Commissioning scenarios and tests for the LHC collimation system

The physics reach of the LHC requires unprecedented luminosity and beam intensity in proton-proton collisions. The maximum intensity in the LHC is directly coupled to the maximum peak beam loss rate and the cleaning efficiency from the collimation system. A sophisticated LHC collimation system is implemented in two cleaning insertions and in the experimental areas. In a first phase 88 collimators are installed, being controlled by 344 stepping motors in total. The work of this PhD analyzes the achievable cleaning efficiency with realistic imperfections, defines the required collimator settings and establishes available tolerances for collimator setup and transient optics changes. An optimal setup strategy can optimize cleaning efficiency, ensure passive protection, maximize tolerances, minimize the required beam time for setup of the system and support the expected evolution in LHC beam intensity. Such an optimized strategy is described

External Electron Injection for the AWAKE Experiment

We summarize and explain the realization of witness particle injection into wakefields for the AWAKE experiment. In AWAKE, the plasma wakefields are driven by a self-modulating relativistic proton bunch. To demonstrate that these wakefields can accelerate charged particles, we inject a \unit[10-20]{MeV} electron bunch produced by a photo-injector. We summarize the experimental challenges of this injection process and present our plans for the near future.Comment: 4 pages, 3 figure

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

The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner

HERC E3 subfamily members are parts of the E3 ubiquitin ligases and key players for a wide range of cellular functions. Though the involvement of the Ubiquitin Proteasome System in blood disorders has been broadly studied, so far the role of large HERCs in this context remains unexplored. In the present study we examined the expression of the large HECT E3 Ubiquitin Ligase, HERC1, in blood disorders. Our findings revealed that HERC1 gene expression was severely downregulated both in acute and in chronic myelogenous leukemia at diagnosis, while it is restored after complete remission achievement. Instead, in Philadelphia the negative myeloproliferative neoplasm HERC1 level was peculiarly controlled, being very low in Primary Myelofibrosis and significantly upregulated in those Essential Thrombocytemia specimens harboring the mutation in the calreticulin gene. Remarkably, in CML cells HERC1 mRNA level was associated with the BCR-ABL1 kinase activity and the HERC1 protein physically interacted with BCR-ABL1. Furthermore, we found that HERC1 was directly tyrosine phosphorylated by the ABL kinase. Overall and for the first time, we provide original evidence on the potential tumor-suppressing or -promoting properties, depending on the context, of HERC1 in myeloid related blood disorders

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

Variable but consistent pattern of Meningioma 1 gene (MN1) expression in different genetic subsets of acute myelogenous leukaemia and its potential use as a marker for minimal residual disease detection

Meningioma 1 (MN1) gene overexpression has been reported in acute myeloid leukaemia (AML) patients and identified as a negative prognostic factor. In order to characterize patients presenting gene overexpression and to verify if MN1 transcript could be a useful marker for minimal residual disease detection, MN1 was quantified in 136 AML patients with different cytogenetic risk and in 50 normal controls. In 20 patients bearing a fusion gene transcript suitable for minimal residual disease quantitative assessment and in 8 patients with NPM1 mutation, we performed a simultaneous analysis of MN1 and the fusion-gene transcript or NPM1 mutation during follow-up. Sequential MN1 and WT1 analysis was also performed in 13 AML patients lacking other molecular markers. The data obtained show that normal cells consistently express low levels of MN1 transcript. In contrast, high levels of MN1 expression are present in 47% of patients with normal karyotype and in all cases with inv(16). MN1 levels during follow-up were found to follow the pattern of other molecular markers (fusion gene transcripts, NPM1 and WT1). Increased MN1 expression in the BM during follow up was always found to be predictive of an impending hematological relapse