans l’ADN tumoral, a l’aide de techniques de sequencage a haut debit des parties codantes du genome (« exome sequencing »), est une premiere approche pour apprehender cette question. Materiel et methodes Materiel biologique : les echantillons tumoraux etaient obtenus soit en peroperatoire (punch), soit sur coupe histologique ; l’ADN controle etait obtenu sur sang peripherique. Au total, on disposait de 293 BCCs preleves sur 236 patients. Recherche de mutations : elle a ete realisee par sequencage d’exome dans un premier temps (n = 126), puis par sequencage d’un panel de 387 genes candidats (n = 167). Analyse d’expression : elle a ete realisee par RNA-sequencing comparatif entre tissu tumoral et peau saine sur 61 paires BCCs/peau adjacente. Resultats Le taux moyen de mutations pour les BCC etait de 65/Mb, soit le chiffre le plus eleve de tous les cancers humains. Ces mutations portaient la signature-UV dans 90 % des cas. Dans 85 % des BCCs, on trouvait des mutations affectant la voie hedgehog (PTCH, SMO, SUFU) et dans 63 % des mutations de P53. Cependant, 85 % des BCCs presentaient d’autres mutations sur des genes impliques dans d’autres cancers. Il s’agissait de mutations affectant MYCN (30 %), PPP6C (15 %), STK19 (10 %), LATS1 (8 %), ERBB2 (4 %), PIK3CA (2 %), ainsi que NRAS, KRAS et HRAS (2 %).D’autres mutations induisant une perte de fonction etaient presentes dans PTPN14 (23 %), RB1 (8 %) et FBXW7 (5 %). L’analyse d’expression des BCCs mutes pour MYCN et PTPN14 confirmait une surexpression des genes impliques dans ces 2 voies. De meme, les BCCs mutes pour les genes PTCH, SMO ou SUFU induisaient une activation de la voie hedgehog. Discussion Cette etude de sequencage a haut debit de 293 BCCs confirme l’implication des genes cles de la voie hedgehog. Surtout, comme cela a ete constate dans d’autres cancers ou hedgehog actives (e.g. medulloblastome), elle met en evidence des evenements moleculaires supplementaires, responsables de l’activation des voie MYCN ou YAP-Hippo. On entrevoit de surcroit une correlation avec certains sous-types histologiques plus agressifs. Conclusion L’ensemble de ces resultats offre de nouvelles cibles therapeutiques pour les BCCs complexes, inaccessibles au traitement chirurgical. C’est une premiere etape au decryptage moleculaire des evenements initiateurs du developpement tumoral ainsi que de la progression clinique des BCCs.

The HSA21 encoded Single-minded 2 (SIM2) transcription factor has key neurological functions and is a good candidate to be involved in the cognitive impairment of Down syndrome. We aimed to explore the functional capacity of SIM2 by mapping its DNA binding sites in mouse embryonic stem cells. ChIP-sequencing revealed 1229 high-confidence SIM2-binding sites. Analysis of the SIM2 target genes confirmed the importance of SIM2 in developmental and neuronal processes and indicated that SIM2 may be a master transcription regulator. Indeed, SIM2 DNA binding sites share sequence specificity and overlapping domains of occupancy with master transcription factors such as SOX2, OCT4 (Pou5f1), NANOG or KLF4. The association between SIM2 and these pioneer factors is supported by co-immunoprecipitation of SIM2 with SOX2, OCT4, NANOG or KLF4. Furthermore, the binding of SIM2 marks a particular sub-category of enhancers known as super-enhancers. These regions are characterized by typical DNA modifications and Mediator co-occupancy (MED1 and MED12). Altogether, we provide evidence that SIM2 binds a specific set of enhancer elements thus explaining how SIM2 can regulate its gene network in neuronal features.

The standard three-neutrino oscillation paradigm, associated with small squared mass splittings $\ll 0.1\ \mathrm{eV^2}$, has been successfully built up over the last 15 years using solar, atmospheric, long baseline accelerator and reactor neutrino experiments. However, this well-established picture might suffer from anomalous results reported at very short baselines in some of these experiments. If not experimental artifacts, such results could possibly be interpreted as the existence of at least an additional fourth sterile neutrino species, mixing with the known active flavors with an associated mass splitting $\ll 0.1\ \mathrm{eV^2}$, and being insensitive to standard weak interactions. Precision measurements at very short baselines (5 to 15 m) with intense MeV electronic antineutrino emitters can be used to probe these anomalies. In this article, the expected antineutrino signal and backgrounds of a generic experiment which consists of deploying an intense beta minus radioactive source inside or in the vicinity of a large liquid scintillator detector are studied. The technical challenges to perform such an experiment are identified, along with quantifying the possible source and detector induced systematics, and their impact on the sensitivity to the observation of neutrino oscillations at short baselines., 21 pages, 27 figures, generated with pdflatex, accepted for publication in Phys. Rev. D

Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans' lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.

Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21. Stem Cells 2015;33:2077–2084 Video Highlight: https://youtu.be/MoMwXg2azGo

We describe a muon track reconstruction algorithm for the reactor anti-neutrino experiment Double Chooz. The Double Chooz detector consists of two optically isolated volumes of liquid scintillator viewed by PMTs, and an Outer Veto above these made of crossed scintillator strips. Muons are reconstructed by their Outer Veto hit positions along with timing information from the other two detector volumes. All muons are fit under the hypothesis that they are through-going and ultrarelativistic. If the energy depositions suggest that the muon may have stopped, the reconstruction fits also for this hypothesis and chooses between the two via the relative goodness-of-fit. In the ideal case of a through-going muon intersecting the center of the detector, the resolution is ∼40 mm in each transverse dimension. High quality muon reconstruction is an important tool for reducing the impact of the cosmogenic isotope background in Double Chooz., National Science Foundation (U.S.), United States. Department of Energy

Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down's syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina-associated (LADs) and replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results indicate that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes.

Variations occur throughout our genome. These variations can cause genes to be expressed (switched on) in slightly different ways among individuals. Moreover, the same gene can also be expressed in different ways in different cells within an individual. A third level of variation is supplied by epigenetic markers: these are molecules that bind to the DNA at specific points and can have profound effects on the expression of nearby genes. One such epigenetic marker is the addition of a methyl group to a cytosine base, a process that is known as DNA methylation. DNA methylation usually happens when a cytosine base is next to a guanine base, forming a CpG site. In mammals, most CpG sites have methyl groups attached, although regions with a lot of CpG sites (called CpG islands) are mostly unmethylated. Initial studies suggested that methylation prevented particular genes from being expressed, but more recent work has indicated that methylation can be associated with both reduced and increased expression of genes. Moreover, it is not clear if this association is active (i.e., changes in methylation drive changes in gene expression) or passive (DNA methylation is the result of gene regulation). Now, Gutierrez-Arcelus et al. have carried out a large-scale study to clarify the relationships between three different types of gene-related variations among individuals. They extracted fibroblasts, T-cells and lymphoblastoid cells from the umbilical cords of 204 babies, and analysed them for variations in DNA sequence, gene expression and DNA methylation. Their results show that the associations between the three are more complex than was previously thought. Gutierrez-Arcelus et al. show that the mechanisms that control the association between the variations in DNA methylation and gene expression in individuals are likely to be different to those that are responsible for the establishment of methylation patterns during the process of cell differentiation. They also find that the association between DNA methylation and gene expression can be either active or passive, and can depend on the context in which they occur in our genome. Finally, where the two copies or alleles of a gene are not equally expressed in a given cell, the difference in expression is primarily regulated by DNA sequence variation, with DNA methylation having little or no role on its own. Equally complex interactions and effects are expected in further studies of genetic and epigenetic variation.

Double Chooz is unique among modern reactor-based neutrino experiments studying ν¯e disappearance in that data can be collected with all reactors off. In this paper, we present data from 7.53 days of reactor-off running. Applying the same selection criteria as used in the Double Chooz reactor-on oscillation analysis, a measured background rate of 1.0±0.4 events/day is obtained. The background model for accidentals, cosmogenic β-n-emitting isotopes, fast neutrons from cosmic muons, and stopped-μ decays used in the oscillation analysis is demonstrated to be correct within the uncertainties. Kinematic distributions of the events, which are dominantly cosmic-ray-produced correlated-background events, are provided. The background rates are scaled to the shielding depths of two other reactor-based oscillation experiments, Daya Bay and RENO., United States. Dept. of Energy, National Science Foundation (U.S.)

Association studies have revealed expression quantitative trait loci (eQTLs) for a large number of genes. However, the causative variants that regulate gene expression levels are generally unknown. We hypothesized that copy-number variation of sequence repeats contribute to the expression variation of some genes. Our laboratory has previously identified that the rare expansion of a repeat c.-174CGGGGCGGGGCG in the promoter region of the CSTB gene causes a silencing of the gene, resulting in progressive myoclonus epilepsy. Here, we genotyped the repeat length and quantified CSTB expression by quantitative real-time polymerase chain reaction in 173 lymphoblastoid cell lines (LCLs) and fibroblast samples from the GenCord collection. The majority of alleles contain either two or three copies of this repeat. Independent analysis revealed that the c.-174CGGGGCGGGGCG repeat length is strongly associated with CSTB expression (P = 3.14 × 10(-11)) in LCLs only. Examination of both genotyped and imputed single-nucleotide polymorphisms (SNPs) within 2 Mb of CSTB revealed that the dodecamer repeat represents the strongest cis-eQTL for CSTB in LCLs. We conclude that the common two or three copy variation is likely the causative cis-eQTL for CSTB expression variation. More broadly, we propose that polymorphic tandem repeats may represent the causative variation of a fraction of cis-eQTLs in the genome.

Down syndrome caused by trisomy 21 is a collection of phenotypes with variable expressivity and penetrance. The significant advances in exploring the human genome now provide the tools to better understand the contribution of trisomy 21 in the different manifestations of Down syndrome, and the functional links between the genome variability and the phenotypic variability.

Nature 508, 345–350 (2014); doi:10.1038/nature13200 Owing to a labelling error in the input files, one of the two replicate data sets used for Fig. 5d and e and Supplementary Fig. 6d of this Article was incorrect. We have now repeated the analysis with a correct, independent replicate experiment. This confirms our previous conclusion that there are no detectable differences in nuclear lamina interactions between the normal and trisomy 21 twin cells.

The Nucifer detector will be deployed in the next few months at the Osiris research reactor in France. Nucifer is a 1-ton Gd-doped liquid scintillator detector devoted to reactor antineutrino studies. It will be installed 7 m away from the compact core of the Osiris reactor. The design of such small volume detector has been focused on high detection efficiency and good background rejection. Over the last decades, our understanding of the neutrino properties has been improved and allows today the possibility to apply the detection of antineutrinos to automatic and to non intrusively survey nuclear power plant. This has triggered the interest of the International Atomic Energy Agency (IAEA), which is interested by developing new safeguard techniques for next generation reactors. The sensitivity of such technique has to be proved and demonstrated. On the other hand there is still some issues in our understanding of the neutrino properties as the observed deficit in the antineutrino rate at short distances (< 100 m) that can not be explained by oscillations in the 3-flavors neutrino model. If a global systematic error is rejected, such anomaly opens the door to new physic that can be assessed with small detectors placed close to the core. Here we review the Nucifer detector in this context and the tests we are performing.

The study of fission yields has a major impact on the characterization and understanding of the fission process and is mandatory for reactor applications. While the yields are known for the major actinides ( 235 U, 239 Pu) in the thermal neutron-induced fission, only few measurements have been performed on 242 Am. The interest of 242 Am concerns the reduction of radiotoxicity of 241 Am in nuclear wastes using transmutation reactions. This paper presents the measurement of the fission mass yields from the reaction 241 Am(2nth,f) performed at the Lohengrin mass spectrometer (ILL, France) for both the light and the heavy peaks: a total of 41 mass yields have been measured. The experiment was also meant to determine whether there is a difference in mass yields between the isomeric state and the ground state as it exists in fission and capture cross sections. The method used to address this question is based on a repeated measurement of a set of fission mass yields as a function of the ratio between the 242g Am and the 242m Am fission rates. The presented experiment is also a first step towards the measurement of the isotopic fission yields of 242 Am .