Evaluation of Candidate Theranostics for 227Th/89Zr Paired Radioimmunotherapy of Lymphoma.

227Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223Ra as its first daughter. There is an ample supply of 227Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227Th4+ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion 89Zr-labeled PET agent. Results: 227Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227Th-HEHA-ofatumumab showed moderate in vitro stability. 227Th-DFOcyclo*-ofatumumab presented excellent 227Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). 227Th-L804-ofatumumab coordinated 227Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89Zr-L804-ofatumumab, showed organ distribution matching that of 227Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89Zr/227Th quantitative imaging and α-particle therapy.

Effect of hand position on EMG activity of the posterior shoulder musculature during a horizontal abduction exercise.

The reverse fly machine is a popular exercise for strengthening the horizontal shoulder abductors including the posterior deltoid. There seems to be little consensus as to which hand position most effectively targets the posterior deltoid despite this option on most machines. This study investigated the impact of varying one's hand position, and consequently altering shoulder joint rotation, on muscle activity in various glenohumeral muscles during exercise on the reverse fly machine. Nineteen resistance-trained men (mean age = 23.2 ± 4.3 years; height = 176.9 ± 7.1 centimeters; body mass = 81.3 ± 10.5 kilograms; body mass index = 25.9 ± 2.6) were recruited from a university population to participate in the study. In a repeated measures design, subjects grasped the hand bars on the machine with either a pronated (PRO) or neutral (NEU) grip and performed dynamic horizontal abduction repetitions to muscular failure using a load equating to approximately 75% body weight. The order of performance of the hand positions was counterbalanced between participants so that approximately half of the subjects performed PRO first and the other half performed NEU first. Surface electromyography was used to record both mean and peak muscle activity of the posterior deltoid, middle deltoid, and infraspinatus. Results showed that mean electromyography activity for the posterior deltoid was significantly greater in NEU compared with PRO (p = 0.046; 95% CI = 0.1-7.4% maximal voluntary isometric contraction). Similarly, mean electromyography activity of the infraspinatus also was significantly greater in NEU compared with PRO (p = 0.002; 95% CI = 3.7-13.6% maximal voluntary isometric contraction). The results of this study show that performing exercise on the reverse fly machine with a neutral hand position significantly increases activity of the posterior deltoid and infraspinatus muscles compared with a PRO hand position.

The effects of exercise on food intake and hunger: relationship with acylated ghrelin and leptin.

This study investigated the effects of a long bout of aerobic exercise on hunger and energy intake and circulating levels of leptin and acylated ghrelin. Ten healthy male subjects undertook two, 4 h trials in a randomized crossover design. In the exercise trial subjects ran for 105 min at 50% of maximal oxygen uptake and the last 15 min at 70% of maximal oxygen uptake followed by a 120 min rest period. In the control trial, subjects rested for 4 h. Subjects consumed a buffet test meal at 180 min during each trial. Hunger ratings, acylated ghrelin, leptin, glucose and insulin concentrations were measured at 0, 1, 2, 3 and 4 h. No differences were found at baseline values for hunger, acylated ghrelin, leptin, insulin and glucose for both trials (p > 0.05). The estimated energy expenditure of the exercise trial was 1550 ± 136 kcal. Exercise did not change subsequent absolute energy intake, but produced a significant decrease (p < 0.05) in relative energy intake. A two-way ANOVA revealed a significant (p < 0. 05) interaction effect for hunger and acylated ghrelin. In conclusion, this exercise regimen had a positive effect on reducing appetite which is related to reduced acylated ghrelin responses over time. This finding lends support for a role of exercise in weight management. Key pointsPhysical exercise is a strategy used to counteract obesity, since it lowers the energetic balance by increasing energy expenditure. However, because any energy expended in exercise elevates the intensity of hunger and drives food consumption, it is pertinent to ask how effective exercise could be in helping people to lose weight or to prevent weight gain.The effects of exercise on hunger sensations and food intake are fairly controversial and depend on the intensity and duration of exercise.120 min prolonged treadmill exercise with mix intensity, temporarily decreased hunger sensations, acylated ghrelin and relative energy intake.Variations in exercise intensity should theoretically be a useful means of weight loss.