Cadmium influences the 5-fluorouracil cytotoxic effects on breast cancer cells

The aim of the research was to evaluate a heavy metal, cadmium (Cd), which was used to produce alterations in human breast cancer cell line MCF-7. Moreover, we analyzed both immunohistochemical and ultrastructural alterations induced by the antineoplastic drug, 5-fluorouracil (5-FU), after exposure to different concentrations of cd. Also, we compared the effects of these compounds on actin and tubulin cytoskeleton proteins. Under ultramicroscopic observation, control cells looked polymorphous with filopodia. In cells already treated with small concentrations of Cd, after brief times of incubation, we observed an intense metabolic activity with larger, clearer, and elongated mitochondria characterized by thin and numerous dilated cristae. 5-FU-treated cells showed cytotoxicity signs with presence of pore-like alterations in the cell membrane and evident degeneration of cytoplasm and cell nuclei. The addition of 5-FU (1.5 µM) to the cells treated with Cd (5 µM–20 µM) did not induce significant ultrastructural changes in comparison with cells treated only with Cd. In Cd+5FU-treated cells mitochondria with globular aspect and regular cristae indicated the active metabolic state. In cells treated only with Cd we observed alterations in actin distribution, while tubulin branched out throughout the cytoplasm. With the association of Cd+5FU, we observed less morphological alterations in both tubulin and actin cytoskeleton proteins. Although the mechanism remains unknown at present, our findings suggest that Cd prevents the cytotoxic effect of 5-FU on breast cancer cells. These preliminary results could have an important clinical application in patients with breast cancer

Interaction of divalent cations with peptide fragments from Parkinson’s disease genes

Protected Ac-PDEKHEL-NH2 (PK9-H) and Ac-FCGDGANDCG-NH2 (PK9-C) peptide fragments corresponding to sequences from residues 1165 to 1171 and 1184 to 1193, respectively, in the Park9 encoded protein from Parkinson’s disease gene, were tested for their protonation and complex formation capabilities with Cu(II), Zn(II) and Mn(II) ions by potentiometric and UV-Vis measurements. The effects of peptide titration with the metal ions have been followed by mono- and bi-dimensional NMR spectroscopy in order to support the potentiometric results and to understand the details of metal binding. Only mononuclear complexes have been evidenced for all the checked metal ions with PH9-H peptide. Mononuclear and bis-complexes with PK9-C peptide have been evidenced with Cu(II) and Zn(II) metal ions. From the dissociation-constants and pM values obtained for the binary competition diagrams for the systems containing Cu(II), Zn(II) or Mn(II) and the two ligands, Cu(II) ion is able of binding more efficiently than Zn(II) and Mn(II) metal ions to both ligands

Silica and carbon decorated silica nanosheet impact on primary human immune cells

Silica nanosheets (SiO 2 NS) are considered to be a promising material in clinical practice for diagnosis and therapy applications. However, an appropriate surface functionalization is essential to guarantee high biocompatibility and molecule loading ability. Although SiO 2 NS are chemically stable, its effects on immune systems are still being explored. In this work, we successfully synthesized a novel 2D multilayer SiO 2 NS and SiO 2 NS coated with carbon (C/SiO 2 NS), and evaluated their impact on human Peripheral Blood Mononuclear Cells (PBMCs) and some immune cell subpopulations. We demonstrated that the immune response is strongly dependent on the surface functionalities of the SiO 2 NS. Ex vivo experiments showed an increase in biocompatibility of C/SiO 2 NS compared to SiO 2 NS, resulting in a lowering of hemoglobin release together with a reduction in cellular toxicity and cellular activation. However, none of them are directly involved in the activation of the acute inflammation process with a consequent release of pro-inflammatory cytokines. The obtained results provide an important direction towards the biomedical applications of silica nanosheets, rendering them an attractive material for the development of future immunological therapies. � 2018 Elsevier B.V.This publication was made possible by an NPRP award [NPRP 6- 892-1-169 ] from the Qatar National Research Fund (a member of The Qatar Foundation) . The biocompatibility studies were partially supported through FLAG-ERA MIUR (G-IMMUNOMICS project) , the European Union HORIZON 2020 research and innovation program under MSCA RISE 2016 project Carbo-Immap grant. n. 734381 and Italian MIUR (project: 2015TWP83Z ). The statements made herein are solely the responsibility of the authors.Scopu

Oncogenic states dictate the prognostic and predictive connotations of intratumoral immune response

BackgroundAn immune active cancer phenotype typified by a T helper 1 (Th-1) immune response has been associated with increased responsiveness to immunotherapy and favorable prognosis in some but not all cancer types. The reason of this differential prognostic connotation remains unknown.MethodsTo explore the contextual prognostic value of cancer immune phenotypes, we applied a multimodal pan-cancer analysis among 31 different histologies (9282 patients), encompassing immune and oncogenic transcriptomic analysis, mutational and neoantigen load and copy number variations.ResultsWe demonstrated that the favorable prognostic connotation conferred by the presence of a Th-1 immune response was abolished in tumors displaying specific tumor-cell intrinsic attributes such as high transforming growth factor-beta (TGF-beta) signaling and low proliferation capacity. This observation was independent of mutation rate. We validated this observation in the context of immune checkpoint inhibition. WNT-beta catenin, barrier molecules, Notch, hedgehog, mismatch repair, telomerase activity and AMPK signaling were the pathways most coherently associated with an immune silent phenotype together with mutations of driver genes including IDH1/2, FOXA2, HDAC3, PSIP1, MAP3K1, KRAS, NRAS, EGFR, FGFR3, WNT5A and IRF7.ConclusionsThis is the first systematic study demonstrating that the prognostic and predictive role of a bona fide favorable intratumoral immune response is dependent on the disposition of specific oncogenic pathways. This information could be used to refine stratification algorithms and prioritize hierarchically relevant targets for combination therapies.Surgical oncolog