| 1. |
- Guerova, G., et al.
(author)
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National Status Reports
- 2020
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In: Advanced GNSS Tropospheric Products for Monitoring Severe Weather Events and Climate. - Cham : Springer International Publishing. - 9783030139001 ; , s. 403-481
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Book chapter (other academic/artistic)abstract
- In this section a summary of the national progress reports is given. GNSS4SWEC Management Committee (MC) members provided outline of the work conducted in their countries combining input from different partners involved. In the COST Action paticipated member from 32 COST countries, 1 Near Neighbour Country and 8 Intrantional Partners from Australia, Canada, Hong Kong and USA. The text reflects the state as of 1 January 2018.
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| 2. |
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| 3. |
- Garcia-Alonso, Luz, et al.
(author)
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Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro
- 2021
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:12, s. 1698-
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Journal article (peer-reviewed)abstract
- The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively.
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| 4. |
- Lindskog, Magnus, et al.
(author)
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Ilixadencel, a Cell-based Immune Primer, plus Sunitinib Versus Sunitinib Alone in Metastatic Renal Cell Carcinoma: A Randomized Phase 2 Study
- 2022
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In: European Urology Open Science. - : Elsevier BV. - 2666-1691 .- 2666-1683. ; 40, s. 38-45
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Journal article (peer-reviewed)abstract
- Background: The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial. Objective: To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC. Design, setting, and participants: A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients).Outcome measurements and statistical analysis: The primary endpoints were 18mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests.Results and limitations: The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42-1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival. Conclusions: The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy.Patient summary: We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).
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| 5. |
- Loera-Valencia, R, et al.
(author)
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High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus
- 2021
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 3736-
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Journal article (peer-reviewed)abstract
- Alterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.
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| 6. |
- Pablos, Isabel, et al.
(author)
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Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL(pro) substrate degradome
- 2021
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In: Cell Reports. - : Cell Press. - 2211-1247. ; 37:4
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Journal article (peer-reviewed)abstract
- The main viral protease (3CL(pro)) is indispensable for SARS-CoV-2 replication. We delineate the human protein substrate landscape of 3CL(pro) by TAILS substrate-targeted N-terminomics. We identify more than 100 substrates in human lung and kidney cells supported by analyses of SARS-CoV-2-infected cells. Enzyme kinetics and molecular docking simulations of 3CL(pro) engaging substrates reveal how noncanonical cleavage sites, which diverge from SARS-CoV, guide substrate specificity. Cleaving the interactors of essential effector proteins, effectively stranding them from their binding partners, amplifies the consequences of proteolysis. We show that 3CL(pro) targets the Hippo pathway, including inactivation of MAP4K5, and key effectors of transcription, mRNA processing, and translation. We demonstrate that Spike glycoprotein directly binds galectin-8, with galectin-8 cleavage disengaging CALCOCO2/NDP52 to decouple antiviral-autophagy. Indeed, in post-mortem COVID-19 lung samples, NDP52 rarely colocalizes with galectin-8, unlike in healthy lungs. The 3CL(pro) substrate degradome establishes a foundational substrate atlas to accelerate exploration of SARSCoV-2 pathology and drug design.
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| 7. |
- Strom, Peter, et al.
(author)
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Artificial intelligence for diagnosis and grading of prostate cancer in biopsies : a population-based, diagnostic study
- 2020
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In: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 21:2, s. 222-232
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Journal article (peer-reviewed)abstract
- BackgroundAn increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading.MethodsWe digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50–69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa.FindingsThe AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994–0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972–0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95–0·97) for the independent test dataset and 0·87 (0·84–0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60–0·73).InterpretationAn AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist.
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| 8. |
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| 9. |
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| 10. |
- Bowman, Chelsie N., et al.
(author)
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Integrated sedimentary, biotic, and paleoredox dynamics from multiple localities in southern Laurentia during the late Silurian (Ludfordian) extinction event
- 2020
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In: Palaeogeography, Palaeoclimatology, Palaeoecology. - : Elsevier BV. - 0031-0182. ; 553
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Journal article (peer-reviewed)abstract
- The Silurian was a time of major climatic transition punctuated by multiple biotic crises and global carbon cycle perturbations. The most severe of these biotic events was the late Silurian (Ludfordian) Lau/Kozlowskii extinction event (LKE) and the associated Lau carbon isotope excursion (CIE). Although the extinction event and Lau CIE are globally documented, the only records thus far of local and global marine paleoredox conditions through this interval are from a single region in Scandinavia. Here we examine four sections along a bathymetric transect of mixed carbonate-siliciclastic sediments from western Tennessee, USA. A novel approach using a multi-proxy dataset combining high-resolution geochemical data and microfacies analyses from multiple localities explores the possibilities of local/regional-scale redox heterogeneities during a time of widespread environmental upheaval on a global scale. Paired positive excursions recorded in carbonate carbon isotopes and carbonate-associated sulfate sulfur isotopes support recent work from carbonate and siliciclastic successions from Scandinavia, suggesting a global enhancement of organic carbon and pyrite burial driven by an expansion of euxinic (anoxic and sulfidic water column) conditions in the oceans during the mid-Ludfordian. Furthermore, positive excursions in organic carbon isotopes and pyrite sulfur isotopes reflect the global changes in redox. Stratigraphic trends in I/Ca ratios imply a local expansion of low-oxygen conditions, with low, but non-zero values during the rising limb and peak of the CIE. The fossil assemblages vary across the shelf and through the CIE interval. Stratigraphic changes in fossil assemblages and I/Ca are closely associated with local and global changes in oxygenation and sea level during the mid-Ludfordian. The collective data indicate significant biotic reorganization in response to changes in marine redox conditions and in conjunction with sea-level variation during the LKE interval, but detailed macroscopic biodiversity is currently unconstrained for this region.
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| 11. |
- Gorreja, Frida, et al.
(author)
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MEFV and NLRP3 Inflammasome Expression Is Attributed to Immature Macrophages and Correlates with Serum Inflammatory Proteins in Crohn ' s Disease Patients
- 2022
-
In: Inflammation. - : Springer Science and Business Media LLC. - 0360-3997 .- 1573-2576. ; 45, s. 1631-1650
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Journal article (peer-reviewed)abstract
- Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn ' s disease (CD) pathogenesis, yet the contribution of inflammasomes in intestinal epithelial cells (IECs) versus lamina propria (LP) macrophages is poorly understood. Whether inflammasome expression in intestinal tissue reflects the serum inflammatory protein profile of patients is also not known. We aimed to determine the intestinal cell types where inflammasome expression is increased in CD and if they correlate with the serum protein profile. RT-PCR and NanoString nCounter technology were used to characterize inflammasome gene expression in CD patients and controls. The mucosa, LP and IEC cell fractions and FACS-sorted cells were analyzed. Proximity extension assay with a 92-protein panel was used to determine the serum inflammatory protein profile. Compositional analysis was used to correlate ileum inflammasome gene expression with intestinal mononuclear phagocyte populations. We show that NLRP3 and MEFV inflammasome sensors and downstream effector expression including IL-1 beta are increased in inflamed mucosa of IBD patients and correlate with disease activity. Inflammasome gene expression increased with the abundance of immature intestinal macrophages, and increased IL-1 beta released by CD LP cells correlated with immature macrophage frequency. Inflammasome gene expression was also increased in circulating monocytes, the precursors of immature intestinal macrophages. Finally, the serum inflammatory profile of CD patients correlates with ileal expression of genes related to NLRP3 and MEFV inflammasomes. Overall, we show that MEFV and NLRP3 inflammasome expression in CD intestine is attributed to the accumulation of immature macrophages and correlates with serum inflammatory proteins.
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| 12. |
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| 13. |
- Hofstedt, Annika, et al.
(author)
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Pilot data findings from the Gothenburg treatment for gaming disorder: a cognitive behavioral treatment manual
- 2023
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In: Frontiers in Psychiatry. - 1664-0640. ; 14
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Journal article (peer-reviewed)abstract
- Background: Gaming disorder (GD) is a new diagnosis included in the latest edition of the International Classification of Disease -11. Recently conducted international studies suggest a prevalence rate close to 2% for GD, highlighting the need for effective treatments for this patient population. Internationally there are few studies investigating effective treatments specifically designed for this condition. In this pilot study, we wanted to test a newly developed method, the Gothenburg Treatment for Gaming Disorder (GOT-TO-GO) manual; a 15-week cognitive behavioral therapy treatment for GD.Method: This study utilized a single group design with pretest, post-test and a three- and six-month follow-up, with measures of severity of GD and mood. The participants (n = 28) were treatment-seeking adults with GD, aged 17 to 49 years.Results: The results show a statistically significant decrease in symptoms of GD after treatment. Hours of gaming per week also decreased concomitantly with a 100% increase in non-gaming leisure hours. The decrease in symptoms of GD was maintained at the 3-months follow-up after treatment. Correspondingly we saw a decrease in both depression and anxiety that also was upheld 3 months after treatment.Conclusion: As GD is a new diagnostic concept more research is needed, also taking psychiatric comorbidity into consideration, to arrive at evidence-based conclusions regarding effective treatments. Considering the promising results in this small pilot study with large behavioral changes and reduced symptoms of GD, upheld at least 3 months after treatment, a larger randomized controlled study is warranted.
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| 14. |
- Juvrud, Joshua, et al.
(author)
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High quality social environment buffers infants’ cognitive development from poor maternal mental health : Evidence from a study in Bhutan
- 2022
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In: Developmental Science. - : John Wiley & Sons. - 1363-755X .- 1467-7687. ; 25:3
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Journal article (peer-reviewed)abstract
- Poor maternal mental health negatively impacts cognitive development from infancy to childhood, affecting both behavior and brain architecture. In a non-western context (Thimphu, Bhutan), we demonstrate that culturally-moderated factors such as family, community social support, and enrichment may buffer and scaffold the development of infant cognition when maternal mental health is poor. We used eye-tracking to measure early building blocks of cognition: attention regulation and social perception, in 9-month-old Bhutanese infants (N = 121). The cognitive development of Bhutanese infants in richer social environments was buffered from poor maternal mental health, while for infants in environments with lower rates of protective social environment factors, worse maternal mental health significantly predicted greater costs for infant attention, a fundamental building block cognition. International policies and interventions geared to improve maternal mental health and child health outcomes should incorporate each regions’ unique family, cultural, and community support structures.
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| 15. |
- Kozik, Nevin P., et al.
(author)
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Progressive marine oxygenation and climatic cooling at the height of the Great Ordovician Biodiversification Event
- 2023
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In: Global and Planetary Change. - 0921-8181. ; 227
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Journal article (peer-reviewed)abstract
- The oxygen content of ancient seawater has been hypothesized to be a major controlling factor for biodiversity throughout Earth's history. The Great Ordovician Biodiversification Event (GOBE) represents one of the largest increases in biodiversity during the Phanerozoic, with peak rates of diversity occurring in the Middle–Late Ordovician. Multiple causal factors have resulted in this long-term adaptive radiation, but direct links to marine oxygen levels remain poorly characterized. Here we utilize a multiproxy dataset from the Röstånga-2 drillcore, Skåne (Scania), southernmost Sweden, to constrain local and global marine paleoredox dynamics using a multi-proxy approach throughout the Middle–Late Ordovician (Darriwilian–early Sandbian stages). Pyrite sulfur isotopes (δ34Spyr), iron speciation and trace metal concentrations (V, U, and Mo) all indicate pervasive locally reducing conditions, and thallium (ε205Tl) isotopic compositions indicate significant changes in global Mn-oxide burial. This is one of the first studies to utilize direct local and global paleoredox proxies to identify changes in marine oxygen associated with peak rates of biodiversification in the Ordovician. Our new thallium isotope and pyrite sulfur isotope trends from black shale are combined with previously published carbonate-based redox proxy data (δ238U and δ34SCAS–carbonate-associated sulfate) from time equivalent successions in Baltica, Laurentia and Argentine Precordillera, indicating a global shift towards enhanced Mn-oxide burial, decreased anoxic seafloor area, and decreased pyrite burial, respectively. Thus, oceanic conditions during the Middle–Late Ordovician are interpreted to have transitioned from pervasive, highly reducing conditions towards more oxygenated marine settings. These changes in global paleoredox coincide with paleotemperature proxy data that indicated an overall climatic cooling trend during this time. Significant cooling of Ordovician oceans and climate would have permitted enhanced ventilation of marine environments, that in turn likely facilitated new ecospace development/utilization and ultimately drove marine biodiversification. Our results show a protracted, yet progressive oxygenation of marine environments over an interval of ∼11 Myr coinciding with peak rates of biodiversification during the GOBE.
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| 16. |
- Kozik, Nevin P., et al.
(author)
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Protracted oxygenation across the Cambrian–Ordovician transition : A key initiator of the Great Ordovician Biodiversification Event?
- 2023
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In: Geobiology. - : Wiley. - 1472-4677 .- 1472-4669. ; 21:3, s. 323-340
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Journal article (peer-reviewed)abstract
- Fluctuations in marine oxygen concentrations have been invoked as a primary driver for changes in biodiversity throughout Earth history. Expansions in reducing marine conditions are commonly invoked as key causal mechanisms for mass extinctions, while increases in marine oxygenation are becoming an increasingly common causal mechanism invoked for biodiversification events. Here we utilize a multiproxy approach to constrain local and global marine paleoredox conditions throughout the late Cambrian–Early Ordovician from two drill core successions in Baltoscandia. Local paleoredox proxies such as manganese concentrations and iron speciation reveal that both sites in the Baltic paleobasin had persistently anoxic and predominantly euxinic (anoxic and sulfidic) bottom water conditions throughout the study interval. Corresponding trace metal datasets indicate nuanced contraction and expansion of global anoxic and euxinic conditions along continental margins during the late Cambrian–Early Ordovician. Lastly, thallium isotope data from these locally reducing sections suggest a global expansion of oxygenated shelf and deeper marine environments from the late Cambrian into the Early Ordovician. This evidence for increasingly oxic marine environments coincides with increases in burrowing depth and tiering in marine animals, as well as diversification of body fossils throughout this ~8-million-year interval. The collective geochemical datasets provide some of the first direct paleoredox evidence for an increase in marine oxygen concentrations as a key mechanism for the Ordovician radiation of marine life.
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| 17. |
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| 18. |
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| 19. |
- Lin, CH, et al.
(author)
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Human ex vivo spinal cord slice culture as a useful model of neural development, lesion, and allogeneic neural cell therapy
- 2020
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In: Stem cell research & therapy. - : Springer Science and Business Media LLC. - 1757-6512. ; 11:1, s. 320-
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Journal article (peer-reviewed)abstract
- BackgroundThere are multiple promising treatment strategies for central nervous system trauma and disease. However, to develop clinically potent and safe treatments, models of human-specific conditions are needed to complement in vitro and in vivo animal model-based studies.MethodsWe established human brain stem and spinal cord (cross- and longitudinal sections) organotypic cultures (hOCs) from first trimester tissues after informed consent by donor and ethical approval by the Regional Human Ethics Committee, Stockholm (lately referred to as Swedish Ethical Review Authority), and The National Board of Health and Welfare, Sweden. We evaluated the stability of hOCs with a semi-quantitative hOC score, immunohistochemistry, flow cytometry, Ca2+signaling, and electrophysiological analysis. We also applied experimental allogeneic human neural cell therapy after injury in the ex vivo spinal cord slices.ResultsThe spinal cord hOCs presented relatively stable features during 7–21 days in vitro (DIV) (except a slightly increased cell proliferation and activated glial response). After contusion injury performed at 7 DIV, a significant reduction of the hOC score, increase of the activated caspase-3+cell population, and activated microglial populations at 14 days postinjury compared to sham controls were observed. Such elevation in the activated caspase-3+population and activated microglial population was not observed after allogeneic human neural cell therapy.ConclusionsWe conclude that human spinal cord slice cultures have potential for future structural and functional studies of human spinal cord development, injury, and treatment strategies.
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| 20. |
- Lindskog, Anders, et al.
(author)
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Coupled biostratigraphy and chemostratigraphy at Lanna, Sweden : A key section for the Floian–lower Darriwilian interval (Lower–Middle Ordovician)
- 2023
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In: Palaeogeography, Palaeoclimatology, Palaeoecology. - : Elsevier BV. - 0031-0182. ; 615
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Journal article (peer-reviewed)abstract
- The Lanna area in the province of Närke, south-central Sweden, hosts a succession of cool-water carbonate strata that are largely devoid of tectonic and diagenetic alteration, and span the Floian through lower Darriwilian Global stages (Ottenbyan–Kundan Regional stages). In this study we assess the integrated biostratigraphic and chemostratigraphic framework for the Ordovician sequence at Lanna, utilizing trilobites and conodonts coupled with bulk-rock carbon and oxygen isotopes (δ13Ccarb and δ18Ocarb). The local succession is thin but relatively complete; biostratigraphic details are similar to coeval successions in Baltoscandia. The new high-resolution δ13C and δ18O data are broadly consistent with other chemostratigraphic records at the regional scale, but notable differences in δ13C are obvious compared to global records. δ13C trends diverge markedly in the Dapingian and intra- and inter-regional differences become increasingly pronounced through younger strata. This may largely be explained by an overall low eustatic sea level, which led to more widespread oceanic restriction of epeiric seas. As a result, δ13C records became more influenced by local variables, muddling the global δ13C signal. This, in turn, suggests that sea level played a larger role than long-term changes within the global carbon cycle for regulating local–regional δ13C gradients in the Middle Ordovician. Regardless of the underlying cause(s), the documented variability poses significant challenges for using δ13C as a tool for detailed stratigraphic correlations. The limited expression of many named ‘carbon isotope excursions’ (CIEs) in the studied interval indicate that they are artefacts of local overprinting rather than reflective of changes to the global carbon cycle. Thus, these CIEs are of questionable correlative importance and validity. Although the scatter in numeric values is relatively large, long-term δ18O trends are overall consistent at the global scale, tentatively supporting the notion that climate cooled during the studied time interval.
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| 21. |
- Lindskog, A., et al.
(author)
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In Situ Calibration of Transmission System Power Grid Energy Meters Using Energy Measurements and Kalman Filter
- 2023
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In: IEEE Transactions on Power Delivery. - : Institute of Electrical and Electronics Engineers Inc.. - 0885-8977 .- 1937-4208. ; 38:2, s. 988-997
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Journal article (peer-reviewed)abstract
- Correct energy measurement is vital for electric energy trading. There are often stringent legal demands on the revenue metering that require periodic in situ substation verification. Traditional energy metering testing methods are not possible in IEC 61850 digital stations using a process bus. In this article we will show that it is possible to use data analysis to verify the accuracy of energy measurement systems in substations. Our algorithms can be used as a part of the legal verification and runs remotely on-line. As a consequence, some of the periodic accuracy verification including substation visits can be abandoned. The on-line algorithms makes it possible to decrease the errors in both revenue metering systems and in other energy measurements systems in the Swedish transmission system. Measurement errors are now detected and amended much faster which reduces incorrect billing. The estimated value of incorrect billing is decreased by more than a million EUR annually. Our algorithms also provide a solution to bridge the problem to verify measurements in future fully digital substations.
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| 22. |
- Lindskog, Anders, et al.
(author)
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Middle ordovician carbonate facies development, conodont biostratigraphy and faunal diversity patterns at the Lynna River, northwestern Russia
- 2020
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In: Estonian Journal of Earth Sciences. - : Estonian Academy Publishers. - 1736-4728. ; 69:1, s. 37-61
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Journal article (peer-reviewed)abstract
- The Ordovician Period has emerged as a highly dynamic time in Earth history. Comprehensive work on chrono, chemo-and biostratigraphy has resulted in an overall wellconstrained systemic framework, but several local successions around the globe still await detailed analysis in many respects. Herein we perform a highresolution analysis of abiotic and biotic signals in the Lynna River section, a key locality in northwestern Russia. As this section has been pivotal in documenting the temporal evolution of the Great Ordovician Biodiversification Event on Baltica, the macroscopic and microscopic characteristics of the local succession reveal important paleoenvironmental information that ties into the global development during the Middle Ordovician. The results add particularly to the understanding of the characteristics and largescale sedimentary ‘behavior’ of the Baltoscandian paleobasin. Microfacies vary consistently with the macroscopic appearance of the rocks, with intervals characterized by competent limestone being associated with coarser carbonate textures and intervals dominated by marly beds associated with finer textures. Along with carbonate textures, fossil grain assemblages vary in a rhythmic (~cyclic) manner. The local rocks are commonly partly dolomitized, with the proportion of dolomitization increasing upsection. Regional comparisons suggest that the changes in overall macro and microfacies were strongly related to variations in sea level. New highresolution conodont biostratigraphic data largely confirm previous regional correlations based on lithostratigraphy and trilobite faunas, and enable more robust correlations worldwide.
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| 23. |
- Lindskog, Anders, et al.
(author)
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Oxygenation of the Baltoscandian shelf linked to Ordovician biodiversification
- 2023
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In: Nature Geoscience. - 1752-0894. ; 16:11, s. 1047-1053
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Journal article (peer-reviewed)abstract
- Marine biodiversity increased markedly during the Ordovician Period (~487–443 million years ago). Some intervals within the Ordovician were associated with unusually rapid and prominent rises in taxonomic richness, the reasons for which remain debated. Links between increased oxygenation and biodiversification have been proposed, although supporting marine oxygen proxy data are limited. Here we present an expansive multi-site iodine-to-calcium (I/Ca) record from Lower–Middle Ordovician marine carbonates in Baltoscandia that provides a detailed account of the spatio-temporal development of oxygen conditions across this palaeoshelf. The data document progressive oxygenation of regional seafloor environments, with well-oxygenated waters sourced from the palaeoequatorward Iapetus Ocean and peak I/Ca values (that is, dissolved oxygen concentrations) coinciding with the most pronounced biodiversity increases and ecosystem reorganizations during this time interval. This occurred while the climate cooled, global sea level dropped and carbonate deposits became regionally dominant. The results suggest that ventilation of shelves played a critical role in regulating early Palaeozoic marine biodiversity via development of ecospace and aerobic–metabolic conditions.
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| 24. |
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| 25. |
- Méar, Loren, et al.
(author)
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Transcriptomics and Spatial Proteomics for Discovery and Validation of Missing Proteins in the Human Ovary
- 2024
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 23:1, s. 238-248
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Journal article (peer-reviewed)abstract
- Efforts to understand the complexities of human biology encompass multidimensional aspects, with proteins emerging as crucial components. However, studying the human ovary introduces unique challenges due to its complex dynamics and changes over a lifetime, varied cellular composition, and limited sample access. Here, four new RNA-seq samples of ovarian cortex spanning ages of 7 to 32 were sequenced and added to the existing data in the Human Protein Atlas (HPA) database www.proteinatlas.org, opening the doors to unique possibilities for exploration of oocyte-specific proteins. Based on transcriptomics analysis of the four new tissue samples representing both prepubertal girls and women of fertile age, we selected 20 protein candidates that lacked previous evidence at the protein level, so-called "missing proteins" (MPs). The proteins were validated using high-resolution antibody-based profiling and single-cell transcriptomics. Fourteen proteins exhibited consistent single-cell expression patterns in oocytes and granulosa cells, confirming their presence in the ovary and suggesting that these proteins play important roles in ovarian function, thus proposing that these 14 proteins should no longer be classified as MPs. This research significantly advances the understanding of MPs, unearthing fresh avenues for prospective exploration. By integrating innovative methodologies and leveraging the wealth of data in the HPA database, these insights contribute to refining our understanding of protein roles within the human ovary and opening the doors for further investigations into missing proteins and human reproduction.
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| 26. |
- Olsson, Henrik, et al.
(author)
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Estimating diagnostic uncertainty in artificial intelligence assisted pathology using conformal prediction
- 2022
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Unreliable predictions can occur when an artificial intelligence (AI) system is presented with data it has not been exposed to during training. We demonstrate the use of conformal prediction to detect unreliable predictions, using histopathological diagnosis and grading of prostate biopsies as example. We digitized 7788 prostate biopsies from 1192 men in the STHLM3 diagnostic study, used for training, and 3059 biopsies from 676 men used for testing. With conformal prediction, 1 in 794 (0.1%) predictions is incorrect for cancer diagnosis (compared to 14 errors [2%] without conformal prediction) while 175 (22%) of the predictions are flagged as unreliable when the AI-system is presented with new data from the same lab and scanner that it was trained on. Conformal prediction could with small samples (N = 49 for external scanner, N = 10 for external lab and scanner, and N = 12 for external lab, scanner and pathology assessment) detect systematic differences in external data leading to worse predictive performance. The AI-system with conformal prediction commits 3 (2%) errors for cancer detection in cases of atypical prostate tissue compared to 44 (25%) without conformal prediction, while the system flags 143 (80%) unreliable predictions. We conclude that conformal prediction can increase patient safety of AI-systems.
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| 27. |
- Omenn, Gilbert S., et al.
(author)
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Progress Identifying and Analyzing the Human Proteome : 2021 Metrics from the HUPO Human Proteome Project
- 2021
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 20:12, s. 5227-5240
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Journal article (peer-reviewed)abstract
- The 2021 Metrics of the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18 357 (92.8%) of the 19 778 predicted proteins coded in the human genome, a gain of 483 since 2020 from reports throughout the world reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 478 to 1421. This represents remarkable progress on the proteome parts list. The utilization of proteomics in a broad array of biological and clinical studies likewise continues to expand with many important findings and effective integration with other omics platforms. We present highlights from the Immunopeptidomics, Glycoproteomics, Infectious Disease, Cardiovascular, MusculoSkeletal, Liver, and Cancers B/D-HPP teams and from the Knowledge-base, Mass Spectrometry, Antibody Profiling, and Pathology resource pillars, as well as ethical considerations important to the clinical utilization of proteomics and protein biomarkers.
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| 28. |
- Omenn, Gilbert S., et al.
(author)
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The 2022 Report on the Human Proteome from the HUPO Human Proteome Project
- 2023
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 22:4, s. 1024-1042
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Journal article (peer-reviewed)abstract
- The 2022 Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18 407 (93.2%) of the 19 750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from data sets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from 1421 to 1343. This represents continuing experimental progress on the human proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, “A Function for Each Protein”.
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| 29. |
- Omenn, Gilbert S., et al.
(author)
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The 2023 Report on the Proteome from the HUPO Human Proteome Project
- 2024
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 23:2, s. 532-549
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Research review (peer-reviewed)abstract
- Since 2010, the Human Proteome Project (HPP), the flagship initiative of the Human Proteome Organization (HUPO), has pursued two goals: (1) to credibly identify the protein parts list and (2) to make proteomics an integral part of multiomics studies of human health and disease. The HPP relies on international collaboration, data sharing, standardized reanalysis of MS data sets by PeptideAtlas and MassIVE-KB using HPP Guidelines for quality assurance, integration and curation of MS and non-MS protein data by neXtProt, plus extensive use of antibody profiling carried out by the Human Protein Atlas. According to the neXtProt release 2023-04-18, protein expression has now been credibly detected (PE1) for 18,397 of the 19,778 neXtProt predicted proteins coded in the human genome (93%). Of these PE1 proteins, 17,453 were detected with mass spectrometry (MS) in accordance with HPP Guidelines and 944 by a variety of non-MS methods. The number of neXtProt PE2, PE3, and PE4 missing proteins now stands at 1381. Achieving the unambiguous identification of 93% of predicted proteins encoded from across all chromosomes represents remarkable experimental progress on the Human Proteome parts list. Meanwhile, there are several categories of predicted proteins that have proved resistant to detection regardless of protein-based methods used. Additionally there are some PE1–4 proteins that probably should be reclassified to PE5, specifically 21 LINC entries and ∼30 HERV entries; these are being addressed in the present year. Applying proteomics in a wide array of biological and clinical studies ensures integration with other omics platforms as reported by the Biology and Disease-driven HPP teams and the antibody and pathology resource pillars. Current progress has positioned the HPP to transition to its Grand Challenge Project focused on determining the primary function(s) of every protein itself and in networks and pathways within the context of human health and disease.
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| 30. |
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| 31. |
- Rosenblad, Andreas, Fil. dr, 1973-, et al.
(author)
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Surgical waiting times and all-cause mortality in patients with non-metastatic renal cell carcinoma
- 2022
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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 56:5-6, s. 383-390
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Journal article (peer-reviewed)abstract
- Objective To examine the association between surgical waiting times (SWTs) and all-cause mortality (ACM) in non-metastatic patients with RCC, in relation to tumour stage. Patients and methods This nation-wide population-based cohort study included 9,918 M0 RCC patients registered in the National Swedish Kidney Cancer Register, between 2009 and 2021, followed-up for ACM until 9 December 2021, and having measured SWTs. The associations between primarily SWTs from date of radiological diagnosis to date of surgery (WRS) and secondarily SWTs from date of radiological diagnosis to date of treatment decision (WRT) and date of treatment decision to date of surgery (WTS), in relation to ACM, were analysed using Cox regression analysis, adjusted for clinical and demographic characteristics, stratified and unstratified according to T-stage. Results During a mean follow-up time of 5 years (49,873 person-years), 23% (n = 2291) of the patients died. The adjusted hazard ratio (AHR) for WRS (months) for all patients was 1.03 (95% confidence interval [CI] = 1.02-1.04; p < 0.001). When subdividing WRS on T-stage, the AHRs were 1.03 (95% CI = 1.01-1.04; p < 0.001) and 1.05 (95% CI = 1.02-1.08; p = 0.003) for stages T1 and T3, respectively, while non-significant for T2 (p = 0.079) and T4 (p = 0.807). Similar results were obtained for WRT and WTS. Conclusions Prolonged SWTs significantly increased the risk of early overall death among patients with RCC. The increased risk of early death from any cause show the importance of shortening SWTs in clinical work of patients with this malignant disease.
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| 32. |
- Sinclair, Georges, et al.
(author)
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Adaptive radiosurgery based on two simultaneous dose prescriptions in the management of large renal cell carcinoma brain metastases in critical areas: Towards customization
- 2020
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In: Surgical Neurology International. - : Scientific Scholar. - 2229-5097 .- 2152-7806. ; 11, s. 21-21
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Research review (peer-reviewed)abstract
- The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario.Case Description:A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (<1 cc) in the left temporal lobe (Met 3). Met 2 and Met 3 underwent RRR and SF-GKRS, respectively.Results:Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR.Conclusion:Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.
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| 33. |
- Sjostedt, Evelina, et al.
(author)
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TGFBR3L-An Uncharacterised Pituitary Specific Membrane Protein Detected in the Gonadotroph Cells in Non-Neoplastic and Tumour Tissue.
- 2020
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In: Cancers. - BASEL SWITZERLAND : MDPI AG. - 2072-6694. ; 13:1
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Journal article (peer-reviewed)abstract
- Here, we report the investigation of transforming growth factor beta-receptor 3 like (TGFBR3L), an uncharacterised pituitary specific membrane protein, in non-neoplastic anterior pituitary gland and pituitary neuroendocrine tumours. A polyclonal antibody produced within the Human Protein Atlas project (HPA074356) was used for TGFBR3L staining and combined with SF1 and FSH for a 3-plex fluorescent protocol, providing more details about the cell lineage specificity of TGFBR3L expression. A cohort of 230 pituitary neuroendocrine tumours were analysed. In a subgroup of previously characterised gonadotroph tumours, correlation with expression of FSH/LH, E-cadherin, oestrogen (ER) and somatostatin receptors (SSTR) was explored. TGFBR3L showed membranous immunolabeling and was found to be gonadotroph cell lineage-specific, verified by co-expression with SF1 and FSH/LH staining in both tumour and non-neoplastic anterior pituitary tissues. TGFBR3L immunoreactivity was observed in gonadotroph tumours only and demonstrated intra-tumour heterogeneity with a perivascular location. TGFBR3L immunostaining correlated positively to both FSH (R = 0.290) and LH (R = 0.390) immunostaining, and SSTR3 (R = 0.315). TGFBR3L correlated inversely to membranous E-cadherin staining (R = -0.351) and oestrogen receptor β mRNA (R = -0.274). In conclusion, TGFBR3L is a novel pituitary gland specific protein, located in the membrane of gonadotroph cells in non-neoplastic anterior pituitary gland and in a subset of gonadotroph pituitary tumours.
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| 34. |
- Stenman, Maria, M.D. 1987-, et al.
(author)
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Metastatic renal cell carcinoma to the brain : optimizing patient selection for gamma knife radiosurgery
- 2021
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In: Acta Neurochirurgica. - : Springer Nature. - 0001-6268 .- 0942-0940. ; 163:2, s. 333-342
-
Journal article (peer-reviewed)abstract
- IntroductionThe effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied.Methods and materialsClear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005–2014 at three European centres were retrospectively analysed (n = 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE).ResultsOne hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS.ConclusionsWe identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.
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| 35. |
- Stratmann, Svea, 1989-, et al.
(author)
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Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children
- 2023
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In: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 37:3, s. 550-559
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Journal article (peer-reviewed)abstract
- Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.
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