Challenges in multiple myeloma diagnosis and treatment
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Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia
X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients.
A UK population-based case-control study of blood tests before cancer diagnosis in patients with non-specific abdominal symptoms
Abnormal results in commonly used primary care blood tests could be early markers of cancer in patients presenting with non-specific abdominal symptoms.
Prognostic relevance of the neurological symptom burden in brain metastases from breast cancer
Existing prognostic models for breast cancer (BC) brain metastases (BM) overlook neurological symptoms. Thus, we explored the incidence and prognostic relevance of neurological symptoms in a real-world cohort of BC patients with BM.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Inhibition of CDC27 O-GlcNAcylation coordinates the antitumor efficacy in multiple myeloma through the autophagy-lysosome pathway
Multiple myeloma (MM) is a prevalent hematologic malignancy characterized by abnormal proliferation of cloned plasma cells. Given the aggressive nature and drug resistance of MM cells, identification of novel genes could provide valuable insights for treatment. In this study we performed machine learning in the RNA microarray data of purified myeloma plasma cell samples from five independent MM cohorts with 957 MM patients, and identified O-GlcNAcylation transferase (OGT) and cell division cycle 27 (CDC27) as the key prognostic genes for MM. We demonstrated a close link between OGT and CDC27 in MM cells by knockdown of OGT with siOGT, pharmacological inhibition of O-GlcNAcylation with OSMI-1 and pharmacological accumulation of O-GlcNAcylation with Thiamet G. Using mass spectrometry and immunoprecipitation, we identified the O-GlcNAcylated CDC27 protein as a key target protein that may be directly downregulated by OSMI-1 in MM.1S cells. We further revealed that O-GlcNAcylation maintained CDC27 protein stability by blocking the autophagy-lysosome pathway (ALP). Moreover, we demonstrated the enhanced antitumor efficacy of combined OSMI-1 and bortezomib (BTZ) treatment in MM cells both in vivo and in vitro. Thus, this study identifies a novel function of O-GlcNAcylation-related ALP in regulating CDC27 protein stability and a potential therapeutic strategy for treating MM.
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