Engineering small-molecule and protein drugs for targeting bone tumors.

Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and death. Currently, treatments such as chemotherapy, hormone therapy, and radiation therapy are used to treat bone cancer, but they often only shrink or slow tumor growth and do not eliminate cancer completely. The bone microenvironment contributes unique signals that influence cancer growth, immunogenicity, and metastasis. Traditional cancer therapies have limited effectiveness due to off-target effects and poor distribution on bones. As a result, therapies with improved specificity and efficacy for treating bone tumors are highly needed. One of the most promising strategies involves the targeted delivery of pharmaceutical agents to the site of bone cancer by introduction of bone-targeting moieties, such as bisphosphonates or oligopeptides. These moieties have high affinities to the bone hydroxyapatite matrix, a structure found exclusively in skeletal tissue, and can enhance the targeting ability and efficacy of anticancer drugs when combating bone tumors. This review focuses on the engineering of small molecules and proteins with bone-targeting moieties for the treatment of bone tumors.

Individualizing Basketball-Specific Interval Training Using Anaerobic Speed Reserve: Effects on Physiological and Hormonal Adaptations.

PURPOSE: We compared the adaptive responses to supramaximal high-intensity interval training (HIIT) individualized according to anaerobic speed reserve (ASR), the 30-15 Intermittent Fitness Test (VIFT), and velocity associated with maximum oxygen uptake (MAS) to determine which approach facilitates more identical adaptations across athletes with different profiles. METHODS: Thirty national-level basketball players (age = 28.4 [5] y; body mass = 88.9 [6.3] kg; height = 190 [4.8] cm) were randomly assigned to 3 training groups performing 2 sets of 4, 6, 8, 6, 8, and 10-minute runs (from first to sixth week, respectively), consisting of 15-second running at Δ%20ASR (MAS + 0.2 × ASR), 95%VIFT, and 120%MAS, with 15 seconds recovery between efforts and a 3-minute relief between sets. RESULTS: All 3 interval interventions significantly (P < .05) enhanced maximum oxygen uptake (V˙O2max), oxygen pulse (V˙O2/HR), first and second ventilatory threshold (VT1 and VT2), cardiac output (Q˙max), stroke volume, peak and average power output, testosterone levels, and testosterone-to-cortisol ratio following the training period. Different values of interindividual variability (coefficient of variation) for the percentage changes of the measured variables were observed in response to HIITASR, HIITvIFT, and HIITMAS for V˙O2max (8.7%, 18.8%, 34.6%, respectively), V˙O2/HR (9.5%, 15.0%, 28.6%), VT1 (9.6%, 19.6%, 34.6%), VT2 (21.8%, 32.4%, 56.7%), Q˙max (8.2%, 16.9%, 28.8%), stroke volume (7.9%, 15.2%, 23.5%), peak power output (20%, 22%, 37.3%), average power output (21.1%, 21.3%, 32.5%), testosterone (52.9%, 61.6%, 59.9%), and testosterone-to-cortisol ratio (55.1%, 59.5%, 57.8%). CONCLUSIONS: Supramaximal HIIT performed at Δ%20ASR resulted in more uniform physiological adaptations than HIIT interventions prescribed using VIFT or MAS. Although hormonal changes do not follow this approach, all the approaches induced an anabolic effect.

Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis.

Immunotherapy is a promising approach for treating metastatic breast cancer (MBC), offering new possibilities for therapy. While checkpoint inhibitors have shown great progress in the treatment of metastatic breast cancer, their effectiveness in patients with bone metastases has been disappointing. This lack of efficacy seems to be specific to the bone environment, which exhibits immunosuppressive features. In this study, we elucidate the multiple roles of the sialic acid-binding Ig-like lectin (Siglec)-15/sialic acid glyco-immune checkpoint axis in the bone metastatic niche and explore potential therapeutic strategies targeting this glyco-immune checkpoint. Our research reveals that elevated levels of Siglec-15 in the bone metastatic niche can promote tumor-induced osteoclastogenesis as well as suppress antigen-specific T cell responses. Next, we demonstrate that antibody blockade of the Siglec-15/sialic acid glyco-immune checkpoint axis can act as a potential treatment for breast cancer bone metastasis. By targeting this pathway, we not only aim to treat bone metastasis but also inhibit the spread of metastatic cancer cells from bone lesions to other organs.