Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma.

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRASG12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRASG12D mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRASG12D LUAD tumors. The critical requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRASG12D tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRASG12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.

Preliminary results of customized bone graft made by robocasting hydroxyapatite and tricalcium phosphates for oral surgery.

OBJECTIVE: The objective of this study was to assess the mechanical characteristics and the clinical usefulness of beta-tricalcium phosphate (ß-TCP) and hydroxyapatite (HA) bioblocks grafted in edentulous jaws of 12 patients. METHODS: The scaffolds were produced by robocasting ceramic inks containing 80%/20% ß-TCP and HA, respectively, with an overall porosity of 60%, with a macropore size between 300 and 500 µm. The mechanical performance of cylindrical vs conical specimens was compared using a universal testing machine. The clinical study was performed on 12 edentulous patients who received 4 cylindrical bone bioblocks. After 10 to 16 weeks of osseointegration, the bioblocks were explanted with trephine for histologic analysis by Goldner and Von Kossa staining. RESULTS: Conical shapes were significantly stronger (96.4 ± 8.7 MPa) than cylindrical shapes (87.8 ± 12.2 MPa). The overall degree of porosity ranged from 53.4% to 58.1% in the coronal region to 62.5% to 66.9% at the apex. After the maturation period, 41 valid bioblocks (85.4%) were obtained for histologic study. Bone showing some cellularity was found in 68.4% of the samples, indicating biologically active bone, and adequate calcification was found in 31.7% of the samples. In terms of biomaterial degradation, 73.2% of the samples were completely resorbed or showed significant resorption. CONCLUSIONS: The 80%/20% ß-TCP and HA grafts customized by robocasting appear adequate for regenerating self-contained defects.

Noble gas isotopes reveal degassing-derived eruptions at Deception Island (Antarctica): implications for the current high levels of volcanic activity.

Deception Island is one of the most active volcanoes in Antarctica with more than twenty explosive eruptions in the past two centuries. Any future volcanic eruption(s) is a serious concern for scientists and tourists, will be detrimental to marine ecosystems and could have an impact to global oceanographic processes. Currently, it is not possible to carry-out low and high frequency volcanic gas monitoring at Deception Island because of the arduous climatic conditions and its remote location. Helium, neon and argon isotopes measured in olivine samples of the main eruptive events (pre-, syn- and post caldera) offer insights into the processes governing its volcanic history. Our results show that: (i) ascending primitive magmas outgassed volatiles with a MORB-like helium isotopic signature (3He/4He ratio); and (ii) variations in the He isotope ratio, as well as intensive degassing evidenced by fractionated 4He/40Ar* values, occurred before the beginning of the main eruptive episodes. Our results show how the pre-eruptive noble gas signals of volcanic activity is an important step toward a better understanding of the magmatic dynamics and has the potential to improve eruption forecasting.

Mesenchymal Stromal Cell Irradiation Interferes with the Adipogenic/Osteogenic Differentiation Balance and Improves Their Hematopoietic-Supporting Ability.

Bone marrow mesenchymal stromal cells (MSCs) are precursors of adipocytes and osteoblasts and key regulators of hematopoiesis. Irradiation is widely used in conditioning regimens. Although MSCs are radio-resistant, the effects of low-dose irradiation on their behavior have not been extensively explored. Our aim was to evaluate the effect of 2.5 Gy on MSCs. Cells from 25 healthy donors were either irradiated or not (the latter were used as controls). Cells were characterized following International Society for Cellular Therapy criteria, including in vitro differentiation assays. Apoptosis was evaluated by annexin V/7-amino-actinomycin staining. Gene expression profiling and reverse transcriptase (RT)-PCR of relevant genes was also performed. Finally, long-term bone marrow cultures were performed to test the hematopoietic-supporting ability. Our results showed that immunophenotypic characterization and viability of irradiated cells was comparable with that of control cells. Gene expression profiling showed 50 genes differentially expressed. By RT-PCR, SDF-1 and ANGPT were overexpressed, whereas COL1A1 was downregulated in irradiated cells (P = .015, P = .007, and P = .031, respectively). Interestingly, differentiation of irradiated cells was skewed toward osteogenesis, whereas adipogenesis was impaired. Higher expression of genes involved in osteogenesis as SPP1 (P = .039) and lower of genes involved in adipogenesis, CEBPA and PPARG (P = .003 and P = .019), together with an increase in the mineralization capacity (Alizarin Red) was observed in irradiated cells. After differentiation, adipocyte counts were decreased in irradiated cells at days 7, 14, and 21 (P = .018 P = .046, and P = .018, respectively). Also, colony-forming unit granulocyte macrophage number in long-term bone marrow cultures was significantly higher in irradiated cells after 4 and 5 weeks (P = .046 and P = .007). In summary, the irradiation of MSCs with 2.5 Gy improves their hematopoietic-supporting ability by increasing osteogenic differentiation and decreasing adipogenesis.