A new rapid desensitization protocol for chemotherapy agents

Background: Desensitization has been used for some decades to treat patients with the allergenic drug when an alternative drug with similar effi cacy and safety is not available. We present the results from a series of oncology patients desensitized at our hospital during the last 2 years. Objective: To assess the effi cacy of a new desensitization protocol in patients allergic to chemotherapy drugs. Methods: We performed an observational retrospective study of 11 women (6 breast cancer and 5 ovarian cancer) who underwent our desensitization protocol. Four patients had immediate reactions to carboplatin, 3 to docetaxel, 3 to paclitaxel, and 1 to both docetaxel and paclitaxel. Premedication was administered in all cases. A 5-step protocol based on 5 different dilutions of the drugs was used. Results: We performed 39 desensitization procedures: 14 to carboplatin, 3 to oxaliplatin, 16 to docetaxel, and 6 to paclitaxel. Eight patients tolerated the full dose in 36 procedures. One patient suffered an anaphylactic reaction to carboplatin that reverted with treatment. One patient had dyspnea after a paclitaxel cycle. One patient experienced dyspnea due to chronic pulmonary thromboembolism related to her disease. Conclusion: Desensitization is a useful procedure in patients who are allergic to their chemotherapy agents

Dominant induction of the inflammasome by the SARS-CoV-2 accessory protein ORF9b, abrogated by small-molecule ORF9b homodimerization inhibitors

Viral accessory proteins play critical roles in viral escape form host innate immune responses and in viral inflammatory pathogenesis. Here we show that the SARS-CoV-2 accessory protein, ORF9b, but not other SARS-CoV-2 accessory proteins (ORF3a, ORF3b, ORF6, ORF7, ORF8, ORF9c, ORF10), strongly activates inflammasomedependent caspase-1 in A549 lung carcinoma cells and THP-1 monocyte-macrophage cells. Exposure to lipopolysaccharide (LPS) and ATP additively enhanced the activation of caspase-1 by ORF9b, suggesting that ORF9b and LPS follow parallel pathways in the activation of the inflammasome and caspase-1. Following rational in silico approaches, we have designed small molecules capable of inhibiting the homodimerization of ORF9b, which experimentally inhibited ORF9b-ORF9b homotypic interactions, caused mitochondrial eviction of ORF9b, inhibited ORF9b-induced activation of caspase-1 in A549 and THP-1 cells, cytokine release in THP-1 cells, and restored type I interferon (IFN-I) signaling suppressed by ORF9b in both cell models. These small molecules are first-in-class compounds targeting a viral accessory protein critical for viral-induced exacerbated inflammation and escape from innate immune responses, with the potential of mitigating the severe immunopathogenic damage induced by highly pathogenic coronaviruses and restoring antiviral innate immune responses curtailed by viral infection.This work was funded by the Spanish National Research Council (CSIC, project numbers CSIC-COV19-006, CSIC-COV-19-201, 202020E079 and 202320E187), the Catalan Agency for Management of University and Research Grants (AGAUR, 2020PANDE00048, 2021SGR1490, 2021SGR00350), the CSIC’s Global Health Platform (PTI Salud Global), The Networked Center for Biomedical Research in Liver and Digestive Diseases (CIBER-EHD), the Spanish Structures and Excellence María de Maeztu program (CEX2021-001202-M) and the European Commission-Next Generation EU (Regulation EU 2020/2094).N

Inflammasome activation by SARS-CoV-2 accessory protein: Development of novel inhibitors of the SARS-CoV-2 accessory protein ORF9b

1 p.-5 fig.SARS-CoV-2 can activate the inflammasome, which, when unbridled, contributes to pathogenic inflammatory responses and to severe COVID-19. Several SARS-CoV-2 components have been shown to participate in this activation. Here, we have systematically assayed SARS-CoV-2 accessory proteins (ORF3a, ORF3b, ORF6, ORF7,ORF8, ORF9b, ORF9c and ORF10) for their ability to modulate inflammasome activity. We have found that among all accessory proteins, only ORF9b, a protein that locates in mitochondria, triggers a strong activation of caspase-1 activity and cytokine release in A549 lung epithelial cells and THP-1 monocyte-macrophage cells. This induction is observed both by transducing ORF9b alone or upon concomitant transduction of all accessory proteins. Based on the solved structure of ORF9b, we have conducted an in silico drug discovery effort to identify small molecules capable of disrupting the ORF9b homodimer and to attenuate its observed activity. Iterative steps of blind massive docking and molecular dynamics led to the identification of small molecules predicted to prevent ORF9b homodimeric interactions. This prediction was experimentally validated by means of surface plasmon resonance, yielding two active molecules. These molecules showed a potent inhibition of ORF9b-induced caspase-1 activation and cytokine release, and caused a remarkable eviction of ORF9b from mitochondria. These novel first-in-class ORF9b inhibitors are currently being tested for their ability to mitigate viral cytopathogenic effects.Peer reviewe

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum