Summary Background Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely ...unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention. Methods We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status. Results Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio OR 0·85, 95% CI 0·76–0·96, p=0·008; 34 trials, 69 224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49–0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78–0·96, p=0·003; 51 trials, 77 549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35 535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66–0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59–0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63–0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 95% CI 1·44–4·82 per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12–0·83, p=0·009). Interpretation Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer. Funding None.
Summary Background Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also ...reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. Methods Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. Findings Of 17 285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio HR 0·64, 95% CI 0·48–0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38–0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53–1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35–0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50–0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28–0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11–0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15–0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34–0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53–0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84–1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. Interpretation That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis. Funding None.
Cell-cell communication is an important mechanism for information exchange promoting cell survival for the control of features such as population density and differentiation. We determined that ...Plasmodium falciparum-infected red blood cells directly communicate between parasites within a population using exosome-like vesicles that are capable of delivering genes. Importantly, communication via exosome-like vesicles promotes differentiation to sexual forms at a rate that suggests that signaling is involved. Furthermore, we have identified a P. falciparum protein, PfPTP2, that plays a key role in efficient communication. This study reveals a previously unidentified pathway of P. falciparum biology critical for survival in the host and transmission to mosquitoes. This identifies a pathway for the development of agents to block parasite transmission from the human host to the mosquito.
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•Malaria-infected red blood cells communicate using exosome-like vesicles•Communication via exosome-like vesicles promotes differentiation to sexual forms•Pathway of P. falciparum biology for survival in host and mosquito transmission•Identification of a pathway for development of agents to block parasite transmission
The malaria-causing pathogen Plasmodium falciparum infects red blood cells and uses exosome-like vesicles to directly communicate within a population. These vesicles transmit information required for parasite survival, population density, and sexual differentiation within the host.
The Jovian Auroral Distributions Experiment (JADE) on Juno provides the critical
in situ
measurements of electrons and ions needed to understand the plasma energy particles and processes that fill ...the Jovian magnetosphere and ultimately produce its strong aurora. JADE is an instrument suite that includes three essentially identical electron sensors (JADE-Es), a single ion sensor (JADE-I), and a highly capable Electronics Box (EBox) that resides in the Juno Radiation Vault and provides all necessary control, low and high voltages, and computing support for the four sensors. The three JADE-Es are arrayed 120
∘
apart around the Juno spacecraft to measure complete electron distributions from ∼0.1 to 100 keV and provide detailed electron pitch-angle distributions at a 1 s cadence, independent of spacecraft spin phase. JADE-I measures ions from ∼5 eV to ∼50 keV over an instantaneous field of view of 270
∘
×90
∘
in 4 s and makes observations over all directions in space each 30 s rotation of the Juno spacecraft. JADE-I also provides ion composition measurements from 1 to 50 amu with
m
/Δ
m
∼2.5, which is sufficient to separate the heavy and light ions, as well as O+ vs S+, in the Jovian magnetosphere. All four sensors were extensively tested and calibrated in specialized facilities, ensuring excellent on-orbit observations at Jupiter. This paper documents the JADE design, construction, calibration, and planned science operations, data processing, and data products. Finally, the
Appendix
describes the Southwest Research Institute SwRI electron calibration facility, which was developed and used for all JADE-E calibrations. Collectively, JADE provides remarkably broad and detailed measurements of the Jovian auroral region and magnetospheric plasmas, which will surely revolutionize our understanding of these important and complex regions.
Most randomized trials of treatment for asthma study highly selected patients under idealized conditions.
We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world ...effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire MiniAQLQ score ≤6) or inadequate asthma control (Asthma Control Questionnaire ACQ score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial.
Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval CI for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups.
Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).
Hydrogen chloride was discovered in the atmosphere of Mars for the first time during the global dust storm in Mars year (MY) 34 (July 2018) using the Atmospheric Chemistry Suite mid-infrared channel ...(ACS MIR) on the ExoMars Trace Gas Orbiter. The simultaneity of variations in dust and HCl, and a correlation between water vapour and HCl, led to the proposal of a novel surface-atmosphere coupling analogous to terrestrial HCl production in the troposphere from salt aerosols. After seasonal dust activity restarted in MY 35 (August 2020), we have been monitoring HCl activity to determine whether such a coupling was validated. Here we present a new technique for analysing the absorption features of trace gases close to the ACS MIR noise level and report that HCl mixing ratios are observed to rapidly increase in both hemispheres coincidentally with the onset of the MY 35 perihelion dust season. We present the temporal evolution of the vertical distribution of HCl (0.1–6 ppbv) and of dust activity in both hemispheres. We also report two observations of >2 ppbv HCl below 10 km in the northern hemisphere during the aphelion period.
Sickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively ...lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD.
BP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR.
Diastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice.
Relative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.
Oxidative phosphorylation provides most of the ATP that higher animals and plants use to support life and is responsible for setting and maintaining metabolic homeostasis. The pathway incorporates ...three consecutive near equilibrium steps for moving reducing equivalents between the intramitochondrial NAD+/NADH pool to molecular oxygen, with irreversible reduction of oxygen to bound peroxide at cytochrome c oxidase determining the net flux. Net flux (oxygen consumption rate) is determined by demand for ATP, with feedback by the energy state (ATP/ADPPi) regulating the pathway. This feedback affects the reversible steps equally and independently, resulting in the rate being coupled to (ATP/ADPPi)3. With increasing energy state, oxygen consumption decreases rapidly until a threshold is reached, above which there is little further decrease. In most cells, ATP and Pi are much higher than ADP and change in ADP is primarily responsible for the change in energy state. As a result, the rate of ATP synthesis, plotted against ADP, remains low until ADP reaches about 30 μm and then increases rapidly with further increase in ADP. The dependencies on energy state and ADP near the threshold can be fitted by the Hill equation with a Hill coefficients of about −2.6 and 4.2, respectively. The homeostatic set point for metabolism is determined by the threshold, which can be modulated by the PO2 and intramitochondrial NAD+/NADH. The ability of oxidative phosphorylation to precisely set and maintain metabolic homeostasis is consistent with it being permissive of, and essential to, development of higher plants and animals.
Integration of oxidative phosphorylation into cellular metabolism made possible the evolutionary development of higher organisms. Progressive improvements in control of oxidative phosphorylation supported the increasing demands of specialized tissues, in particular muscles and neurons. One of these improvements, replacing arginine kinase with creatine kinase, was permissive of the evolutionary development of vertebrates.
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