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Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia.

Introduction:Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge.

Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

We have studied the protamine scombrine αfrom the mackerel Scomber scombrus. Scombrine αis found phosphorylated in spermatid nuclei, but not in nuclei of ripe sperm. It is a typical fish protamine, made up of two distinct molecular species, each of 34 amino acid residues. The primary structure of the main component of scombrine αis 100% identical to scombrine γ, the nonmicroheterogeneous protamine from Scomber australasicus[11]. The second component of scombrine αis a very minor molecular species that has an isoleucine instead of a valine in position 11. Nuclear sperm-specific basic proteins display an enormous interspecific variability and it is very surprising that two different species show identical protamines. In this work we suggest that evolutionary changes in primary structure of protamines are restricted by several constitutive factors, especially when protamines either lack or have a low degree of microheterogeneity.

A novel nonsense mutation associated with the skipping of constitutive exon 2 of the 3-hydroxy-3-methylglutaryl-CoA lyase gene was found in two patients, from Portugal and Morocco, with 3-hydroxy-3-methylglutaric acidemia. By reverse transcriptase PCR and single-strand conformational polymorphism a G–T transversion was located, at nucleotide 109, of the 3-hydroxy-3-methylglutaryl-CoA lyase cDNA, within exon 2. Two mRNAs were produced as a result of this nonsense mutation: one of the expected size that contains the premature stop codon UAA, and the other with a deletion of 84 bp corresponding to the whole of exon 2. This deletion produced the loss of the last seven amino acids of the leader peptide and the first 21 amino acids of the mature protein. The nonsense mutation was found in a purine-rich GGAAG sequence, which is equal to, or similar to, others reported to be exonic splicing enhancers (ESE). We suggest that the nonsense mutation may affect a possible ESE on exon 2, which would hinder the splice site selection and facilitate an aberrant splice with the skipping of this exon. Determination by quantitative PCR shows that the ratio of mRNA with the nonsense mutation to the mRNA with the deletion is approx. 3:1.

Levels of mRNA for the two 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthases, (HMG-S1 and HMG-S2), and for HMG-CoA reductase (HMG-R) of Blattella germanicawere analyzed in the fat body during the first gonadotrophic cycle. HMG-S2 and HMG-R showed the highest mRNA levels on day 0 and decreased thereafter, whereas HMG-S1, showed faint expression. Western blot using specific antibodies for HMG-S1 and HMG-S2 showed no detectable levels for HMG-S1 but a clear pattern for HMG-S2. Both results point to a very limited role for HMG-CoA synthase-1 in B. germanicafat body and suggest that the functional enzyme in this organ is HMG-CoA synthase-2. HMG-CoA reductase and synthase proteins shared a cyclic pattern (maximum levels at day 4 and minimum levels on days 0 and 8), which was coincident with the pattern of activity. The delay between gene transcription and protein synthesis suggests a finely regulated translation mechanism. Moreover, the pattern of mevalonate synthesis parallels that of vitellogenin production, suggesting a coordinate mechanism between the mevalonate pathway and the production of vitellogenin.

Abstract.: We have determined the primary structure of protamine R3 from ratfish (Hydrolagus colliei), a species belonging to the order Chimaeriformes (an old phylogenetic line among the chondrichthyes). Protamine R3 contains 48 residues organized as follows: ARRRH SMKKK RKSVR RRKTR KNQRK RKNSL GRSFK (Q/A)HGFL KQPPR FRP. Comparison of this sequence with both protamine Z3 from Scyliorhinus canicula (a chondrichthyan) and typical protamines from bony fish generates an apparent contradiction: Two relatively close species (H. colliei and S. canicula, both chondichthyes) display different protamines, whereas species more distant in evolution (S. canicula and bony fish) contain very similar protamine molecules. We note that this is not an isolated case in the evolution of sperm nuclear basic proteins (SNBPs) and discuss the possible significance of this fact.

Salamero: Daichii Sankyo: Honoraria; Pfizer: Consultancy; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Somervaille:Novartis: Consultancy, Honoraria; Imago Bioscience: Research Funding. Gutierrez:Oryzon Genomics: Current Employment. Bullock:Oryzon Genomics: Current Employment. Buesa:Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch:Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Astra Zeneca: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Jansen: Honoraria. Montesinos:Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy.

Introduction:Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a higher incidence in older people. Most elderly AML patients are unfit for intensive chemotherapy and their treatment remains a challenge. Remission and survival rates decrease with age, and there is rather limited treatment success with standard (chemo)therapy, leading to 5-year survival rates of 20% or lower. Recent combinations of hypomethylating agents with pro-apoptotic agents such as venetoclax, a Bcl-2 inhibitor, have shown improved therapeutic prospects in early phase clinical trials, which still need to be supported by data from ongoing phase III confirmatory trials.

Buesa: Oryzon Genomics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Mendelion SL: Membership on an entity's Board of Directors or advisory committees. Somervaille:Novartis: Consultancy. Arevalo:Oryzon Genomics: Employment. Xaus:Oryzon Genomics: Employment. Gutierrez:Oryzon Genomics: Employment. Bullock:Oryzon Genomics: Consultancy.

Introduction:

DNA microarray technology is based on the principle of hybridization between 2 complementary strands of nucleic acids, one being fixed into a solid membrane, the other being the sample to analyze. This has resulted in a very powerful method to examine differential gene expression between samples, and has been widely used in the study of tumors. The application of DNA microarray technology to the study of the nervous system has to consider several properties of the nervous tissue: composition of various neuronal types, as well as astrocytes, oligodendrocytes, and microglia; regional and area differences; developmental and age-dependent variations; and functional and pathological status. Moreover, human samples are usually obtained postmortem following variable agonal periods and postmortem delays between death and tissue preservation, which are accompanied by variable RNA degradation. Yet human postmortem nervous tissue stored in brain banks offers a unique opportunity to facilitate material for the study of diseases of the nervous system and to gain direct understanding on the mechanisms of disease. This review analyzes the application of DNA microarray technology to current practice using brain-banked tissues in order to recognize and minimize sub-optimal processing of brain samples and to correct pitfalls due to inadequate procedures. Also discussed are RNA preservation and RNA degradation effects on expression pattern assessments, analysis of individual versus pooled samples, array normalization, types of DNA chip platforms, whole genomic analysis versus specialized chips, and microgenomics. Minimizing RNA degradation and improving detection of resistant RNA in postmortem brain has been considered in detail in order to improve the efficiency and reliability of DNA microarray technology employed in the study of human postmortem nervous tissue.