Synthesis and Characterization of Symmetrically versus Unsymmetrically Proton-Bridged Hexa-Iron Clusters

Syntheses and magnetic and structural characterization of hexa-iron complexes of derivatized salicylaldoximes are discussed. Complexation of Fe(BF4)2·6H2O with each ligand (H2 L1 and H4 L2) in a methanolic-pyridine solution resulted in hexa-iron compounds (C1 and C2, respectively), which each contain two near-parallel metal triangles of [Fe3-μ3-O], linked by six fluoride bridges and stabilized by a hydrogen-bonded proton between the μ3-O groups. Within each metal triangle of C2, Fe(III) ions are connected via the amine "straps" of (H4 L2-2H). Variable-temperature magnetic susceptibility and Mössbauer data of C1 and C2 indicate the presence of dominant antiferromagnetic interactions between the high-spin (S = 5/2) Fe(III) centers. For C1, two quadrupole doublets are observed at room temperature and 5 K, consistent with structural data from which discrete but disordered [Fe3-μ3-O] and [Fe3-μ3-OH] species were inferred. For C2, a single sharp quadrupole doublet with splitting intermediate between those determined for C1 was observed, consistent with the symmetric [Fe3-μ3-O···H···μ3-O-Fe3] species inferred crystallographically from the very short μ3-O···μ3-O separation. The differences in the physical properties of the complexes, as seen in the Mössbauer, X-ray, and magnetic data, are attributed to the conformational flexibility imparted by the nature of the linkages between the closely related ligands

Valence tautomerism versus spin crossover in pyridinophane-cobalt-dioxolene complexes: an experimental and computational study

Compounds [Co(L-N4R2)(dbdiox)](BPh4) (L-N4R2 = N,N′-di-alkyl-2,11-diaza[3.3]-(2,6)pyridinophane, R = iPr (1a), Et (2a); dbdiox = 3,5-di-tert-butyldioxolene) and [M(L-N4iPr2)(dbdiox)](BPh4) (M = Mn (3a), Fe (4a)) have been synthesized and investigated with a view to possible valence tautomeric (VT) or spin crossover (SCO) interconversions. Single crystal X-ray diffraction data for all compounds at 100 or 130 K indicate trivalent metal cations and di-tert-butylcatecholate (dbcat2−) dioxolene ligands. Variable temperature magnetic susceptibility data for all species between 2 and 340 K are consistent with these redox states, with low spin configurations for the cobalt(III) ions and high spin for the manganese(III) and iron(III) ions. Above 340 K, compound 1a exhibits an increase in magnetic susceptibility, suggesting the onset of a VT interconversion from low spin Co(III)-dbcat to high spin Co(II)-dbsq (dbsq− = di-tert-butylsemiquinonate) that is incomplete up to 400 K. In solution, variable temperature electronic absorption spectra and Evans NMR method magnetic susceptibility data indicate reversible VT interconversions for 1a in several solvents, with the transition temperature varying with solvent. Variable temperature electronic absorption spectra are temperature-invariant for 3a and 4a, while spectra for 2a in 1,2-dichloroethane suggest the onset of a VT transition at the highest temperatures measured. Density functional theory calculations on all four compounds and literature analogues provide key insights into the relative energies of the different electromeric forms and the possibilities for VT versus SCO interconversions in this family of compounds

Uric acid and thiocyanate as competing substrates of lactoperoxidase

The physiological function of urate is poorly understood. It may act as a danger signal, an antioxidant, or a substrate for heme peroxidases. Whether it reacts sufficiently rapidly with lactoperoxidase (LPO) to act as a physiological substrate remains unknown. LPO is a mammalian peroxidase that plays a key role in the innate immune defense by oxidizing thiocyanate to the bactericidal and fungicidal agent hypothiocyanite. We now demonstrate that urate is a good substrate for bovine LPO

Ceruloplasmin is an endogenous inhibitor of myeloperoxidase

Myeloperoxidase is a neutrophil enzyme that promotes oxidative stress in numerous inflammatory pathologies. It uses hydrogen peroxide to catalyze the production of strong oxidants including chlorine bleach and free radicals. A physiological defense against the inappropriate action of this enzyme has yet to be identified. We found that myeloperoxidase oxidized 75% of the ascorbate in plasma from ceruloplasmin knock-out mice, but there was no significant loss in plasma from wild type animals. When myeloperoxidase was added to human plasma it became bound to other proteins and was reversibly inhibited. Ceruloplasmin was the predominant protein associated with myeloperoxidase. When the purified proteins were mixed, they became strongly but reversibly associated. Ceruloplasmin was a potent inhibitor of purified myeloperoxidase, inhibiting production of hypochlorous acid by 50% at 25 nM

Dynamic control of neurochemical release with ultrasonically-sensitive nanoshell-tethered liposomes

The unique surface plasmon resonance of hollow gold nanoshells can be used to achieve drug release from liposomes upon laser stimulation, and adapted to mimic the intricate dynamics of neurotransmission ex vivo in brain preparations. However, to induce a physiological response in vivo requires the degree of temporal precision afforded by laser stimulation, but with a greater depth of penetration through tissue. Here we report that the attachment of hollow gold nanoshells to the surface of robust liposomes results in a construct that is highly sensitive to ultrasonic stimulation. The resulting construct can be remotely triggered by low intensity, therapeutic ultrasound. To our knowledge, this is the first example of nanoparticle-liposome system that can be activated by both laser and acoustic stimulation. The system is capable of encapsulating the neurochemical dopamine, and repeatedly releasing small amounts on-demand in a circulating environment, allowing for precise spatiotemporal control over the release profile

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival