Increased Plasma Concentrations of Extracellular Vesicles Are Associated with Pro-Inflammatory and Pro-Thrombotic Characteristics of Left and Right Ventricle Mechanical Support Devices.

Mechanical circulatory support (MCS) allows for functional left and right heart ventricle replacement. MCS induces a systemic inflammatory reaction and prothrombotic state leading to an increased risk of thrombus formation. The extracellular vesicles (EVs) are nanoparticles released from active/injured cells characterized by prothrombotic properties. Simple inflammatory parameters from whole blood count analysis have established a clinical role in everyday practice to describe immune-inflammatory activation. We hypothesized that increased plasma concentrations of EVs might be associated with the proinflammatory and pro-thrombotic characteristics of left ventricle assist device (LVAD) and right ventricle assist device (RVAD) devices. We presented a pilot study showing the concentration of peripheral blood serum, right and left ventricle mechanical assist device extracellular concentration in relation to thrombotic complication in patients treated with a biventricular pulsatile assist device (BIVAD). The observation was based on 12 replacements of pulsatile pumps during 175 days of observation. The proinflammatory characteristics of LVAD were noted. The proinflammatory and procoagulant activation by RVAD was observed. The results may provide possible explanations for the worse results of right-sided mechanical supports observed in clinical practice.

Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy.

Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer. SIGNIFICANCE: We have developed an orally available, small-molecule intracellular arginase 1 and 2 inhibitor as a potential enhancer in cancer immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.

A practical preparation of the key intermediate for penems and carbapenems synthesis.

A novel, practical and stereoselective synthesis of (3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone, a key intermediate in the preparation of ß-lactam antibiotics is reported. The crucial step of the synthesis is based on the Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade between silyl protected (R)-3-butyn-2-ol and the nitrone derived from benzyl hydroxylamine and benzyl glyoxylate. The obtained adduct is subjected to debenzylation with sodium, or lithium in liquid ammonia followed by oxidation with lead tetraacetate to afford the final product.