3D Models of Surrogate Multiple Myeloma Bone Marrow Microenvironments: Insights on Disease Pathophysiology and Patient-Specific Response to Drugs

Multiple Myeloma (MM) develops almost exclusively within the Bone Marrow (BM), highlighting the critical role of the microenvironment in conditioning disease progression and resistance to drugs. Indeed, while the therapeutic armamentarium for MM has significantly improved over the past 20 years, the disease remains ultimately incurable. This failure may depend on the high phenotypic and genetic heterogeneity of MM, but also on the paucity and inadequacy of two-dimensional (2D) conventional preclinical models in reproducing MM within the BM. In the present paper, we provide a brief updated overview on MM BM microenvironment. We then discuss newly developed preclinical models mimicking MM/microenvironment interactions, including three-dimensional (3D), gel-based, in vitro models and a novel ex vivo system of isolated tumor and stromal cells cultured in bioreactor. Potential applications of each model, relative to investigation of MM pathogenic mechanisms and prediction of the best drug/combination for each individual patient will be also evaluated

Hypoxia inducible factor-1β regulates a pro-invasive phenotype in acute monocytic leukemia

Hypoxia inducible transcription factors (HIFs) are the main regulators of adaptive responses to hypoxia and are often activated in solid tumors, but their role in leukemia is less clear. In acute myeloid leukemia (AML), in particular, controversial new findings indicate that HIF-1β can act either as an oncogene or a tumor suppressor gene, and this may depend on the stage of leukemia development and/or the AML sub-type. In this study, we find that HIF-1β promotes leukemia progression in the acute monocytic leukemia sub-type of AML through activation of an invasive phenotype. By applying a list of validated HIF-1β-target genes to different AML sub-types, we identified a HIF-1β signature that typifies acute monocytic leukemia when compared with all other AML sub-types. We validated expression of this signature in cell lines and primary cells from AML patients. Interestingly, this signature is enriched for genes that control cell motility at different levels. As a consequence, inhibiting HIF- 1β impaired leukemia cell migration, chemotaxis, invasion and transendothelial migration in vitro, and this resulted in impaired bone marrow homing and leukemia progression in vivo. Our data suggest that in acute monocytic leukemia an active HIF-1β-dependent pro-invasive pathway mediates the ability of leukemic cells to migrate and invade extramedullary sites and may be targeted to reduce leukemia dissemination

Age determination and authentication of ceramics: advancements in the thermoluminescence dating laboratory in Torino (Italy)

13Classified as an absolute dating method, thermoluminescence (TL) is a well-established radiation-based technique for the age determination and authentication of ceramic materials. Specifically, this method allows the determination of the time elapsed since kiln firing (or later fire events) by evaluating the luminescent emission of ceramics under heating at high temperatures. This paper provides a comprehensive presentation of the TL laboratory developed over the last decade at the Physics Department of the University of Torino. The laboratory was set up in collaboration with TecnArt S.r.l. and is also currently operating within the cultural heritage network of the National Institute of Nuclear Physics (INFN-CHNet). More than 10 years of experience in the field has resulted in improvements in procedures, with the development of customised alpha- and beta-irradiation systems and the optimisation of sampling approaches and chemical pre-treatment. Thanks to TecnArt S.r.l., the laboratory has been employed for dating and authenticating hundreds of archaeological sites and artworks, some of which are discussed in this work and compared, when possible, with radiocarbon dating.openopenGuidorzi, Laura; Fantino, Fulvio; Durisi, Elisabetta; Ferrero, Marco; Re, Alessandro; Vigorelli, Luisa; Visca, Lorenzo; Gulmini, Monica; Dughera, Giovanni; Giraudo, Giuseppe; Angelici, Debora; Panero, Elisa; Lo Giudice, AlessandroGuidorzi, Laura; Fantino, Fulvio; Durisi, Elisabetta; Ferrero, Marco; Re, Alessandro; Vigorelli, Luisa; Visca, Lorenzo; Gulmini, Monica; Dughera, Giovanni; Giraudo, Giuseppe; Angelici, Debora; Panero, Elisa; Lo Giudice, Alessandr

Rationally modified estrogen receptor protein as a bio-recognition element for the detection of EDC pollutants: strategies and opportunities

The estrogen receptor protein (ER) can bind a vast number of organic pollutants widely spread in the environment and collectively known as Endocrine Disrupting Chemicals, EDCs. Its broad selectivity makes it an ideal bio-recognition element for the detection of EDCs. Here we describe the strategy and rationale for the design of ER based biosensors and assays that generate a signal in the presence of EDCs. The opportunity to use either natural or rationally modified ER molecules is discussed. The latter approach was successfully applied in the EU-FP7 project RADAR, with the aim to develop a novel biosensor for the detection of organic pollutants both in the environment and in commercial water products

Transcriptional Hallmarks of Noonan Syndrome and Noonan-Like Syndrome with Loose Anagen Hair

Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is genetically heterogeneous, being caused by germline mutations affecting various genes implicated in the RAS signaling network. This network transduces extracellular signals into intracellular biochemical and transcriptional responses controlling cell proliferation, differentiation, metabolism, and senescence. To explore the transcriptional consequences of NS-causing mutations, we performed global mRNA expression profiling on peripheral blood mononuclear cells obtained from 23 NS patients carrying heterozygous mutations in PTPN11 or SOS1. Gene expression profiling was also resolved in five subjects with Noonan-like syndrome with loose anagen hair (NS/LAH), a condition clinically related to NS and caused by an invariant mutation in SHOC2. Robust transcriptional signatures were found to specifically discriminate each of the three mutation groups from 21 age- and sex-matched controls. Despite the only partial overlap in terms of gene composition, the three signatures showed a notable concordance in terms of biological processes and regulatory circuits affected. These data establish expression profiling of peripheral blood mononuclear cells as a powerful tool to appreciate differential perturbations driven by germline mutations of transducers involved in RAS signaling and to dissect molecular mechanisms underlying NS and other RASopathies. Hum Mutat 33:703–709, 2012. © 2012 Wiley Periodicals, Inc