| 1. |
- Axelsson, Rebecca, et al.
(författare)
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Finite element model of mechanical imaging of the breast
- 2022
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Ingår i: Journal of Medical Imaging. - 2329-4302. ; 9:3, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Malignant breast lesions can be distinguished from benign lesions by their mechanical properties. This has been utilized for mechanical imaging in which the stress distribution over the breast is measured. Mechanical imaging has shown the ability to identify benign or normal cases and to reduce the number of false positives from mammography screening. Our aim was to develop a model of mechanical imaging acquisition for simulation purposes. To that end, we simulated mammographic compression of a computer model of breast anatomy and lesions. Approach: The breast compression was modeled using the finite element method. Two finite element breast models of different sizes were used and solved using linear elastic material properties in open-source virtual clinical trial (VCT) software. A spherical lesion (15 mm in diameter) was inserted into the breasts, and both the location and stiffness of the lesion were varied extensively. The average stress over the breast and the average stress at the lesion location, as well as the relative mean pressure over lesion area (RMPA), were calculated. Results: The average stress varied 6.2-6.5 kPa over the breast surface and 7.8-11.4 kPa over the lesion, for different lesion locations and stiffnesses. These stresses correspond to an RMPA of 0.80 to 1.46. The average stress was 20% to 50% higher at the lesion location compared with the average stress over the entire breast surface. Conclusions: The average stress over the breast and the lesion location corresponded well to clinical measurements. The proposed model can be used in VCTs for evaluation and optimization of mechanical imaging screening strategies.
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| 2. |
- Allard, Christina, et al.
(författare)
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Rasbiologiskt språkbruk i statens rättsprocess mot sameby
- 2015
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Ingår i: Dagens Nyheter. - 1101-2447.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Statens hantering av forskningsresultat i rättsprocessen med Girjas sameby utgör ett hot mot Sverige som rättsstat och kunskapsnation. Åratal av svensk och internationell forskning underkänns och man använder ett språkbruk som skulle kunna vara hämtat från rasbiologins tid. Nu måste staten ta sitt ansvar och börja agera som en demokratisk rättsstat, skriver 59 forskare.
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| 3. |
- Allard, Christina, et al.
(författare)
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Rasbiologiskt språkbruk i statens rättsprocess mot sameby : DN Debatt 2015-06-11
- 2015
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Annan publikation (populärvet., debatt m.m.)abstract
- Statens hantering av forskningsresultat i rättsprocessen med Girjas sameby utgör ett hot mot Sverige som rättsstat och kunskapsnation. Åratal av svensk och internationell forskning underkänns och man använder ett språkbruk som skulle kunna vara hämtat från rasbiologins tid. Nu måste staten ta sitt ansvar och börja agera som en demokratisk rättsstat, skriver 59 forskare.
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| 4. |
- Almqvist, Helena, et al.
(författare)
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CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.
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| 5. |
- Axelsson, Anna, et al.
(författare)
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Patient-reported QoL in anal cancer survivors 3 and 6 years after treatment-results from the Swedish national ANCA study
- 2022
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Ingår i: Supportive Care in Cancer. - : Springer Science and Business Media LLC. - 0941-4355 .- 1433-7339. ; 30:5, s. 4169-4178
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The impact of anal cancer treatment for the patients is best evaluated by the patients themselves. The purpose of this study was to investigate quality of life (QoL) in patients with anal cancer at 3 and 6 years after treatment. Methods A Swedish national cross-sectional prospective cohort study with patients diagnosed with anal cancer between 2011 and 2013. Patients were invited to respond to a QoL questionnaire at 3 and 6 years, with focus on bowel, urinary and sexual function, social and mental function, co-morbidity, lifestyle, daily activities, personal characteristics, and perceived QoL. It also contained questions on the severity of the symptoms regarding occurrence, frequency, and duration and the level of "bother" experienced related to functional symptoms. QoL and prevalence of bother with urinary, sexual, bowel dysfunction, and anal pain were described. The prevalence of impaired QoL was compared with a healthy reference population. The association between QoL and experiencing bother was quantified by regression models. Results From an original cohort of 464 patients with anal cancer, 264 (57%) were alive and contacted at 3 years and 230 (50%) at 6 years. One hundred ninety-five (74%) patients responded to the 3-year and 152 (66%) to the 6-year questionnaire. Sixty percent reported low QoL at both 3 and 6 years. Impaired QoL was more prevalent among patients with major bother due to bowel dysfunction (at 3 years RR 1.42, 95% CI (1.06-1.9) p-value 0.020, at 6 years RR 1.52, 95% CI (1.03-2.24) p-value 0.034) and urinary dysfunction (at 6 years RR 1.44, 95% CI (1.08-1.91) p-value 0.013). There was a tendency to a positive relationship between the number of bodily functions causing bother and risk for impaired QoL. Conclusion Patients treated for anal cancer reported bother regarding several bodily functions as well as poor QoL both at 3 and 6 years without much improvement. Bother was also associated with low QoL indicating that function-related bother should be addressed.
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| 6. |
- Axelsson, Ida, et al.
(författare)
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Impact of storage time prior to cryopreservation on mechanical properties of aortic homografts
- 2024
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Ingår i: Cell and Tissue Banking. - : Springer Science and Business Media LLC. - 1389-9333 .- 1573-6814. ; 25:1, s. 27-37
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Tidskriftsartikel (refereegranskat)abstract
- Optimal time spans in homograft procurement are still debatable among tissue banks and needs to be further investigated. Cell viability decreases at longer preparation intervals, but the effect on collagen and elastic fibers has not been investigated to the same extent. These fibers are of importance to the homograft elasticity and strength. The objective of this study was to analyze the mechanical properties of homograft tissue at different time spans in the procurement process. Ten aortic homografts were collected at the Tissue Bank in Lund. Twelve samples were obtained from each homograft, cryopreserved in groups of three after 2–4 days, 7–9 days, 28–30 days, and 60–62 days in antibiotic decontamination. Mechanical testing was performed with uniaxial tensile tests, calculating elastic modulus, yield stress and energy at yield stress. Two randomly selected samples were assessed with light microscopy. Procurement generated a total of 120 samples, with 30 samples in each time group. Elastic modulus and yield stress was significantly higher in samples cryopreserved after 2–4 days (2.7 MPa (2.5-5.0) and 0.78 MPa (0.68-1.0)) compared to 7–9 days (2.2 MPa (2.0-2.6) and 0.53 MPa (0.46–0.69)), p = 0.008 and 0.011 respectively. Light microscopy did not show any difference in collagen and elastin at different time spans. There was a significant decrease in elastic modulus and yield stress after 7 days of decontamination at 4 °C compared to 2–4 days. This could indicate some deterioration of elastin and collagen at longer decontamination intervals. Clinical significance of these findings remains to be clarified.
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| 7. |
- Axelsson, Malin, et al.
(författare)
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Differences in diagnostic patterns of obstructive airway disease between areas and sex in Sweden and Finland : The Nordic EpiLung Study
- 2021
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Ingår i: Journal of Asthma. - : Taylor & Francis. - 0277-0903 .- 1532-4303. ; 58:9, s. 1196-1207
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the current prevalence of physician-diagnosed obstructive airway diseases by respiratory symptoms and by sex in Sweden and Finland. Method: In 2016, a postal questionnaire was answered by 34,072 randomly selected adults in four study areas: Västra Götaland and Norrbotten in Sweden, and Seinäjoki-Vaasa and Helsinki in Finland. Results: The prevalence of asthma symptoms was higher in Norrbotten (13.2%), Seinäjoki-Vaasa (14.8%) and Helsinki (14.4%) than in Västra Götaland (10.7%), and physician-diagnosed asthma was highest in Norrbotten (13.0%) and least in Västra Götaland (10.1%). Chronic productive cough was most common in the Finnish areas (7.7-8.2 % versus 6.3-6.7 %) while the prevalence of physician-diagnosed chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD) varied between 1.7-2.7% in the four areas. Among individuals with respiratory symptoms, the prevalence of asthma was most common in Norrbotten, while a diagnosis of COPD or CB was most common in Västra Götaland and Seinäjoki-Vaasa. More women than men with respiratory symptoms reported a diagnosis of asthma in Sweden and Seinäjoki-Vaasa but there were no sex differences in Helsinki. In Sweden, more women than men with symptoms of cough or phlegm reported a diagnosis of CB or COPD, while in Finland the opposite was found. Conclusion: The prevalence of respiratory symptoms and corresponding diagnoses varied between and within the countries. The proportion reporting a diagnosis of obstructive airway disease among individuals with respiratory symptoms varied, indicating differences in diagnostic patterns both between areas and by sex.
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| 8. |
- Axelsson, Rebecca, et al.
(författare)
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Computer model of mechanical imaging acquisition for virtual clinical trials
- 2021
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Ingår i: Medical Imaging 2021 : Physics of Medical Imaging - Physics of Medical Imaging. - : SPIE. - 1605-7422. - 9781510640191 ; 11595, s. 1-115950
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Konferensbidrag (refereegranskat)abstract
- Malignant breast tumours can be distinguished from benign lesions and normal tissue based on their mechanical properties. Our pilot studies have demonstrated the potential of using Mechanical Imaging (MI) combined with mammography to reduce recalls and false positives in breast cancer screening by more accurately identifying benign lesions. To enable further optimization of MI we propose a computer simulation of the MI acquisition, for use in a Virtual Clinical Trial (VCT) framework. VCTs are computer simulated clinical trials used to efficiently evaluate clinical imaging systems. A linear elastic finite element (FE) model of the breast under dynamic compression was implemented using an open-source FE solver. A spherical tumour (15 mm in diameter) was inserted into the simulated predominantly adipose breast. The location and stiffness of the tumour was varied. The average stress on the compressed breast surface was calculated and compared with the local average stress at the tumour location and the Relative Mean Pressure over lesion Area (RMPA) was calculated. Preliminary results were within a realistic range with an average stress on the breast (tumour) of 5.9-16.6 kPa which is in agreement with published values between 1.0 - 22.5 kPa. This corresponds to RMPA values of 0.96-2.15 depending on stiffness and location of the tumour. This can lead to more detailed validation of various MI acquisition schemes through VCTs before their use in clinical studies.
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| 9. |
- Barufaldi, Bruno, et al.
(författare)
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Virtual Clinical Trials in Medical Imaging System Evaluation and Optimisation
- 2021
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Ingår i: Radiation Protection Dosimetry. - : Oxford University Press (OUP). - 1742-3406 .- 0144-8420. ; 195:3-4, s. 363-371
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Tidskriftsartikel (refereegranskat)abstract
- Virtual clinical trials (VCTs) can be used to evaluate and optimise medical imaging systems. VCTs are based on computer simulations of human anatomy, imaging modalities and image interpretation. OpenVCT is an open-source framework for conducting VCTs of medical imaging, with a particular focus on breast imaging. The aim of this paper was to evaluate the OpenVCT framework in two tasks involving digital breast tomosynthesis (DBT). First, VCTs were used to perform a detailed comparison of virtual and clinical reading studies for the detection of lesions in digital mammography and DBT. Then, the framework was expanded to include mechanical imaging (MI) and was used to optimise the novel combination of simultaneous DBT and MI. The first experiments showed close agreement between the clinical and the virtual study, confirming that VCTs can predict changes in performance of DBT accurately. Work in simultaneous DBT and MI system has demonstrated that the system can be optimised in terms of the DBT image quality. We are currently working to expand the OpenVCT software to simulate MI acquisition more accurately and to include models of tumour growth. Based on our experience to date, we envision a future in which VCTs have an important role in medical imaging, including support for more imaging modalities, use with rare diseases and a role in training and testing artificial intelligence (AI) systems.
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| 10. |
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| 11. |
- Borhade, Sanjay R, et al.
(författare)
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Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides
- 2014
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 3:6, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure-activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.
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| 12. |
- Engen, Karin, et al.
(författare)
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Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening
- 2016
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Ingår i: Assay and drug development technologies. - : Mary Ann Liebert Inc. - 1540-658X .- 1557-8127. ; 14:3, s. 180-193
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Tidskriftsartikel (refereegranskat)abstract
- Intracerebroventricular injection of angiotensin IV, a ligand of insulin-regulated aminopeptidase (IRAP), has been shown to improve cognitive functions in several animal models. Consequently, IRAP is considered a potential target for treatment of cognitive disorders. To identify nonpeptidic IRAP inhibitors, we adapted an established enzymatic assay based on membrane preparations from Chinese hamster ovary cells and a synthetic peptide-like substrate for high-throughput screening purposes. The 384-well microplate-based absorbance assay was used to screen a diverse set of 10,500 compounds for their inhibitory capacity of IRAP. The assay performance was robust with Z-values ranging from 0.81 to 0.91, and the screen resulted in 23 compounds that displayed greater than 60% inhibition at a compound concentration of 10M. After hit confirmation experiments, purity analysis, and promiscuity investigations, three structurally different compounds were considered particularly interesting as starting points for the development of small-molecule-based IRAP inhibitors. After resynthesis, all three compounds confirmed low M activity and were shown to be rapidly reversible. Additional characterization included activity in a fluorescence-based orthogonal assay and in the presence of a nonionic detergent and a reducing agent, respectively. Importantly, the characterized compounds also showed inhibition of the human ortholog, prompting our further interest in these novel IRAP inhibitors.
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| 13. |
- Fagerström, Cecilia, Docent, 1973-, et al.
(författare)
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The role of ICT in nursing practice : An integrative literature review of the Swedish context
- 2017
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Ingår i: Scandinavian Journal of Caring Sciences. - : Wiley-Blackwell. - 0283-9318 .- 1471-6712. ; 31:3, s. 434-448
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Forskningsöversikt (refereegranskat)abstract
- Background: The Swedish healthcare system employs information and communication technologies (ICT) in nursing practice to meet quality-, security- and efficiency-related demands. Although ICT is integrated with nursing practices, nurses do not always feel that they are convenient to use it. We need to improve our knowledge of the role of ICT in healthcare environments and so we decided to complement existing experience of how ICT influences nursing practice. Aim: This study aimed to review and synthesise the available literature on the role of ICT in nursing practice in Swedish healthcare settings. Method: To consolidate previous studies based on diverse methodologies, an integrative literature review was carried out. Three databases were used to search for literature, 20 articles met the inclusion criteria. Results: The literature review indicates that ICT integration into nursing practice is a complex process that impacts nurses’ communication and relationships in patient care, working conditions, and professional identities and development. Nurses are found to express ambiguous views on ICT as a usable service in their everyday practice since it impacts both positively and negatively. Discussion and conclusion: Although ICT cannot replace physical presence, it can be considered a complementary service that gives rise to improved patient care. However, nonverbal communication cues may be missed when ICT is used as mediating tool and ICT can be limiting because it is not always designed to meet nurse and patient needs. The meaning of an encounter appears to change when ICT is used in nursing practice, not only for patient relationships but also for interpersonal communication.
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| 14. |
- 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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| 15. |
- Halldorsdottir, Anna Margret, et al.
(författare)
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Mantle cell lymphoma displays a homogenous methylation profile : A comparative analysis with chronic lymphocytic leukemia
- 2012
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Ingår i: American Journal of Hematology. - : John Wiley & Sons. - 0361-8609 .- 1096-8652. ; 87:4, s. 361-367
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.
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| 16. |
- Halldorsdottir, Anna Margret, et al.
(författare)
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Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia
- 2012
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 87:4, s. 361-367
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL. Am. J. Hematol., 2012. (C) 2012 Wiley Periodicals, Inc.
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| 17. |
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| 18. |
- Herold, Nikolas, et al.
(författare)
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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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| 19. |
- Ideland, Malin, 1970-, et al.
(författare)
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”En hemlig skola röjer det orimliga"
- 2020
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Ingår i: Svenska Dagbladet. - Stockholm : Svenska Dagbladet. - 1101-2412. ; :2020-08-30
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Det är affärslogiken som styr när statistik om skolor och betyg nu ska sekretessbeläggas. Samtidigt visar detta hemlighetsmakeri tydligt att friskolan blivit norm och att andra värden felaktigt får stå tillbaka, skriver forskare.
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| 20. |
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| 21. |
- Jonsson, Josefin, et al.
(författare)
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Does 18F-FDG PET/CT change the surgical management of potentially resectable colorectal liver metastases?
- 2022
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Ingår i: Scandinavian Journal of Surgery. - : Sage Publications. - 1457-4969 .- 1799-7267. ; 111:1
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Resectability assessment of patients with colorectal liver metastases is based on computed tomography and liver magnetic resonance imaging. Addition of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography has been recommended, but the impact of the added information remains unclear. The primary aim of this study was to determine how preoperative positron emission tomography/computed tomography changed management in patients with potentially resectable colorectal liver metastases. The secondary aim was to investigate whether findings on positron emission tomography/computed tomography correlated to metastatic disease in cases with extended surgery and influenced oncological outcomes. METHODS: A retrospective observational study of the impact of adding positron emission tomography/computed tomography to conventional imaging in the surgical decision-making of colorectal liver metastases. All patients with colorectal liver metastases diagnosed by conventional imaging were included and assessed by a multidisciplinary team conference at Umeå University Hospital between June 2013 and December 2017. Eligibility criteria were all patients with potentially resectable colorectal liver metastases. Patients who underwent preoperative positron emission tomography/computed tomography in addition to conventional radiology were compared with those who underwent conventional imaging only. RESULTS: 151/220 patients underwent preoperative positron emission tomography/computed tomography. Findings on positron emission tomography/computed tomography changed the management in 10.6% of the patients. Eight patients were excluded from surgery after detection by positron emission tomography/computed tomography of extrahepatic disease. Eight patients underwent more extended surgery than initially planned due to positron emission tomography/computed tomography. Five of these positron emission tomography-positive resected sites were verified by pathology as metastatic disease. No difference in overall survival was seen following surgical resection in patients with and without a preoperative positron emission tomography/computed tomography. CONCLUSIONS: Preoperative positron emission tomography/computed tomography resulted in a changed surgical management in 10.6% of cases in a selected cohort.
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| 22. |
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| 23. |
- Mateus, André, 1986-, et al.
(författare)
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Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:30, s. E6231-E6239
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Tidskriftsartikel (refereegranskat)abstract
- Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F-ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F-ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F-ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.
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| 24. |
- Maurin Söderholm, Hanna, et al.
(författare)
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Stimulerad medkänsla
- 2021
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Ingår i: Didaktisk dialog i högre utbildning. - Lund : Studentlitteratur AB. - 9789144139029 ; , s. 163-182
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 25. |
- Maurin Söderholm, Hanna, et al.
(författare)
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Stimulerad medkänsla
- 2021
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Ingår i: Didaktisk dialog i högre utbildning. - 9789144139029 ; , s. 163-181
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Kollegiala samtal är ett viktigt verktyg för att stärka kvaliteten och utveckla undervisningen. Ändå är sådana diskussioner fortfarande sällsynta inom högre utbildning. Den här boken presenterar en modell för kollegiala samtal - så kallade didaktiska utvecklingsdialoger - med utgångspunkt i autentiska undervisningssituationer, hämtade från universitetslärares vardagsarbete inom olika utbildningar. Exempel på teman som belyses och diskuteras i boken är: utmaningen i att behandla ett omfattande ämnesinnehåll på få undervisningstimmar; lärstrukturer för distansstudenter; studenters negativa attityder till ett visst ämnesinnehåll; och relationen mellan vardagsföreställningar och teoretiskt grundad begreppsförståelse. Varje tema illustreras genom reflektion i flera steg, i en dialog mellan universitetslärare, forskare och pedagogiska utvecklare från olika lärosäten runt om i Sverige. Didaktisk dialog i högre utbildning är lämplig som litteratur på högskolepedagogiska kurser, och riktar sig också till enskilda universitetslärare och lärarlag som vill utveckla sin undervisning. Förhoppningen är att dialogerna ska ge inspiration och utmana, och också fungera som modell för samtal om undervisning och om det akademiska lärarskapets komplexitet.
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| 26. |
- Nilsonne, Gustav, et al.
(författare)
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A multimodal brain imaging dataset on sleep deprivation in young and old humans
- 2017
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The Stockholm Sleepy Brain Study I is a functional brain imaging study of 48 younger (20-30 years) and 36 older (65-75 years) healthy participants, with magnetic resonance imaging after normal sleep and partial sleep deprivation in a crossover design. We performed experiments investigating emotional mimicry, empathy for pain, and cognitive reappraisal, as well as resting state functional magnetic resonance imaging (fMRI). We also acquired T1- and T2-weighted structural images and diffusion tensor images (DTI). On the night before imaging, participants were monitored with ambulatory polysomnography and were instructed to sleep either as usual or only three hours. Participants came to the scanner the following evening. Besides MRI scanning, participants underwent behavioral tests and contributed blood samples, which have been stored in a biobank and used for DNA analyses. Participants also completed a variety of self-report measures. The resulting multimodal dataset may be useful for hypothesis generation or independent validation of effects of sleep deprivation and aging, as well as investigation of cross-sectional associations between the different outcomes. V. 2 of this manuscript published 2017-10-12. Changes: new co-author (Claus Lamm), changed affiliations for Kristoffer Månsson, minor changes in the abstract, and revisions of the main text and figures.
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| 27. |
- Page, Brent D. G., et al.
(författare)
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Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADPribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.
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| 28. |
- Reisdorf, Bianca Christin, et al.
(författare)
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Living Offline : A Qualitative Study of Internet Non-Use in Great Britain and Sweden
- 2012
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Ingår i: Selected Papers of Internet Research; IR 13. - : Association of Internet Researchers. - 2162-3317.
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Konferensbidrag (refereegranskat)abstract
- This study explores and compares attitudes and feelings of middle-aged British and Swedish Internet non-users as well as their reasons for being offline. The rich qualitative data are conceptualized and presented according to various reasons for non-use, positive and negative feelings regarding non-use, and the positive as well as negative influence of and dependence on social networks. The comparison shows both unique and common perceptions of the British and Swedish respondents, some of which can be attributed to social, economic, or socio-economic factors. However, it also displays vast differences between middle-aged non-users in both countries. The analysis paints a complex picture of decisions for and against the use of the Internet and the need for more research to understand these highly complex phenomena, which cannot simply be attributed to socio-economic backgrounds as has been done in most previous research. The analysis shows that more complex reasons, such as lack of interest or discomfort with technologies, as well as the somewhat surprising finding that social networks can prevent non-users from learning how to use the Internet, as it is more convenient to stay a proxy-user, should be considered in future research and policies regarding digital inequalities.
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| 29. |
- Rudd, Sean, et al.
(författare)
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Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy
- 2020
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Ingår i: EMBO Molecular Medicine. - : Blackwell Publishing Ltd. - 1757-4676 .- 1757-4684.
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Tidskriftsartikel (refereegranskat)abstract
- The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara-C efficacy by hydrolysing the active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1-mediated barrier to ara-C efficacy in primary blasts and mouse models of AML, displaying SAMHD1-dependent synergy with ara-C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara-CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara-C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML. © 2020 The Authors. Published under the terms of the CC BY 4.0 license
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| 30. |
- Seashore-Ludlow, Brinton, et al.
(författare)
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Quantitative Interpretation of Intracellular Drug Binding and Kinetics Using the Cellular Thermal Shift Assay
- 2018
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 57:48, s. 6715-6725
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Tidskriftsartikel (refereegranskat)abstract
- Evidence of physical interaction with the target protein is essential in the development of chemical probes and drugs. The cellular thermal shift assay (CETSA) allows evaluation of drug binding in live cells but lacks a framework to support quantitative interpretations and comparisons with functional data. We outline an experimental platform for such analysis using human kinase p38 alpha. Systematic variations to the assay's characteristic heat challenge demonstrate an apparent loss of compound potency with an increase in duration or temperature, in line with expectations from the literature for thermal shift assays. Importantly, data for five structurally diverse inhibitors can be quantitatively explained using a simple model of linked equilibria and published binding parameters. The platform further distinguishes between ligand mechanisms and allows for quantitative comparisons of drug binding affinities and kinetics in live cells and lysates. We believe this work has broad implications in the appropriate use of the CETSA for target and compound validation.
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| 31. |
- Sennfält, Karin, et al.
(författare)
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Costs and effect of biennial prostate cancer screening in Sweden : results from a randomized trial in a defined population
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The aim was to estimate the lifetime cost in relation to the extra number of detected localized and potentially curable cancers, and to estimate the economic impact on health care of repeated screening for prostate cancer in Sweden in a cohort of men aged 50-64 years.Material and Methods: From the total male population in the city of Gothenburg born between 1930-1944 (n=32,298), 10,000 men were randornized to prostate cancer screening beginning in January 1995, and 10,000 men were randomized to serve as a control group. PSA tests were offered every 2nd year until the age of 70. All health care costs for administration of the screening programme, screening tests, diagnostic procedures, and treatments were included. Data on detected cancers were collected from the prospective programme and from patient records. A Markov model was developed to calculate the cost-effectiveness and the total extra cost of the screening programme.Results: For the period from the start of the screening programme until death, the estimates were 17.7 extra localized cancers per 1,000 men and 7.3 extra cases of curative aimed treatments per 1,000 men. The incremental cost per extra detected localized cancer was calculated at 98,000 SEK, and per cancer with curative aimed treatment the figure was 236,000 SEK. Introducing this screening programme for prostate cancer in Sweden would yield 92 million SEK annually in additional costs for screening and management compared to a non-screening strategy.Conclusion: Introduction of prostate cancer screening with PSA would increase the total economic burden of prostate cancer for society by approximately 30 percent. Due to the lack of scientific data concerning possible survival benefits from prostate cancer screening, we must wait several years before the true cost-effectiveness of the programme can be calculated.
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| 32. |
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| 33. |
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| 34. |
- Tomic, Hanna, et al.
(författare)
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Virtual clinical trial of simultaneous digital breast tomosynthesis and mechanical imaging: : model calibration and the effect of tumor depth
- 2022
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Ingår i: Medical Imaging 2022: : Physics of Medical Imaging - Physics of Medical Imaging. - : SPIE. ; 12031
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Konferensbidrag (refereegranskat)abstract
- Simultaneous Digital Breast Tomosynthesis (DBT) and mechanical imaging (MI), called DBTMI, is a novel breast imaging method aimed at improving sensitivity and specificity of breast cancer screening. DBTMI combines improved cancer detection by three-dimensional DBT imaging, with the analysis of local stress over the compressed breast by MI, which can reduce false positive findings. The MI signal is affected by various factors, e.g., breast size, composition, tumor depth, etc. Assessing the individual effect of those factors using clinical data is difficult, due to their interdependence. These open clinical questions can be addressed by virtual clinical trials. Our current work is focused on the effects of tumor depth on the DBTMI signal. We simulated the breast anatomy by a matrix of adipose and glandular tissue compartments. Spherical tumors were inserted at various depths. The MI sensor is modeled by a compound material of PMMA and Ag. We calculated the local stress on the compressed breast surface at the tumor location and simulated the MI sensor output. We also simulated the corresponding DBT images and calculated the signal-difference-to-noise ratio (SDNR) with and without pre-processing to analyze the reduction in artifacts. Our preliminary analysis of 24 simulated tumors has shown 16% reduction in the local stress, when increasing tumor depth by 15 mm (10-25 mm from the breast surface). The SDNR improvement was highest for tumors near the sensor and the effect of pre-processing decreased with increasing tumor depth.
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| 35. |
- Zhang, Si Min, et al.
(författare)
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Development of a chemical probe against NUDT15
- 2020
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 16:10, s. 1120-1128
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Tidskriftsartikel (refereegranskat)abstract
- The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.
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