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- Svedman, F. C., et al.
(författare)
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Plasma Thymidine Kinase Activity as a Novel Biomarker in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibitors
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Background. Immune checkpoint inhibitors (ICI) are effective in fractions of patients with disseminated melanoma. This study is the first to analyze the plasma activity of thymidine kinase (TK), an enzyme involved in DNA synthesis and repair, as a biomarker in melanoma patients. Meth-ods. Plasma samples were collected prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with ICI (anti-CTLA-4 and/or anti-PD-1). Plasma TK activity (TKa) levels were determined using the DiviTum TKa ELISA assay. TKa levels were correlated with patients’ baseline characteristics, response rate (RR), progression-free survival (PFS), and overall survival (OS). Results. In the 90 study patients, the median TKa level was 42 Du/L (range <20–1787 Du/L). A significantly higher plasma TKa was found in patients with ECOG performance status ≥1 (p = 0.003), M1c-d disease (p = 0.015), and elevated lactate dehydrogenase levels (p < 0.001). The RR was 63.2% and 30.3% in those with low or high TKa, respectively (p = 0.022). The median PFS was 19.9 and 12.6 months in patients with low or high TKa, respectively (hazard ratio (HR) 1.83 (95% CI, 1.08–3.08), p = 0.024). The median OS was >60 months and 18.5 months in patients with low or high TKa, respectively (HR: 2.25 (95% CI, 1.25–4.05), p = 0.011. Conclusions. High pretreatment plasma TKa levels were significantly associated with worse baseline characteristics and poor response and survival in ICI-treated melanoma patients. TKa is hence a novel and interesting plasma biomarker in melanoma and should be further studied to define its role as a prognostic and predictive marker in this disease. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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- Andersson, Stefan S., et al.
(författare)
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Mineral paragenesis and sulphide trace element distribution in the metamorphosed Lovisa Zn-Pb deposit, Bergslagen (Sweden), as revealed by 3D X-ray tomography, ore petrography and LA-ICP-MS analysis
- 2022
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Ingår i: Ore Geology Reviews. - : Elsevier BV. - 0169-1368 .- 1872-7360. ; 140
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Tidskriftsartikel (refereegranskat)abstract
- This study encompasses the ore mineralogy, textures and sulphide trace element chemistry of the Palaeoproterozoic Lovisa stratiform Zn-Pb deposit and the stratigraphically underlying Lovisa Fe Formation in the Bergslagen ore province (Sweden). We investigate the relative timing of formation and subsequent modifications of its ores in relation to the c. 1.87-1.80 Ga Svecokarelian orogeny. The Lovisa Zn-Pb deposit consists of several different ore types. The massive sphalerite-galena ore is distinctly deformed, exhibiting a multiple-scale "ball ore" texture with rounded silicate clasts within a deformed, fine-grained sulphide matrix. Underlying the massive ore is a locally folded, sphalerite-rich laminated ore, interpreted to represent a metamorphosed relict primary lamination. Several generations of sphalerite-galena fracture fillings and veins occur adjacent to the main ore zones and they cross-cut early ductile structures and metamorphic features. The trace element signatures of the sphalerite-galena infillings generally mimic those of the two main ore zones, thus supporting an origin by localised remobilisation of the primary sulphide ore and demonstrating limited trace element redistribution during this process. In contrast, discrete sulphosalt-rich fracture fillings cross-cutting earlier galena-chalcopyriterich fracture fillings and veinlets in the Lovisa Fe Formation suggest a significant but still relatively localised redistribution of metals. Trace element mapping of sulphides from the Lovisa Zn-Pb deposit reveals that inclusion-free overgrowths on pyrite crystals are locally Co-enriched compared to the cores, which resulted from the redistribution of Co during late metamorphic processes. Combined textural and geochemical evidence suggest that the originally syngenetic exhalative sulphide ore at Lovisa was locally strongly affected by polyphase deformation and remobilisation. This was initiated during the first stage of amphibolite facies grade regional metamorphism and deformation (D1, c. 1.87-1.85 Ga) but is mostly evident from the later stages (D2) and the evolution to retrograde and brittle conditions (c. 1.83-1.80 Ga and later).
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- Huckriede, Joram, et al.
(författare)
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Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days.
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- Lagedal, Rickard, et al.
(författare)
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Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients
- 2022
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival. Methods: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure. Results: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively. Conclusion: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.
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