Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the ...other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = -0.18, p = 2.2e-16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.
To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study ...is a continuation of earlier work establishing the role of CITED1 in mammary gland development.
CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype. In patients treated with tamoxifen, higher CITED1 correlated with better outcome, suggesting a role in anti-estrogen response. The effect was particularly evident in the subset of estrogen-receptor positive, lymph-node negative (ER+/LN-) patients although noticeable divergence of the groups was apparent only after five years. Tissue microarray (TMA) analysis further validated the association of CITED1 protein, by immunohistochemistry, with favourable outcome in ER+, tamoxifen-treated patients. Although we also found a favourable response to anti-endocrine treatment in a larger TCGA dataset, the tamoxifen-specific effect was not replicated. Finally, MCF7 cells overexpressing CITED1 showed selective amplification of AREG but not TGFα suggesting that maintenance of specific ERα-CITED1 mediated transcription is important for the long-term response to anti-endocrine therapy. These findings together confirm the proposed mechanism of action of CITED1 and support its potential use as a prognostic biomarker.
To better understand and characterize chromosomal structural variation during breast cancer progression, we enumerated chromosomal rearrangements for 11 patients by performing low-coverage ...whole-genome sequencing of 11 primary breast tumors and their 13 matched distant metastases. The tumor genomes harbored a median of 85 (range 18-404) rearrangements per tumor, with a median of 82 (26-310) in primaries compared to 87 (18-404) in distant metastases. Concordance between paired tumors from the same patient was high with a median of 89% of rearrangements shared (range 61-100%), whereas little overlap was found when comparing all possible pairings of tumors from different patients (median 3%). The tumors exhibited diverse genomic patterns of rearrangements: some carried events distributed throughout the genome while others had events mostly within densely clustered chromothripsis-like foci at a few chromosomal locations. Irrespectively, the patterns were highly conserved between the primary tumor and metastases from the same patient. Rearrangements occurred more frequently in genic areas than expected by chance and among the genes affected there was significant enrichment for cancer-associated genes including disruption of TP53, RB1, PTEN, and ESR1, likely contributing to tumor development. Our findings are most consistent with chromosomal rearrangements being early events in breast cancer progression that remain stable during the development from primary tumor to distant metastasis.
•Seagrass ecosystem services were of substantial importance for food security•Seagrasses were the most often fished on substrates/habitats in the study sites•seagrass ecosystem services were of ...substantial importance for monetary income•Seagrass-derived fish contributes to food security and is important for income•provision of fishing grounds was the most valued seagrass ecosystem service•Seagrass-derived invertebrates are an important complement to fish
Small-scale fisheries(SSF) are crucialfor food security and poverty alleviation. Many SSF are however under pressure, and in need of better management paying special attention to the key seascape ecosystems which are supporting them. This study investigates the importance of seagrass beds for SSF households and their food security in southwestern Madagascar. The specific aims of this study were to: i) analyze if and how seagrass-associated fish contributes to subsistence and/or the economy of local fishing households, ii) identify and compare seagrass ecosystem goods and services valued by local fishers in a rural and an urban setting, and iii) analyze links between local people and seagrasses in terms of local ecological knowledge, use and traditions. The results showed that seagrasses were the most important fishing habitats for most fishers. Seagrass-associated fish species were both the economically most important and most commonly fished species, and are a major source of protein in the region. Further, seagrass-derived sea urchins are important complements to local people’s diets. Thefindings illustrate that seagrasses contribute both through subsistence and income generation to food security and wellbeing of coastal people in southwestern Madagascar. This highlights the need to consider seagrass ecosystems in management towards sustainable SSFand their ability to sustain food security for future generations.
Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell‐free circulating tumor DNA (ctDNA) contains tumor‐specific chromosomal ...rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow‐up. Using an approach combining low‐coverage whole‐genome sequencing of primary tumors and quantification of tumor‐specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA‐based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0–37 months), whereas patients with long‐term disease‐free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.
Synopsis
Serial measurement of circulating tumor DNA (ctDNA) is shown to be a robust and accurate occult metastatic disease biomarker in patients diagnosed with primary breast cancer. Measured ctDNA levels are a quantitative risk factor for poor outcomes.
A combination of low‐coverage whole‐genome sequencing with personalized droplet digital PCR, analytical methods, and a bioinformatics pipeline was developed for quantification of ctDNA in blood plasma samples collected during clinical follow‐up of patients with primary (non‐metastatic) breast cancer.
ctDNA analysis can discriminate patients with eventual metastasis from those with long‐term disease‐free survival with 93% sensitivity and 100% specificity (ROC area 0.98, P = 0.001).
ctDNA‐based detection of occult metastatic disease preceded clinical detection for 86% of patients by an average 11 months and in some cases by 3 years.
No ctDNA could be detected at any time‐point after surgery for patients with long‐term disease‐free survival.
The level of ctDNA was a quantitative risk factor for clinical metastatic disease (logistic regression odds ratio 2.1 for each doubling of ctDNA levels, P = 0.02) and death (odds ratio 1.3 per ctDNA doubling, P = 0.04).
Serial measurement of circulating tumor DNA (ctDNA) is shown to be a robust and accurate occult metastatic disease biomarker in patients diagnosed with primary breast cancer. Measured ctDNA levels are a quantitative risk factor for poor outcomes.
By convention, a contralateral breast cancer (CBC) is treated as a new primary tumor, independent of the first cancer (BC1). Although there have been indications that the second tumor (BC2) sometimes ...may represent a metastatic spread of BC1, this has never been conclusively shown. We sought to apply next-generation sequencing to determine a "genetic barcode" for each tumor and reveal the clonal relationship of CBCs.
Ten CBC patients with detailed clinical information and available fresh frozen tumor tissue were studied. Using low-coverage whole genome DNA-sequencing data for each tumor, chromosomal rearrangements were enumerated and copy number profiles were generated. Comparisons between tumors provided an estimate of clonal relatedness for tumor pairs within individual patients.
Between 15-256 rearrangements were detected in each tumor (median 87). For one patient, 76 % (68 out of 90) of the rearrangements were shared between BC1 and BC2, highly consistent with what has been seen for true primary-metastasis pairs (>50 %) and thus confirming a common clonal origin of the two tumors. For most of the remaining cases, BC1 and BC2 had similarly low overlap as unmatched randomized pairs of tumors from different individuals, suggesting the CBC to represent a new independent primary tumor.
Using rearrangement fingerprinting, we show for the first time with certainty that a contralateral BC2 can represent a metastatic spread of BC1. Given the poor prognosis of a generalized disease compared to a new primary tumor, these women need to be identified at diagnosis of CBC for appropriate determination of treatment. Our approach generates a promising new method to assess clonal relationship between tumors. Additional studies are required to confirm the frequency of CBCs representing metastatic events.
More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene
), the most important factor for directing anti-estrogenic endocrine therapy (ET). ...Recently, mutations in
were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET.
We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of
mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses.
We identified
resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of
mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test
< .001 and
= .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors.
These population-based results indicate that
mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor
screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
Den här uppsatsen analyserar hur miljö och utveckling framställs i de svenska läroplanernas allmänna del (Lgr 62, Lgr 69, Lgr 80, Lpo 94, Lgr 11) samt kursplanerna för ämnet geografi i årskur 7-9. ...Syftet är att se de svenska läroplanernas framställning av miljöproblematik och förändringar över tid. Det empiriska material som används för analysen är läroplanerna för grundskolan och dess kursplaner i geografi för årskurs 7-9. Jag har använt mig av textanalys för att ta fram explicita miljöbegrepp och formuleringar och en diskursanalys för att ta fram de underförstådda betydelserna av miljöproblematik och utveckling. Resultatet av studien visar att det skett förändringar i hur miljöproblematik framställs och särskilt från att begreppet hållbar utveckling myntades 1987 och infördes i läroplanerna från Lpo 94. Resultatet visar också att FN och UNESCO har varit av stor betydelse för utvecklingen av undervisning i miljövård.
Badrummet hos Ester Niilimaa. Lovikkavantar som har tvättats hänger på tork. Aviga.
1978:4:15-17
Sverige
Norrbotmuseum
1978:4:15-17
Sverige
Norrbotmuseum
The bathroom at Ester Niilimaa. Lovikkavantar ...that has been washed hangs on dryer. Aviga
1978: 4: 15-17
Sweden
Norrbotmuseum
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