Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with ²¹²Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of ²¹²Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of ²¹²Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of ²¹²Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of ²¹²Pb-NG001.     

Historical narratives as strategic resources: analysis of the Turkish international contracting sector

The Turkish contracting sector has an enviable reputation for operating in high-risk international markets. The sector’s ability to respond to market instability could meaningfully be construed as sectoral-level capability. We aim to demonstrate how history can be mobilised in a formalised “strategy text” to create a strategic narrative on the sectoral level. The Geography of Contractors as published by the Turkish Contractors Association (TCA) ostensively portrays the strategic development of Turkish international contractors over four decades. Such quasi-historical narratives are routinely mobilised for the purposes of creating a shared memory on the sectoral level. The chosen strategy text draws from multiple narrative fragments derived from past experience to generate a strategic agenda for the future. The representation given to multiple voices reflects the pluralistic nature of strategy making praxis. The overarching strategy narrative reflects a performative intent in legitimising some practices whilst discrediting others. Narrative analysis demonstrates the way in which actors, actions and events are positioned within a plot structure, with direct implications for the enactment of future strategic practices. The findings suggest that strategic actions can only ever be identified in retrospect and that such arguments are always made with an eye on the future.     

The three Rs of river ecosystem resilience: Resources,recruitment, and refugia

Resilience in river ecosystems requires that organisms must persist in the face of highly dynamic hydrological and geomorphological variations. Disturbance events such as floods and droughts are postulated to shape life history traits that support resilience, but river management and conservation would benefit from greater understanding of the emergent effects in communities of river organisms. We unify current knowledge of taxonomic‐, phylogenetic‐, and trait‐based aspects of river communities that might aid the identification and quantification of resilience mechanisms. Temporal variations in river productivity, physical connectivity, and environmental heterogeneity resulting from floods and droughts are highlighted as key characteristics that promote resilience in these dynamic ecosystems. Three community‐wide mechanisms that underlie resilience are (a) partitioning (competition/facilitation) of dynamically varying resources, (b) dispersal, recolonization, and recruitment promoted by connectivity, and (c) functional redundancy in communities promoted by resource heterogeneity and refugia. Along with taxonomic and phylogenetic identity, biological traits related to feeding specialization, dispersal ability, and habitat specialization mediate organism responses to disturbance. Measures of these factors might also enable assessment of the relative contributions of different mechanisms to community resilience. Interactions between abiotic drivers and biotic aspects of resource use, dispersal, and persistence have clear implications for river conservation and management. To support these management needs, we propose a set of taxonomic, phylogenetic, and life‐history trait metrics that might be used to measure resilience mechanisms. By identifying such indicators, our proposed framework can enable targeted management strategies to adapt river ecosystems to global change.     

Performance of Holstein and Swedish-Red × Jersey/Holstein crossbred dairy cows within low- and medium-concentrate grassland-based systems

This 2 × 2 factorial design experiment was conducted to compare the performance of spring-calving Holstein dairy cows (HOL, n = 34) with Swedish Red × Jersey/Holstein crossbred (SR × J/HOL, n = 34) dairy cows within low and medium concentrate input grassland-based dairy systems. The experiment commenced when cows calved and encompassed 1 full lactation. Cows were offered diets containing grass silage and concentrates [70:30 dry matter (DM) ratio, and 40:60 DM ratio, for low and medium, respectively] until turnout, grazed grass plus either 1.0 or 4.0 kg of concentrate/d during the grazing period (low and medium, respectively), and grass silage and concentrates (85:15 DM ratio, and 70:30 DM ratio, for low and medium, respectively) from rehousing and until drying off. No significant genotype × system interactions were present for any of the feed intake or full-lactation milk production data examined. Full-lactation concentrate DM intakes were 769 and 1,902 kg/cow for the low and medium systems, respectively, whereas HOL cows had a higher total DM intake than SR × J/HOL cows in early lactation, but not in late lactation. Although HOL cows had a higher lactation milk yield than SR × J/HOL cows, the latter produced milk with a higher fat and protein content, and thus fat plus protein yield was unaffected by genotype. Milk produced by the SR × J/HOL cows had a higher degree of saturation of fatty acids than milk produced by the HOL cows, and the somatic cell score of milk produced by the former was also higher. Throughout the lactation, HOL cows were on average 30 kg heavier than SR × J/HOL cows, whereas the SR × J/HOL cows had a higher body condition score than the HOL cows. Holstein cows had a higher incidence of mastitis and ovarian dysfunction that SR × J/HOL cows.     

Urea hydrolysis and precipitation dynamics in a urine-collecting system

Blockages caused by inorganic precipitates are a major problem of urine-collecting systems. The trigger of precipitation is the hydrolysis of urea by bacterial urease. While the maximum amount of precipitates, i.e. the precipitation potential, can be estimated with equilibrium calculations, little is known about the dynamics of ureolysis and precipitation. To gain insight in these processes, we performed batch experiments with precipitated solids and stored urine from a urine-collecting system and later simulated the results with a computer model. We found that urease-active bacteria mainly grow in the pipes and are flushed into the collection tank. Both, bacteria and free urease, hydrolyse urea. Only few days are necessary for complete urea depletion in the collection tank. Two experiments with precipitated solids from the pipes showed that precipitation sets in soon after ureolysis has started. At the end of the experiments, 11% and 24% of urea was hydrolysed while the mass concentration of newly formed precipitates already corresponded to 87% and 97% of the precipitation potential, respectively. We could simulate ureolysis and precipitation with a computer model based on the surface dislocation approach. The simulations showed that struvite and octacalcium phosphate (OCP) are the precipitating minerals. While struvite precipitates already at low supersaturation, OCP precipitation starts not until a high level of supersaturation is reached. Since measurements and computer simulations show that hydroxyapatite (HAP) is the final calcium phosphate mineral in urine solutions, OCP is only a precursor phase which slowly transforms into HAP.     

Water and solute mass balance of five small, relatively undisturbed watersheds in the U.S

Geochemical mass balances were computed for water years 1992-1997 (October 1991 through September 1997) for the five watersheds of the U.S. Geological Survey Water, Energy, and Biogeochemical Budgets (WEBB) Program to determine the primary regional controls on yields of the major dissolved inorganic solutes. The sites, which vary markedly with respect to climate, geology, physiography, and ecology, are: Allequash Creek, Wisconsin (low-relief, humid continental forest); Andrews Creek, Colorado (cold alpine, taiga/tundra, and subalpine boreal forest); Río Icacos, Puerto Rico (lower montane, wet tropical forest); Panola Mountain, Georgia (humid subtropical piedmont forest); and Sleepers River, Vermont (humid northern hardwood forest). Streamwater output fluxes were determined by constructing empirical multivariate concentration models including discharge and seasonal components. Input fluxes were computed from weekly wet-only or bulk precipitation sampling. Despite uncertainties in input fluxes arising from poorly defined elevation gradients, lack of dry-deposition and occult-deposition measurements, and uncertain sea-salt contributions, the following was concluded: (1) for solutes derived primarily from rock weathering (Ca, Mg, Na, K, and H(4)SiO(4)), net fluxes (outputs in streamflow minus inputs in deposition) varied by two orders of magnitude, which is attributed to a large gradient in rock weathering rates controlled by climate and geologic parent material; (2) the net flux of atmospherically derived solutes (NH(4), NO(3), SO(4), and Cl) was similar among sites, with SO(4) being the most variable and NH(4) and NO(3) generally retained (except for NO(3) at Andrews); and (3) relations among monthly solute fluxes and differences among solute concentration model parameters yielded additional insights into comparative biogeochemical processes at the sites.     

Relative Elevation Topographic Surface Modelling of a Large Alluvial River Floodplain and Applications for the Study and Management of Riparian Landscapes

This paper presents a novel and useful spatial modelling technique to create a topographic surface that estimates a floodplain's elevation relative to the average low-flow water surface elevation of a river channel. This model was applied to a 121 km study area of the middle Sacramento River, California, USA, where it was tested as a surrogate for observed water table depth and an observed 3.3 year recurrence interval flood inundation surface using independent data sets. The modelled relative elevation topographic surface correlated significantly (p < 0.005) to observed well water depths suggesting that the modelled surface reflected a reasonable approximation of vertical distance to the water table. Results from a flood inundation pattern analysis indicated an overall accuracy of 79% for correctly predicting inundated and non-inundated zones. The model was then used to measure relative channel bank height and the distribution of riparian plant communities to examine landscape ecological relationships.     

Atmospheric deposition of trace elements around point sources and human health risk assessment. II. Uptake of arsenic and chromium by vegetables grown near a wood preservation factory.

Kale, lettuce, carrots and potatoes were grown in 20 experimental plots surrounding a wood preservation factory, to investigate the amount and pathways for plant uptake of arsenic and chromium. Arsenate used in the wood preservation process is converted to the more toxic arsenite by incineration of waste wood and is emitted into the atmosphere. Elevated concentrations of inorganic arsenic and chromium were found both in the test plants and in the soil around the factory. Multivariate statistical analysis of the results indicated that the dominating pathway of arsenic and chromium from the factory to the leafy vegetables grown nearby was by direct atmospheric deposition, while arsenic in the root crops originated from both the soil and the atmosphere. Consumption of vegetables grown near the source would result in an increased intake of inorganic arsenic, but the intake via the total diet was estimated to be below the provisional tolerable daily intake for inorganic arsenic established by FAO/WHO.