Antibody-Drug-Conjugate Therapy for Hematological Cancers: Matching Cell Biology with Clinical Benefit

Progress in the development and clinical efficacy of antibody-drug conjugates (ADCs) has attracted the interests of both academic researchers and the industry. The rationale for developing ADCs is based on the inherent non-selectivity of chemotherapy for tumor cells, leading to side effects that can be severe and life threatening. Another major consequence of chemotherapy is the development of drug resistance. For these reasons, targeted drug delivery (TDD) systems are being developed to specifically deliver the cytotoxic drug into the target cell. A variety of carriers that can deliver drugs to the surface or into cancer cells, one of which is the use of monoclonal antibodies, with to date ten ADCs having received FDA approval. This review will focus on the development and clinical application of five ADCs currently approved for the treatment of hematological malignancies. Following a short history that led to their regulatory approval, the review will focus on the important link between the biology of the ADC, the cell surface component targeted by the antibody component, and clinical efficacy and conclude by highlighting newer developments that strengthen this link, so that ADCs can provide long-term clinical benefit to patients with hematological cancers.     

Direct Aerobic Oxidation of Secondary Alcohols Catalysed by Pt(0) Nanoparticles Stabilized by PV2Mo10O40 5− Polyoxmetalate

Pt(0) nanoparticles stabilized by the H₅PV₂Mo₁₀O₄₀ polyoxometalate were prepared in water by a sequence of redox reactions and supported on α-alumina. Characterization by TEM showed an average particle size of 2.6 nm with an approximate size dispersion of about ±25%. EDS analysis confirmed the amounts of metal and polyoxometalate as indicated from the reaction stoichiometry. These nanoparticles were further used as catalysts for the oxidation of secondary alcohols with molecular oxygen to the corresponding carbonyl products. The oxidation of secondary alcohols was further improved by the use of Pt nanoparticles stabilized by Rh_1.7PV₂Mo₁₀O₄₀.     

Electrocarboxylation of benzyl chlorides at silver cathode at the preparative scale level

The electrocarboxylation of benzyl chlorides to the corresponding carboxylic acids performed at silver cathodes was investigated both theoretically and experimentally in order to find the influence of the operative parameters on the selectivity and on the Faradic efficiency of the process. Theoretical considerations were confirmed by the electrocarboxylation of 1-phenyl-1-chloroethane performed in undivided cells equipped with sacrificial anodes both in a bench-scale electrochemical batch reactor and in a continuous batch recirculation reaction system equipped with a parallel plate electrochemical cell. Selectivity and Faradic yields higher than 80% and 70%, respectively, were obtained by working under anhydrous conditions both under amperostatic and potentiostatic alimentation at appropriate values of either current density or applied potential.     

Direct electrochemical detosylation of tetratosylcyclen to cyclen with carbon cathodes

The electrochemical detosylation of tetratosylcyclen to cyclen (1,4,7,10-tetraazacyclododecane) in aprotic solvents at a carbon cathode was investigated both in a bench-scale batch electrochemical reactor and in a continuous batch recirculation reaction system equipped with a parallel-plate electrochemical cell. Yields and faradaic efficiency in cyclen, respectively, of 80 and 55% were obtained in the bench-scale reactor working in acetonitrile. It was found that the faradaic efficiency in cyclen depends on the competition between the reduction of the tetratosylcyclen and parasitic processes as the reduction of the tetraalkylammonium cations present in the supporting electrolyte. We have observed that the nature of the anolyte and catholyte and the concentrations of the substrate, the supporting electrolyte and the proton donor species dramatically influence the performances of the process.     

Growth of GaN nanotubes by halide vapor phase epitaxy

We have investigated low temperature growth of GaN nanostructures using halide vapor phase epitaxy on c-oriented Al(2)O(3) and Au coated Al(2)O(3) substrates. Depending on the III/V ratio and the growth temperature, the shape and density of the structures could be controlled. By increasing the GaCl partial pressure, the structure changed from dot-like to nanotubes. The nanotubes, which could be open or closed, were about 1 μm long with a diameter of typically 200 nm. In addition, it was observed that the nanostructures were spontaneously nucleated at droplets of Ga or, when using Au coated Al(2)O(3), on droplets of Au/Ga alloy. By varying the growth temperature, the inner diameter of the nanotubes could be controlled. The experimental results suggest that this approach with pre-patterned Au coated Al(2)O(3)substrates has the potential for fabrication of well-organized nanotubes with a high density.     

Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus

The agr locus in the commensal human pathogen, Staphylococcus aureus, is a two‐promoter regulon with allelic variability that produces a quorum‐sensing circuit involved in regulating virulence within the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentrations by AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. The finding that staphylococcal virulence can be inhibited through antagonism of this quorum‐sensing pathway has fueled tremendous interest in understanding the structure–activity relationships underlying the AIP–AgrC interaction. The defining structural feature of the AIP is a 16‐membered, thiolactone‐containing macrocycle. Surprisingly, the importance of ring size on agr activation or inhibition has not been explored. In this study, we address this deficiency through the synthesis and functional analysis of AIP analogues featuring enlarged and reduced macrocycles. Notably, this study is the first to interrogate AIP function by using both established cell‐based reporter gene assays and newly developed in vitro AgrC‐I binding and autophosphorylation activity assays. Based on our data, we present a model for robust agr activation involving a cooperative, three‐points‐of‐contact interaction between the AIP macrocycle and AgrC.     

The Relationship between COVID-19 and Hypothalamic–Pituitary–Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess—The CAPISCO International Expert Panel

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic–pituitary–adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.