Mouse Anti-Human Erythrocyte Hybridoma [27-9]

Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [C-14]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [C-14]-pevonedistat 25 mg/m(2). In part B (n = 7), patients received pevonedistat 25 or 20 mg/m(2) on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m(2) or carboplatin AUC5 plus paclitaxel 175 mg/m(2) on day 1 every 3 weeks. Following the single dose of [C-14]-pevonedistat 25 mg/m(2) in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC(infinity) of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.

Red blood cells or erythrocytes, constituting 40 to 45 percent of the total volume of human blood are vesicles filled with hemoglobin with a fluid-like lipid bilayer membrane connected to a 2D spectrin network. The shape, volume, hemoglobin mass, and membrane stiffness of RBCs are important characteristics that influence their ability to circulate through the body and transport oxygen to tissues. In this study, we show that a simple two-LED set up in conjunction with standard microscope imaging can accurately determine the physical and mechanical properties of single RBCs. The Beer-Lambert law and undulatory motion dynamics of the membrane have been used to measure the total volume, hemoglobin mass, membrane tension coefficient, and bending modulus of RBCs. We also show that this method is sensitive enough to distinguish between the mechanical properties of RBCs during morphological changes from a typical discocyte to echinocytes and spherocytes. Measured values of the tension coefficient and bending modulus are 1.27 x 10(-6) J m(-2) and 7.09 x 10(-20) J for discocytes, 4.80 x 10(-6) J m(-2) and 7.70 x 10(-20) J for echinocytes, and 9.85 x 10(-6) J m(-2) and 9.69 x 10(-20) J for spherocytes, respectively. This quantitative light absorption imaging reduces the complexity related to the quantitative imaging of the biophysical and mechanical properties of a single RBC that may lead to enhanced yet simplified point of care devices for analyzing blood cells.