Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.

Significance: Programmed ribosomal frameshifting (PRF) is important to many viruses, but how structures in mRNA stimulate PRF remains uncertain. By studying a frameshift signal stimulating very high PRF in West Nile virus (WNV), we identify features that differ from other structures stimulating more modest PRF levels. Using single-molecule force spectroscopy to mimic the effects of tension applied to the RNA by the ribosome during translation, we find that the WNV frameshift signal exhibits exceptionally heterogeneous conformational dynamics, forming several different pseudoknots and multiple combinations of hairpins, all connected on 2 mutually exclusive pathways. This work supports a role for conformational heterogeneity in PRF, suggesting that dynamic fluctuations rather than static properties play a key role in stimulating PRF efficiently.

Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates −1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of −1 PRF in SARS-CoV-2 also inhibited −1 PRF in a range of bat CoVs—the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on −1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed −1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit −1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics.

$-1$ programmed ribosomal frameshifting ($-1\mathrm{PRF}$) is stimulated by structures in messenger RNA (mRNA), but the factors determining $-1\mathrm{PRF}$ efficiency are unclear. We show that $-1\mathrm{PRF}$ efficiency varies directly with the conformational heterogeneity of the stimulatory structure, quantified as the Shannon entropy of the state occupancy, for a panel of stimulatory structures with efficiencies from 2% to 80%. The correlation is force dependent and vanishes at forces above those applied by the ribosome. These results support the hypothesis that heterogeneous conformational dynamics are a key factor in stimulating $-1\mathrm{PRF}$.

The COVID crisis of the past three years has greatly impacted stakeholder relationships between scientists, health providers, policy makers, pharmaceutical industry employees, and the public. Lockdowns and restrictions of civil liberties strained an already fraught relationship between the public and policy makers, with scientists also seen as complicit in providing the justification for the abrogation of civil liberties. This was compounded by the suppression of open debate over contentious topics of public interest and a violation of core bioethical principles embodied in the Nuremberg Code. Overall, the policies chosen during the pandemic have had a corrosive impact on public trust, which is observable in surveys and consumer behaviour. While a loss of trust is difficult to remedy, the antidotes are accountability and transparency. This narrative review presents an overview of key issues that have motivated public distrust during the pandemic and ends with suggested remedies. Scientific norms and accountability must be restored in order to rebuild the vital relationship between scientists and the public they serve.

Pharmacovigilance databases are showing evidence of injury in the context of the modified COVID-19 mRNA products. According to recent publications, adverse event reports linked to the mRNA COVID-19 injections largely point to the spike protein as an aetiological agent of adverse events, but we propose that the platform itself may be culpable. To assess the safety of current and future mRNA vaccines, further analysis is needed on the risks due to the platform itself, and not specifically the expressed antigen. If harm can be exclusively and conclusively attributed to the spike protein, then it is possible that future mRNA vaccines expressing other antigens will be safe. If harms are attributable to the platform itself, then regardless of the toxicity, or lack thereof, of the antigen to be expressed, the platform may be inherently unsafe, pending modification. In this work, we examine previous studies of RNA-based delivery by a lipid nanoparticle (LNP) and break down the possible aetiological elements of harm.