117 research outputs found
Hematopoietic stem cell transplantation for aplastic anemia and paroxysmal nocturnal hemoglobinuria: Current evidence and recommendations
No full textSMNPAG/HLA-mutations: HLA mutations
No full textHLA mutational pipeline for targeted, whole exome and whole genome sequencing.
For research use only.
Publications:
Molecular landscape of immune pressure and escape in aplastic anemia.
Pagliuca S, Gurnari C, Hercus C, Hergalant S, Nadarajah N, Wahida A, Terkawi L, Mori M, Zhou W, Visconte V, Spellman S, Gadalla SM, Zhu C, Zhu P, Haferlach T, Maciejewski JP.
Leukemia. 2023 Jan;37(1):202-211. doi: 10.1038/s41375-022-01723-w. Epub 2022 Oct 17.
PMID: 36253429
Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.
Gurnari C, Pagliuca S, Prata PH, Galimard JE, Catto LFB, Larcher L, Sebert M, Allain V, Patel BJ, Durmaz A, Pinto AL, Inacio MCB, Hernandez L, Dhedin N, Caillat-Zucman S, Clappier E, Sicre de Fontbrune F, Voso MT, Visconte V, Peffault de Latour R, Soulier J, Calado RT, Socié G, Maciejewski JP.
J Clin Oncol. 2023 Jan 1;41(1):132-142. doi: 10.1200/JCO.22.00710. Epub 2022 Sep 2.
PMID: 3605488
Digging into the HLA pockets: A new association with acute leukaemias
No full textAcute leukaemias represent a highly heterogeneous group of clonal proliferations of myeloid or lymphoid blasts. In the last decade, the contribution of immunogenetics to cancer biology has elicited a renewed interest in the structures of immune adaptive responses, due to the growing body of evidence concerning their involvement into disease pathogenesis and treatment. The report by Boukouaci and colleagues suggests new associations between patterns of distribution of specific human leukocyte antigen motifs and leukaemogenesis
The Figure of the Limit: Metalepsis
No full textIn 1972, Gérard Genette introduced in narratology the figure of metalepsis, that is «any intrusion by the extradiegetic narrator or narratee into the diegetic universe (or by diegetic characters into a metadiegetic universe, etc.), or the inverse». In other words, metalepsis is a transgression of narrative levels, a perturbation of hierarchy that raises the question of the porosity of boundaries between diegetic and metadiegetic, author and reader, fact and fiction.
In my presentation, I will show how this phenomenon is ubiquitous nowadays, and how it is settled both in highbrow and lowbrow cultural representations across various media.
Furthermore, I wish I can discuss the role of metalepsis in poetics: in my opinion, it is possible to relate this device with the history of the novel. In XVIII and XIX centuries authorial narrators made extensive use of rhetoric metalepsis for humoristic purposes (such as playing with the story-time and the discourse-time) or to exhibit their authority (through the manipulation of different threads of the narration). With Naturalism and Modernism metalepsis disappeared, according to the poetic of impersonality: authors stopped being intrusive and eclipsed behind their characters. The golden era of the figure came in the temper of Postmodernism, where ontological metalepsis flourished and the public got used to author and reader literary entering the fiction or characters exiting from it and chitchatting with their creators
Alternative Splicing in Myeloid Malignancies
No full textAlternative RNA splicing (AS) is an essential physiologic function that diversifies the human proteome. AS also has a crucial role during cellular development. In fact, perturbations in RNA-splicing have been implicated in the development of several cancers, including myeloid malignancies. Splicing dysfunction can be independent of genetic lesions or appear as a direct consequence of mutations in components of the RNA-splicing machinery, such as in the case of mutations occurring in splicing factor genes (i.e., SF3B1, SRSF2, U2AF1) and their regulators. In addition, cancer cells exhibit marked gene expression alterations, including different usage of AS isoforms, possibly causing tissue-specific effects and perturbations of downstream pathways. This review summarizes several modalities leading to splicing diversity in myeloid malignancies
Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia
No full textAcute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by abnormal proliferation, lack of cellular differentiation, and infiltration of bone marrow, peripheral blood, or other organs. Induction failure and in general resistance to chemotherapeutic agents represent a hindrance for improving survival outcomes in AML. Here, we review the latest insights in AML biology concerning refractoriness to therapies with a specific focus on cytarabine and daunorubicin which still represent milestones agents for inducing therapeutic response and disease eradication. However, failure to achieve complete remission in AML is still high especially in elderly patients (40–60% in patients >65 years old). Several lines of basic and clinical research have been employed to improve the achievement of complete remission. These lines of research include molecular targeted therapy and more recently immunotherapy. In terms of molecular targeted therapies, specific attention is given to DNMT3A and TP53 mutant AML by reviewing the mechanisms underlying epigenetic therapies’ (e.g., hypomethylating agents) resistance and providing critical points and hints for possible future therapies overcoming AML refractoriness
Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments
No full textMyelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, progressive cytopenias and increased risk of transformation to acute myeloid leukemia. The improved understanding of the underlying biology and genetics of MDS has led to better disease and risk classification, paving the way for novel therapeutic opportunities. Indeed, we now have a vast pipeline of targeted agents under pre-clinical and clinical development, potentially able to modify the natural history of the diverse disease spectrum of MDS. Here, we review the latest therapeutic approaches (investigational and approved agents) for MDS treatment. A deep insight will be given to molecularly targeted therapies by reviewing new agents for individualized precision medicine
Current Opinions on the Clinical Utility of Ravulizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria
No full textParoxysmal nocturnal hemoglobinuria (PNH) is a rare disorder of hematopoietic stem cells genetically defined by the acquisition of somatic mutations in the X-linked phosphatidylinositol glycan anchor biosynthesis, class A (PIGA) gene. PIGA is essential for the synthesis of glycosyl phosphatidylinositol (GPI) anchor proteins and its mutations result in a deficiency of such molecules on the membrane of blood cells derived from the mutant clone. In particular, the lack of the GPI-linked complement regulatory proteins CD55 and CD59 is responsible for the increased sensitivity of PNH erythrocytes to complement mediated destruction. Indeed, the classical clinical picture of PNH includes signs and symptoms of intravascular hemolysis along with variable degrees of cytopenia and a strong tendency to thrombosis, hallmarks of the disease. Before the introduction of anti complement inhibitors, PNH was characterized by a high mortality primarily due to thrombotic events. The approval of the terminal anti-complement inhibitor eculizumab in 2007 introduced a paradigm shift in the treatment of the disease with improvement of the chronic hemolytic process and dramatic reduction of the thrombotic rate. However, eculizumab has a relatively short half-life when considering a life-long treatment, with obvious consequences as to the quality of life of treated patients necessitating relatively frequent drug administrations. Moreover, up to 30% of PNH patients undergoing eculizumab therapy show a suboptimal response, continuing to require red cell transfusions because of extravascular hemolysis or breakthrough hemolytic episodes. In 2019, the FDA approved the second generation C5 inhibitor ravulizumab, a long-lasting agent with a better control of disease manifestations. Herein, we discuss the use of ravulizumab in PNH, its differences with first generation C5 inhibitors, the research evidence supporting the safety and efficacy of this drug and its impact on costs for health systems and quality of life of PNH patients
The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies
No full textThe study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a window of therapeutic opportunities between normal and neoplastic cells, considering that all or most of the metabolic pathways important for cancer ontogeny may also regulate physiological cell functions. Targeted therapies have used the properties of leukemic cells to produce altered metabolic products when mutated. This is the case of IDH1/2 mutations generating the abnormal conversion of α-ketoglutarate (KG) to 2-hydroxyglutarate, an oncometabolite inhibiting KG-dependent enzymes, such as the TET family of genes (pivotal in characterizing leukemia cells either by mutations, e.g., TET2, or by altered expression, e.g., TET1/2/3). Additional observations derive from the high sensitivity of leukemic cells to oxidative phosphorylation and its amelioration using BCL-2 inhibitors (Venetoclax) or by disrupting the mitochondrial respiration. More recently, nicotinamide metabolism has been described to mediate resistance to Venetoclax in patients with acute myeloid leukemia. Herein, we will provide an overview of the latest research on the link between metabolic pathways interactome and leukemogenesis with a comprehensive analysis of the metabolic consequences of driver genetic lesions and exemplificative druggable pathways
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