The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties

Background Osteosarcoma (OS) is the most common type of primary bone cancer affecting children and adolescents. OS has a high propensity to spread meaning the disease is often incurable and fatal. There have been no improvements in survival rates for decades. This highlights an urgent need for the development of novel therapeutic strategies. Here, we report in vitro and in vivo data that demonstrates the role of purinergic signalling, specifically, the B isoform of the purinergic receptor P2RX7 (P2RX7B), in OS progression and metastasis. Methods TE85 and MNNG-HOS OS cells were transfected with P2RX7B. These cell lines were then characterised and assessed for proliferation, cell adhesion, migration and invasion in vitro. We used these cells to perform both paratibial and tail vein injected mouse studies where the primary tumour, bone and lungs were analysed. We used RNA-seq to identify responsive pathways relating to P2RX7B. Results Our data shows that P2RX7B expression confers a survival advantage in TE85 + P2RX7B and MNNG-HOS + P2RX7B human OS cell lines in vitro that is minimised following treatment with A740003, a specific P2RX7 antagonist. P2RX7B expression reduced cell adhesion and P2RX7B activation promoted invasion and migration in vitro, demonstrating a metastatic phenotype. Using an in vivo OS xenograft model, MNNG-HOS + P2RX7B tumours exhibited cancer-associated ectopic bone formation that was abrogated with A740003 treatment. A pro-metastatic phenotype was further demonstrated in vivo as expression of P2RX7B in primary tumour cells increased the propensity of tumour cells to metastasise to the lungs. RNA-seq identified a novel gene axis, FN1/LOX/PDGFB/IGFBP3/BMP4, downregulated in response to A740003 treatment. Conclusion Our data illustrates a role for P2RX7B in OS tumour growth, progression and metastasis. We show that P2RX7B is a future therapeutic target in human OS

Human infection challenge in the pandemic era and beyond, HIC-Vac annual meeting report, 2022

HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting

Validity of International Health Regulations in Reporting Emerging Infectious Diseases

Understanding which emerging infectious diseases are of international public health concern is vital. The International Health Regulations include a decision instrument to help countries determine which public health events are of international concern and require reporting to the World Health Organization (WHO) on the basis of seriousness, unusualness, international spread and trade, or need for travel restrictions. This study examined the validity of the International Health Regulations decision instrument in reporting emerging infectious disease to WHO by calculating its sensitivity, specificity, and positive predictive value. It found a sensitivity of 95.6%, a specificity of 38%, and a positive predictive value of 35.5%. These findings are acceptable if the notification volume to WHO remains low. Validity could be improved by setting more prescriptive criteria of seriousness and unusualness and training persons responsible for notification. However, the criteria should be balanced with the need for the instrument to adapt to future unknown threats

Persistent pulmonary hypertension and abnormal prostaglandin E levels in preterm infants after maternal treatment with naproxen.

Twins and a singleton were born at 30 weeks' gestation although naproxen (d-2 (6'methoxy-2-naphthyl) propionic acid) had been given to the mothers in an attempt to delay parturition. Inhibition of prostaglandin synthesis was shown by very low plasma concentrations of prostaglandin E and the ductus arteriosus remained closed despite signs of pulmonary hypertension with severe hypoxaemia. Abnormalities in blood clotting, renal function, and bilirubin metabolism were also found and one infant died. Further studies of the benefits and risks of the inhibition of prostaglandin synthesis are required before this treatment of preterm labour is accepted