Role of haemoglobin in the protection of cultured lymphocytes against diepoxybutane (DEB), assessed by in vitro induced chromosome breakage.

Mutat Res. 2003 Apr 20;536(1-2):61-7. Role of haemoglobin in the protection of cultured lymphocytes against diepoxybutane (DEB), assessed by in vitro induced chromosome breakage. Porto B, Chiecchio L, Gaspar J, Faber A, Pinho L, Rueff J, Malheiro I. Laboratory of Cytogenetics, Instituto Ciências Biomédicas Abel Salazar (ICBAS), Largo do Prof. Abel Salazar, No. 2, 4099-003, Porto, Portugal. Abstract Diepoxybutane (DEB) is an alkylating agent that can be used to assess chromosome instability in repair-deficient subjects. Previous authors investigated the role of red blood cells (RBC) in determining individual susceptibility to DEB in normal healthy donors, and demonstrated that a polymorphic enzyme in RBC, Glutathione S-transferase T1 (GSTT1), is involved in DEB detoxification. In the present work we studied the influence of individual GSTM1 and GSTT1 genotypes and the presence of RBC on the frequency of DEB-induced chromosome breakage in lymphocyte cultures from normal individuals and, in particular, the influence of isolated components of RBC: RBC membranes, RBC lysate, and haemoglobin. Our results confirm that individual GSTT1 genotypes modulate the level of genetic lesions induced by DEB; however, this effect was not sufficient to explain the highly significant variation in chromosome breakage between whole blood and RBC-depleted cultures. We showed that RBC can protect cultured lymphocytes against chromosome breakage induced by DEB and we demonstrated the particular role of haemoglobin in the protective effect. PMID: 12694746 [PubMed - indexed for MEDLINE

Subclonal TP53 copy number is associated with prognosis in multiple myeloma

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survival and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM – a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 (IL-6) expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26

Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma

Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10 -9). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors

Genetic factors influencing the risk of multiple myeloma bone disease

A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10-9) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10-7). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM

Performance Assessment of Coupled Tests: The Effects of Statistical Non-Independence

Peer Reviewe

The older the better? The strange case of empirical ground motion models in the near-source of moderate-to-large magnitude earthquakes

This paper aims at providing a quantitative evaluation of the performance of a set of empirical ground motion models (GMMs), by testing them in a magnitude and distance range (Mw = 5.5 ÷ 7.0 and Joyner-Boore source-to-site distance Rjb ≤ 20&nbsp;km) which dominates hazard in the highest seismicity areas of Italy for the return periods of upmost interest for seismic design. To this end, we made use of the very recent release of the NESS2.0 dataset (Sgobba et al. NESS2.0: an updated version of the worldwide dataset for calibrating and adjusting ground motion models in near-source. Istituto Nazionale di Geofisica e Vulcanologia (INGV), 2021. https://doi.org/10.13127/NESS.2.0), that collects worldwide near-source strong motion records with detailed metadata. After selection of an ample set of GMMs, based on either their application in past seismic hazard assessment (SHA) studies or for their recent introduction, a quantification of between- and within-event residuals of predictions with respect to records was performed, with the final aim of shedding light on the performance of existing GMMs in the near-source of moderate-to-large earthquakes, also in view of their potential improvement by taking advantage of results from 3D physics-based numerical simulations