Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

Bone tissue constitutes a fertile 'soil' for metastatic tumours, notably breast cancer. High concentrations of growth factors in bone matrix favour cancer cell proliferation and survival, and a vicious cycle settles between bone matrix, osteoclasts and cancer cells. Classically, bisphosphonates interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption. We and others recently reported that bisphosphonates can also induce human breast cancer cell death in vitro, which could contribute to their beneficial clinical effects. We hypothesised that bisphosphonates could inhibit the favourable effects of 'bone-derived' growth factors, and indeed found that bisphosphonates reduced or abolished the stimulatory effects of growth factors (IGFs, FGF-2) on MCF-7 and T47D cell proliferation and inhibited their protective effects on apoptotic cell death in vitro under serum-free conditions. This could happen through an interaction with growth factors' intracellular phosphorylation transduction pathways, such as ERK1/2-MAPK. In conclusion, we report that bisphosphonates antagonised the stimulatory effects of growth factors on human breast cancer cell survival and reduced their protective effects against apoptotic cell death. Bisphosphonates and growth factors thus appear to be concurrent compounds for tumour cell growth and survival in bone tissue. This could represent a new mechanism of action of bisphosphonates in their protective effects against breast cancer-induced osteolysis.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021

Living with oropharyngeal dysphagia: effects of bolus modification on health-related quality of life—a systematic review

Purpose - Difficulty swallowing, oropharyngeal dysphagia, is widespread among many patient populations (such as stroke and cancer groups) and aged community-dwelling individuals. It is commonly managed with bolus modification: altering food (usually cutting, mashing or puréeing) or fluids (typically thickening) to make them easier or safer to swallow. Although this treatment is ubiquitous, anecdotal evidence suggests patients dislike this management, and this may affect compliance and well-being. This review aimed to examine the impact of bolus modification on health-related quality of life. Methods - A systematic review of the literature was conducted by speech pathologists with experience in oropharyngeal dysphagia. The literature search was completed with electronic databases, PubMed and Embase, and all available exclusion dates up to September 2012 were used. The search was limited to English-language publications which were full text and appeared in peer-reviewed journals. Results - Eight studies met the inclusion criteria. Generally, bolus modification was typically associated with worse quality of life. Modifications to foods appeared to be more detrimental than modifications to fluids, but this may be due to the increased severity of dysfunction that is implied by the necessity for significant alterations to foods. The number of studies retrieved was quite small. The diverse nature of methodologies, terminologies and assessment procedures found in the studies makes the results difficult to generalise. Conclusion - Overall, even though the severity of dysphagia may have been a confounding factor, the impact of bolus modification on health-related quality of life in patients with oropharyngeal dysphagia appears to be negative, with increased modification of food and fluids often correlating to a decreased quality of life. Further, associated disease factors, such as decreased life expectancy, may also have affected health-related quality of life. More research is needed