Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including and, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on and promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs. These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. .

Simple SummaryDairy farm system practices aimed at reducing nitrate leaching can also reduce emissions of the greenhouse gases methane and nitrous oxide. A study comparing ‘current’ and ‘improved’ grazed dairy system practices showed that ‘improved’ systems generally produced lower greenhouse gas emissions while milk production was maintained. The amount of feed eaten per hectare was the key driver of total greenhouse gas emissions per area, with ‘improved’ systems generally exhibiting lower total enteric methane and less N flowing through the herd.AbstractAn important challenge facing the New Zealand (NZ) dairy industry is development of production systems that can maintain or increase production and profitability, while reducing impacts on receiving environments including water and air. Using research ‘farmlets’ in Waikato, Canterbury, and Otago (32–200 animals per herd), we assessed if system changes aimed at reducing nitrate leaching can also reduce total greenhouse gas (GHG) emissions (methane and nitrous oxide) and emissions intensity (kg GHG per unit of product) by comparing current and potential ‘improved’ dairy systems. Annual average GHG emissions for each system were estimated for three or four years using calculations based on the New Zealand Agricultural Inventory Methodology, but included key farmlet-specific emission factors determined from regional experiments. Total annual GHG footprints ranged between 10,800 kg and 20,600 kg CO2e/ha, with emissions strongly related to the amount of feed eaten. Methane (CH4) represented 75% to 84% of the total GHG footprint across all modelled systems, with enteric CH4 from lactating cows grazing pasture being the major source. Excreta deposition onto paddocks was the largest source of nitrous oxide (N2O) emissions, representing 7–12% of the total GHG footprint for all systems. When total emissions were represented on an intensity basis, ‘improved’ systems are predicted to generally result in lower emissions intensity. The ‘improved’ systems had lower GHG footprints than the ‘current’ system, except for one of the ‘improved’ systems in Canterbury, which had a higher stocking rate. The lower feed supplies and associated lower stocking rates of the ‘improved’ systems were the key drivers of lower total GHG emissions in all three regions. ‘Improved’ systems designed to reduced N leaching generally also reduced GHG emissions.

A long-term phosphorus (P) fertiliser and sheep grazing experiment at the AgResearch Research Station at Ballantrae (1975-2022) provides a unique resource to examine long-term changes in net herbage accumulation (NHA) and animal production under conditions where soil P fertility have been non-limiting for more than 35 years. This paper examined historical NHA, soil phosphorus (P) and nitrogen (N) fertility from the high fertiliser (HF) farmlet, and pasture growth trends using the climate driven pasture growth module AgPasture within the Agricultural Production Systems Simulator (APSIM). On the medium slope of the HF farmlet, NHA in 2020-21 was only 87% of that measured on the same farmlet between 1982-88, even though P was non-limiting. The measured decline in NHA aligned with a reduction of on-site nominal sheep stocking rates since the late 1990’s. Prior to this paper, climate driven modelling has often predicted a likely positive outcome in NHA for this environment into the future. Understanding the apparent discrepancy between predictions into the future with what is happening on the ground today is discussed in the paper.

Between 2011 and 2016, small-scale farm trials were run across three dairy regions of New Zealand (Waikato, Canterbury, Otago) to compare the performance of typical regional farm systems with farm systems implementing a combination of mitigation options most suitable to the region. The trials ran for at least three consecutive years with detailed recording of milk production and input costs. Nitrate leaching per hectare of the milking platform (where lactating cows are kept) was estimated using either measurements (suction cups), models, or soil mineral nitrogen measurements. Post-trial, detailed farm information was used in the New Zealand greenhouse gas inventory methodology to calculate the emissions from all sources; dairy platform, dairy support land used for wintering non-lactating cows (where applicable) and replacement stock, and imported supplements. Nitrate leaching was also estimated for the support land and growing of supplements imported from off-farm using the same methods as for the platform. Operating profit (NZ$/ha/year), nitrate leaching (kg N/ha/year), and greenhouse gas emissions (t CO2-equivalent/ha/year) were all expressed per hectare of milking platform to enable comparisons across regions. Nitrate leaching mitigations adopted in lower-input (less purchased feed and nitrogen fertiliser) farm systems reduced leaching by 22 to 30 per cent, and greenhouse gas emissions by between nine and 24 per cent. The exception was the wintering barn system in Otago, where nitrate leaching was reduced by 45 per cent, but greenhouse gas emissions were unchanged due to greater manure storage and handling. Important drivers of a lower environmental footprint are reducing nitrogen fertiliser and purchased feed. Their effect is to reduce feed flow through the herd and drive down both greenhouse gas emissions and nitrate leaching. Emission reductions in the lower-input systems of Waikato and Canterbury came at an average loss of profit of approximately NZ$100/t CO2-equivalent (three to five per cent of industry-average profit per hectare).

This project aimed to develop a dataset containing animal policies, production efficiencies, and greenhouse gas (GHG) emissions of a large number of sheep and beef farms, and to examine the relationships between farm management and farm physical constraints, and GHG emissions. We used the farm-scale model Farmax to estimate feed inventories, livestock policies and GHG emissions of 170 New Zealand sheep and beef farms. Emissions were calculated from Farmax outputs using Agricultural Inventory methodology. We used a quantitative approach to cluster farms based on physical constraints and management attributes. Mean annual biological GHG emissions from the modelled farms were 3,662 kg CO2 equivalents (CO2-e) per effective hectare, and ranged from 157 to 7,096 kg CO2-e/effective ha. As stocking rate and animal product (wool + net carcass weight) per effective hectare increased, GHG emissions increased. However, there was considerable variability in the data; farms with GHG emissions of approximately 4,000 kg CO2-e/effective ha had an almost three-fold difference in animal product (range 129 to 360 kg/effective ha). Our work provides a holistic assessment of the farm-scale drivers of GHG emissions and a comprehensive current state of affairs or baseline from which future trends in farm-scale GHG emissions can be established.