Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence

General purpose readout board {\pi} LUP: overview and results

This work gives an overview of the PCI-Express board $\pi$LUP, focusing on the motivation that led to its development, the technological choices adopted and its performance. The $\pi$LUP card was designed by INFN and University of Bologna as a readout interface candidate to be used after the Phase-II upgrade of the Pixel Detector of the ATLAS and CMS experiments at LHC. The same team in Bologna is also responsible for the design and commissioning of the ReadOut Driver (ROD) board - currently implemented in all the four layers of the ATLAS Pixel Detector (Insertable B-Layer, B-Layer, Layer-1 and Layer-2) - and acquired in the past years expertise on the ATLAS readout chain and the problematics arising in such experiments. Although the $\pi$LUP was designed to fulfill a specific task, it is highly versatile and might fit a wide variety of applications, some of which will be discussed in this work. Two 7$^{th}$-generation Xilinx FPGAs are mounted on the board: a Zynq-7 with an embedded dual core ARM Processor and a Kintex-7. The latter features sixteen 12.5$\,$Gbps transceivers, allowing the board to interface easily to any other electronic board, either electrically and/or optically, at the current bandwidth of the experiments for LHC. Many data-transmission protocols have been tested at different speeds, results will be discussed later in this work. Two batches of $\pi$LUP boards have been fabricated and tested, two boards in the first batch (version 1.0) and four boards in the second batch (version 1.1), encapsulating all the patches and improvements required by the first version.Comment: 6 pages, 10 figures, 21th Real Time Conference, winner of "2018 NPSS Student Paper Award Second Prize

Current treatment approaches in CML.

Take home messages Five tyrosine kinase inhibitors are available, the treatment strategy is still challenging. Baseline risk, comorbidities, and patient and physician expectations play a pivotal role. Treatment-free remission is a new opportunity

HOLOBIOMICS - Use of microbiomics for the exploration of microbial communities in holobionts.

Introducing more than a decade ago the High-Throughput Sequencing techniques we have exponentially increased our opportunities of shedding light on complex microbial communities. This revolution opened a ‘golden era’ in the new-born field of microbiomics, avoiding the culturing step that always represented a limiting factor in the characterization of particular and fastidious groups of microorganisms. Furthermore, it is clear the advantage of retrieving all the taxonomic and functional information encoded within a microbiome directly by sequencing a sample deriving from an environment of interest. The huge amount of information produced in studies relying on NGS represents a challenging task, constituting the main driver for the creation of the computational microbiologist: a new figure alongside the molecular microbiologist and classic microbiologist. This researcher’s work starts when the laboratory work ends and the sequencing process is completed: the aim of a computational microbiologist work is to deal with the vast amount of data generated by the sequencing process, producing biologically meaningful data. During my PhD I have focused on these latter tasks, dealing with the characterization at different levels of various holobionts, ranging from wild animals to humans, giving attention at the bacterial, fungal and viral fractions in ecosystems. In the present work I report the main achievements of my research work, whose common denominator is the bioinformatic approach to microbiome data. In the cases I studied, I observed a mutualistic microbiome that may follows adaptive strategies aimed at the conservation of the homeostasis of the total ecosystem. This work contributes to enrich the overall knowledge on the holobiont, also exploring some peculiar ecosystems for the first time. The data presented here may form the basis for future developments in the field, in order to obtain a more comprehensive profiling of bacterial, viral and fungal fractions within complex ecosystems

ACTA, SOPA, les bibliothèques et le droit de l’information

Mémoire de fin d\u27étude du diplôme de conservateur, promotion DCB 21, portant sur ACTA (Anti-Counterfeiting Trade Agreement) et SOPA (Stop Online Piracy Act), deux projets de règlementation – internationale et nationale – du droit de l’information visant à lutter contre la contrefaçon et le piratage

Studying the impact of presence of alpha acid glycoprotein and protein glycoprotein in chronic myeloid leukemia patients treated with imatinib mesylate in the State of Qatar

Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha- 1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment

Targeting leukemic stem cells in chronic myeloid leukemia: Is it worth the effort?

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal transloca-tion, that converts it into a leukemic stem cell (LSC). The resulting BCR‐ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell‐intrinsic and ‐extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML

Aurora kinase inhibitors: which role in the treatment of chronic myelogenous leukemia patients resistant to imatinib?

At present, there are no compounds in clinical development in the field of chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) that have been documented to harbor significant activity against the imatinib-resistant T315I mutation. Recent reports on the pre-clinical activity of some emerging tyrosine kinase inhibitors such as ON012380, VX-680 and PHA-739358 promise possible clinical efficacy against this specific Bcr-Abl mutant form. Here, we focus on the role of aurora kinase inhibitor VX-680 and PHA-739358 in blocking the leukemogenic pathways driven by wild-type and T315I-Bcr-Abl in CML or Ph+ ALL by reviewing recent research evidence. We also discuss the possibility of employing aurora kinase inhibitors as a promising new therapeutic approach in the treatment of CML and Ph+ ALL patients resistant to first and second generation TK inhibitors