Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development

Seven classes of mitogen-activated protein kinase (MAPK) intracellular signalling cascades exist, four of which are implicated in breast disease and function in mammary epithelial cells. These are the extracellular regulated kinase (ERK)1/2 pathway, the ERK5 pathway, the p38 pathway and the c-Jun N-terminal kinase (JNK) pathway. In some forms of human breast cancer and in many experimental models of breast cancer progression, signalling through the ERK1/2 pathway, in particular, has been implicated as being important. We review the influence of ERK1/2 activity on the organised three-dimensional association of mammary epithelial cells, and in models of breast cancer cell invasion. We assess the importance of epidermal growth factor receptor family signalling through ERK1/2 in models of breast cancer progression and the influence of ERK1/2 on its substrate, the oestrogen receptor, in this context. In parallel, we consider the importance of these MAPK-centred signalling cascades during the cycle of mammary gland development. Although less extensively studied, we highlight the instances of signalling through the p38, JNK and ERK5 pathways involved in breast cancer progression and mammary gland development

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

A quantitative tomotectonic plate reconstruction of Western North America and the Eastern Pacific Basin

Plate reconstructions since the breakup of Pangaea are mostly based on the preserved spreading history of ocean basins, within absolute reference frames that are constrained by a combination of age‐progressive hotspot tracks and palaeomagnetic data. The evolution of destructive plate margins is difficult to constrain from surface observations as much of the evidence has been subducted. Seismic tomography can directly constrain palaeo‐trench locations by imaging subducted lithosphere in the mantle. This new evidence, combined with the geological surface record of subduction, suggests that several intra‐oceanic arcs existed between the Farallon Ocean and North America during late Mesozoic times – in contrast to existing quantitative models that typically show long‐lived subduction of the Farallon plate beneath the continental margin. We present a continuously closing plate model for the eastern Pacific basin from 170 Ma to present, constrained using ‘tomotectonic analysis’ – the integration of surface and subsurface data. During the Middle to Late Jurassic, we show simultaneous eastward and westward subduction of oceanic plates under an archipelago composed of Cordilleran arc terranes. As North America drifts westward, it diachronously overrides the archipelago and its arcs, beginning in the latest Jurassic. During and post‐accretion, Cordilleran terranes are translated thousands of kilometers along the continental margin, as constrained by palaeomagnetic evidence. Final accretions to North America occur during the Eocene, ending ~100 million years of archipelago override. This model provides a detailed, quantitative tectonic history for the eastern Pacific domain, paving the way for tomotectonic analysis to be used in other palaeo‐oceanic regions

A Quantitative Tomotectonic Plate Reconstruction of Western North America and the Eastern Pacific Basin

Plate reconstructions since the breakup of Pangaea are mostly based on the preserved spreading history of ocean basins, within absolute reference frames that are constrained by a combination of age‐progressive hotspot tracks and palaeomagnetic data. The evolution of destructive plate margins is difficult to constrain from surface observations as much of the evidence has been subducted. Seismic tomography can directly constrain palaeo‐trench locations by imaging subducted lithosphere in the mantle. This new evidence, combined with the geological surface record of subduction, suggests that several intra‐oceanic arcs existed between the Farallon Ocean and North America during late Mesozoic times – in contrast to existing quantitative models that typically show long‐lived subduction of the Farallon plate beneath the continental margin. We present a continuously closing plate model for the eastern Pacific basin from 170 Ma to present, constrained using ‘tomotectonic analysis’ – the integration of surface and subsurface data. During the Middle to Late Jurassic, we show simultaneous eastward and westward subduction of oceanic plates under an archipelago composed of Cordilleran arc terranes. As North America drifts westward, it diachronously overrides the archipelago and its arcs, beginning in the latest Jurassic. During and post‐accretion, Cordilleran terranes are translated thousands of kilometers along the continental margin, as constrained by palaeomagnetic evidence. Final accretions to North America occur during the Eocene, ending ~100 million years of archipelago override. This model provides a detailed, quantitative tectonic history for the eastern Pacific domain, paving the way for tomotectonic analysis to be used in other palaeo‐oceanic regions

Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial

Purpose: It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confrm the feasibility of such a protocol with a view to conducting a larger trial. Methods: We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge. Results: Compared with usual temperature management, active management signifcantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature diference between groups was greatest in the frst 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51–1.96, P=1.0). There were no statistically signifcant diferences between groups in ICU-free days or survival to day 90. Conclusions: Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small.The REACTOR study was endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group and funded by the Health Research Council of New Zealand (16/488). The study was coordinated by the Medical Research Institute of New Zealand in New Zealand and the George Institute for Global Health in Australia. The Medical Research Institute of New Zealand is supported by Independent Research Organisation funding by the Health Research Council of New Zealan