12 research outputs found
ATM kinase dead: from ataxia telangiectasia syndrome to cancer
No full textATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3'end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. ATM mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of ATM mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM
Reduction of EpCAM-Positive Cells from a Cell Salvage Product Is Achieved by Leucocyte Depletion Filters Alone
No full textIntraoperative cell salvage reduces the need for allogeneic blood transfusion in complex cancer surgery, but concerns about the possibility of it re-infusing cancer cells have hindered its application in oncology. We monitored the presence of cancer cells on patient-salvaged blood by means of flow cytometry; next, we simulated cell salvage, followed by leucodepletion and irradiation on blood contaminated with a known amount of EpCAM-expressing cancer cells, assessing also residual cancer cell proliferation as well as the quality of salvaged red blood cell concentrates (RBCs). We observed a significant reduction of EpCAM-positive cells in both cancer patients and contaminated blood, which was comparable to the negative control after leucodepletion. The washing, leucodepletion and leucodepletion plus irradiation steps of cell salvage were shown to preserve the quality of RBCs in terms of haemolysis, membrane integrity and osmotic resistance. Finally, cancer cells isolated from salvaged blood lose their ability to proliferate. Our results confirm that cell salvage does not concentrate proliferating cancer cells, and that leucodepletion allows for the reduction of residual nucleated cells, making irradiation unnecessary. Our study gathers pieces of evidence on the feasibility of this procedure in complex cancer surgery. Nevertheless, it highlights the necessity of finding a definitive consensus through prospective trials
First results from the full-scale prototype for the Fluorescence detector Array of Single-pixel Telescopes
No full textThe Fluorescence detector Array of Single-pixel Telescopes (FAST) is a design concept for the next generation of ultrahigh-energy cosmic ray (UHECR) observatories, addressing the require- ments for a large-area, low-cost detector suitable for measuring the properties of the highest en- ergy cosmic rays. In the FAST design, a large field of view is covered by a few pixels at the focal plane of a mirror or Fresnel lens. Motivated by the successful detection of UHECRs using a prototype comprised of a single 200 mm photomultiplier-tube and a 1 m2 Fresnel lens system [Astropart.Phys. 74 (2016) 64-72], we have developed a new full-scale prototype consisting of four 200 mm photomultiplier-tubes at the focus of a segmented mirror of 1.6 m in diameter. In October 2016 we installed the full-scale prototype at the Telescope Array site in central Utah, USA, and began steady data taking. We report on first results of the full-scale FAST prototype, including measurements of artificial light sources, distant ultraviolet lasers, and UHECRs.Toshihiro Fujii, Max Malacari, Justin Albury, Jose A. Bellido, John Farmer, Aygul Galimova, Pavel Horvath, Miroslav Hrabovsky, Dusan Mandat, Ariel Matalon, John N. Matthews, Maria Merolle, Xiaochen Ni, Libor Nozka, Miroslav Palatka, Miroslav Pech, Paolo Privitera, Petr Schovanek, Stan B. Thomas, Petr Travnicek (FAST Collaboration
The prototype opto-mechanical system for the Fluorescence detector Array of Single-pixel Telescopes
No full textPublished: July 4, 2017The Fluorescence detector Array of Single-pixel Telescopes is a proposed low-cost, large-area, next-generation experiment for the detection of ultrahigh-energy cosmic rays via the atmospheric fluorescence technique. The proposed design involves the deployment of several hundred large field-of-view fluorescence telescopes on a regular grid of several thousand square kilometers in ground area. This paper describes the optical design of the prototype telescope, as well as its mechanical support structure.D. Mandat, M. Palatka, M. Pech, P. Schovanek, P. Travnicek, L. Nozka, M. Hrabovsky, P. Horvath, T. Fujii, P. Privitera, M. Malacari, J. Farmer, A. Galimova, A. Matalon, M. Merolle, X. Ni, J.A. Bellido, J.N. Matthews and S.B. Thoma
Fuori dall'ombra di Giuseppe Cesari : Mattia Merolle nel santuario di Santa Maria a Parete a Liveri
No full text
Glioblastoma Cells Do Not Affect Axitinib-Dependent Senescence of HUVECs in a Transwell Coculture Model
No full textAxitinib is an orally available inhibitor of tyrosine kinases, with high specificity for vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is approved for the treatment of advanced renal cell carcinoma and is in phase II clinical trials for recurrent glioblastoma (GBM). GBM is a brain tumor peculiar in its ability to induce neoangiogenesis. Since both GBM tumor cells and endothelial cells of tumor vasculature express VEGFRs, Axitinib exerts its inhibitory action on both tumor and endothelial cells. We and others previously demonstrated that Axitinib triggers cellular senescence. In particular, Axitinib-dependent senescence of HUVECs (human umbilical vein endothelial cells) is accompanied by intracellular reactive oxygen species(ROS) increase and early ataxia telangiectasia mutated(ATM) activation. Here we wondered if the presence of glioblastoma tumor cells could affect the HUVEC senescence upon Axitinib exposure. To address this issue, we cocultured HUVECs together with GBM tumor cells in transwell plates. HUVEC senescence did not result in being affected by GBM cells, neither in terms of β galactosidase activity nor of proliferation index or ATM phosphorylation. Conversely, Axitinib modulation of HUVEC gene expression was altered by cocultured GBM cells. These data demonstrate that the GBM secretome modifies HUVECs’ transcriptomic profile upon Axitinib exposure, but does not prevent drug-induced senescence
Combining Multispectral Imaging and XRF Analysis to Examine San Patroba predica ai fedeli di Pozzuoli by Massimo Stanzione
No full textA diagnostic analysis of the painting depicting San Patroba che predica ai fedeli di Pozzuoli by Massimo Stanzione was carried out. The painting was completed in 1635–1637 to decorate the choir of the Cathedral of Saint Procolo in Pozzuoli (Naples, Italy). The technique of X-ray fluorescence (XRF) and multispectral imaging were applied on site to learn about the executive technique, the palette of the painting, and the restoration works, as well as understand the influence of the other painters active in Naples in that period. The results of the research are presented and discussed to draw general aspects and peculiarities of the pigments and the pictorial technique used by this important painter, as well as the restorations
Dendritic cell-mediated responses to secreted <i>Cryptosporidium</i> effectors promote parasite-specific CD8+ T cell responses
No full textCryptosporidium causes debilitating diarrheal disease in patients with primary and acquired defects in T cell function. However, it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. Here, Cryptosporidium was engineered to express a parasite effector protein (MEDLE-2) that contains the major histocompatibility complex-I restricted SIINFEKL epitope which is recognized by T cell receptor transgenic OT-I(OVA-TCR-I) clusters of differentiation (CD)8+T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8+T cells that were a source of interferon-gamma (IFN-γ) that could restrict growth of Cryptosporidium. This T cell response was dependent on the translocation of the effector and similar results were observed with another secreted parasite effector (rhoptry protein 1). Although infection and these translocated effector proteins are restricted to intestinal epithelial cells, type 1 conventional dendritic cells were required to generate CD8+T cell responses to these model antigens. These data sets highlight Cryptosporidium effectors as potential targets of the immune system and suggest that crosstalk between enterocytes and type 1 conventional dendritic cells is crucial for CD8+T cell responses to Cryptosporidium
