Critical halo loss locations in the LHC

Results of simulations with all movable elements of the LHC collimation system [1] are discussed for various operation modes. Compared to previous results, the placing of additional collimators reduced the beam losses by a factor 10 in the ideal machine case, i.e. nominal collimators settings for both 450 GeV and 7 TeV beam energies. First results for Beam 2 are also reviewed. The sensitivity of the system to free orbit oscillations is addressed. These results show that it is sufficient to use a limited number of beam loss monitors (BLMs) for the setup and optimization of the LHC Collimation System

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells

Predicting the Trajectory of a Relativistic Electron Beam for External Injection in Plasma Wakefields

We use beam position measurements over the first part of the AWAKE electron beamline, together with beamline modeling, to deduce the beam average momentum and to predict the beam position in the second part of the beamline. Results show that using only the first five beam position monitors leads to much larger differences between predicted and measured positions at the last two monitors than when using the first eight beam position monitors. These last two positions can in principle be used with ballistic calculations to predict the parameters of closest approach of the electron bunch with the proton beam. In external injection experiments of the electron bunch into plasma wakefields driven by the proton bunch, only the first five beam position monitors measurements remain un-affected by the presence of the much higher charge proton bunch. Results with eight beam position monitors show the prediction method works in principle to determine electron and proton beams closest approach within the wakefields width ($<$1\,mm), corresponding to injection of electrons into the wakefields. Using five beam position monitors is not sufficient.Comment: seven pages, five figures, submitted for EAAC 2019 Proceeding

A novel assay to detect calreticulin mutations in myeloproliferative neoplasms

The myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive (Ph+), chronic myeloid leukemia, or negative: polycythemia vera (PV) essential thrombocythemia (ET), and primary myelofibrosis (PMF). Most Ph negative cases have an activating JAK2 or MPL mutation. Recently, somatic mutations in the calreticulin gene (CALR) were detected in 56–88% of JAK2/MPL-negative patients affected by ET or PMF. The most frequent mutations in CARL gene are type-1 and 2. Currently, CALR mutations are evaluated by sanger sequencing. The evaluation of CARL mutations increases the diagnostic accuracy in patients without other molecular markers and could represent a new therapeutic target for molecular drugs. We developed a novel detection assay in order to identify type-1 and 2 CALR mutations by PNA directed PCR clamping. Seventy-five patients affected by myeloproliferative neoplasms and seven controls were examined by direct DNA sequencing and by PNA directed PCR clamping. The assay resulted to be more sensitive, specific and cheaper than sanger sequencing and it could be applied even in laboratory not equipped for more sophisticated analysis. Interestingly, we report here a case carrying both type 1 and type2 mutations in CALR gene

Biliverdin Protects against Liver Ischemia Reperfusion Injury in Swine

Ischemia reperfusion injury (IRI) in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs

Genetic Screening for Potential New Targets in Chronic Myeloid Leukemia Based on Drosophila Transgenic for Human BCR-ABL1

Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome that originates from the reciprocal translocation t(9;22)(q34;q11.2) and encodes for the constitutively active tyrosine kinase protein BCR-ABL1 from the Breakpoint Cluster Region (BCR) sequence and the Abelson (ABL1) gene. Despite BCR-ABL1 being one of the most studied oncogenic proteins, some molecular mechanisms remain enigmatic, and several of the proteins, acting either as positive or negative BCR-ABL1 regulators, are still unknown. The Drosophila melanogaster represents a powerful tool for genetic investigations and a promising model to study the BCR-ABL1 signaling pathway. To identify new components involved in BCR-ABL1 transforming activity, we conducted an extensive genetic screening using different Drosophila mutant strains carrying specific small deletions within the chromosomes 2 and 3 and the gmrGal4,UAS-BCR-ABL1 4M/TM3 transgenic Drosophila as the background. From the screening, we identified several putative candidate genes that may be involved either in sustaining chronic myeloid leukemia (CML) or in its progression. We also identified, for the first time, a tight connection between the BCR-ABL1 protein and Rab family members, and this correlation was also validated in CML patients. In conclusion, our data identified many genes that, by interacting with BCR-ABL1, regulate several important biological pathways and could promote disease onset and progression

Comparison of Carbon and Hi-Z Primary Collimators for the LHC Phase II Collimation System

A current issue with the LHC collimation system is single-diffractive, off-energy protons from the primary collimators that pass completely through the secondary collimation system and are absorbed immediately downbeam in the cold magnets of the dispersion suppressor section. Simulations suggest that the high impact rate could result in quenching of these magnets. We have studied replacing the 60 cm primary graphite collimators, which remove halo mainly by inelastic strong interactions, with 5.25 mm tungsten, which remove halo mainly by multiple coulomb scattering and thereby reduce the rate of single-diffractive interactions that cause losses in the dispersion suppressor