CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity

The scenario of paediatric acute myeloid leukaemia (AML), particularly non-Down syndrome acute megakaryoblastic leukaemia (non-DS-AMKL), has been recently revolutionized by the advent of large-scale, genomic sequencing technologies. In this changing landscape, a significantly relevant discovery has been represented by the identification of the CBFA2T3-GLIS2 fusion gene, which is the result of a cryptic inversion of chromosome 16. It is the most frequent chimeric oncogene identified to date in non-DS-AMKL, although it seems not to be exclusively restricted to the French-American-British M7 subgroup. The CBFA2T3-GLIS2 fusion gene characterizes a subtype of leukaemia that is specific to paediatrics, having never been identified in adults. It characterizes an extremely aggressive leukaemia, as the presence of this fusion is associated with a grim outcome in almost all of the case series reported, with overall survival rates ranging between 15% and 30%. Although the molecular basis that underlies this leukaemia subtype is still far from being completely elucidated, unique functional properties induced by CBFA2T3-GLIS2 in the leukaemogenesis driving process have been recently identified. We here review the peculiarities of CBFA2T3-GLIS2-positive AML, describing its intriguing clinical and biological behaviour and providing some challenging targeting opportunities

Are Induced Pluripotent Stem Cells a Step towards Modeling Pediatric Leukemias?

Despite enormous improvements in pre-clinical and clinical research, acute leukemia still represents an open challenge for pediatric hematologists; both for a significant relapse rate and for long term therapy-related sequelae. In this context, the use of an innovative technology, such as induced pluripotent stem cells (iPSCs), allows to finely reproduce the primary features of the malignancy and can be exploited as a model to study the onset and development of leukemia in vitro. The aim of this review is to explore the recent literature describing iPSCs as a key tool to study different types of hematological malignancies, comprising acute myeloid leukemia, non-down syndrome acute megakaryoblastic leukemia, B cell acute lymphoblastic leukemia, and juvenile myelomonocytic leukemia. This model demonstrates a positive impact on pediatric hematological diseases, especially in those affecting infants whose onsets is found in fetal hematopoiesis. This evidence highlights the importance of achieving an in vitro representation of the human embryonic hematopoietic development and timing-specific modifications, either genetic or epigenetic. Moreover, further insights into clonal evolution studies shed light in the way of a new precision medicine era, where patient-oriented decisions and therapies could further improve the outcome of pediatric cases. Nonetheless, we will also discuss here the difficulties and limitations of this model

Role of CBL Mutations in Cancer and Non-Malignant Phenotype

CBL plays a key role in different cell pathways, mainly related to cancer onset and progres-sion, hematopoietic development and T cell receptor regulation. Somatic CBL mutations have been reported in a variety of malignancies, ranging from acute myeloid leukemia to lung cancer. Growing evidence have defined the clinical spectrum of germline CBL mutations configuring the so-called CBL syndrome; a cancer-predisposing condition that also includes multisystemic involvement char-acterized by variable phenotypic expression and expressivity. This review provides a comprehensive overview of the molecular mechanisms in which CBL exerts its function and describes the clinical manifestation of CBL mutations in humans

Development and tests of a new prototype detector for the XAFS beamline at Elettra Synchrotron in Trieste

The XAFS beamline at Elettra Synchrotron in Trieste combines X-ray absorption spectroscopy and X-ray diffraction to provide chemically specific structural information of materials. It operates in the energy range 2.4-27 keV by using a silicon double reflection Bragg monochromator. The fluorescence measurement is performed in place of the absorption spectroscopy when the sample transparency is too low for transmission measurements or the element to study is too diluted in the sample. We report on the development and on the preliminary tests of a new prototype detector based on Silicon Drift Detectors technology and the SIRIO ultra low noise front-end ASIC. The new system will be able to reduce drastically the time needed to perform fluorescence measurements, while keeping a short dead time and maintaining an adequate energy resolution to perform spectroscopy. The custom-made silicon sensor and the electronics are designed specifically for the beamline requirements.Comment: Proceeding of the 6YRM 12th-14th Oct 2015 - L'Aquila (Italy). Accepted for publication on Journal of Physics: Conference Serie

LOFT - a Large Observatory For x-ray Timing

The high time resolution observations of the X-ray sky hold the key to a number of diagnostics of fundamental physics, some of which are unaccessible to other types of investigations, such as those based on imaging and spectroscopy. Revealing strong gravitational field effects, measuring the mass and spin of black holes and the equation of state of ultradense matter are among the goals of such observations. At present prospects for future, non-focused X-ray timing experiments following the exciting age of RXTE/PCA are uncertain. Technological limitations are unavoidably faced in the conception and development of experiments with effective area of several square meters, as needed in order to meet the scientific requirements. We are developing large-area monolithic Silicon Drift Detectors offering high time and energy resolution at room temperature, which require modest resources and operation complexity (e.g., read-out) per unit area. Based on the properties of the detector and read-out electronics that we measured in the lab, we developed a realistic concept for a very large effective area mission devoted to X-ray timing in the 2-30 keV energy range. We show that effective areas in the range of 10-15 square meters are within reach, by using a conventional spacecraft platform and launcher of the small-medium class.Comment: 13 pages, 8 figures, 1 table, Proceedings of SPIE Vol. 7732, Paper No. 7732-66, 201

Effects of pneumoperitoneum and Trendelenburg position on intracranial pressure assessed using different non-invasive methods

$\textbf{Background:}$ The laparoscopic approach is becoming increasingly frequent for many different surgical procedures. However, the combination of pneumoperitoneum and Trendelenburg positioning associated with this approach may increase the patient's risk for elevated intracranial pressure (ICP). Given that the gold standard for the measurement of ICP is invasive, little is known about the effect of these common procedures on ICP. $\textbf{Methods:}$ We prospectively studied 40 patients without any history of cerebral disease who were undergoing laparoscopic procedures. Three different methods were used for non-invasive estimation of ICP: ultrasonography of the optic nerve sheath diameter (ONSD); transcranial Doppler-based (TCD) pulsatility index (ICP$_{\text{PI}}$); and a method based on the diastolic component of the TCD cerebral blood flow velocity (ICP$_{\text{FVd}}$). The ONSD and TCD were measured immediately after induction of general anaesthesia, after pneumoperitoneum insufflation, after Trendelenburg positioning, and again at the end of the procedure. $\textbf{Results:}$ The ONSD, ICP$_{\text{FVd}}$, and ICP$_{\text{PI}}$ increased significantly after the combination of pneumoperitoneum insufflation and Trendelenburg positioning. The ICP$_{\text{FVd}}$ showed an area under the curve of 0.80 [95% confidence interval (CI) 0.70-0.90] to distinguish the stage associated with the application of pneumoperitoneum and Trendelenburg position; ONSD and ICP$_{\text{PI}}$ showed an area under the curve of 0.75 (95% CI 0.65-0.86) and 0.70 (95% CI 0.58-0.81), respectively. $\textbf{Conclusions:}$ The concomitance of pneumoperitoneum and the Trendelenburg position can increase ICP as estimated with non-invasive methods. In high-risk patients undergoing laparoscopic procedures, non-invasive ICP monitoring through a combination of ONSD ultrasonography and TCD-derived ICP$_{\text{FVd}}$ could be a valid option to assess the risk of increased ICP.Cambridge Commonwealth European and International Trust Scholarship (D.C.); Woolf Fisher Trust Scholarship (J.D.); Gates Cambridge Trust Scholarship (X.L.); CNPQ Scholarship (Research Project 203792/2014-9 to B.C.); NIHR Brain Injury Healthcare Technology Co-operative, Cambridge (M.C. and D.C.)

Mailed Outreach Invitations Significantly Improve HCC Surveillance Rates in Patients With Cirrhosis: A Randomized Clinical Trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147207/1/hep30129-sup-0001-Appendix.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147207/2/hep30129_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147207/3/hep30129.pd

First results of a novel Silicon Drift Detector array designed for low energy X-ray fluorescence spectroscopy

We developed a trapezoidal shaped matrix with 8 cells of Silicon Drift Detectors (SDD) featuring a very low leakage current (below 180 pA/cm2 at 20 \ub0C) and a shallow uniformly implanted p+ entrance window that enables sensitivity down to few hundreds of eV. The matrix consists of a completely depleted volume of silicon wafer subdivided into 4 square cells and 4 half-size triangular cells. The energy resolution of a single square cell, readout by the ultra-low noise SIRIO charge sensitive preamplifier, is 158 eV FWHM at 5.9 keV and 0 \ub0C. The total sensitive area of the matrix is 231 mm2 and the wafer thickness is 450\u3bcm. The detector was developed in the frame of the INFN R&D project ReDSoX in collaboration with FBK, Trento. Its trapezoidal shape was chosen in order to optimize the detection geometry for the experimental requirements of low energy X-ray fluorescence (LEXRF) spectroscopy, aiming at achieving a large detection angle. We plan to exploit the complete detector at the TwinMic spectromicroscopy beamline at the Elettra Synchrotron (Trieste, Italy). The complete system, composed of 4 matrices, increases the solid angle coverage of the isotropic photoemission hemisphere about 4 times over the present detector configuration. We report on the layout of the SDD matrix and of the experimental set-up, as well as the spectroscopic performance measured both in the laboratory and at the experimental beamline. \ua9 2015 Elsevier B.V