Search

BackgroundThe calcaneal enthesis, an osseous footprint where the Achilles tendon seamlessly integrates with the bone, represents a complex interface crucial for effective force transmission. Bone adapts to mechanical stress and remodels based on the applied internal and external forces. This study explores the relationship between the elasticity of the Achilles tendon enthesis and the bone microstructure in the calcaneal crescent.MethodsIn total, 19 calcaneal-enthesis sections, harvested from 10 fresh-frozen human cadaveric foot-ankle specimens (73.8 ± 6.0 years old, seven female), were used in this study. Indentation tests were performed at the enthesis region, and Hayes' elastic modulus was calculated for each specimen. Micro-CT scanning was performed at 50-micron voxel size to assess trabecular bone microstructure within six regions of interest (ROIs) and the cortical bone thickness along the calcaneal crescent.ResultsSignificant Spearman correlations were observed between the enthesis elastic modulus and trabecular bone thickness in the distal entheseal (ROI 3) and proximal plantar (ROI 4) regions (R = 0.786 and 0.518, respectively).ConclusionThis study highlights the potential impacts of Achilles tendon enthesis on calcaneal bone microstructure, which was pronounced in the distal calcaneal enthesis, suggesting regional differences in load transfer mechanism that require further investigation.

The role of cells expressing stem cell markers deltaNp63 and CD44v has not yet been elucidated in peripheral-type lung squamous cell carcinoma ( pLSCC) carcinogenesis. Female A/J mice were painted topically with N-nitroso-tris-chloroethylurea ( NTCU) for induction of pLSCC, and the histopathological and molecular characteristics of NTCU-induced lung lesions were examined. Histopathologically, we found atypical bronchiolar hyperplasia, squamous metaplasia, squamous dysplasia, and pLSCCs in the treated mice. Furthermore, we identified deltaNp63pos CD44vpos CK5/6pos CC10pos clara cells as key constituents of early precancerous atypical bronchiolar hyperplasia. In addition, deltaNp63pos CD44vpos cells existed throughout the atypical bronchiolar hyperplasias, squamous metaplasias, squamous dysplasias, and pLSCCs. Overall, our findings suggest that NTCU induces pLSCC through an atypical bronchiolar hyperplasia-metaplasia-dysplasia- SCC sequence in mouse lung bronchioles. Notably, Ki67-positive deltaNp63pos CD44vpos cancer cells, cancer cells overexpressing phosphorylated epidermal growth factor receptor and signal transducer and activator of transcription 3, and tumor-associated macrophages were all present in far greater numbers in the peripheral area of the pLSCCs compared with the central area. These findings suggest that deltaNp63pos CD44vpos clara cells in mouse lung bronchioles might be the origin of the NTCU-induced pLSCCs. Our findings also suggest that tumor-associated macrophages may contribute to creating a tumor microenvironment in the peripheral area of pLSCCs that allows deltaNp63pos CD44vpos cancer cell expansion through activation of epidermal growth factor receptor signaling, and that exerts an immunosuppressive effect through activation of signal transducer and activator of transcription 3 signaling. [ABSTRACT FROM AUTHOR]

Aims: Lateral femoral cutaneous nerve (LFCN) injury is a complication after periacetabular osteo-tomy (PAO) using an anterior approach, which might adversely affect the outcome. However, no prospective study has assessed the incidence and severity of this injury and its effect on the clinical outcomes over a period of time for longer than one year after PAO. The aim of this study was to assess the incidence and severity of the symptoms of LFCN injury for ≥ three years after PAO and report its effect on clinical outcomes., Methods: A total of 40 hips in 40 consecutive patients who underwent PAO between May 2016 and July 2018 were included in the study, as further follow-up of the same patients from a previous study. We prospectively evaluated the incidence, severity, and area of symptoms following LFCN injury. We also recorded the clinical scores at one year and ≥ three years postoperatively using the 36-Item Short Form Health Survey (SF-36) and Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ) scores., Results: A total of 20 patients (50%) had symptoms of a LFCN injury at one year after PAO. At ≥ three years postoperatively, the symptoms had completely resolved in seven of these patients and 13 (33%) had persistent symptoms. The severity and area of symptoms did not significantly differ between one and ≥ three years postoperatively. The JHEQ showed significant differences in the patient satisfaction and mental scores between those with and those without sypmtoms of LFCN injury at ≥ three years postoperatively, while there was no significant difference in the mean SF-36 scores., Conclusion: The incidence of LFCN injury after PAO using an anterior approach is high. The outcome of PAO, ≥ three years postoperatively, is poorer in patients with persistent symptoms from a perioperative LFCN injury, in that patient satisfaction and mental health scores are adversely affected., Competing Interests: None declared., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Aim: To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178., Methods: Using the state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect "direct target engagement" of proteins intact cells, in vitro and in vivo assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML)., Results: Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2. We also present evidence that, in addition to its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a microtubule network disrupting agent both in vitro and in intact cells. Interestingly, we separately demonstrate that simultaneous SphK inhibition and microtubule disruption synergistically induces apoptosis in AML cell lines. Furthermore, we demonstrate that SKI-178 is well tolerated in normal healthy mice. Most importantly, we demonstrate that SKI-178 has therapeutic efficacy in several mouse models of AML., Conclusion: SKI-178 is a multi-targeted agent that functions both as an inhibitor of the SphKs as well as a disruptor of the microtubule network. SKI-178 induced apoptosis arises from a synergistic interaction of these two activities. SKI-178 is safe and effective in mouse models of AML, supporting its further development as a multi-targeted anti-cancer therapeutic agent.