The productivity, metabolism and carbon cycle of two lowland tropical forest plots in south-western Amazonia

Background: The forests of western Amazonia are known to be more dynamic that the better-studied forests of eastern Amazonia, but there has been no comprehensive description of the carbon cycle of a western Amazonian forest. Aims: We present the carbon budget of two forest plots in Tambopata in south-eastern Peru, western Amazonia. In particular, we present, for the first time, the seasonal variation in the detailed carbon budget of a tropical forest. Methods: We measured the major components of net primary production (NPP) and total autotrophic respiration over 3-6 years. Results: The NPP for the two plots was 15.1 ± 0.8 and 14.2 ± 1.0 Mg C ha −1 year −1 , the gross primary productivity (GPP) was 35.5 ± 3.6 and 34.5 ± 3.5 Mg C ha −1 year −1 , and the carbon use efficiency (CUE) was 0.42 ± 0.05 and 0.41 ± 0.05. NPP and CUE showed a large degree of seasonality. Conclusions: The two plots were similar in carbon cycling characteristics despite the different soils, the most notable difference being high allocation of NPP to canopy and low allocation to fine roots in the Holocene floodplain plot. The timing of the minima in the wet-dry transition suggests they are driven by phenological rhythms rather than being driven directly by water stress. When compared with results from forests on infertile forests in humid lowland eastern Amazonia, the plots have slightly higher GPP, but similar patterns of CUE and carbon allocation

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Abstracts from the NIHR INVOLVE Conference 2017

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Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Using motivation to assess welfare. Are we measuring what we think we're measuring?

The measurement of motivation has become an important tool used to assess the resources and experiences that an animal values, and subsequently to aid in determining its welfare. However, the relationship between these measurements and welfare state is not well defined, with conclusions normally being based on the assumption that an animal's welfare is reduced if a 'highly valued' resource is not provided. The aim of the research reported here was to investigate the mechanism/s that drive motivation in a behavioural demand feed test and investigate the effect of energy availability on motivational strength, as well as potentially, to provide a better understanding of the relationship between motivation and welfare state. The experiment undertaken involved investigating the relationship between net energy and motivation for food in a behavioural demand test i.e. is the reason motivation decreases in a feed-based demand test due to the animal reaching a point of energetic balance (energy expended = energy consumed)? Sheep were tested to see how many times in a 23-hour period they would walk a specific distance for a small (5g) food reward and it was hypothesised that they would stop walking (lack motivation) once they had reached a zero energy balance. Eight sheep were trained in a 50m laneway to access a double-sided feeder and gained a food reward with each access event. The distance the sheep walked in the laneway to access this reward was increased progressively on a logarithmic scale (1.5, 6.1, 12.3, 24.8, 50.0, 60.2, 72.5, 87.5, 105.5m) with each test period. Sheep were randomly allocated to one of two treatments (14-hr restriction and an unrestricted control). The results indicate that both control and restricted sheep worked beyond a zero energy balance and the level of prior food availability had no effect on the distance they were willing to walk (p&gt;0.05). Interestingly, the zero balance occurred at approximately the same point as motivation first began to decrease (Pmax). These results indicate that energy input alone does not fully explain changes in motivation for food in a behavioural demand test. Further studies will investigate other possible mechanisms that may contribute to motivation in this specific situation

Automated measurement of sheep movement order: consistent, stable and useful to identify the risk of welfare compromise?

This pilot study investigated how the movement order of a flock of sheep in an extensive environment differed over time to determine if order, as recorded by radio frequency identification tags, was stable and if deviations in position might be used to identify animals with compromised welfare state. The hypothesis was that flock 'free' movement order would be relatively stable and repeatable. Two hundred mature Merino ewes were trained to walk a distance of 1 km following a handler carrying a bucket of grain. The sheep were allowed to move at their own pace and, provided they were not grazing, were not pushed from the rear. Thirteen runs around a fenced track occurred over an eight week period during mid-pregnancy. General health (lameness, demeanour, posture) were recorded at each run, a blood sample to assess various haematological parameters (e.g. RBC, HCT, WBC, neutrophil, lymphocyte and eosinophil concentrations) was taken from each ewe between the 12th and 13th runs and a temperament test was conducted at the completion of the runs

Opioid reward systems may influence willingness to walk for food in a motivation test

The measurement of strength of motivation has become a frequently used tool to assess the resources that an animal values and, subsequently, to aid in determining its welfare. However, the relationship between animal motivation and welfare state is not well defined with conclusions based on the assumption that welfare is reduced if a 'valued' resource is not provided. One way to better identify the relationship between the level of motivation and welfare state is by investigating the determinants which underlie changes in motivation. This study therefore aimed to test the hypothesis that manipulation of the opioid system, through administration of the antagonist naltrexone (NTX), would decrease the willingness of sheep to walk for food in a demand test and that this decrease could be modulated by the energy density of the food. Ten sheep were trained in a 50m U-shaped laneway to access a double-sided feeder and gained a reward with each access event. NTX was administered at 1mg/kg and sheep were tested to see how many times in a 20h period they would walk a specific distance for a 4g food reward (high energy (HE) or low energy (LE)). The distance the sheep walked varied between 1.5-70m and each sheep was exposed to four random distances at each of the four treatment levels (NTX + HE, no NTX + HE, NTX + LE, no NTX + LE). Data were analysed using REMLs and the preliminary results indicate that significant effects of distance (p0.1). These preliminary results indicate that NTX does appear to decrease the willingness of sheep to walk for food in a demand test and that energy density and the opioid reward system may act independently to alter the motivation of a ruminant for food. However, further research will be necessary to confirm this

Remote monitoring for wellbeing in grazing sheep: are social behaviours useful?

The increase in the use of electronic identification ear tags means that production traits specific to an individual sheep can be recorded and that presence, and possibly wellbeing, of individual sheep may be able to be monitored remotely. If data from monitoring systems is to be used to identify wellbeing status of individual sheep then behavioural measures recorded need to stable in a group of healthy individuals, have a short lag time and, where possible, reflect a variety of welfare and health issues. To date roll call, movement order and social networks have been assessed as potential measures of wellbeing. These measures are not ideal as identifiers of change in welfare state of grazing sheep as they do not meet the time frame or stability and repeatability requirements. Further work on a variety of other measures is underway using additional technologies such as temperature sensing microchips and video image analysis