Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity

All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-trans-retinoic acid in the treatment of cancer is significantly hampered by its toxicity and the prompt emergence of resistance, believed to be caused by increased all-trans-retinoic acid metabolism. Inhibitors of all-trans-retinoic acid metabolism may therefore prove valuable in the treatment of cancer. In this study, we characterize R116010 as a new anticancer drug that is a potent inhibitor of all-trans-retinoic acid metabolism. In vitro, R116010 potently inhibits all-trans-retinoic acid metabolism in intact T47D cells with an IC50-value of 8.7 nM. In addition, R116010 is a selective inhibitor as indicated by its inhibition profile for several other cytochrome P450-mediated reactions. In T47D cell proliferation assays, R116010 by itself has no effect on cell proliferation. However, in combination with all-trans-retinoic acid, R116010 enhances the all-trans-retinoic acid-mediated antiproliferative activity in a concentration-dependent manner. In vivo, the growth of murine oestrogen-independent TA3-Ha mammary tumours is significantly inhibited by R116010 at doses as low as 0.16 mg kg−1. In conclusion, R116010 is a highly potent and selective inhibitor of all-trans-retinoic acid metabolism, which is able to enhance the biological activity of all-trans-retinoic acid, thereby exhibiting antitumour activity. R116010 represents a novel and promising anticancer drug with an unique mechanism of action

Allopurinol and oxypurinol promote osteoblast differentiation and increase bone formation

AbstractAllopurinol and its active metabolite, oxypurinol are widely used in the treatment of gout and hyperuricemia. They inhibit xanthine oxidase (XO) an enzyme in the purine degradation pathway that converts xanthine to uric acid. This investigation examined the effect of allopurinol and oxypurinol on bone formation, cell number and viability, gene expression and enzyme activity in differentiating and mature, bone-forming osteoblasts. Although mRNA expression remained relatively constant, XO activity decreased over time with mature osteoblasts displaying reduced levels of uric acid (20% decrease). Treatment with allopurinol and oxypurinol (0.1–1µM) reduced XO activity by up to 30%. At these concentrations, allopurinol and oxypurinol increased bone formation by osteoblasts ~4-fold and ~3-fold, respectively. Cell number and viability were unaffected. Both drugs increased tissue non-specific alkaline phosphatase (TNAP) activity up to 65%. Osteocalcin and TNAP mRNA expression was increased, 5-fold and 2-fold, respectively. Expression of NPP1, the enzyme responsible for generating the mineralisation inhibitor, pyrophosphate, was decreased 5-fold. Col1α1 mRNA expression and soluble collagen levels were unchanged. Osteoclast formation and resorptive activity were not affected by treatment with allopurinol or oxypurinol. Our data suggest that inhibition of XO activity promotes osteoblast differentiation, leading to increased bone formation in vitro

Evaluation of antimicrobial effectiveness of pimaricin-loaded thermosensitive nanohydrogels in grape juice

Pimaricin-loaded poly(N-isopropylacrylamide) nanohydrogels with and without acrylic acid, were evaluated as food-spoilage inhibitors in a model system and a real food product: grape juice. Pimaricin was proposed as a non-allergenic alternative to sulphites for protecting juices against recontamination. However, pimaricin may degrade under conditions and treatments (heating, acidification, lighting) commonly applied in producing fresh juices. Nanohydrogel encapsulation may be a feasible procedure to avoid pimaricin degradation, improving its antimicrobial activity. Pimaricin-free nanohydrogels did not affect the growth of the indicator yeast either in the food model system or in grape juice. Conversely, pimaricin-loaded nanohydrogels effectively inhibited the growth of the indicator yeast. In some cases, the inhibition was extended even further than using free pimaricin. For instance, in the food model system, pimaricin-loaded nanohydrogels with acrylic acid (NPPNIPA-20AA(5)) prevented the yeast growth for more than 81 h while free pimaricin was only effective for 12 h. Despite pimaricin-loaded nanohydrogels without acrylic acid (NPPNIPA(5)) were able to reduce maximum yeast growth, as in all treatments with pimaricin, the extent of the inhibitory effect was not significantly (p>0.05) different to that achieved with free pimaricin. In grape juice, both free pimaricin and NPPNIPA-20AA(5) treatment completely inhibited the growth of the indicator yeast until the end of the bioassay. However, the latter provided similar inhibition levels using a smaller amount of pimaricin due to PNIPA-20AA(5) protection and its controlled release from the nanohydrogel. Therefore, nanohydrogel encapsulation may help to optimise antifungal treatments and decrease the incidence of food allergies.Funded by grant (MAT 2006-11662-CO3-CO2-C01/MAT 2010-21509-C03-01/EUI 2008-00115) from the “Ministerio de Educación y Ciencia” (Spain). Grant (SFRH/BPD/87910/2012) from the Fundação para a Ciência e Tecnologia (FCT, Portugal). Marie Curie COFUND Postdoctoral Research Fellow

New Strategy for Rapid Diagnosis and Characterization of Fungal Infections: The Example of Corneal Scrapings

PURPOSE: The prognosis of people infected with Fungi especially immunocompromised depends on rapid and accurate diagnosis to capitalize on time administration of specific treatments. However, cultures produce false negative results and nucleic-acid amplification techniques require complex post-amplification procedures to differentiate relevant fungal types. The objective of this work was to develop a new diagnostic strategy based on real-time polymerase-chain reaction high-resolution melting analysis (PCR-HRM) that a) detects yeasts and filamentous Fungi, b) differentiates yeasts from filamentous Fungi, and c) discriminates among relevant species of yeasts. METHODS: PCR-HRM detection limits and specificity were assessed with a) isolated strains; b) human blood samples experimentally infected with Fungi; c) blood experimentally infected with other infectious agents; d) corneal scrapings from patients with suspected fungal keratitis (culture positive and negative) and e) scrapings from patients with suspected bacterial, viral or Acanthamoeba infections. The DNAs were extracted and mixed with primers diluted in the MeltDoctor® HRM Master Mix in 2 tubes, the first for yeasts, containing the forward primer CandUn (5'CATGCCTGTTTGAGCGTC) and the reverse primer FungUn (5'TCCTCCGCTT ATTGATATGCT) and the second for filamentous Fungi, containing the forward primer FilamUn (5'TGCCTGTCCGAGCGTCAT) and FungUn. Molecular probes were not necessary. The yields of DNA extraction and the PCR inhibitors were systematically monitored. RESULTS: PCR-HRM detected 0.1 Colony Forming Units (CFU)/µl of yeasts and filamentous Fungi, differentiated filamentous Fungi from yeasts and discriminated among relevant species of yeasts. PCR-HRM performances were higher than haemoculture and sensitivity and specificity was 100% for culture positive samples, detecting and characterizing Fungi in 7 out 10 culture negative suspected fungal keratitis. CONCLUSIONS: PCR-HRM appears as a new, sensitive, specific and inexpensive test that detects Fungi and differentiates filamentous Fungi from yeasts. It allows direct fungal detection from clinical samples and experimentally infected blood in less than 2.30 h after DNA extraction

Search for nonresonant Higgs boson pair production in the four leptons plus two b jets final state in proton-proton collisions at s\sqrt{s} = 13 TeV

A preprint version of the article is available at arXiv:2206.10657v2 [hep-ex], https://arxiv.org/abs/2206.10657 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at this http URL (CMS Public Pages). Report number: CMS-HIG-20-004, CERN-EP-2022-114.The first search for nonresonant production of Higgs boson pairs (HH) with one H decaying into four leptons and the other into a pair of b quarks is presented, using proton-proton collisions recorded at a center-of-mass energy of s = 13 TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 138 fb−1. A 95% confidence level upper limit of 32.4 is set on the signal strength modifier μ, defined as the ratio of the observed HH production rate in the HH→ ZZ∗b b ¯ → 4 ℓb b ¯ decay channel to the standard model (SM) expectation. Possible modifications of the H trilinear coupling λ HHH with respect to the SM value are investigated. The coupling modifier κλ, defined as λ HHH divided by its SM prediction, is constrained to be within the observed (expected) range −8.8 (−9.8) < κλ < 13.4 (15.0) at 95% confidence level. [Figure not available: see fulltext.].SCOAP3

Search for long-lived particles decaying to a pair of muons in proton-proton collisions at √s = 13 TeV

A preprint version of the article is available at arXiv:2205.08582v2 [hep-ex], https://arxiv.org/abs/2205.08582 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables, including additional supplementary figures and tables, can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/EXO-21-006 (CMS Public Pages).An inclusive search for long-lived exotic particles decaying to a pair of muons is presented. The search uses data collected by the CMS experiment at the CERN LHC in proton-proton collisions at s = 13 TeV in 2016 and 2018 and corresponding to an integrated luminosity of 97.6 fb−1. The experimental signature is a pair of oppositely charged muons originating from a common secondary vertex spatially separated from the pp interaction point by distances ranging from several hundred μm to several meters. The results are interpreted in the frameworks of the hidden Abelian Higgs model, in which the Higgs boson decays to a pair of long-lived dark photons ZD, and of a simplified model, in which long-lived particles are produced in decays of an exotic heavy neutral scalar boson. For the hidden Abelian Higgs model with m(ZD) greater than 20 GeV and less than half the mass of the Higgs boson, they provide the best limits to date on the branching fraction of the Higgs boson to dark photons for cτ(ZD) (varying with m(ZD)) between 0.03 and ≈0.5 mm, and above ≈0.5 m. Our results also yield the best constraints on long-lived particles with masses larger than 10 GeV produced in decays of an exotic scalar boson heavier than the Higgs boson and decaying to a pair of muons. [Figure not available: see fulltext.].SCOAP3

Search for top squarks in the four-body decay mode with single lepton final states in proton-proton collisions at √s = 13 TeV

A preprint version of the article is available at arXiv:2301.08096v2 [hep-ex], https://arxiv.org/abs/2301.08096 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/SUS-21-003 (CMS Public Pages).A search for the pair production of the lightest supersymmetric partner of the top quark, the top squark (t ~1), is presented. The search targets the four-body decay of the t ~1 , which is preferred when the mass difference between the top squark and the lightest supersymmetric particle is smaller than the mass of the W boson. This decay mode consists of a bottom quark, two other fermions, and the lightest neutralino (χ~10), which is assumed to be the lightest supersymmetric particle. The data correspond to an integrated luminosity of 138 fb−1 of proton-proton collisions at a center-of-mass energy of 13 TeV collected by the CMS experiment at the CERN LHC. Events are selected using the presence of a high-momentum jet, an electron or muon with low transverse momentum, and a significant missing transverse momentum. The signal is selected based on a multivariate approach that is optimized for the difference between m(t ~1) and m(χ~10). The contribution from leading background processes is estimated from data. No significant excess is observed above the expectation from standard model processes. The results of this search exclude top squarks at 95% confidence level for masses up to 480 and 700 GeV for m(t ~1) − m(χ~10) = 10 and 80 GeV, respectively. [Figure not available: see fulltext.].SCOAP3

Search for a vector-like quark T′ → tH via the diphoton decay mode of the Higgs boson in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for the electroweak production of a vector-like quark T′, decaying to a top quark and a Higgs boson is presented. The search is based on a sample of proton-proton collision events recorded at the LHC at = 13 TeV, corresponding to an integrated luminosity of 138 fb−1. This is the first T′ search that exploits the Higgs boson decay to a pair of photons. For narrow isospin singlet T′ states with masses up to 1.1 TeV, the excellent diphoton invariant mass resolution of 1–2% results in an increased sensitivity compared to previous searches based on the same production mechanism. The electroweak production of a T′ quark with mass up to 960 GeV is excluded at 95% confidence level, assuming a coupling strength κT = 0.25 and a relative decay width Γ/MT′ < 5%