491 research outputs found
Targeted Therapies for Pediatric AML: Gaps and Perspective
No full textAcute myeloid leukemia (AML) is a hematopoietic disorder characterized by numerous cytogenetic and molecular aberrations that accounts for ~25% of childhood leukemia diagnoses. The outcome of children with AML has increased remarkably over the past 30 years, with current survival rates up to 70%, mainly due to intensification of standard chemotherapy and improvements in risk classification, supportive care, and minimal residual disease monitoring. However, childhood AML prognosis remains unfavorable and relapse rates are still around 30%. Therefore, novel therapeutic approaches are needed to increase the cure rate. In AML, the presence of gene mutations and rearrangements prompted the identification of effective targeted molecular strategies, including kinase inhibitors, cell pathway inhibitors, and epigenetic modulators. This review will discuss several new drugs that recently received US Food and Drug Administration approval for AML treatment and promising strategies to treat childhood AML, including FLT3 inhibitors, epigenetic modulators, and Hedgehog pathway inhibitors
Use of Single Nucleotide Polymorphism Array Technology to Improve the Identification of Chromosomal Lesions in Leukemia
No full textAcute leukemias are characterized by recurring chromosomal and genetic abnormalities that disrupt normal development and drive aberrant cell proliferation and survival. Identification of these abnormalities plays important role in diagnosis, risk assessment and patient classification. Until the last decade methods to detect these aberrations have included genome wide approaches, such as conventional cytogenetics, but with a low sensitivity (5-10%), or gene candidate approaches, such as fluorescent in situ hybridization, having a greater sensitivity but being limited to only known regions of the genome. Single nucleotide polymorphism (SNP) technology is a screening method that has revolutionized our way to find genetic alterations, enabling linkage and association studies between SNP genotype and disease as well as the identification of alterations in DNA content on a whole genome scale. The adoption of this approach for the study of lymphoid and myeloid leukemias contributed to the identification of novel genetic alterations, such as losses/gains/uniparental disomy not visible by cytogenetics and implicated in pathogenesis, improving risk assessment and patient classification and in some cases working as targets for tailored therapies. In this review, we reported recent advances obtained in the knowledge of the genomic complexity of chronic myeloid leukemia and acute leukemias thanks to the use of high-throughput technologies, such as SNP array
Targeting Hedgehog pathway in pediatric acute myeloid leukemia: challenges and opportunities
No full textNo abstract availabl
A novel DAG-dependent mechanism links PKCα and cyclin B1 regulating the G2/M progression of cell cycle
No full textProtein kinase C α has been reported to regulate cell cycle in several cell lines. Most of the reports describe a role for PKCα in G1/S transition but little is known about its possible involvement in G2/M progression. Our studies on the effects of PKC inhibitors, PKCα silencing and overexpression demonstrated a novel and positive role for PKCα in cyclin B1 regulation in human erythroleukemia cell line, K562. On the other hand, using PKC inhibitors and a PKCα inactive mutant, we could report that PKCα activity was not necessary for cyclin B1 regulation. Moreover, immunoprecipitation and immunocytochemistry experiments showed that these two proteins could physically interact each other and enter into the nuclei during G2/M progression. In order to better understand this mechanism, we investigated how PKCα could be attracted into the nuclei. We found a high increase of nuclear DAG during the G2/M phase. Then, using PMA and PLC inhibitors, we showed that PKCα translocation was due to the increase in nuclear DAG. Surprisingly, we saw the same effect on cyclin B1. Finally, in order to discover which PLC was involved, we silenced the nuclear localized PLCβ1 finding a decrease in PKCα and cyclin B1 nuclear amount. Taken together, our data demonstrated the existence of a novel DAG dependent mechanism linking PKCα and cyclin B1 which can regulate their entry into the nuclei during the G2/M phase of cell cycle
Single nucleotide polymorphisms as genomic markers for high-throughput pharmacogenomic studies
No full textGenetic variations in patients have strong impact on their drug therapies and responses because the variations may contribute to the efficacy and/or produce undesirable side effects for any given drug. The Drug Metabolizing Enzymes and Transporters (DMET) assay is a high-throughput technology by Affymetrix that is able to simultaneously genotype variants in multiple genes involved in absorption, distribution, metabolism, and excretion of drugs for subsequent clinical applications, i.e., the assay allows for a precise genetic map that can guide therapeutic interventions and avoid side effects
Identification of a cytogenetic and molecular subgroup of acute myeloid leukemias showing sensitivity to L-Asparaginase.
No full textL-Asparaginase (L-Asp) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid, and its depletion induces leukemic cell death. L-Asp is an important component of treatment regimens for Acute Lymphoblastic Leukemia (ALL). Sensitivity to L-Asp is due to the absence of L-Asparagine synthetase (ASNS), the enzyme that catalyzes the biosynthesis of L-asparagine. ASNS gene is located on 7q21.3, and its increased expression in ALLs correlates with L-Asp resistance. Chromosome 7 monosomy (-7) is a recurrent aberration in myeloid disorders, particularly in adverse-risk Acute Myeloid Leukemias (AMLs) and therapy-related myeloid neoplasms (t-MN), that leads to a significant downregulation of the deleted genes, including ASNS. Therefore, we hypothesized that -7 could affect L-Asp sensitivity in AMLs. By treating AML cell lines and primary cells from pediatric patients with L-Asp, we showed that -7 cells were more sensitive than AML cells without -7. Importantly, both ASNS gene and protein expression were significantly lower in -7 AML cell lines, suggesting that haploinsufficiency of ASNS might induce sensitivity to L-Asp in AMLs. To prove the role of ASNS haploinsufficiency in sensitizing AML cells to L-Asp treatment, we performed siRNA-knockdown of ASNS in AML cell lines lacking -7, and observed that ASNS knockdown significantly increased L-Asp cytotoxicity. In conclusion, -7 AMLs showed high sensitivity to L-Asp treatment due to low expression of ASNS. Thus, L-Asp may be considered for treatment of AML pediatric patients carrying -7, in order to improve the outcome of adverse-risk AMLs and t-MN patients
"Si tout sujet est portrait” : figurations du moi dans Le Monde désert de Jouve et La Mort difficile de Crevel
No full textThe analysis of two novels from the 1920s selected as emblematic cases – Le Monde désert by Jouve and La Mort difficile by Crevel – leads the author to point out the connections between the figuration of the subject in literature and the portrait in painting. Indeed, the survival of the portrait itself as a pictorial genre can be seen as a sign of its involvement in the enquiry of identity and subjectivity. This article describes the three main axes that organise subjectivity as a portrait: the fluctuation between stasis and movement, the relational dimension and the fictional one. The portrait becomes the ideal model of a subject conceived as the result of a creative process. Hence, painting is not to be considered a mere narrative theme but a key to the interpretation of the novels and a metaphor of the construction of the subject
«Una strania fenice». Marco Santagata: gli studi, le opere
No full textIl libro raccoglie contributi sulla figura e le opere di Marco Santagata, italianista e scrittore. Ne sono autori Annalisa Andreoni, Gian Mario Anselmi, Gabriele Baldassari, Roberto Barbolini, Pietro G. Beltrami, Claudia Berra, Alberto Bertoni, Laura Bosio, Cristiana Brunelli, Alberto Casadei, Roberta Cella, Michele Feo, Francesco Ferretti, Gianfranco Fioravanti, Serena Fornasiero, Christian Genetelli, Klaus W. Hempfer, Giuseppe Indizio, Vincenzo Manca, Grazia Melli, Cristina Montagnani, Matteo Palumbo, Laura Paolino, Diego Quaglioni, Amedeo Quondam, Gerhard Regn, Laura Regnicoli, Francisco Rico, Raffaele Ruggiero, Gino Ruozzi, Salvatore Settis, Silvana Tamiozzo, Chiara Tognarelli, Paola Vecchi Galli, Tiziano Zanato. Chiude il volume la Bibliografia degli scritti di Marco Santagata.
Marco Santagata (Zocca, 28 aprile 1947 ‒ Pisa, 9 novembre 2020) è stato studioso di letteratura italiana e romanziere. A lungo docente all’Università di Pisa, è autore di studi fondamentali su Petrarca – culminati nel commento al Canzoniere (1996, 20042) –, su Dante, Boccaccio, la poesia del Quattrocento e Boiardo, e sulla tradizione lirica fino a Leopardi, Pascoli e d’Annunzio. A ciò ha affiancato una felice produzione narrativa: tra i suoi romanzi Il copista (2000), Il maestro dei santi pallidi (2002, Premio Campiello 2003), L'amore in sé (2006, Premio Stresa), Come donna innamorata (2015, finalista al Premio Strega). La sua poliedrica natura di intellettuale impegnato e curioso del mondo lo ha portato anche ad occuparsi attivamente di politica culturale e universitaria e di divulgazione.The book collects contributions on the figure and works of Marco Santagata, scholar of Italian literature and novelist. The authors are Annalisa Andreoni, Gian Mario Anselmi, Gabriele Baldassari, Roberto Barbolini, Pietro G. Beltrami, Claudia Berra, Alberto Bertoni, Laura Bosio, Cristiana Brunelli, Alberto Casadei, Roberta Cella, Michele Feo, Francesco Ferretti, Gianfranco Fioravanti, Serena Fornasiero, Christian Genetelli, Klaus W. Hempfer, Giuseppe Indizio, Vincenzo Manca, Grazia Melli, Cristina Montagnani, Matteo Palumbo, Laura Paolino, Diego Quaglioni, Amedeo Quondam, Gerhard Regn, Laura Regnicoli, Francisco Rico, Raffaele Ruggiero, Gino Ruozzi, Salvatore Settis, Silvana Tamiozzo, Chiara Tognarelli, Paola Vecchi Galli, Tiziano Zanato. The volume closes with the Bibliography of Marco Santagata's writings.
Marco Santagata (Zocca (Modena), 28 April 1947 ‒ Pisa, 9 November 2020) was a scholar of Italian literature and novelist. Long a professor at the University of Pisa, he is the author of fundamental studies on Petrarch - culminating in the commentary on the "Canzoniere" (1996, 20042) -, on Dante, Boccaccio, fifteenth-century poetry and Boiardo, and on the lyric tradition up to Leopardi, Pascoli and d'Annunzio. Alongside this he has a successful narrative production: among his novels "Il copista" (2000), "Il maestro dei santi pallidi" (2002, Campiello Prize 2003), "L'amore in sé" (2006, Stresa Prize), "Come donna innamorata" (2015, finalist for the Strega Prize). His multifaceted nature as a engaged intellectual has also led him to actively deal with cultural and university politics and dissemination
BCR-ABL1 transcript detection in patients with Philadelphia-positive Acute Lymphoblastic Leukemia (ALL) using a new and high sensitive nanofluidic method
No full textBackground: Detection of residual leukemic cells by measuring BCR-ABL1 transcript level with assays based on quantitative polymerase chain reaction (qPCR) is necessary in the monitoring of minimal residual disease in patients with BCR-ABL1 positive ALL.
Aim: To investigate the efficacy of a high sensitive method based on nanofluidic platform (Fluidigm Corporation, South San Francisco, CA) to detect and quantify residual and rare BCR-ABL1 copies, we compared results obtained by conventional qPCR with those obtained by the nanofluidic approach.
Patients and methods: We analyzed 60 BCR-ABL1 positive ALL samples expressing p190 (42) or p210 (18) isoform, first by TaqMan absolute qPCR (Applied Biosystems 7900HT Fast Real-Time PCR System). BCR-ABL1 target gene and ABL1 control gene copies were derived by the interpolation of cycle threshold values to the appropriate standard curve obtained using serial plasmid dilutions containing known BCR-ABL1 or ABL1 gene copies.
Results: Samples resulted in complete (22) or major (38) molecular response (BCR-ABL1/ABL1 ratio ≪ 0.001 or < 0.1, respectively; 3,8 BCR-ABL1 mean copy number copies).
Subsequently we reanalyzed the samples using the 12.765 Digital array (Fluidigm) and the integrated BioMark Digital PCR Analysis software (Fluidigm). The nanofluidic biochip consists in twelve panels, each containing 765 individual reaction chambers where samples are portioned prior to qPCR. As fluorescent signal is produced only in chambers containing copies of the target sequence, digital array provides an absolute quantification by counting the number of positive reactions.
Sensitivity and reproducibility of the assay were assessed using six serial dilutions of plasmids (Ipsogen) expressing known BCR-ABL1 p190 transcript copy number (10000; 1000; 100; 50; 10; 1 copies). A 2 μl volume of input cDNA was loaded and two panel for each dilution were used. Results showed a detection rate until a copy of target sequence and a pairing significantly effective between replicates. We then analyzed duplicates of BCR-ABL1 ALL samples: digital array resulted positive in 21 of major molecular response samples (2,13 BCR-ABL1 mean copy number copies) and in any complete molecular response samples.
In conclusion, the Fluidigm nanofluidic platform provides a high sensitive assay, able to detect until a single copy of BCR-ABL1 transcript, and it could provide an accurate monitoring method for BCR-ABL1-positive ALL CR patients. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integreted program (PIO), Programma di Ricerca Regione – Università 2007 – 2009
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