Rituximab (RTX) is widely administered to patients with autoimmune disease (AID). This study aimed to estimate the incidence of serious infectious events (SIEs) after RTX initiation in patients with ...AID. We also described the characteristics and risk factors of SIEs, and immunoglobulin replacement therapy (IgRT) strategies.
Patients treated between 2005 and 2016 were included in this retrospective monocentric cohort study. An RTX course was defined as the complete RTX treatment regimen received by a given patient for AID. SIEs and IgRT were right-censored at 24 months after RTX initiation.
Two hundred twenty-one patients were included (corresponding to 276 RTX courses). Reasons for RTX initiation included connective tissue disease (38%), systemic vasculitis (36%), and autoimmune cytopenia (22%). The 1- and 2-year incidences of SIEs were 17.3 (95% confidence interval CI, 12.0-22.5) and 11.3 (95% CI, 8.1-14.5) per 100 person-years, respectively. Forty-seven SIEs were observed, mostly comprising pneumonias (45%) and bacteremias (21%). When documented, the microorganisms were bacterial (55%) and fungal (12%). Identified risk factors of SIEs were age, history of diabetes, history of cancer, concomitant steroid treatment, and low CD4 lymphocyte count at RTX initiation. IgRT was started in 22 RTX courses (8%).
In patients with AID treated with RTX, the 1- and 2-year incidence of SIE was 17.3 and 11.3 per 100 person-years, respectively. Reports of SIE characteristics, risk factors, and IgRT strategies highlight the need for an appropriate and individualized assessment prior to and following RTX to prevent SIEs, particularly in patients with comorbidities.
The first addition of alcohols to carbodiimides catalyzed by transition‐metal‐free compounds employs 1,5,7‐triazabicyclo4.4.0dec‐5‐ene (TBD) and its alkali metal salts. Isoureas are obtained in short ...reaction times and high yields when TBDK is used as the catalyst. Control of the coordination sphere of potassium with exogenous chelating ligands, in combination with mechanistic DFT calculations, demonstrated the role and positive influence of the alkali‐metal cation on the kinetics.
The addition of alcohols to carbodiimides is catalyzed by transition‐metal‐free compounds such as 1,5,7‐triazabicyclo4.4.0dec‐5‐ene (TBD) and its alkali‐metal salts. Isoureas are obtained in short reaction times and high yields when TBDK is used as the catalyst.
The kinetics of the oxidative additions of haloheteroarenes HetX (X=I, Br, Cl) to Pd0(PPh3)2 (generated from Pd0(PPh3)4) have been investigated in THF and DMF and the rate constants have been ...determined. In contrast to the generally accepted concerted mechanism, Hammett plots obtained for substituted 2‐halopyridines and solvent effects reveal a reaction mechanism dependent on the halide X of HetX: an unprecedented SNAr‐type mechanism for X=Br or Cl and a classical concerted mechanism for X=I. These results are supported by DFT studies.
X changes everything: Kinetics of the oxidative additions of HetX (X=I, Br, Cl) to Pd0(PPh3)2 generated from Pd0(PPh3)4 and DFT calculations reveal a mechanism that, contrary to the generally accepted concerted mechanism, depends on the nature of X. The data point to an unprecedented SNAr‐type mechanism for X=Br or Cl, whereas a classical concerted mechanism is at play for X=I (see scheme).
Research into environmentally friendly strategies for hydrogen transfer reduction is increasing, along with the need for more elaborate heterocyclic platforms. Within this context, we develop a new ...approach for substituted dihydrobenzoccarbazoles and indoles. These compounds were synthesized through an iron-catalyzed hydrogen transfer reduction of nitroarenes, followed by intramolecular cyclization. This transformation involves using a Knölker-type catalyst, Cs2CO3 as the base, and benzyl alcohol as the non-expensive and low volatile hydrogen donor. We synthesize 30 examples of aza-heterocycles with moderate to excellent yields by applying this strategy. Additionally, DFT calculations demonstrated that the pathway reaction could follow an anionic mechanism.
In pursuing more eco-compatible strategies in hydrogen transfer reduction, we developed a novel robust strategy for synthesizing dihydrobenzoccarbazoles and indoles, based on an iron-catalyzed reductive cyclization of nitroraryls. In addition, DFT modelings demonstrated a new pathway reaction with the Knölker complex. Display omitted
Objectives
Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is crucial for studying long‐term immunity and vaccine strategies. We ...quantified IFNγ‐secreting T cells reactive against the main viral SARS‐CoV‐2 antigens using a standardised enzyme‐linked immunospot assay (ELISpot).
Methods
Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T‐CoV‐Spot assay, we assessed T‐cell and antibody responses in mild, moderate and severe SARS‐CoV‐2 patients and in control samples collected before the outbreak.
Results
Specific T cells were assessed in 60 consecutive patients (mild, n = 26; moderate, n = 10; and severe patients, n = 24) during their follow‐up (median time from symptom onset interquartile range: 36 days 28;53). T cells against M, N and S peptide pools were detected in n = 60 (100%), n = 56 (93.3%), n = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T‐CoV‐Spot assay showed a specificity of 96.7% (95% CI, 88.5–99.6%) and a specificity of 90.3% (75.2–98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti‐S1 and anti‐RBD serum antibodies.
Conclusion
IFNγ T‐CoV‐Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long‐lived memory T‐cell response after vaccination. Our study demonstrates that SARS‐CoV‐2 patients developing a severe disease achieve a higher adaptive immune response.
We quantified IFNg‐secreting T cells reactive against the M, N and S viral SARS‐CoV‐2 proteins using a standardized enzyme‐linked immunospot assay in 60 patients. The frequency of reactive T cells correlated with severity, and with levels of anti‐S1 and anti‐RBD (receptor binding domain) serum antibodies, demonstrating a higher adaptive immune response after developing a more severe disease. IFNg T‐CoV‐Spot assay may also become a useful tool to assess the long‐lived memory T cell response after vaccination.
•A low-valent non-innocent iron complex supported by phen-type ligands efficiently promotes reductive coupling of heteroaryl halides;•High efficiency of this complex in alkyne 2+2+2 cycloaddition is ...enhanced by assistance of main-group salts;•Analysis of the non-innocent electronic structure of this complex by means of DFT calculations allows a thorough analysis of its temperature-variable 1H NMR spectral properties.
We report in this work the spectroscopic and reactivity properties of a non-innocent paramagnetic iron complex (bcp•–)2FeII featuring formally a Fe° center stabilized by two bathocuproine (bcp) ligands. The origin of the paramagnetic 1H NMR behavior is analyzed by means of DFT calculations, and shows that two electronic states of the complex contribute to its spectroscopic properties. The dynamics of the coordination sphere in (bcp•–)2FeII is governed by the duality between the two electronic descriptions (bcp•–)2FeII, and (bcp)2Fe0. The strong antiferromagnetic coupling between the reduced bcp scaffolds and the ferrous ion in (bcp•–)2FeII makes substitution of the bcp•– ligand difficult; however, the reduced (bcp)2Fe° character allows substitution of bcp by π-accepting ligands, such as alkynes, which can be activated in catalytic cycloadditions with the assistance of main-group salts. (bcp•–)2FeII also shows reductive activity towards a variety of organic electrophiles, and preliminary results using this complex as a catalyst for the reductive coupling of heteroaryl chlorides are discussed.
Display omitted
A one‐step conversion of CO2 into heteroaromatic esters is presented under metal‐free conditions. Using fluoride anions as promoters for the C−Si bond activation, pyridyl, furanyl, and thienyl ...organosilanes are successfully carboxylated with CO2 in the presence of an electrophile. The mechanism of this unprecedented reaction has been elucidated based on experimental and computational results, which show a unique catalytic influence of CO2 in the C−Si bond activation of pyridylsilanes. The methodology is applied to 18 different esters, and it has enabled the incorporation of CO2 into a polyester material for the first time.
Metal free! A novel methodology is described to convert CO2 into heteroaromatic esters in the presence of organosilanes and organic halides using fluoride anions as promoters for the C−Si bond activation (see scheme). CO2 exhibits a unique catalytic influence in the C−Si bond cleavage of pyridylsilanes, serving as a traceless activator.
The association of the ferrous complex FeIICl2(dmpe)2 (1) with alkali bases M(hmds) (M = Li, Na, K) proves to be an efficient platform for the activation of Ar–H bonds. Two mechanisms can be ...observed, leading to either Ar–FeII species by deprotonative ferration or hydrido species Ar–FeII–H by oxidative addition of transient Fe0(dmpe)2 generated by reduction of 1. Importantly, the nature of the alkali cation in M(hmds) has a strong influence on the preferred path. Starting from the same iron precursor, diverse catalytic applications can be explored by a simple modulation of the MI cation. Possible strategies enabling cross-coupling using arenes as pro-nucleophiles, reductive dehydrocoupling, or deuteration of B–H bonds are discussed.
Eosinophils are multifunctional leukocytes that are involved in innate and adaptive immune responses through the expression of various receptors and mediators. Previously, we showed that human ...eosinophils and T cells shared cytotoxic activities against tumor cells that involved the γ-δ TCR and cell-cell contact. In this study, we investigated the molecules involved in eosinophil-tumor cell interactions. Given the role of IL-18 in cell adhesion and in protecting against colon cancer, we evaluated its role in eosinophil-mediated cytotoxicity against Colo-205, a human colon carcinoma cell line. We found that human eosinophils exerted dose- and time-dependent tumoricidal activity against Colo-205 cells. Neutralization of IL-18 significantly reduced eosinophil-mediated Colo-205 apoptosis and inhibited cell-cell adhesion. Moreover, addition of rIL-18 led to upregulation of CD11a and ICAM-1 adhesion molecules, which were involved in the contact between eosinophils and Colo-205 cells. Our results indicated that IL-18 was involved in the eosinophil-mediated death of Colo-205 by facilitating contact between effector and target cells. These data underscored the involvement of an additional mediator in eosinophil-mediated antitumor cytotoxicity. Our findings support existing evidence that eosinophils could play a beneficial role in the context of colon cancer.
PDF
