Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

BCR-ABL1-negative myeloproliferative neoplasms are classically represented by primary myelofibrosis, polycythemia vera, and essential thrombocythemia. These entities are stem cell-derived clonal disorders characterized by hematopoietic progenitor autonomy or hypersensitivity to cytokines, most of them presenting mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL). Deregulation of pro- and antiapoptotic genes is also claimed as an important mechanism involved in cell resistance to cell death and accumulation of myeloid cells in myeloproliferative neoplasms. Apoptosis, as one of the best-characterized types of programmed cell death, has a clear role in hematopoiesis control. However, the exact pathways affected in BCR-ABL1-negative myeloproliferative neoplasms have not yet been fully clarified. This chapter will explore the modifications affecting programmed cell death pathways involved in myeloid proliferation and how these alterations might be exploited in single or combined targeted therapeutic strategies

Selection and characterization of the probiotic potential of some lactic acid bacteria isolated from infant feces

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Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report

Somatic frameshift mutations in exon 9 of calreticulin (CALR) gene are recognized as disease drivers in primary myelofibrosis (PMF), one of the three classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Type 1/type 1-like CALR mutations particularly confer a favorable prognostic and survival advantage in PMF patients. We report an unusual case of PMF incidentally diagnosed in a 68-year-old woman known with hepatitis C virus (HCV) cirrhosis who developed a progressive painful splenomegaly, without anomalies in blood cell counts. While harboring a type 1 CALR mutation, the patient underwent a leukemic transformation in less than 1 year from diagnosis, with a lethal outcome. Analysis of paired DNA samples from chronic and leukemic phases by a targeted next-generation sequencing (NGS) panel and single-nucleotide polymorphism (SNP) microarray revealed that the leukemic clone developed from the CALR-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline NRAS Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining NRAS G12D in the blast phase. SNP microarray analysis showed five clinically significant copy number losses at regions 7q22.1, 8q11.1-q11.21, 10p12.1-p11.22, 11p14.1-p11.2, and Xp11.4, revealing a complex karyotype already in the chronic phase. We discuss how additional mutations, detected by NGS, as well as HCV infection and antiviral therapy, might have negatively impacted this type 1 CALR-mutated PMF. We suggest that larger studies are required to determine if more careful monitoring would be needed in MPN patients also carrying HCV and receiving anti-HCV treatment

Antitumoral materials with regenerative function obtained using a layer-by-layer technique

Denisa Ficai,1 Maria Sonmez,1,2 Madalina Georgiana Albu,2 Dan Eduard Mihaiescu,1 Anton Ficai,1 Coralia Bleotu3 1Faculty of Applied Chemistry and Material Science, Politehnica University of Bucharest, 2Leather and Footwear Research Institute, National Research and Development Institute for Textiles and Leather, 3Stefan S Nicolau Institute of Virology, Romanian Academy, Bucharest, Romania Abstract: A layer-by layer technique was successfully used to obtain collagen/hydroxyapatite-magnetite-cisplatin (COLL/HAn-Fe3O4-CisPt, n=1–7) composite materials with a variable content of hydroxyapatite intended for use in the treatment of bone cancer. The main advantages of this system are the possibility of controlling the rate of delivery of cytostatic agents, the presence of collagen and hydroxyapatite to ensure more rapid healing of the injured bone tissue, and the potential for magnetite to be a passive antitumoral component that can be activated when an appropriate external electromagnetic field is applied. In vitro cytotoxicity assays performed on the COLL/HAn-Fe3O4-CisPt materials obtained using a layer-by layer method confirmed their antitumoral activity. Samples with a higher content of hydroxyapatite had more antitumoral activity because of their better absorption of cisplatin and consequently a higher amount of cisplatin being present in the matrices. Keywords: multifunctional materials, antitumoral activity, scaffold, bone graft

Not all complex disjunctions are alike: On inclusive and conjunctive interpretations in child Romanian

We investigate the interpretation of disjunction in child and adult Romanian via a replication of Tieu et al. (2017). Specifically, we target the simple disjunction 'sau' ‘or’ (with two intonation patterns: neutral and marked), and the complex disjunction markers 'sau…sau' and 'fie…fie' ‘either…or’. In a predictive Truth Value Judgment Task, participants evaluated a puppet’s disjunctive guesses ('The hen pushed the bus or the plane') after seeing the outcome. Adults assigned predominantly exclusive interpretations to both simple and complex disjunctions ('The hen pushed only one'). Children, however, generally interpreted 'sau' (with both intonational patterns) and 'sau…sau' inclusively (The hen pushed one and possibly both), while they interpreted 'fie…fie' conjunctively ('The hen pushed both'). It would appear that at an initial developmental stage, morphological/prosodic markedness does not affect children’s interpretation of disjunction. We discuss several possible accounts for the observed variation among complex disjunctions in child Romanian