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

Platelet-Activating Factor and Kinin-Dependent Vascular Leakage as a Novel Functional Activity of the Soluble Terminal Complement Complex

AbstractThe infrequent occurrence of septic shock in patients with inherited deficiencies of the terminal complement components experiencing meningococcal disease led us to suspect that the terminal complement complex is involved in vascular leakage. To this end, the permeabilizing effect of the cytolytically inactive soluble terminal complement complex (SC5b-9) was tested in a Transwell system measuring the amount of fluorescein-labeled BSA (FITC-BSA) leaked through a monolayer of endothelial cells. The complex caused increased permeability to FITC-BSA after 15 min as opposed to the prompt response to bradykinin (BK). The effect of SC5b-9 was partially reduced by HOE-140 or CV-3988, two selective antagonists of BK B2 and platelet-activating factor receptors, respectively, and was completely neutralized by the mixture of the two antagonists. Also, DX-88, a specific inhibitor of kallikrein, partially inhibited the activity of SC5b-9. The permeabilizing factor(s) released after 30 min of incubation of endothelial cells with SC5b-9 caused a prompt leakage of albumin like BK. Intravital microscopy confirmed both the extravasation of circulating FITC-BSA across mesenteric microvessels 15 min after topical application of SC5b-9 and the complete neutralization by the mixture of HOE-140 and CV-3988. SC5b-9 induced opening of interendothelial junctions in mesenteric endothelium documented by transmission electron microscopy

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

Squamous Cell Carcinoma Developing in a Buccal Mucosa Graft after Urethroplasty: A Report of 2 Cases of Malignant Degeneration

Buccal mucosa graft (BMG) was originally described in 1992 for the treatment of challenging cases of hypospadias (proximal or redo cases) and has gained increasingly popularity also when dealing with complicated urethral stenosis, as it is associated with a good outcome. The development of a malignancy in a BMG urethroplasty was reported for the first time in 2017. We report two more cases of a malignant degeneration of a BMG used in a urethroplasty to treat recurrent urethral stricture

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