SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas

<p>Abstract</p> <p>Background</p> <p>Genomic alterations are common features of cancer cells, and some of these changes are proven to be neoplastic-specific. Such alterations may serve as valuable tools for diagnosis and classification of tumors, prediction of clinical outcome, disease monitoring, and choice of therapy as well as for providing clues to the location of crucial cancer-related genes.</p> <p>Endometrial carcinoma (EC) is the most frequently diagnosed malignancy of the female genital tract, ranking fourth among all invasive tumors affecting women. Cytogenetic studies of human ECs have not produced very conclusive data, since many of these studies are based on karyotyping of limited number of cases and no really specific karyotypic changes have yet been identified. As the majority of the genes are conserved among mammals, the use of inbred animal model systems may serve as a tool for identification of underlying genes and pathways involved in tumorigenesis in humans. In the present work we used spectral karyotyping (SKY) to identify cancer-related aberrations in a well-characterized experimental model for spontaneous endometrial carcinoma in the BDII rat tumor model.</p> <p>Results</p> <p>Analysis of 21 experimental ECs revealed specific nonrandom numerical and structural chromosomal changes. The most recurrent numerical alterations were gains in rat chromosome 4 (RNO4) and losses in RNO15. The most commonly structural changes were mainly in form of chromosomal translocations and were detected in RNO3, RNO6, RNO10, RNO11, RNO12, and RNO20. Unbalanced chromosomal translocations involving RNO3p was the most commonly observed structural changes in this material followed by RNO11p and RNO10 translocations.</p> <p>Conclusion</p> <p>The non-random nature of these events, as documented by their high frequencies of incidence, is suggesting for dynamic selection of these changes during experimental EC tumorigenesis and therefore for their potential contribution into development of this malignancy. Comparative molecular analysis of the identified genetic changes in this tumor model with those reported in the human ECs may provide new insights into underlying genetic changes involved in EC development and tumorigenesis.</p

The Nordic Seas carbon budget: Sources, sinks, and uncertainties

A carbon budget for the Nordic Seas is derived by combining recent inorganic carbon data from the CARINA database with relevant volume transports. Values of organic carbon in the Nordic Seas' water masses, the amount of carbon input from river runoff, and the removal through sediment burial are taken from the literature. The largest source of carbon to the Nordic Seas is the Atlantic Water that enters the area across the Greenland-Scotland Ridge; this is in particular true for the anthropogenic CO2. The dense overflows into the deep North Atlantic are the main sinks of carbon from the Nordic Seas. The budget show that presently 12.3 ± 1.4 Gt C yr−1 is transported into the Nordic Seas and that 12.5 ± 0.9 Gt C yr−1 is transported out, resulting in a net advective carbon transport out of the Nordic Seas of 0.17 ± 0.06 Gt C yr−1. Taking storage into account, this implies a net air-to-sea CO2 transfer of 0.19 ± 0.06 Gt C yr−1 into the Nordic Seas. The horizontal transport of carbon through the Nordic Seas is thus approximately two orders of magnitude larger than the CO2 uptake from the atmosphere. No difference in CO2 uptake was found between 2002 and the preindustrial period, but the net advective export of carbon from the Nordic Seas is smaller at present due to the accumulation of anthropogenic CO2

Loss of glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma

Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions

Seasonal dynamics of the marine CO2 system in Adventfjorden, a West Spitsbergen fjord

Time series of the marine CO2 system and related parameters at the IsA Station, by Adventfjorden, Svalbard, were investigated between March 2015 and November 2017. The physical and biogeochemical processes that govern changes in total alkalinity (TA), total dissolved inorganic carbon (DIC) and the saturation state of the calcium carbonate mineral aragonite (ΩAr) were assessed on a monthly timescale. The major driver for TA and DIC was changes in salinity, caused by river runoff, mixing and advection. This accounted for 77 and 45%, respectively, of the overall variability. It contributed minimally to the variability in ΩAr (5%); instead, biological activity was responsible for 60% of the monthly variations. For DIC, the biological activity was also important, contributing 44%. The monthly effect of air–sea CO2 fluxes accounted for 11 and 15% of the total changes in DIC and ΩAr, respectively. Net community production (NCP) during the productive season ranged between 65 and 85 g C m−2, depending on the year and the presence of either Arctic water or transformed Atlantic water (TAW). The annual NCP as estimated from DIC consumption was 34 g C m−2 yr−1 in 2016, which was opposite in direction but similar in magnitude to the integrated annual air–sea CO2 flux (i.e., uptake of carbon from the atmosphere) of −29 g C m−2 yr−1 for the same year. The results showed that increased intrusions of TAW into Adventfjorden in the future could possibly lower the NCP, with the potential to reduce the CO2buffer capacity and ΩAr over the summer season.publishedVersio

Norwegian fisheries in the Svalbard zone since 1980. Regulations, profitability and warming waters affect landings

-The Svalbard archipelago in the High Arctic is influenced by cold Arctic water masses from the north-east and the warm West Spitsbergen Current flowing northwards along its western coast. The eastern waters and the fjords are normally frozen during the winter months, while the coastal waters west of the archipelago remain open. Norwegian fishers have been harvesting from Svalbard waters for decades and detailed records of catches exists from 1980 onwards. We analyze the catch records from the Svalbard zone (approximately ICES area IIb). The large fishery for capelin in summer yielding annual catches up to 737 000 tons was closed by a Norwegian fishery regulation in the mid nineteen nineties. Demersal fisheries have been continuous, and the results clearly indicate a northward trend in landings of Northeast Arctic cod, haddock, ling and Atlantic halibut. Fisheries of Northern shrimp have been more variable and shown no clear geographic trends. A “gold rush” fishery for scallops north of Svalbard lasted for about 10 years (1986–1995) only, and ended due to low profitably. These results are discussed in relation to the possibility of further northward extension of fisheries subjected to climate change

Variability and decadal trends in the Isfjorden (Svalbard) ocean climate and circulation – An indicator for climate change in the European Arctic

Isfjorden, a broad Arctic fjord in western Spitsbergen, has shown significant changes in hydrography and inflow of Atlantic Water (AW) the last decades that only recently have been observed in the Arctic Ocean north of Svalbard. Variability and trends in this fjord’s climate and circulation are therefore analysed from observational and reanalysis data during 1987 to 2017. Isfjorden experienced a shift in summer ocean structure in 2006, from AW generally in the bottom layer to AW (with increasing thickness) higher up in the water column. This shift, and a concomitant shift to less fast ice in Isfjorden are linked to positive trends in the mean sea surface temperature (SST) and volume weighted mean temperature (VT) in winter (SSTw/VTw: 0.7 ± 0.1/0.9 ± 0.3 °C 10 yr−1) and summer (SSTS/VTS: 0.7 ± 0.1/0.6 ± 0.1 °C 10 yr−1). Hence, the local mean air temperature shows similar trends in winter (1.9 ± 0.4 °C 10 yr−1) and summer (0.7 ± 0.1 °C 10 yr−1). Positive trends in volume weighted mean salinity in winter (0.21 ± 0.06 10 yr−1) and summer (0.07 ± 0.05 10 yr−1) suggest increased AW advection as a main reason for Isfjorden’s climate change. Local mean air temperature correlates significantly with sea ice cover, SST, and VT, revealing the fjord’s impact on the local terrestrial climate. In line with the shift in summer ocean structure, Isfjorden has changed from an Arctic type fjord dominated by Winter Deep and Winter Intermediate thermal and haline convection, to a fjord dominated by deep thermal convection of Atlantic type water (Winter Open). AW indexes for the mouth and Isfjorden proper show that AW influence has been common in winter over the last decade. Alternating occurrence of Arctic and Atlantic type water at the mouth mirrors the geostrophic control imposed by the Spitsbergen Polar Current (carrying Arctic Water) relative to the strength of the Spitsbergen Trough Current (carrying AW). During high AW impact events, Atlantic type water propagates into the fjord according to the cyclonic circulation along isobaths corresponding to the winter convection. Tides play a minor role in the variance in the currents, but are important in the side fjords where exchange with the warmer Isfjorden proper occurs in winter. This study demonstrates that Isfjorden and its ocean climate can be used as an indicator for climate change in the Arctic Ocean. The used methods may constitute a set of helpful tools for future studies also outside the Svalbard Archipelago.publishedVersio

The PanCareSurFup consortium:research and guidelines to improve lives for survivors of childhood cancer

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF. Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public. Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case–control studies of subsequent malignancies and cardiac disease in 5-year survivors. Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health

The impact of the temporal sequence of cranial radiotherapy and platin-based chemotherapy on hearing impairment in pediatric and adolescent CNS and head-and-neck cancer patients: A report from the PanCareLIFE consortium.

The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin-based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head-and-neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time-to-onset analysis. Eighty-eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow-up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P < .01). A time-to-onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P < .01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors

Non-Redfield carbon and nitrogen cycling in the Arctic: Effects of ecosystem structure and dynamics

The C:N ratio is a critical parameter used in both global ocean carbon models and field studies to understand carbon and nutrient cycling as well as to estimate exported carbon from the euphotic zone. The so-called Redfield ratio (C:N = 6.6 by atoms) [Redfield et al., 1963] is widely used for such calculations. Here we present data from the NE Greenland continental shelf that show that most of the C:N ratios for particulate (autotrophic and heterotrophic) and dissolved pools and rates of transformation among them exceed Redfield proportions from June to August, owing to species composition, size, and biological interactions. The ecosystem components that likely comprised sinking particles and had relatively high C:N ratios (geometric means) included (1) the particulate organic matter (C:N = 8.9) dominated by nutrient-deficient diatoms, resulting from low initial nitrate concentrations (approximately 4 μM) in Arctic surface waters; (2) the dominant zooplankton, herbivorous copepods (C:N = 9.6), having lipid storage typical of Arctic copepods; and (3) copepod fecal pellets (C:N = 33.2). Relatively high dissolved organic carbon concentrations (median 105 μM) were approximately 25 to 45 μM higher than reported for other systems and may be broadly characteristic of Arctic waters. A carbon-rich dissolved organic carbon pool also was generated during summer. Since the magnitude of carbon and nitrogen uncoupling in the surface mixed layer appeared to be greater than in other regions and occurred throughout the productive season, the C:N ratio of particulate organic matter may be a better conversion factor than the Redfield ratio to estimate carbon export for broad application in northern high-latitude systems

Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n =465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Miillerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P= 3.0 x 10(-4)) between rs11668344 of BRSK 1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score >= 8000 mg/m(2)), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer