Female Sex but Not Oestrogen Receptor Expression Predicts Survival in Advanced Gastroesophageal Adenocarcinoma—A Post-hoc Analysis of the GO2 Trial

Gastroesophageal adenocarcinoma is a disease of older adults that is associated with a very poor prognosis. It is less common and has better outcomes in females. The reason for this is unknown but may relate to signalling via the main oestrogen receptors (ER) α and β. In this study, we sought to investigate this using the GO2 clinical trial patient cohort. GO2 recruited older and/or frail patients with advanced gastroesophageal cancer. Immunohistochemistry was performed on tumour samples from 194 patients. The median age of the population was 76 years (range 52–90), and 25.3% were female. Only one (0.5%) tumour sample was positive for ERα, compared to 70.6% for ERβ expression. There was no survival impact according to ERβ expression level. Female sex and younger age were associated with lower ERβ expression. Female sex was also associated with improved overall survival. To our knowledge, this is the largest study worldwide of ER expression in a cohort of patients with advanced gastroesophageal adenocarcinoma. It is also unique, given the age of the population. We have demonstrated that female sex is associated with better survival outcomes with palliative chemotherapy but that this does not appear to be related to ER IHC expression. The differing ER expression according to age supports the concept of a different disease biology with age

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma

Background: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. Materials and methods: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). Results: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. Conclusions: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma

BackgroundAn improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA.Materials and methodsTranscriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430).ResultsIn the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME.ConclusionsOur results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours

Interglacials of the last 800,000 years

Interglacials, including the present (Holocene) period, are warm, low land ice extent (high sea level), end‐members of glacial cycles. Based on a sea level definition, we identify eleven interglacials in the last 800,000 years, a result that is robust to alternative definitions. Data compilations suggest that despite spatial heterogeneity, Marine Isotope Stages (MIS) 5e (last interglacial) and 11c (~400 ka ago) were globally strong (warm), while MIS 13a (~500 ka ago) was cool at many locations. A step change in strength of interglacials at 450 ka is apparent only in atmospheric CO2 and in Antarctic and deep ocean temperature. The onset of an interglacial (glacial termination) seems to require a reducing precession parameter (increasing Northern Hemisphere summer insolation), but this condition alone is insufficient. Terminations involve rapid, nonlinear, reactions of ice volume, CO2, and temperature to external astronomical forcing. The precise timing of events may be modulated by millennial‐scale climate change that can lead to a contrasting timing of maximum interglacial intensity in each hemisphere. A variety of temporal trends is observed, such that maxima in the main records are observed either early or late in different interglacials. The end of an interglacial (glacial inception) is a slower process involving a global sequence of changes. Interglacials have been typically 10-30 ka long. The combination of minimal reduction in northern summer insolation over the next few orbital cycles, owing to low eccentricity, and high atmospheric greenhouse gas concentrations implies that the next glacial inception is many tens of millennia in the future

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction

Can we predict the duration of an interglacial?

Differences in the duration of interglacials have long been apparent in palaeoclimate records of the Late and Middle Pleistocene. However, a systematic evaluation of such differences has been hampered by the lack of a metric that can be applied consistently through time and by difficulties in separating the local from the global component in various proxies. This, in turn, means that a theoretical framework with predictive power for interglacial duration has remained elusive. Here we propose that the interval between the terminal oscillation of the bipolar seesaw and three thousand years (kyr) before its first major reactivation provides an estimate that approximates the length of the sea-level highstand, a measure of interglacial duration. We apply this concept to interglacials of the last 800 kyr by using a recently-constructed record of interhemispheric variability. The onset of interglacials occurs within 2 kyr of the boreal summer insolation maximum/precession minimum and is consistent with the canonical view of Milankovitch forcing pacing the broad timing of interglacials. Glacial inception always takes place when obliquity is decreasing and never after the obliquity minimum. The phasing of precession and obliquity appears to influence the persistence of interglacial conditions over one or two insolation peaks, leading to shorter (~ 13 kyr) and longer (~ 28 kyr) interglacials. Glacial inception occurs approximately 10 kyr after peak interglacial conditions in temperature and CO2, representing a characteristic timescale of interglacial decline. Second-order differences in duration may be a function of stochasticity in the climate system, or small variations in background climate state and the magnitude of feedbacks and mechanisms contributing to glacial inception, and as such, difficult to predict. On the other hand, the broad duration of an interglacial may be determined by the phasing of astronomical parameters and the history of insolation, rather than the instantaneous forcing strength at inception

Workplace policies in public education: a review focusing on HIV/AIDS

Policy governs many aspects of the professional lives of educators. It is also central to their and the sector's response to crises such as the HIV/AIDS epidemic. As such policy can contribute directly to curtailing the attrition of educators, by encouraging and providing protection against threats such as HIV/AIDS, and by creating a positive and supportive working environment. This study examines workplace and HIV/AIDS policies from the Department of Education (DoE) and the HIV/AIDS policies of two trade unions, as part of a broader study looking at the attrition of educators. The policies themselves were found to be well written and if implemented, would create a good environment for educators. A number of successes were noted, particularly in terms of the transformation of education structures. The findings suggest that problems are centered on a lack of policy implementation, resulting from disjunctures between the national office and provincial and district offices, as well as a lack of resources and inadequate planning and preparation for implementation

Age and duration of Laschamp and Iceland Basin geomagnetic excursions in the South Atlantic Ocean

International audienc

Generalizing a model of health behaviour change and AIDS stigma for use with sexually transmitted infection clinic patients in Cape Town, South Africa

We tested the Information/Motivation/Behavioural Skills (IMB) model of AIDS preventive behaviour in South Africa. Prospective path analyses were performed on measures collected from 131 men and 60 women with sexually transmitted infections (STI) in Cape Town. Results showed that IMB constructs collected at baseline predicted risk reduction behaviour 3 months later. Risk reduction intentions were positively associated with risk reduction self-efficacy and self-efficacy was in turn positively associated with protective behaviour 3 months later. In a second model, AIDS-related stigmas correlated inversely with AIDS knowledge and there was a trend toward AIDS stigmas correlating inversely with behavioural intentions. Accounting for AIDS-related stigmas did not improve model fit. These findings parallel similar tests of the IMB model in US samples and suggest that the IMB model may generalize to South Africa and may therefore be useful in guiding HIV risk reduction interventions.