The Derivation of Transfer Parameters in the Assessment of Radiological Impacts on Arctic Marine Biota

The initial stage of an environmental impact assessment requires quantification of radionuclide transfer in the study area. This paper evaluates the robustness of the concentration factor (CF) approach in assessing radiological impact on reference Arctic marine biota. By comparing region-specific data sets with recommended generic values for CFs, we tested the hypothesis that transfers to Arctic biota differ from transfers observed in temperate areas for 90Sr, 137Cs, 239, 240Pu and 99Tc. Despite the general paucity of data and great uncertainty regarding radionuclide CFs in reference biota, we conclude that the use of Arctic-specific CFs for Sr and Pu can be justified in some cases where differences from generic CFs seem apparent. Where CF data are absent, a biokinetic modelling approach with allometric considerations might be used to bridge data gaps. Such an approach has been used here to estimate the trophic transfer of 137Cs and 239Pu in a marine food chain consisting of four trophic levels. For the simulation concerning 137Cs, the preliminary results suggest that it takes more than five years to attain equilibrium for higher trophic levels (polar cod and harp seal). Biomagnification appears to occur at the lower trophic levels, but not at the highest (seal). For 239Pu, transfer to successively higher trophic levels is low: there is a fall of several orders of magnitude between primary producers, represented by phytoplankton, and polar cod, representing trophic levels 3 and 4. However, the model predicts that this decreasing trend in activity concentrations along the food chain is reversed for the highest trophic level, represented by seal. The simulated results for seal display equilibrium activity concentrations about two orders of magnitude higher than those observed for polar cod (one of its prey species). However, equilibrium (165 years) is not reached during the life span of a seal. The equilibrium 137Cs CFs are approximately 50 l/kg for zooplankton, 130l/kg for polar cod, and 70 l/kg for seal. The predicted equilibrium 239Pu CFs are 2.5·10³ l/kg for zooplankton and 25 l/kg for polar cod. For seal, following a one-year equilibration period, a CF of approximately 75 l/kg is predicted.Le stade initial d'une étude d'impact environnemental nécessite une évaluation quantitative du transfert de radionucléides dans la zone d'étude. Cet article évalue la robustesse de la méthode du facteur de concentration (FC) pour déterminer l'impact radiologique sur un biote marin arctique de référence. En comparant des ensembles de données spécifiques à une région avec des valeurs génériques recommandées pour les facteurs de concentration, on a testé l'hypothèse selon laquelle les transferts au biote arctique diffèrent des transferts observés dans des régions tempérées pour 90Sr, 137Cs, 239,240Pu et 99Tc. Malgré la pénurie générale de données et un haut niveau d'incertitude concernant les FC des radionucléides dans le biote de référence, on conclut que l'utilisation de FC spécifiques à l'Arctique pour Sr et Pu peut être justifiée dans certains cas où les différences d'avec les FC génériques semblent apparentes. Là où il n'existe pas de données sur les FC, on peut recourir à la modélisation biocinétique tenant compte des éléments allométriques afin de combler les lacunes dans les données. C'est cette approche que l'on a utilisée ici pour estimer le transfert trophique de 137Cs et de 239Pu dans une chaîne alimentaire marine comprenant quatre niveaux trophiques. Pour la simulation relative à 137Cs, les résultats préliminaires suggèrent qu'il faut plus de cinq ans pour atteindre l'équilibre aux niveaux trophiques supérieurs (morue polaire et phoque annelé). La bioamplification semble se produire aux niveaux trophiques inférieurs, mais pas au plus élevé (phoque). Pour 239Pu, le transfert aux niveaux trophiques supérieurs est faible: on constate une baisse de plusieurs ordres de grandeur entre les producteurs primaires, représentés par le phytoplancton, et la morue polaire, qui représente les niveaux trophiques 3 et 4. Le modèle prédit toutefois que cette tendance à la baisse dans l'activité volumique le long de la chaîne alimentaire s'inverse au niveau trophique le plus élevé, représenté par le phoque. Les résultats simulés pour le phoque affichent des activités volumiques à l'équilibre environ deux ordres de grandeur plus élevées que celles observées chez la morue polaire (l'une des espèces-proies du phoque). L'équilibre (165 ans) n'est cependant pas atteint durant la durée de vie du phoque. Les FC de 137Cs à l'équilibre sont environ de 50 l/kg pour le zooplancton, de 130 l/kg pour la morue polaire et de 70 l/kg pour le phoque. Les FC de 239Pu projetés à l'équilibre sont de 2,5·10³ l/kg pour le zooplancton et de 25 l/kg pour la morue polaire. Pour le phoque, après une période d'équilibre d'une année, on prédit un FC d'environ 75 l/kg

FOXC2 expression and epithelial–mesenchymal phenotypes are associated with castration resistance, metastasis and survival in prostate cancer

Epithelial–mesenchymal transition (EMT) is important for tumour cell invasion and metastasis and is a feature of aggressive carcinomas. EMT is characterised by reduced E‐cadherin and increased N‐cadherin expression (EN‐switch), and increased expression of the EMT‐regulating transcription factor Forkhead box protein C2 (FOXC2) has been associated with progression and poor prognosis in various malignancies. FOXC2 was recently highlighted as a novel therapy target in prostate cancer, but survival data on FOXC2 are lacking. This study evaluates the expression of FOXC2, E‐cadherin and N‐cadherin in different prostatic tissues focusing on EMT, clinico‐pathological phenotype, recurrence and patient survival. Tissue microarray sections from 338 radical prostatectomies (1986–2007) with long and complete follow‐up, 33 castration resistant prostate cancers, 33 non‐skeletal metastases, 13 skeletal metastases and 41 prostatic hyperplasias were stained immunohistochemically for FOXC2, E‐cadherin and N‐cadherin. FOXC2 was strongly expressed in primary carcinomas, including castration resistant tumours and metastatic lesions as compared to benign prostatic hyperplasia. A hybrid epithelial–mesenchymal phenotype, with co‐expression of E‐cadherin and N‐cadherin, was found in the majority of skeletal metastases and in a substantial proportion of castration resistant tumours. In localised carcinomas, the EN‐switch was associated with adverse clinico‐pathological variables, such as extra‐prostatic extension, high pathological stage and lymph node infiltration. In univariate survival analyses of the clinically important, large subgroup of 199 patients with Gleason score 7, high FOXC2 expression and EN‐switching were significantly associated with shorter time to clinical recurrence, skeletal metastases and cancer specific death. In multivariate Cox' survival analysis, high FOXC2 and the EN‐switch, together with Gleason grade group (GG3 versus GG2), were independent predictors of time to these end‐points. High FOXC2 gene expression (mRNA) was also related to patient outcome, validating our immunohistochemical findings. FOXC2 and factors signifying EMT or its intermediate states may prove important as biomarkers for aggressive disease and are potential novel therapy targets in prostate cancer.publishedVersio

The epithelial–mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients

The prognostic importance of transcription factors promoting epithelial–mesenchymal transition (EMT) and angiogenesis has not been well explored in prostate cancer patients with long follow-up, nor the interplay between these factors. The objective of this study was to assess the individual protein expression and co-expression of Twist, Slug (Snai2), Snail (Snai1), and hypoxia-inducible factor-1 alpha (Hif-1α) in prostate cancer in relation to EMT, angiogenesis, hypoxia, tumour features, disease recurrence, and patient survival. Immunohistochemical staining was performed on tissue microarray sections from 338 radical prostatectomies with long follow-up. In addition, 41 cases of prostatic hyperplasia, 33 non-skeletal metastases, 13 skeletal metastases, and 33 castration-resistant prostate carcinomas were included. Our findings were validated in external gene expression data sets. Twist was overexpressed in primary prostate cancer and markedly reduced in distant metastases (p < 0.0005). Strong expression of Twist and Slug was associated with Hif-1α in localised prostate cancer (p ≤ 0.001), and strong Twist was associated with Hif-1α in castration-resistant carcinomas (p = 0.044). Twist, Slug, and increased Snail at the tumour stromal border were associated with vascular factors (p ≤ 0.045). Each of the three EMT-regulating transcription factors were associated with aggressive tumour features and shorter time to recurrence and cancer-specific death. Notably, the co-expression of factors demonstrated an enhanced influence on outcome. In the subgroup of E-cadherinlow carcinomas, strong Slug was associated with shorter time to all end points and was an independent predictor of time to multiple end points, including cancer-specific death (hazard ratio 3.0, p = 0.041). To conclude, we demonstrate an important relation between EMT, hypoxia, and angiogenesis and a strong link between the investigated EMT regulators and aggressive tumour features and poor patient outcome in prostate cancer. Despite the retrospective nature of this long-term study, our findings could have a significant impact on the future treatment of prostate cancer, where tailored therapies might be directed simultaneously against epithelial–mesenchymal phenotypes, angiogenesis, and tumour hypoxia.publishedVersio

Losing the 'arms race': Multiresistant salmon lice are dispersed throughout the North Atlantic Ocean

Nothing lasts forever, including the effect of chemicals aimed to control pests in food production. As old pesticides have been compromised by emerging resistance, new ones have been introduced and turned the odds back in our favour. With time, however, some pests have developed multi-pesticide resistance, challenging our ability to control them. In salmonid aquaculture, the ectoparasitic salmon louse has developed resistance to most of the available delousing compounds. The discovery of genetic markers associated with resistance to organophosphates and pyrethroids made it possible for us to investigate simultaneous resistance to both compounds in approximately 2000 samples of salmon lice from throughout the North Atlantic in the years 2000–2016. We observed widespread and increasing multiresistance on the European side of the Atlantic, particularly in areas with intensive aquaculture. Multiresistant lice were also found on wild Atlantic salmon and sea trout, and also on farmed salmonid hosts in areas where delousing chemicals have not been used. In areas with intensive aquaculture, there are almost no lice left that are sensitive to both compounds. These results demonstrate the speed to which this parasite can develop widespread multiresistance, illustrating why the aquaculture industry has repeatedly lost the arms race with this highly problematic parasite.publishedVersio

Aquaculture-driven evolution: distribution of pyrethroid resistance in the salmon louse throughout the North Atlantic in the years 2000–2017

The parasitic salmon louse, and its documented resistance to chemotherapeutants, represents the most persistent environmental challenge to global salmonid aquaculture. We used a genetic marker associated with pyrethroid resistance to analyse ∼15 000 lice collected from the North Atlantic in the period 2000–2017. The genotype associated with resistance was not detected in lice collected from throughout the North Atlantic in the year 2000 or 2002. However, by the year 2009 onwards, it was found in lice from fish farms throughout much of the North Atlantic. It was also found in modest frequencies in lice collected from wild Atlantic salmon captured off Greenland. The most recent samples displayed very high frequencies of the genotype associated with resistance, particularly in intensive aquaculture regions of Norway (>90%) and Scotland (>70%). These results closely align with observations from the field. We suggest that pyrethroid resistance first emerged in Europe just before or around the year 2000 and was thereafter dispersed throughout much of the North Atlantic where its increased frequency was driven by extensive pyrethroid use. Although the resistant genotype was not detected in lice from Canada, it is likely to occur in very low frequencies that would quickly increase if pyrethroids were to be used in that region.publishedVersio

Geographical variation in radiological services: a nationwide survey

BACKGROUND: Geographical variation in health care services challenges the basic principle of fair allocation of health care resources. This study aimed to investigate geographical variation in the use of X-ray, CT, MRI and Ultrasound examinations in Norway, the contribution from public and private institutions, and the impact of accessibility and socioeconomic factors on variation in examination rates. METHODS: A nationwide survey of activity in all radiological institutions for the year 2002 was used to compare the rates per thousand of examinations in the counties. The data format was files/printouts where the examinations were recorded according to a code system. RESULTS: Overall rates per thousand of radiological examinations varied by a factor of 2.4. The use of MRI varied from 170 to 2, and CT from 216 to 56 examinations per 1000 inhabitants. Single MRI examinations (knee, cervical spine and head/brain) ranged high in variation, as did certain other spine examinations. For examination of specific organs, the counties' use of one modality was positively correlated with the use of other modalities. Private institutions accounted for 28% of all examinations, and tended towards performing a higher proportion of single examinations with high variability. Indicators of accessibility correlated positively to variation in examination rates, partly due to the figures from the county of Oslo. Correlations between examination rates and socioeconomic factors were also highly influenced by the figures from this county. CONCLUSION: The counties use of radiological services varied substantially, especially CT and MRI examinations. A likely cause of the variation is differences in accessibility. The coexistence of public and private institutions may be a source of variability, along with socioeconomic factors. The findings represent a challenge to the objective of equality in access to health care services, and indicate a potential for better allocation of overall health care resources. PREVIOUS PUBLICATION: The data applied in this article was originally published in Norwegian in: Børretzen I, Lysdahl KB, Olerud HM: Radiologi i Noreg – undersøkingsfrekvens per 2002, tidstrendar, geografisk variasjon og befolkningsdose. StrålevernRapport 2006:6. Østerås: The Norwegian Radiation Protection Authority. The Norwegian Radiation Protection Authority has given the authors permission to republish the data

Aquaculture-driven evolution of the salmon louse mtDNA genome

Resistance toward the antiparasitic pyrethroid, deltamethrin, is reported in the Atlantic salmon louse (Lepeophtheirus salmonis salmonis), a persistent ectoparasite of farmed and wild salmonids. The resistance mechanism is linked to mitochondrial DNA (mtDNA), where genetic markers for resistance have been identified. Here, we investigated how widespread pyrethroid use in aquaculture may have influenced mtDNA variation in lice, and the dispersion of resistant haplotypes across the North Atlantic, using historical (2000–2002 “pre-resistance”) and contemporary (2014–2017 “post-resistance”) samples. To study this, we sequenced ATPase 6 and cytochrome b, genotyped two genetic markers for deltamethrin resistance, and genotyped microsatellites as “neutral” controls of potential population bottlenecks. Overall, we observed a modest reduction in mtDNA diversity in the period 2000–2017, but no reduction in microsatellite variation was observed. The reduction in mtDNA variation was especially distinct in two of the contemporary samples, fixed for one and two haplotypes, respectively. By contrast, all historical samples consisted of close to one mtDNA haplotype per individual. No population genetic structure was detected among the historical samples for mtDNA nor microsatellites. By contrast, significant population genetic differentiation was observed for mtDNA among some of the contemporary samples. However, the observed population genetic structure was tightly linked with the pattern of deltamethrin resistance, and we therefore conclude that it primarily reflects the transient mosaic of pyrethroid usage in time and space. Two historically undetected mtDNA haplotypes dominated in the contemporary samples, both of which were linked to deltamethrin resistance, demonstrating primarily two origins of deltamethrin resistance in the North Atlantic. Collectively, these data demonstrate that the widespread use of pyrethroids in commercial aquaculture has substantially altered the patterns of mtDNA diversity in lice across the North Atlantic, and that long-distance dispersion of resistance is rapid due to high level of genetic connectivity that is observed in this species.publishedVersio

A phase I prospective, non-randomized trial of autologous dendritic cell-based cryoimmunotherapy in patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is an immunologically cold disease with dismal outcomes. Cryoablation destroys cancer tissue, releases tumor-associated antigens and creates a pro-inflammatory microenvironment, while dendritic cells (DCs) activate immune responses through processing of antigens. Immunotherapy combinations could enhance the anti-tumor efficacy. This open-label, single-arm, single-center phase I trial determined the safety and tolerability of combining cryoablation and autologous immature DC, without and with checkpoint inhibitors. Immune responses and clinical outcomes were evaluated. Patients with mCRPC, confirmed metastases and intact prostate gland were included. The first participants underwent prostate cryoablation with intratumoral injection of autologous DCs in a 3 + 3 design. In the second part, patients received cryoablation, the highest acceptable DC dose, and checkpoint inhibition with either ipilimumab or pembrolizumab. Sequentially collected information on adverse events, quality of life, blood values and images were analyzed by standard descriptive statistics. Neither dose-limiting toxicities nor adverse events > grade 3 were observed in the 18 participants. Results indicate antitumor activity through altered T cell receptor repertoires, and 33% durable (> 46 weeks) clinical benefit with median 40.7 months overall survival. Post-treatment pain and fatigue were associated with circulating tumor cell (CTC) presence at inclusion, while CTC responses correlated with clinical outcomes. This trial demonstrates that cryoimmunotherapy in mCRPC is safe and well tolerated, also for the highest DC dose (2.0 × 108) combined with checkpoint inhibitors. Further studies focusing on the biologic indications of antitumor activity and immune system activation could be considered through a phase II trial focusing on treatment responses and immunologic biomarkers.publishedVersio