There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human and zebrafish or murine together with in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by expression alone. UPLC-MS-based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention. These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma. http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg .

The plantar fascia (PF) and major ligaments play important roles in keeping the static foot arch structure. Their functions and relative contributions to the arch stability have not been well studied. A three-dimensional finite element foot model was created based on the reconstruction of magnetic resonance images. During balanced standing, four cases after individual releases of the PF, spring ligament (SL), and long and short plantar ligaments (LPL and SPL) were simulated, to compare their biomechanical consequences with the normal predictions under the intact structure. Although the predictions showed the arch did not collapse obviously after each structure sectioning, the internal mechanical behaviors changed considerably. The PF release resulted in the maximal increases of approximately 91%, 65% and 47% in the tensions of the LPF, SPL and SL, produced the largest changes in all bone rotations, and brought an obvious shift of high stress from the medial metatarsals to the lateral metatarsals. The SL release mainly enhanced bone rotation angles and weakened the joint stability of the arch structure. The LPL and the SPL performed the roles of mutual compensation as either one was released. The influence of the LPL on the load distribution among metatarsals was greater than for the SPL and the SL.

BackgroundHallux valgus (HV) deformity is closely correlated to the hypermobility of the first metatarsal-cuneiform joint, but adequate understanding of the three-dimentional (3D) mobility of this joint in normal or HV feet is lacking. This study was conducted to investigate the mobility of the first metatarsal-cuneiform joint in multiple planes during body weight-bearing conditions for both normal and HV patients.MethodsA total of 10 female volunteers (20 feet) and 10 female HV patients (20 feet) participated in this study. Using a custom-made foot-loading device, computerized tomography (CT) scans of each pair of feet were taken under both unloaded and body weight-bearing conditions. 3D models were reconstructed for the first metatarsal and the medial cuneiform. Rotational and translational motions of the first metatarsal-cuneiform joint in multiple planes from unloaded to loaded conditions were quantitatively evaluated by reverse-engineering software.ResultsDuring body weight-bearing conditions, the first metatarsal-cuneiform joint in HV feet dorsiflexed at an average of 2.91° (standard deviation, SD 1.71) versus 1.18° (SD 0.47) in controls (t = 4.158, P = 0.001); supinated 2.17° (SD 2.28) versus 0.98° (SD 0.81) in controls (t = 2.080, P = 0.045); and internally rotated 2.65° (SD 2.22) versus 0.96° (SD 0.57) in controls (t = 3.114, P = 0.006). Moreover, the joint in HV feet widened significantly compared with the controls (t = 2.256, P = 0.030) and tended to translate more in the dorsal-plantar direction (t = 1.928, P = 0.063); the translation in the medial-lateral direction was not significantly different between the two groups.ConclusionsDuring weight-loading process, the first metatarsal-cuneiform joint turns dorsiflexed, supinated, and internally rotated. For HV feet, hypermobility of the first metatarsal-cuneiform joint can be observed in multiple planes. This study promotes further understanding of the physiological and pathological mobility of the first metatarsal-cuneiform joint.

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