huBC1-IL12, an immunocytokine which targets EDB-containing oncofetal fibronectin in tumors and tumor vasculature,shows potent anti-tumor activity in human tumor models

IL-12 is a cytokine which showed anti-tumor effects in clinical trials, but also produced serious toxicity. We describe a fusion protein, huBC1-IL12, designed to achieve an improved therapeutic index by specifically targeting IL-12 to tumor and tumor vasculature. huBC-1 is a humanized antibody that targets a cryptic sequence of the human ED-B-containing fibronectin isoform, B-FN, present in the subendothelial extracellular matrix of most aggressive tumors. B-FN is oncofetal and angiogenesis-associated, and is undetectable in most normal adult tissues. The original murine BC-1 antibody has been used successfully for immunoscintigraphy to image brain tumor mass in glioblastoma patients. In huBC1-IL12, each of the IgG heavy chains is genetically fused to the N-terminus of the IL-12 p35 subunit, which in turn is disulfide-bonded to the p40 subunit, resulting in a hexameric molecule of MW of ∼300 kDa. Since human IL-12 has no biological activity in mice, we produced huBC1-muIL12 as a surrogate molecule for animal tumor models. Despite the relatively poor PK profile of this molecule in mice and the apparent drawbacks of xenogeneic models in SCID mice, which lack T and B cells, one cycle of treatment with huBC1-muIL12 was efficacious in the PC3mm2, A431, and HT29 subcutaneous tumor models and PC3mm2 lung metastasis model. This molecule also was found to have surprisingly low toxicity in immunocompetent mice. A fusion protein that contains human IL-12 (huBC1-huIL12), which is a suitable molecule for investigation as a therapeutic, has also been produced. This protein has been shown to have a longer serum half-life than huBC1-muIL12 in mice, and retains both antigen binding and IL-12 activity in in vitro assays.     

Kettlebell swing training improves maximal and explosive strength

The aim of this study was to establish the effect that kettlebell swing (KB) training had on measures of maximum (half squat-HS-1 repetition maximum [1RM]) and explosive (vertical jump height-VJH) strength. To put these effects into context, they were compared with the effects of jump squat power training (JS-known to improve 1RM and VJH). Twenty-one healthy men (age = 18-27 years, body mass = 72.58 ± 12.87 kg) who could perform a proficient HS were tested for their HS 1RM and VJH pre- and post-training. Subjects were randomly assigned to either a KB or JS training group after HS 1RM testing and trained twice a week. The KB group performed 12-minute bouts of KB exercise (12 rounds of 30-second exercise, 30-second rest with 12 kg if <70 kg or 16 kg if >70 kg). The JS group performed at least 4 sets of 3 JS with the load that maximized peak power-Training volume was altered to accommodate different training loads and ranged from 4 sets of 3 with the heaviest load (60% 1RM) to 8 sets of 6 with the lightest load (0% 1RM). Maximum strength improved by 9.8% (HS 1RM: 165-181% body mass, p < 0.001) after the training intervention, and post hoc analysis revealed that there was no significant difference between the effect of KB and JS training (p = 0.56). Explosive strength improved by 19.8% (VJH: 20.6-24.3 cm) after the training intervention, and post hoc analysis revealed that the type of training did not significantly affect this either (p = 0.38). The results of this study clearly demonstrate that 6 weeks of biweekly KB training provides a stimulus that is sufficient to increase both maximum and explosive strength offering a useful alternative to strength and conditioning professionals seeking variety for their athletes.     

Quantification of flow during suction feeding in bluegill sunfish

Nearly all aquatic-feeding vertebrates use some amount of suction to capture prey items. Suction prey capture occurs by accelerating a volume of water into the mouth and taking a prey item along with it. Yet, until recently, we lacked the necessary techniques and analytical tools to quantify the flow regime generated by feeding fish. We used a new approach; Digital Particle Image Velocimetery (DPIV) to measure several attributes of the flow generated by feeding bluegill sunfish. We found that the temporal pattern of flow was notably compressed during prey capture. Flow velocity increased rapidly to its peak within 20 ms of the onset of the strike, and this peak corresponded to the time that the prey entered the mouth during capture. The rapid acceleration and deceleration of water suggests that timing is critical for the predator in positioning itself relative to the prey so that it can be drawn into the mouth along with the water. We also found that the volume of water affected by suction was spatially limited. Only rarely did we measure significant flow beyond 1.75 cm of the mouth aperture (in 20 cm fish), further emphasizing the importance of mechanisms, like locomotion, that place the fish mouth in close proximity to the prey. We found that the highest flows towards the mouth along the fish midline were generated not immediately in front of the open mouth, but approximately 0.5 cm anterior to the mouth opening. Away from the midline the peak in flow was closer to the mouth. We propose that this pattern indicates the presence of a bow wave created by the locomotor efforts of the fish. In this scheme, the bow wave acts antagonistically to the flow of water generated by suction, the net effect being to push the region of peak flow away from the open mouth. The peak was located farther from the mouth opening in strikes accompanied by faster locomotion, suggesting faster fish created larger bow waves.