WNT5B drives osteosarcoma stemness, chemoresistance and metastasis.

BACKGROUND: Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. METHODS: Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target. RESULTS: In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression. CONCLUSIONS: Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients. KEY POINTS: WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

Arthroscopic Anatomic Reconstruction of the Anterior Talofibular and Calcaneofibular Ligaments Through a 2-Portal Technique.

Arthroscopic anatomic lateral ligament reconstruction of the ankle joint has proven to be a safe option in the treatment of chronic ankle instability (CAI), with good functional results as well as allowing simultaneous management of associated lesions. We described an arthroscopic technique for anatomic reconstruction of the anterior talofibular ligament and calcaneofibular ligament using only 2 arthroscopic portals. This surgical technique to treat CAI is technically less demanding than other described techniques that use 3 or 4 arthroscopic portals. Moreover, as an anatomic technique, it has the advantage of preserving the biomechanics and kinematics of the ankle joint.

Assessment of social vulnerability impact in care and prognosis of sinonasal cancers in the United States.

KEY POINTS: Social determinants of health interactively influence sinonasal cancer care and prognosis. Housing-transportation and socioeconomic status showed the largest associations with disparities. The social vulnerability index can reveal the social determinants of sinonasal cancers.

Pathology education project (PEP): A pilot program to spark student understanding in pathology as a career.

According to the National Resident Matching Program in 2022, 631 pathology positions were offered. In total, 248 senior applicants from United States (US) allopathic schools filled 36.6% of these positions. To bolster medical student understanding of pathology, a medical school pathology interest group organized a multi-day activity to introduce rising second-year medical students to pathology as a career. Five students completed both pre- and post-activity surveys assessing their knowledge of the specialty. All five students had a BA/BS degree as their highest level of education. Only one student indicated that he or she had previously shadowed a pathologist as a medical laboratory scientist for a duration of four years. Two students indicated that they were interested in internal medicine, one indicated radiology, one forensic pathology or radiology, and one was undecided. During the activity, students biopsied tissue from cadavers in the gross anatomy lab. Thereafter, students participated in the standard tissue processing by shadowing a histotechnologist. Under the guidance of a pathologist, students microscopically examined slides and discussed the clinical findings. Post-activity survey results indicated that participation increased their knowledge of pathology as a career with a median increase of 0.8 points (range: 0.2 to 1.6) on a 5-point Likert scale. Students also indicated that their participation increased their knowledge of pathology skills and techniques-median increase of 1.2 (range: 0.8 to 1.8). This activity can be implemented by medical educators to expose medical students to pathology as a career with the benefit of increasing student knowledge in the specialty.