101 research outputs found

    Acid microenvironment promotes cell survival of human bone sarcoma through the activation of cIAP proteins and NF-κB pathway

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    Extracellular acidification is a very common cause of stress in tumor microenvironment and of Darwinian pressure. In acid areas of the tumor, most cancer cells are-albeit slowly proliferating-more resistant to cell death than those in well-perfused regions. Tumor acidosis can directly regulate the expression of pro-survival proteins since a low extracellular pH activates the caspase-dependent cell death machinery. This mechanism has never been explored in bone sarcomas. We cultured osteosarcoma and Ewing sarcoma cells under low pH (pH 6.5), and we performed deep-sequencing and protein analysis. Both in in vitro and in vivo models, acidification activity enhanced tumor cells survival. However, we did not observe any change in ERK1 phosphorylation. On the contrary, both at the mRNA and protein level, we found a significant induction of TRAF adaptor proteins and of cIAP proteins (BIRC2 and/or BIRC3). As a consequence, the downstream nuclear transcription factor kappa B (NF-κB) survival pathway was increased. Furthermore, the treatment with the cIAP inhibitor LCL161 reverted the protection from apoptosis under low pH. In vitro results were confirmed both in Ewing sarcoma xenograft and in osteosarcoma patients, since the analysis of tumor tissues demonstrated that the levels of expression of TRAF1 or NF-κB1 significantly correlate with the level of expression of the vacuolar ATPase (V-ATPase), the most important proton pump in eukaryotes. Moreover, in the tissue sections of xenograft model, the nuclear translocation of RelB, a key subunit of the NF-κB transcriptional complex, localized in the tumor region that also corresponded to the acid microenvironment associated with the highest levels of expression of LAMP2 and V-ATPase, in the internal area of the tumor, as revealed by immunohistochemistry. Our data confirm that tumor acid microenvironment activates a stress-regulated switch to promote cell survival of bone sarcoma, and support the hypothesis that this mechanism is mediated by the recruitment of TRAF/cIAP complexes. Altogether, these results suggest that TRAF/cIAP can be considered as a target for anti-cancer therapies

    Self-cleaning and colour-preserving efficiency of photocatalytic concrete: case study of the Jubilee Church in Rome

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    The Jubilee Church in the south-eastern outskirts of Rome is one of the first buildings constructed with super white reinforced concrete with self-cleaning photocatalytic cement. However, 16 years after the opening of the building, the self-cleaning and colour-preserving properties arising from the titania particles (TiO2) within the concrete mix are not meeting the design requirements and the concrete is showing premature evidence of decay. While the form of the decay is affecting the appearance of the building and not its structural soundness, the ageing pattern of the building's components is resulting in a high maintenance cost, one not easily affordable within the ordinary budget supported by a small parish. This study comprises the first comprehensive step in understanding the causes of the accelerated ageing pattern of the concrete, highlighting methods to improve the long-term durability of the concrete and therefore reduce the cost of its maintenance. Moreover, this research offered the opportunity to test the durability and the effectiveness of the TiO2 in the real conditions on an actual building featuring non-standard geometries. The findings highlight how the ageing pattern directly connects with the geometry of the building and inadequate consideration of the local weathering at the design stage

    Materials characterisation and software tools as key enablers in Industry 5.0 and wider acceptance of new methods and products

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    Recently, the NMBP-35 Horizon 2020 projects -NanoMECommons, CHARISMA, and Easi-stress -organised a collaborative workshop to increase awareness of their contributions to the industry "commons" in terms of characterisation and digital transformation. They have established interoperability standards for knowledge management in characterisation and introduced new solutions for materials testing, aided by the standardisation of faster and more accurate assessment methods. The lessons learned from these projects and the discussions during the joint workshop emphasised the impact of recent developments and emerging needs in the field of characterisation. Specifically, the focus was on enhancing data quality through harmonisation and stand-ardisation, as well as making advanced technologies and instruments accessible to a broader community with the goal of fostering increased trust in new products and a more skilled society. Experts also highlighted how characterisation and the corresponding experimental data can drive future innovation agendas towards tech-nological breakthroughs. The focus of the discussion revolved around the characterisation and standardisation processes, along with the collection of modelling and characterisation tools, as well as protocols for data ex-change. The broader context of materials characterisation and modelling within the materials community was explored, drawing insights from the Materials 2030 Roadmap and the experiences gained from NMBP-35 pro-jects. This whitepaper has the objective of addressing common challenges encountered by the materials com-munity, illuminating emerging trends and evolving techniques, and presenting the industry's perspective on emerging requirements and past success stories. It accomplishes this by providing specific examples and high-lighting how these experiences can create fresh opportunities and strategies for newcomers entering the market. These advancements are anticipated to facilitate a more efficient transition from Industry 4.0 to 5.0 during the industrial revolution

    Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML

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    Nucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but also sporadically affect exons 9 and 11, causing changes at the protein C-terminal end (tryptophan loss, nuclear export signal [NES] motif creation) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 patients with AML, we found non–exon 12 NPM1 mutations in 5 (1.3%) of 387 NPM1c+ cases. Besides mutations in exons 9 (n = 1) and 11 (n = 1), novel exon 5 mutations were discovered (n = 3). Another exon 5 mutation was identified in an additional 141 patients with AML selected for wild-type NPM1 exon 12. Three NPM1 rearrangements (NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13 979 AML samples screened by cytogenetic/fluorescence in situ hybridization and RNA sequencing. Functional studies demonstrated that in AML cases, new NPM1 proteins harbored an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting AML-associated NPM1 genetic lesions. This study highlights the need to develop new assays for molecular diagnosis and monitoring of NPM1-mutated AML

    Chronic Myeloid Leukemia Patient's Voice About the Experience of Treatment-Free Remission Failure: Results From the Italian Sub-Study of ENESTPath Exploring the Emotional Experience of Patients During Different Phases of a Clinical Trial

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    Background: The main objective of this study is to gain further insights on how chronic myeloid leukemia (CML) patients involved in an interventional clinical trial with the purpose of reaching treatment free remission (TFR) phase, perceived and experienced TFR failure. TFR failure was defined for the individual patient as either not being eligible for drug discontinuation or as having relapse in the TFR phase with reintroduction of nilotinib treatment. Methods: Using a qualitative approach, out of 25 patients with CML who experienced TFR failure 14 were interviewed. Patients' views and experiences were explored using in-depth interviews, analyzed using the Interpretative Phenomenological Analysis (IPA). Results: The analysis of the interviews revealed that the experience of the diagnosis seems to have been lived as a traumatic break that has created a dichotomy, like an ambivalence in the ways in which CML patients perceived and experienced the whole disease journey, with contradictory feelings of both positive and negative emotions (e.g., a diagnosis of cancer, that is something distressing and of being afraid of, but also with a treatment and a life expectancies of which being grateful). This ambivalence of feelings was found to give meaning to the way in which patients cognitively and emotionally experienced the different steps of their disease history. Thus, four main issues, corresponding to different steps of the patients' journey, were identified: (1) the moment of the diagnosis, (2) the experience of the illness journey: disease and treatment, (3) the moment of "TFR failure," and (4) the impact of disease, treatment and relapse on the patient's life. Conclusion: This qualitative analysis helps in understanding patients' perspective, both in terms of getting access to the inner subjective experience of having CML and its strict relationship with the involvement in a trial or its cessation. Clinicians should consider that the way in which CML patients feel engaged in a clinical trial, create expectancies about TFR or experience the TFR failure is linked to the process of coping with the diagnosis, which is characterized by ambivalence
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