Analysis of tidal currents in the North Sea from shipboard acoustic Doppler current profiler data

North Sea tidal currents are determined by applying harmonic analysis to ship-borne acoustic Doppler current profiler data recorded from 1999 to 2016, covering large areas of the northern North Sea. Direct current measurement data sets of this magnitude are rare in the otherwise well investigated North Sea, and thus it is a valuable asset in studying and expanding our understanding of its tidal currents and circulation in general. The harmonic analysis is applied to a least squares fit of the current observations at a set of knot points. Results from the harmonic analysis compare favorably to tidal parameters estimated from observations from moored instruments. The analysis shows that the tides are characterized by strong semi-diurnal component, with amplitudes of the principal Lunar constituent ranging from 1.6 cm/s in the Skagerrak to 67 cm/s in the Fair Isle Channel. Diurnal tides are found to be approximately one fifth the strength of the predominant semi-diurnal constituent. Output from a regional barotropic tide model compares well to tidal current determined from the harmonic analysis of the Acoustic Doppler Current Profiler data.publishedVersio

Our genes, our selves: hereditary breast cancer and biological citizenship in Norway

This is a post-peer-review, pre-copyedit version of an article published in "Medicine, Health Care and Philosophy". The final authenticated version is available online at: http://dx.doi.org/10.1007/s11019-016-9737-y.In this paper we explore the rise of ‘the breast cancer gene’ as a field of medical, cultural and personal knowledge. We address its significance in the Norwegian public health care system in relation to so-called biological citizenship in this particular national context. One of our main findings is that, despite its claims as a measure for health and disease prevention, gaining access to medical knowledge of BRCA 1/2 breast cancer gene mutations can also produce severe instability in the individuals and families affected. That is, although gene testing provides modern subjects with an opportunity to foresee their biological destiny and thereby become patients in waiting, it undoubtedly also comes with difficult existential dilemmas and choices, with implications that resonate beyond the individual and into different family and love relations. By elaborating on this finding we address the question of whether the empowerment slogan, which continues to be advocated through various health, BRCA and breast cancer discourses, reinforces a naïve or an idealized notion of the actively responsible patient: resourceful enough to seek out medical expertise and gain sufficient knowledge, on which to base informed decisions, thereby reducing the future risk of developing disease. In contrast to this ideal, our Norwegian informants tell a different story, in which there is no apparent heroic mastery of genetic fates, but rather a pragmatic attitude to dealing with a dire situation over which they have little control, despite having complied with medical advice through national guidelines and follow-up procedures for BRCA 1/2 carriers. In conclusion we claim that the sense of safety that gene testing and its associated medical solutions allegedly promise to provide proved illusory. Although BRCA-testing offers the potential for protection from adverse DNA-heritage, administered through possibilities for self-monitoring and self-management of the body, the feeling of ‘being in good health’ has hardly been reinforced by the emergence of gene technology.acceptedVersio

Ekspressiv skriving som egenterapeutisk verktøy ett år etter brystkreftdiagnosen - resultater fra en norsk pilotstudie

Expressive writing as a self-help tool one year after the breast cancer diagnosis – results from a Norwegian pilot studyThe article presents findings from a pilot study on expressive writing, a therapeutic method undescribed in a Norwegian scientific context. Objective: 1. Gain qualitative data on breast cancer women’s experiences with expressive writing. 2. Evaluate the intervention’s feasibility, based on participants’ experiences of the instruction, procedure, and circumstances for writing. Method & design: The study has an exploratory descriptive design. Data collection was achieved through in-depth interviews, followed by experiential thematic analysis of transcripts. Results: Two women enrolled, participating in writing/interviews. Analysis revealed three themes: "The experience of the writing process", "Writing as working through and work to clear the mind", "Strength and vulnerability in relation to others". Conclusion: Findings reveal that expressive writing was experienced as achievable for two breast cancer women, one year after diagnosis. Writing provided an opportunity to work through, and sort out, feelings and thoughts connected to participants’ lives and illness experiences. The instruction was evaluated as easy to understand and inspiring. The women became absorbed in electronic writing in their own homes. They both recommended expressive writing for other women with breast cancer, especially in the period after initial diagnosis

Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment.publishedVersio

Simultaneous Quantification of Aromatase Inhibitors and Estrogens in Postmenopausal Breast Cancer Patients

Context Currently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane, and the ultra-low levels of estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing a liquid chromatography–tandem mass spectrometry (MS/MS) method for simultaneous assessment of letrozole, anastrozole, exemestane, and 17-hydroxyexemestane as well as subpicomolar levels of estradiol and estrone. Methods Internal standards, calibrators, serum samples, and quality controls were in fully automated steps transferred to a deep-well plate for a 2-step liquid-liquid extraction. The extracts were reconstituted and analytes were separated chromatographically using 2 serially coupled columns, then subject to MS/MS in electrospray ionization mode. The method was thoroughly validated and is traceable to 2 accredited estrogen methods. Results The measurement range for estrone and estradiol was 0.2 to 12 000 pmol/L and 0.8 to 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had a precision of less than or equal to 13%, and accuracies within 100 ± 8%. As proof of concept, AI and estrogen levels were determined in serum samples from postmenopausal breast cancer patients under treatment. Conclusion We present here an assay suitable for the simultaneous measurement of serum levels of all third-generation AIs and ultra-low levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below the threshold of detection for most routine assays, but still require suppression.publishedVersio

The Active Tamoxifen Metabolite Endoxifen (4OHNDtam) Strongly Down-Regulates Cytokeratin 6 (CK6) in MCF-7 Breast Cancer Cells

Introduction: Tamoxifen is an anti-estrogen drug used in treatment of Estrogen Receptor (ER) positive breast cancer. Effects and side effects of tamoxifen is the sumof tamoxifen and all itsmetabolites. 4-Hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam, endoxifen) both have ER affinity exceeding that of the parent drug tamoxifen. 4OHNDtam is considered the main active metabolite of tamoxifen. Ndesmethyltamoxifen (NDtam) is the major tamoxifen metabolite. It has low affinity to the ER and is not believed to influence tumor growth. However, NDtam might mediate adverse effects of tamoxifen treatment. In this study we investigated the gene regulatory effects of the three metabolites of tamoxifen in MCF-7 breast cancer cells. Material and Methods: Using concentrations that mimic the clinical situation we examined effects of 4OHtam, 4OHNDtam and NDtam on global gene expression in 17β-estradiol (E2) treated MCF-7 cells. Transcriptomic responses were assessed by correspondence analysis, differential expression, gene ontology analysis and quantitative real time PCR (Q-rt-PCR). E2 deprivation and knockdown of Steroid Receptor Coactivator-3 (SRC-3)/Amplified in Breast Cancer 1 (AIB1) mRNA in MCF-7 cells were performed to further characterize specific effects on gene expression. Results: 4OHNDtam and 4OHtamcausedmajor changes in gene expression compared to treatment with E2 alone, with a stronger effect of 4OHNDtam. NDtam had nearly no effect on the global gene expression profile. Treatment ofMCF-7 cells with 4OHNDtam led to a strong down-regulation of the CytoKeratin 6 isoforms (KRT6A, KRT6B and KRT6C). The CytoKeratin 6 mRNAs were also down-regulated inMCF-7 cells after E2 deprivation and after SRC-3/ AIB1 knockdown. Conclusion: Using concentrations that mimic the clinical situation we report global gene expression changes that were most pronounced with 4OHNDtam and minimal with NDtam. Genes encoding CytoKeratin 6, were highly down-regulated by 4OHNDtam, as well as after E2 deprivation and knockdown of SRC-3/AIB1, indicating an estrogen receptor-dependent regulation.publishedVersio

Low Z-4OHtam concentrations are associated with adverse clinical outcome among early stage premenopausal breast cancer patients treated with adjuvant tamoxifen

Low steady‐state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor‐positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z‐endoxifen and Z‐4‐hydroxy‐tamoxifen (Z‐4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n = 191) we confirmed an inferior BC ‐specific survival in patients with the previously described serum concentration threshold of Z‐4OHtam ≤ 3.26 nm (HR = 2.37, 95% CI = 1.02–5.48, P = 0.039). The ‘dose–response’ survival trend in patients categorized to ordinal concentration cut‐points of Z‐4OHtamoxifen (≤ 3.26, 3.27–8.13, > 8.13 nm) was also replicated (P‐trend log‐rank = 0.048). Z‐endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5‐year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.publishedVersio

Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism.publishedVersio

Report from a krill focused survey with RV Kronprins Haakon and land-based predator work in Antarctica during 2018/2019

The primary objective for this krill research activity was twofold 1) to conduct a survey that provides updated estimates of the biomass and distribution of krill which are used in models to estimate sustainable yield in CCAMLR Area 48 and 2) to develop knowledge on the marine environment essential for the implementation of a Feed-Back Management (FBM) system. The survey follows a similar design as a survey initiated by CCAMLR in year 2000 for comparative purposes, but in addition focuses on high krill-density areas, contains state-of-the art methods and employs modern technology for the research topics currently in focus. In terms of FBM, Marine Protected Area (MPA) development in CCAMLR Planning Domain 1 encompasses the major krill fishing grounds. Thus, data supporting FBM are critical if the fishery is to be managed by an empirical understanding of krill density, distribution, availability and predator needs as opposed to purely conservation-based measures. A future developed FBM system, requires acoustic data to be collected, processed and reported continuously during the fishing season as a measure of the available prey field. This information can be integrated with finer-scale knowledge of krill predator feeding strategies and updated through specific scientific studies at regular (multiyear) intervals. The survey and coupled FBM process studies took place during the Austral summer 2018-2019. The work was coordinated by Norway and involved collaborative international efforts as well as vessels from Norway, Association of Responsible Krill fishing companies (ARK) and the Norwegian fishing company Aker BioMarine AS, China, Korea, Ukraine and United Kingdom. This report presents preliminary results from the survey performed with the Norwegian RV Kronprins Haakon during 08th January – 24th February 2019 and the land-based predator research carried out between 21st November 2018 and 20th February 2019.publishedVersio