Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy

Analysis of CHK2 in vulval neoplasia

Structure and expression of the Rad53 homologue CHK2 were studied in vulval neoplasia. We identified the previously described silent polymorphism at codon 84 (A>G at nucleotide 252) in the germ-line of six out of 72, and somatic mutations in two out of 40 cases of vulval squamous cell carcinomas and none of 32 cases of vulval intraepithelial neoplasia. One mutation introduced a premature stop codon in the kinase domain of CHK2, whereas the second resulted in an amino acid substitution in the kinase domain. The two squamous cell carcinomas with mutations in CHK2 also expressed mutant p53. A CpG island was identified close to the putative CHK2 transcriptional start site, but methylation-specific PCR did not detect methylation in any of 40 vulval squamous cell carcinomas, irrespective of human papillomavirus or p53 status. Consistent with this observation, no cancer exhibited loss of CHK2 expression at mRNA or protein level. Taken together, these observations reveal that genetic but not epigenetic changes in CHK2 occur in a small proportion of vulval squamous cell carcinomas

First events from the CNGS neutrino beam detected in the OPERA experiment

The OPERA neutrino detector at the underground Gran Sasso Laboratory (LNGS) was designed to perform the first detection of neutrino oscillations in appearance mode, through the study of nu_mu to nu_tau oscillations. The apparatus consists of a lead/emulsion-film target complemented by electronic detectors. It is placed in the high-energy, long-baseline CERN to LNGS beam (CNGS) 730 km away from the neutrino source. In August 2006 a first run with CNGS neutrinos was successfully conducted. A first sample of neutrino events was collected, statistically consistent with the integrated beam intensity. After a brief description of the beam and of the various sub-detectors, we report on the achievement of this milestone, presenting the first data and some analysis results.Comment: Submitted to the New Journal of Physic

Observation of a first ντ\nu_\tau candidate in the OPERA experiment in the CNGS beam

The OPERA neutrino detector in the underground Gran Sasso Laboratory (LNGS) has been designed to perform the first detection of neutrino oscillations in direct appearance mode through the study of the $\nu_\mu\rightarrow\nu_\tau$ channel. The hybrid apparatus consists of an emulsion/lead target complemented by electronic detectors and it is placed in the high energy long-baseline CERN to LNGS beam (CNGS) 730 km away from the neutrino source. Runs with CNGS neutrinos were successfully carried out in 2008 and 2009. After a brief description of the beam, the experimental setup and the procedures used for the analysis of the neutrino events, we describe the topology and kinematics of a first candidate $\nu_\tau$ charged-current event satisfying the kinematical selection criteria. The background calculations and their cross-check are explained in detail and the significance of the event is assessed.Comment: 19 pages, 3 figure

A study of multi-jet events at the CERN I3p collider and a search for double patton scattering UA2 Collaboration Bern-Cambridge-CERN-Dortmund-Heidelberg-Melbourne-Milano-Orsay (LAL)-Pavia- Perugia-Pisa-Saclay (CEN)

A study of events containing at least four high transverse momentum jets and a search for double parton scattering (DPS) have been performed using data collected with the UA2 detector at the CERN lbp Collider (x/s= 630 GeV). The results are in good agreement with leading order QCD calculations. A value of at~Ps < 0.82 nb at 95% confidence level (CL) is obtained for the DPS cross section