19 research outputs found
A selective p53 activator and anticancer agent to improve colorectal cancer therapy
Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.We thank PT national funds (FCT/MCTES, Fundação para a Ciência e a Tecnologia, and Ministério da Ciência, Tecnologia e Ensino Superior) through grants UIDB/50006/2020, UID/BIO/04469/2019, UIDB/04539/2020, and
UIDP/04539/2020 (CIBB); BioTecNorte operation (NORTE-01-0145-FEDER000004) and Porto Neurosciences and Neurologic Disease Research Initiative at I3S (Norte-01-0145-FEDER-000008) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional
Regional do Norte; Masaryk University (Project MUNI/A/1127/2019) and Ministry of Education, Youth and Sports of the Czech Republic (project nos. LQ1605 and LM2018125); FCT financial support through the fellowships SFRH/BD/119144/2016 (H.R.) and SFRH/BD/117949/2016 (L.R.); Fondazione
AIRC (IG#18985, A.I.); and the Programa Operacional Potencial Humano
(POCH), specifically the BiotechHealth Programme (Doctoral Programme on
Cellular and Molecular Biotechnology Applied to Health Sciences, PD/00016/2012). We thank Dario Rizzotto for assistance in preparing the libraries for RNA sequencing. Funding: This work was supported by PT National Funds (FCT/MCTES, Fundação para a Ciência e Tecnologia, and Ministério da Ciência, Tecnologia e Ensino Superior) via the projects UIDB/50006/2020 (LAQV/REQUIMTE), UIDB/00313/2020, and UIDP/00313/2020, co-funded by COMPETE2020-UE.info:eu-repo/semantics/publishedVersio
Cosmogenic background simulations for neutrinoless double beta decay with the DARWIN observatory at various underground sites
Xenon dual-phase time projections chambers (TPCs) have proven to be a successful technology in studying physical phenomena that require low-background conditions. With 40t of liquid xenon (LXe) in the TPC baseline design, DARWIN will have a high sensitivity for the detection of particle dark matter, neutrinoless double beta decay (0 ν β β), and axion-like particles (ALPs). Although cosmic muons are a source of background that cannot be entirely eliminated, they may be greatly diminished by placing the detector deep underground. In this study, we used Monte Carlo simulations to model the cosmogenic background expected for the DARWIN observatory at four underground laboratories: Laboratori Nazionali del Gran Sasso (LNGS), Sanford Underground Research Facility (SURF), Laboratoire Souterrain de Modane (LSM) and SNOLAB. We present here the results of simulations performed to determine the production rate of 137 Xe, the most crucial isotope in the search for 0 ν β β of 136 Xe. Additionally, we explore the contribution that other muon-induced spallation products, such as other unstable xenon isotopes and tritium, may have on the cosmogenic background
Cosmogenic background simulations for the DARWIN observatory at different underground locations
Xenon dual-phase time projections chambers (TPCs) have proven to be a
successful technology in studying physical phenomena that require
low-background conditions. With 40t of liquid xenon (LXe) in the TPC baseline
design, DARWIN will have a high sensitivity for the detection of particle dark
matter, neutrinoless double beta decay (), and axion-like
particles (ALPs). Although cosmic muons are a source of background that cannot
be entirely eliminated, they may be greatly diminished by placing the detector
deep underground. In this study, we used Monte Carlo simulations to model the
cosmogenic background expected for the DARWIN observatory at four underground
laboratories: Laboratori Nazionali del Gran Sasso (LNGS), Sanford Underground
Research Facility (SURF), Laboratoire Souterrain de Modane (LSM) and SNOLAB. We
determine the production rates of unstable xenon isotopes and tritium due to
muon-included neutron fluxes and muon-induced spallation. These are expected to
represent the dominant contributions to cosmogenic backgrounds and thus the
most relevant for site selection
A Next-Generation Liquid Xenon Observatory for Dark Matter and Neutrino Physics
The nature of dark matter and properties of neutrinos are among the mostpressing issues in contemporary particle physics. The dual-phase xenontime-projection chamber is the leading technology to cover the availableparameter space for Weakly Interacting Massive Particles (WIMPs), whilefeaturing extensive sensitivity to many alternative dark matter candidates.These detectors can also study neutrinos through neutrinoless double-beta decayand through a variety of astrophysical sources. A next-generation xenon-baseddetector will therefore be a true multi-purpose observatory to significantlyadvance particle physics, nuclear physics, astrophysics, solar physics, andcosmology. This review article presents the science cases for such a detector.<br
A next-generation liquid xenon observatory for dark matter and neutrino physics
The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector
Cosmogenic background simulations for neutrinoless double beta decay with the DARWIN observatory at various underground sites
Xenon dual-phase time projections chambers (TPCs) have proven to be a successful technology in studying physical phenomena that require low-background conditions. With of liquid xenon (LXe) in the TPC baseline design, DARWIN will have a high sensitivity for the detection of particle dark matter, neutrinoless double beta decay (0\upnu \upbeta \upbeta ), and axion-like particles (ALPs). Although cosmic muons are a source of background that cannot be entirely eliminated, they may be greatly diminished by placing the detector deep underground. In this study, we used Monte Carlo simulations to model the cosmogenic background expected for the DARWIN observatory at four underground laboratories: Laboratori Nazionali del Gran Sasso (LNGS), Sanford Underground Research Facility (SURF), Laboratoire Souterrain de Modane (LSM) and SNOLAB. We present here the results of simulations performed to determine the production rate of Xe, the most crucial isotope in the search for 0\upnu \upbeta \upbeta of Xe. Additionally, we explore the contribution that other muon-induced spallation products, such as other unstable xenon isotopes and tritium, may have on the cosmogenic background
Reprogramming iPSCs to study age-related diseases: models, therapeutics, and clinical trials
The unprecedented rise in life expectancy observed in the last decades is leading to a global increase in the ageing population, and age-associated diseases became an increasing societal, economic, and medical burden. This has boosted major efforts in the scientific and medical research communities to develop and improve therapies to delay ageing and age-associated functional decline and diseases, and to expand health span. The establishment of induced pluripotent stem cells (iPSCs) by reprogramming human somatic cells has revolutionised the modelling and understanding of human diseases. iPSCs have a major advantage relative to other human pluripotent stem cells as their obtention does not require the destruction of embryos like embryonic stem cells do, and do not have a limited proliferation or differentiation potential as adult stem cells. Besides, iPSCs can be generated from somatic cells from healthy individuals or patients, which makes iPSC technology a promising approach to model and decipher the mechanisms underlying the ageing process and age-associated diseases, study drug effects, and develop new therapeutic approaches. This review discusses the advances made in the last decade using iPSC technology to study the most common age-associated diseases, including age-related macular degeneration (AMD), neurodegenerative and cardiovascular diseases, brain stroke, cancer, diabetes, and osteoarthritis.ALG-01-0145-FEDER-072586info:eu-repo/semantics/publishedVersio
GPU-based optical simulation of the DARWIN detector
Understanding propagation of scintillation light is critical for maximizing the discovery potential of next-generation liquid xenon detectors that use dual-phase time projection chamber technology. This work describes a detailed optical simulation of the DARWIN detector implemented using Chroma, a GPU-based photon tracking framework. To evaluate the framework and to explore ways of maximizing efficiency and minimizing the time of light collection, we simulate several variations of the conventional detector design. Results of these selected studies are presented. More generally, we conclude that the approach used in this work allows one to investigate alternative designs faster and in more detail than using conventional Geant4 optical simulations, making it an attractive tool to guide the development of the ultimate liquid xenon observatory
GPU-based optical simulation of the DARWIN detector
International audienceUnderstanding propagation of scintillation light is critical for maximizing the discovery potential of next-generation liquid xenon detectors that use dual-phase time projection chamber technology. This work describes a detailed optical simulation of the DARWIN detector implemented using Chroma, a GPU-based photon tracking framework. To evaluate the framework and to explore ways of maximizing efficiency and minimizing the time of light collection, we simulate several variations of the conventional detector design. Results of these selected studies are presented. More generally, we conclude that the approach used in this work allows one to investigate alternative designs faster and in more detail than using conventional Geant4 optical simulations, making it an attractive tool to guide the development of the ultimate liquid xenon observatory