| 1. |
- Alvez, Maria Bueno, et al.
(författare)
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Next generation pan-cancer blood proteome profiling using proximity extension assay
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive characterization of blood proteome profiles in cancer patients can contribute to a better understanding of the disease etiology, resulting in earlier diagnosis, risk stratification and better monitoring of the different cancer subtypes. Here, we describe the use of next generation protein profiling to explore the proteome signature in blood across patients representing many of the major cancer types. Plasma profiles of 1463 proteins from more than 1400 cancer patients are measured in minute amounts of blood collected at the time of diagnosis and before treatment. An open access Disease Blood Atlas resource allows the exploration of the individual protein profiles in blood collected from the individual cancer patients. We also present studies in which classification models based on machine learning have been used for the identification of a set of proteins associated with each of the analyzed cancers. The implication for cancer precision medicine of next generation plasma profiling is discussed.
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| 2. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 3. |
- Persson, Fredrik, et al.
(författare)
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USING SIMULATION TO DETERMINE THE SAFETY STOCK LEVEL FOR INTERMITTENT DEMAND
- 2017
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Ingår i: 2017 WINTER SIMULATION CONFERENCE (WSC). - : IEEE. - 9781538634288 ; , s. 3768-3779
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Konferensbidrag (refereegranskat)abstract
- Safety stock calculations are difficult for products with intermittent demand, long production lead times, and high monetary values. Theoretically, forecasts can be used to reduce the need for safety stocks. A high precision forecast minimizes the need for safety stock and forecast evaluation measurements can be used to calculate the safety stock level. However, a more realistic determination of safety stock levels can he obtained by simulation. In this paper, simulation is used to model and experiment on a case with three end products in order to determine the relationship between safety stock levels and service levels. Also, a comparison is made with theoretically calculated safety stocks to see how well basic theoretical models for safety stock calculations fulfill the requirements of service level. The result is that simulation can provide a much more accurate determination of safety stock levels for intermittent demands than theoretical calculations.
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| 4. |
- Akel, Sarah, et al.
(författare)
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Neurofilament light, glial fibrillary acidic protein, and tau in a regional epilepsy cohort: High plasma levels are rare but related to seizures
- 2023
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Ingår i: Epilepsia. - 0013-9580. ; 64:10, s. 2690-2700
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Higher levels of biochemical blood markers of brain injury have been described immediately after tonic-clonic seizures and in drug-resistant epilepsy, but the levels of such markers in epilepsy in general have not been well characterized. We analyzed neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau in a regional hospital-based epilepsy cohort and investigated what proportion of patients have levels suggesting brain injury, and whether certain epilepsy features are associated with high levels.Methods: Biomarker levels were measured in 204 patients with an epilepsy diagnosis participating in a prospective regional biobank study, with age and sex distribution correlating closely to that of all patients seen for epilepsy in the health care region. Absolute biomarker levels were assessed between two patient groups: patients reporting seizures within the 2 months preceding inclusion and patients who did not have seizures for more than 1 year. We also assessed the proportion of patients with above-normal levels of NfL.Results: NfL and GFAP, but not tau, increased with age. Twenty-seven patients had abnormally high levels of NfL. Factors associated with such levels were recent seizures (p = .010) and epileptogenic lesion on radiology (p = .001). Levels of NfL (p = .006) and GFAP (p = .032) were significantly higher in young patients (<65 years) with seizures & LE;2 months before inclusion compared to those who reported no seizures for >1 year. NfL and GFAP correlated weakly with the number of days since last seizure (NfL: r(s) = -.228, p = .007; GFAP: r(s) = -.167, p = .048) in young patients. NfL also correlated weakly with seizure frequency in the last 2 months (r(s) = .162, p = .047).Significance: Most patients with epilepsy do not have biochemical evidence of brain injury. The association with seizures merits further study; future studies should aim for longitudinal sampling and examine whether individual variations in NfL or GFAP levels could reflect seizure activity.
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| 5. |
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| 6. |
- Altena, Renske, et al.
(författare)
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Current status of contemporary diagnostic radiotracers in the management of breast cancer : first steps toward theranostic applications
- 2023
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Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 13:1
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Forskningsöversikt (refereegranskat)abstract
- BackgroundExpanding therapeutic possibilities have improved disease-related prospects for breast cancer patients. Pathological analysis on a tumor biopsy is the current reference standard biomarker used to select for treatment with targeted anticancer drugs. This method has, however, several limitations, related to intra- and intertumoral as well as spatial heterogeneity in receptor expression as well as the need to perform invasive procedures that are not always technically feasible.Main bodyIn this narrative review, we focus on the current role of molecular imaging with contemporary radiotracers for positron emission tomography (PET) in breast cancer. We provide an overview of diagnostic radiotracers that represent treatment targets, such as programmed death ligand 1, human epidermal growth factor receptor 2, polyadenosine diphosphate-ribose polymerase and estrogen receptor, and discuss developments in therapeutic radionuclides for breast cancer management.ConclusionImaging of treatment targets with PET tracers may provide a more reliable precision medicine tool to find the right treatment for the right patient at the right time. In addition to visualization of the target of treatment, theranostic trials with alpha- or beta-emitting isotopes provide a future treatment option for patients with metastatic breast cancer.
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| 7. |
- Altena, Renske, et al.
(författare)
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HER2-låg bröstcancer ny entitet – ökar behandlingsmöjligheterna : [HER2-low breast cancer - A new entity that could expand possibilities of getting treatment]
- 2022
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 119
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Forskningsöversikt (refereegranskat)abstract
- Breast cancer is the most common form of cancer among women in Sweden. Several decades ago it was recognized that the Human epidermal growth factor receptor 2 (HER2) is involved in a critical growth system for breast cancer cells. Overexpression of HER2 (immunohistochemistry [IHC] 2+/3+, in situ hybridization [ISH] positive) is present in 15 percent of all breast cancers. HER2-low breast cancer has been discovered as a separate entity; the most commonly used definition so far is IHC 1+/2+ and ISH negative, but general consensus is still lacking. Clinical studies with the HER2 antibody drug conjugate trastuzumab deruxtecan (Enhertu) have shown impressive antitumor activity among women with advanced HER2-low breast cancer and this is expected to become part of routine treatment in the near future. Research is needed to establish refined ways to define HER2-low breast cancer, and a possible role lies in new imaging methods such as HER2 positron emission tomography (PET) with a [68Ga]Ga-ABY-025 tracer.
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| 8. |
- Altena, Renske, et al.
(författare)
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Human Epidermal Growth Factor Receptor 2 (HER2) PET Imaging of HER2-Low Breast Cancer with [ 68 Ga]Ga-ABY-025 : Results from a Pilot Study
- 2024
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine and Molecular Imaging. - 0161-5505 .- 1535-5667. ; 65:5, s. 700-707
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Tidskriftsartikel (refereegranskat)abstract
- Patients with HER2-low metastatic breast cancer (mBC), defined as an immunohistochemistry (IHC) score of 1+ or 2+ without HER2 gene amplification, may benefit from HER2 antibody-drug conjugates. Identifying suitable candidates is a clinical challenge because of spatial and temporal heterogeneity in HER2 expression and discrepancies in pathologic reporting. We aimed to investigate the feasibility and safety of HER2-specific PET imaging with [ 68 Ga]Ga-ABY-025 for visualization of HER2-low mBC.Methods: A prospective pilot study was done with 10 patients who had HER2-low mBC, as part of a phase 2 basket imaging study with [ 68 Ga]Ga-ABY-025 in HER2-expressing solid tumors. Patients were recruited at the Breast Clinic at the Karolinska University Hospital, Stockholm, Sweden. PET/CT images were acquired 3 h after injection of 200 MBq of [ 68 Ga]Ga-ABY-025. The SUV max was used to quantify tracer uptake. Ultrasound-guided tumor biopsies were guided by results from the HER2 PET. The main outcome-the safety and feasibility of HER2 PET in patients with HER2low mBC, measured the occurrence of possible procedure -related adverse events.Results: Ten patients with HER2-low mBC underwent [ 68 Ga]Ga-ABY-025 PET/CT with paired tumor biopsies. No adverse events occurred. In all patients, [ 68 Ga]Ga-ABY-025-avid lesions with substantial intra- and interindividual heterogeneity in tracer uptake were noted. In 8 of 10 patients with ABY-025-avid lesions, the HER2low status of the corresponding lesions was confirmed by IHC or in situ hybridization. Two patients had an IHC score of 0 in the tumor biopsies:1 in a cutaneous lesion with a low SUV max and 1 in a liver metastasis with a high SUV max but a "cold" core.Conclusion: The visualization of HER2-low mBC with [ 68 Ga]Ga-ABY-025 PET/CT was feasible and safe. Areas of tracer uptake showed varying levels of HER2 expression on IHC. The observed intra- and interindividual heterogeneity in [ 68 Ga]Ga-ABY-025 uptake suggested that HER2 PET might be used as a tool for the noninvasive assessment of disease heterogeneity and has the potential to identify patients in whom HER2-targeted drugs can have a clinical benefit.
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| 9. |
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| 10. |
- Angdal, Henrik, et al.
(författare)
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Trends in Service Sourcing Practices
- 2007
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Ingår i: Journal of Business Market Management. - : Springer Science and Business Media LLC. - 1864-0753 .- 1864-0761. ; 1:3, s. 187-207
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Tidskriftsartikel (refereegranskat)
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