A Platinum(IV) Prodrug-Perfluoroaryl Macrocyclic Peptide Conjugate Enhances Platinum Uptake in the Brain.

Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum(IV) prodrugs of cisplatin and perfluoroaryl peptide macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem-like cells. We investigate the pharmacokinetics of this conjugate in mice and show that the amount of platinum in the brain after treatment with the conjugate is 15-fold greater than with cisplatin after 5 h.

Benefits and Trade-Offs of Dairy System Changes Aimed at Reducing Nitrate Leaching.

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).

Pharmacology beyond the patient - The environmental risks of human drugs.

BACKGROUND: The presence of pharmaceuticals in the environment is a growing global concern and although environmental risk assessment is required for approval of new drugs in Europe and the USA, the adequacy of the current triggers and the effects-based assessments has been questioned. OBJECTIVE: To provide a comprehensive analysis of all regulatory compliant aquatic ecotoxicity data and evaluate the current triggers and effects-based environmental assessments to facilitate the development of more efficient approaches for pharmaceuticals toxicity testing. METHODS: Publicly-available regulatory compliant ecotoxicity data for drugs targeting human proteins was compiled together with pharmacological information including drug targets, Cmax and lipophilicity. Possible links between these factors and the ecotoxicity data for effects on, growth, mortality and/or reproduction, were evaluated. The environmental risks were then assessed based on a combined analysis of drug toxicity and predicted environmental concentrations based on European patient consumption data. RESULTS: For most (88%) of the of 975 approved small molecule drugs targeting human proteins a complete set of regulatory compliant ecotoxicity data in the public domain was lacking, highlighting the need for both intelligent approaches to prioritize legacy human drugs for a tailored environmental risk assessment and a transparent database that captures environmental data. We show that presence/absence of drug-target orthologues are predictive of susceptible species for the more potent drugs. Drugs that target the endocrine system represent the highest potency and greatest risk. However, for most drugs (>80%) with a full set of ecotoxicity data, risk quotients assuming worst-case exposure assessments were below one in all European countries indicating low environmental risks for the endpoints assessed. CONCLUSION: We believe that the presented analysis can guide improvements to current testing procedures, and provide valuable approaches for prioritising legacy drugs (i.e. those registered before 2006) for further ecotoxicity testing. For drugs where effects of possible concern (e.g. behaviour) are not captured in regulatory tests, additional mechanistic testing may be required to provide the highest confidence for avoiding environmental impacts.

The Effects of System Changes in Grazed Dairy Farmlet Trials on Greenhouse Gas Emissions.

An 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.

Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage.

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 JUN and FAM21, 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 JUN and FAM21 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.Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497-509. ©2018 AACR.