Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.

PurposeCurrently, no studies exist, which attest the suitability of the ovine intervertebral disc as a biomechanical in vivo model for preclinical tests of new therapeutic strategies of the human disc. By measuring the intradiscal pressure in vivo, the current study attempts to characterize an essential biomechanical parameter to provide a more comprehensive physiological understanding of the ovine intervertebral disc.MethodsIntradiscal pressure (IDP) was measured for 24 hours within the discs L2-L3 and L4-L5 via a piezo-resistive pressure sensor in one merino sheep. The data were divided into an activity and a recovery phase and the corresponding average pressures for both phases were determined. Additionally, IDPs for different static and dynamic activities were analyzed and juxtaposed to human data published previously. After sacrificing the sheep, the forces corresponding to the measured IDPs were examined ex vivo in an axial compression test.ResultsThe temporal patterns of IDP where pressure decreased during activity and increased during rest were comparable between humans and sheep. However, large differences were observed for different dynamic activities such as standing up or walking. Here, IDPs averaged 3.73 MPa and 1.60 MPa respectively, approximately two to four times higher in the ovine disc compared to human. These IDPs correspond to lower ex vivo derived axial compressive forces for the ovine disc in comparison to the human disc. For activity and rest, average ovine forces were 130 N and 58 N, compared to human forces of 400-600 N and 100 N, respectively.Conclusions In vivo IDPs were found to be higher in the ovine than in the human disc. In contrast, axial forces derived ex vivo were markedly lower in comparison to humans. Both should be considered in future preclinical tests of intradiscal therapies using the sheep. The techniques used in the current study may serve as a protocol for measuring IDP in a variety of large animal models.

The stabilizing effect of the rib cage on the human thoracic spine is still not sufficiently analyzed. For a better understanding of this effect as well as the calibration and validation of numerical models of the thoracic spine, experimental biomechanics data is required. This study aimed to determine (1) the stabilizing effect of the single rib cage structures on the human thoracic spine as well as the effect of the rib cage on (2) the flexibility of the single motion segments and (3) coupled motion behavior of the thoracic spine. Six human thoracic spine specimens including the entire rib cage were loaded quasi-statically with pure moments of ± 2 Nm in flexion/extension (FE), lateral bending (LB), and axial rotation (AR) using a custom-built spine tester. Motion analysis was performed using an optical motion tracking system during load application to determine range of motion (ROM) and neutral zone (NZ). Specimens were tested (1) in intact condition, (2) after removal of the intercostal muscles, (3) after median sternotomy, after removal of (4) the anterior rib cage up to the rib stumps, (5) the right sixth to eighth rib head, and (6) all rib heads. Significant (p < 0.05) increases of the ROM were found after dissecting the intercostal muscles (LB: + 22.4%, AR: + 22.6%), the anterior part of the rib cage (FE: + 21.1%, LB: + 10.9%, AR: + 72.5%), and all rib heads (AR: + 5.8%) relative to its previous condition. Compared to the intact condition, ROM and NZ increased significantly after removing the anterior part of the rib cage (FE: + 52.2%, + 45.6%; LB: + 42.0%, + 54.0%; AR: + 94.4%, + 187.8%). Median sternotomy (FE: + 11.9%, AR: + 21.9%) and partial costovertebral release (AR: + 11.7%) significantly increased the ROM relative to its previous condition. Removing the entire rib cage increased both monosegmental and coupled motion ROM, but did not alter the qualitative motion behavior. The rib cage has a strong effect on thoracic spine rigidity, especially in axial rotation by a factor of more than two, and should therefore be considered in clinical scenarios, in vitro, and in silico.

We established a human herniation model that reliably produced nucleus extrusion during cyclic loading. This is accomplished by choosing only specimens with low disc degeneration, which should be validated by radiographs and intradiscal pressure measurements. An exemplary test with the Barricaid implant showed that it seems to prevent the nucleus from reherniating.

In contrast to the surface-etched implants, the titanium-coated PEEK implants lost some coating material. This was visible to the naked eye. More than half of all particles were of a size range that allows phagocytosis. This study shows that titanium-coated implants are susceptible to impaction-related wear debris.