The RANK-RANKL axis: an opportunity for drug repurposing in cancer?

Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

Establishing an oral anticoagulant monitoring service in a multiethnic developing country.

We describe the establishment of an International Normalized Ratio (INR)-based system for monitoring oral anticoagulant therapy in a multiethnic developing country. There was significant variation in geometric mean normal prothrombin time among ethnic groups: 12.7 s for Indians, 13.4 s for Africans and 13.7 s for subjects of mixed ancestry. About 4129 INR measurements were performed in the first 2 years. The majority (55.2%) of achieved INRs were subtherapeutic. We found 31 (0.8%) instances of severe overanticoagulation (INR > 8.0). There were no bleeding manifestations in 24 (77%) of them. Only two experienced life-threatening haemorrhage. The management of bleeding and excessive anticoagulation was not always in accordance with international recommendations. The high incidence of underanticoagulation in Trinidad and Tobago may be due to genetically determined warfarin resistance or underdosing. Oral anticoagulant monitoring in Trinidad and Tobago could benefit from the centralization of such services to designated clinics with specialized staff and computer-assisted dosing which adopt internationally accepted guidelines for practice.

Prolonged exposure of neutrophils to saline or bronchoalveolar lavage fluid does not alter superoxide anion generation.

The role played by neutrophils (PMNs) in the genesis of lung injury in diverse clinical situations, such as bronchial asthma, idiopathic pulmonary fibrosis, and the adult respiratory distress syndrome, is an area of intensive investigation. Functional studies of PMNs, particularly those obtained from the alveoli by bronchoalveolar lavage, should shed light on their contribution to lung injury. However, it has not been demonstrated whether procedures used to harvest cells from the lung (bronchoalveolar lavage), particularly the potentially prolonged exposure to saline, commonly used to perform lavage, and other components of lavage fluid, can alter the functional characteristics of PMNs. In this report we demonstrate that a 2- to 3-hour exposure of neutrophils to saline from both humans and sheep in vitro does not alter the functional characteristics of PMNs as determined by superoxide anion generation after activation with phorbol myristate acetate (PMA; 6.96 +/- 0.44 vs. 7.60 +/- 0.32 nmol O2-/250,000 PMNs for control and saline-treated human cells, respectively, after a 45-min incubation with 10(-7) M PMA, and 4.73 +/- 0.30 vs. 4.50 +/- 0.42 nmol O2-/250,000 PMNs for control and saline-treated sheep cells). In a second series of experiments, we studied the effect of exposure of human PMNs to bronchoalveolar lavage fluid supernatants obtained from normal volunteers on superoxide anion generation by neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)