The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma.

Expression of the SS18/SYT-SSX fusion protein is believed to underlie the pathogenesis of synovial sarcoma (SS). Recent evidence suggests that deregulation of the Wnt pathway may play an important role in SS but the mechanisms whereby SS18-SSX might affect Wnt signaling remain to be elucidated. Here, we show that SS18/SSX tightly regulates the elevated expression of the key Wnt target AXIN2 in primary SS. SS18-SSX is shown to interact with TCF/LEF, TLE and HDAC but not β-catenin in vivo and to induce Wnt target gene expression by forming a complex containing promoter-bound TCF/LEF and HDAC but lacking β-catenin. Our observations provide a tumor-specific mechanistic basis for Wnt target gene induction in SS that can occur in the absence of Wnt ligand stimulation

LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma

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Biomechanical contribution of spinal structures to stability of the lumbar spine-novel biomechanical insights

BACKGROUND CONTEXT The contribution of anatomical structures to the stability of the spine is of great relevance for diagnostic, prognostic and therapeutic evaluation of spinal pathologies. Although a plethora of literature is available, the contribution of anatomical structures is still not well understood. PURPOSE We aimed to quantify the biomechanical relevance of each of the passive spinal structure trough deliberate biomechanical test series using a stepwise reduction approach on cadavers. STUDY DESIGN Biomechanical cadaveric study. METHODS Fifty lumbar spinal segments originating from 22 human lumbar cadavers were biomechanically tested in a displacement-controlled stepwise reduction study: the intertransverse ligaments, the supraspinous and interspinous ligaments, the facet joint capsules (FJC), the facet joints (FJ), the ligamentum flavum (LF), the posterior longitudinal ligament (PLL), and the anterior longitudinal ligament were subsequently reduced. In the intact state and after each transection step, the segments were physiologically loaded in flexion, extension, axial rotation (AR), lateral bending (LB) and with anterior (AS), posterior (PS) and lateral shear (LS). Thirty-two specimens with only minor degeneration, representing a reasonably healthy subpopulation, were selected for the here presented evaluation. Quantitative values for load and spinal level dependent contribution patterns for the anatomical structures were derived. RESULTS Small variability between of the contribution patterns are observed. The intervertebral disc (IVD) is exposed to about 67% of the applied load in LB and during shear loading, but less by load in flexion, extension and AR (less than 35%). The FJ&FJC are the main stabilizers in AR with 49%, but provide only 10% of the stability in extension. Beside the IVD, the LF and the PLL contribute mainly in flexion (22% and 16%, respectively), while the ALL plays a major role during extension (40%) and also contributes during LB (15%). The contribution of the intertransverse ligaments and the supraspinous and interspinous ligaments are very small in all loading directions (<2% and <6%, respectively). CONCLUSION The IVD takes the main load in LB and absorbs shear loading, while the FJ&FJC stabilize AR. The ALL resists extension while LF and PLL stabilize flexion. With the small variability of contribution patterns, suggesting distinct adaptation of the structures to one another, the biomechanical characteristics of one structure have to be put in context of the whole spinal segment. CLINICAL SIGNIFICANCE The novel information on load distribution helps predict the biomechanical consequences of surgical procedures in more detail

Region- and degeneration dependent stiffness distribution in intervertebral discs derived by shear wave elastography

Information on the local stiffness characteristics of the intervertebral disc (IVD) is crucial for the understanding of its structure-function properties in health and disease and may improve numerical modeling. Previous studies have attempted to map local tissue stiffness by sectioning the disc and performing mechanical testing on these discrete tissue units, which is technically challenging and may bias the results. Shear wave elastography (SWE) represents a nondestructive alternative that can provide spatially continuous elasticity estimates. We investigated the feasibility of SWE for human intervertebral disc elasticity mapping in a laboratory setting. To this end, global spinal segment mechanical behavior was determined in 6 loading directions and served as ground truth data for the validation of the approach. Subsequently, the cranial spinal vertebra was removed and shear wave elastographic scans of the IVD were acquired. SWE-measurements were reconstructed into three-dimensional elastographic maps, discretized into distinct IVD regions and correlated with global segment mechanical parameters. SWE-derived Young’s modulus estimates were compared among different regions and as a function of their state of degeneration. We found annulus shear wave speed to be moderately correlated with segment mechanical behavior irrespective of the loading direction whereas shear wave speed in the nucleus pulposus showed a very weak association (mean (SD) absolute Pearson correlation coefficients: 0.51 (0.14) and 0.17 (0.12), respectively). Young’s modulus mapping of the intervertebral disc revealed stiffness to be highest in the ventral annulus with a stiffness decrease both circumferentially towards the dorsal aspect as well as towards the center of the disc. SWE hence provides a valid alternative to disc sectioning and piecewise mechanical testing.ISSN:0021-9290ISSN:1873-238

Biomechanical Contributions of Spinal Structures with Different Degrees of Disc Degeneration

STUDY DESIGN Biomechanical cadaveric study. OBJECTIVE The aim of this study was to evaluate the effect of degeneration on biomechanical properties of the passive structures of the lumbar spine. SUMMARY OF BACKGROUND DATA Although the load apportionment among the passive structures in healthy spines follows well-defined contribution patterns, it remains unknown how this load distribution and sagittal preload changes by degenerative processes of the intervertebral disc (IVD). METHODS Fifty lumbar spinal segments were tested in a displacement-controlled stepwise reduction study in flexion, extension, axial rotation, lateral bending, anterior, posterior and lateral shear. The intertransverse ligaments (ITLs), supraspinous and interspinous ligaments (ISL&SSL), facet joint capsules (FJC), facet joints (FJ), ligamentum flavum (LF), posterior longitudinal ligament (PLL), anterior longitudinal ligament (ALL), and spondylophytes were subsequently reduced. The results were set in relation to IVD-degeneration, quantified with Pfirrmann classification. RESULTS In flexion, a load redistribution from LF (-28% n.s.) and PLL (-13% n.s.) towards the IVD (+9%, n.s.) is observed comparing grade 2 to 5 IVD degeneration, whereas in all other loading directions, a reduction of IVD-contribution from -12% to -53% is recorded. In axial rotation, anterior and lateral shear, more load is shared by the FJ (+4% n.s., +23% ∗, +13% n.s.). The preload of the ALL, LF, PLL, and IVD is reduced ranging from -0.06 Nm to -0.37 Nm. CONCLUSION IVD degeneration is related to notable load-redistributions between the passive spinal structures. With further degeneration, reduced contribution of the LF and PLL and higher loads on the IVD are observed in flexion. In the other tested loading directions, the relative load on the IVD is reduced, whereas higher FJ-exposure in axial rotation, anterior and lateral shear is observed. Furthermore, the preload of the spinal structures is reduced. These observations can further the understanding of the degenerative cascade in the spine.Level of Evidence: N/A

Biomechanical Contributions of Spinal Structures with Different Degrees of Disc Degeneration

STUDY DESIGN Biomechanical cadaveric study. OBJECTIVE The aim of this study was to evaluate the effect of degeneration on biomechanical properties of the passive structures of the lumbar spine. SUMMARY OF BACKGROUND DATA Although the load apportionment among the passive structures in healthy spines follows well-defined contribution patterns, it remains unknown how this load distribution and sagittal preload changes by degenerative processes of the intervertebral disc (IVD). METHODS Fifty lumbar spinal segments were tested in a displacement-controlled stepwise reduction study in flexion, extension, axial rotation, lateral bending, anterior, posterior and lateral shear. The intertransverse ligaments (ITLs), supraspinous and interspinous ligaments (ISL&SSL), facet joint capsules (FJC), facet joints (FJ), ligamentum flavum (LF), posterior longitudinal ligament (PLL), anterior longitudinal ligament (ALL), and spondylophytes were subsequently reduced. The results were set in relation to IVD-degeneration, quantified with Pfirrmann classification. RESULTS In flexion, a load redistribution from LF (-28% n.s.) and PLL (-13% n.s.) towards the IVD (+9%, n.s.) is observed comparing grade 2 to 5 IVD degeneration, whereas in all other loading directions, a reduction of IVD-contribution from -12% to -53% is recorded. In axial rotation, anterior and lateral shear, more load is shared by the FJ (+4% n.s., +23% ∗, +13% n.s.). The preload of the ALL, LF, PLL, and IVD is reduced ranging from -0.06 Nm to -0.37 Nm. CONCLUSION IVD degeneration is related to notable load-redistributions between the passive spinal structures. With further degeneration, reduced contribution of the LF and PLL and higher loads on the IVD are observed in flexion. In the other tested loading directions, the relative load on the IVD is reduced, whereas higher FJ-exposure in axial rotation, anterior and lateral shear is observed. Furthermore, the preload of the spinal structures is reduced. These observations can further the understanding of the degenerative cascade in the spine.Level of Evidence: N/A

3D printed clamps improve spine specimen fixation in biomechanical testing

This study presents an anatomically customizable fixation technique for biomechanical spine experiments using a 3D printed clamping system. The aim of this study is to evaluate the feasibility and compare the fixation rigidity of the novel technique to PMMA potting with and without screw augmentation. For this purpose, 16 thoracic and lumbar functional spine units of bovine, porcine, ovine and human cadavers (4 each) were consecutively fixed with all three techniques and loaded in six degrees of freedom. The combined relative movement between the cranial and caudal vertebral body and their corresponding fixtures were recorded using a 3D motion capture system. The 3D printed clamps did provide multiple advantages, showed no failures and the fixation rigidity was superior to potting in all loading directions and superior to screw-augmented potting in two of six loading directions (p < 0.05). In conclusion, the here proposed novel fixation method showed equal to superior properties in comparison to both other methods used in this study. When considering all characteristics of 3D printing, 3D printed fixtures can be an effective alternative to potting

Hydrostatic integrity of the intervertebral disc assessed by MRI

Hydrostatic integrity of the intervertebral disc (IVD) is lost during the process of degeneration. Invasive pressure profilometry (IPP) can quantify it, however, is not applicable for clinical use. We aimed to investigate correlations between IPP and MRI findings to assess non-invasive MRI based methods for prediction of hydrostatic integrity of the intervertebral disc. The pressure profiles of 39 lumbar spinal segments originating from 22 human cadavers were recorded during axial compression in the neutral, the flexed and the extended positions. Disc pressure profiles were measured and mathematically transformed to a novel metric that quantifies pressure profile heterogeneity across the disc. The relationship between pressure profile inhomogeneity (“pressure score”) and clinically established magnetic resonance-based classifications systems and demographic parameters was then tested using Spearman correlation tests. Pressure profile inhomogeneities were correlated with IVD degeneration (according to Pfirrmann, rho = 0.43, p = 0.006), endplate defects (according to Rajasekaran, rho = 0.39, p = 0.013), segmental degeneration (according to Farshad, rho = 0.41, p = 0.009) and age (rho = 0.32, p = 0.049). Modic changes per se did not affect the pressure profiles significantly (p = 0.23) and pressure scores did not correlate with BMI (rho = -0.21, p = 0.2). Heterogeneity of segmental IVD pressure profiles is a unique measure of disc function. We demonstrate that established clinical methods for MRI characterization of the intervertebral disc, the endplate and overall segmental degeneration all correlate with the hydrostatic integrity of the IVD and can be used for its assessment.ISSN:0021-9290ISSN:1873-238

Region- and degeneration dependent stiffness distribution in intervertebral discs derived by shear wave elastography

Information on the local stiffness characteristics of the intervertebral disc (IVD) is crucial for the understanding of its structure-function properties in health and disease and may improve numerical modeling. Previous studies have attempted to map local tissue stiffness by sectioning the disc and performing mechanical testing on these discrete tissue units, which is technically challenging and may bias the results. Shear wave elastography (SWE) represents a nondestructive alternative that can provide spatially continuous elasticity estimates. We investigated the feasibility of SWE for human intervertebral disc elasticity mapping in a laboratory setting. To this end, global spinal segment mechanical behavior was determined in 6 loading directions and served as ground truth data for the validation of the approach. Subsequently, the cranial spinal vertebra was removed and shear wave elastographic scans of the IVD were acquired. SWE-measurements were reconstructed into three-dimensional elastographic maps, discretized into distinct IVD regions and correlated with global segment mechanical parameters. SWE-derived Young's modulus estimates were compared among different regions and as a function of their state of degeneration. We found annulus shear wave speed to be moderately correlated with segment mechanical behavior irrespective of the loading direction whereas shear wave speed in the nucleus pulposus showed a very weak association (mean (SD) absolute Pearson correlation coefficients: 0.51 (0.14) and 0.17 (0.12), respectively). Young's modulus mapping of the intervertebral disc revealed stiffness to be highest in the ventral annulus with a stiffness decrease both circumferentially towards the dorsal aspect as well as towards the center of the disc. SWE hence provides a valid alternative to disc sectioning and piecewise mechanical testing

Photodetection of early cancer by laser induced fluorescence of a tumor-selective dye: apparatus design and realization

An apparatus is designed and realized to detect "early" cancer at the surface of the hollow organs in the human body by endoscopic means. The tumor is localized by the laser induced fluorescence of a dye (HPD) which concentrates selectively in the neoplastic tissue after intravenous injection. Fluorescence contrast between the tumor and its normal surroundings is enhanced by subtracting the background autofluorescence which occurs in both types of tissue. This is done by means of 2-color digital images manipulation in real-time. Preliminary clinical tests of the apparatus demonstrated the detection of carcinoma in situ in the esophagus