| 1. |
- Eltahir, mohmo394, et al.
(författare)
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Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients
- 2021
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Ingår i: International Immunopharmacology. - : Elsevier. - 1567-5769 .- 1878-1705. ; 90
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Tidskriftsartikel (refereegranskat)abstract
- Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods. To better recapitulate an in vivo setting, we implemented a unique human whole blood "loop" system to study patient-specific immune responses to rituximab in blood derived from CLL patients. Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature. Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting.
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| 2. |
- Ginman, Beatrice, et al.
(författare)
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Strict self-isolation did not protect Swedish cancer patients on active treatment from the risk of becoming seropositive for SARS-CoV-2
- 2023
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 62:12, s. 1707-1715
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSwedish recommendations to reduce the risk of COVID-19 relied on each citizen’s own sense of responsibility rather than mandatory lockdowns. We studied how COVID-19-related self-isolation and anxiety correlated to SARS-CoV-2 seropositivity and PCR-positivity in patients with active cancer treatment.MethodsIn a longitudinal cohort study at Uppsala University Hospital patients and cancer personnel were included between April 1st 2020 to August 1st 2020. Serological testing for SARS-CoV-2 was done every 8–12-weeks until 30 March 2021. Patients completed a survey at inclusion regarding self-reported COVID-19-related anxiety and self-isolation.ResultsA total of 622 patients [n = 475 with solid malignancies (SM), n = 147 with haematological malignancies (HM)], and 358 healthcare personnel were included. The seropositivity rate was lower for patients than for personnel; 10.5% for SM patients, 6.8% for HM patients, and 16.2% for personnel (p = 0.005). Strict adherence to self-isolation guidelines was reported by 54% of patients but was not associated with a lower risk of becoming seropositive [OR = 1.4 (0.8–2.5), p = 0.2]. High anxiety was expressed by 32% of patients, more often by SM patients than HM patients (34% vs 25% [OR = 1.6 (1.1–2.5, p = 0.03)]). Female gender [OR = 3.5 (2.4–5.2), p < 0.001] and being born outside of Europe [OR = 2.9 (1.4–6.4), p = 0.007] were both associated with high anxiety. Patients reporting high anxiety became seropositive to a similar degree as those with low anxiety [OR = 0.7 (0.3–1.2), p = 0.2]. HM patients with PCR-positive COVID-19 were more likely than SM patients to require oxygen therapy, including non-invasive ventilation/intubation (69% vs. 26%, p = 0.005).ConclusionFor Swedish patients on active cancer treatment, high self-assessed COVID-19-related anxiety or strict adherence to self-isolation guidelines were not associated with a lower risk of COVID-19. Patients with HM were less likely to develop serological antibody response after COVID-19 and were more likely to require advanced hospital care, but expressed less COVID-19-related anxiety than patients with SM.
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| 3. |
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| 4. |
- Hamberg Levedahl, Kerstin, et al.
(författare)
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How persons with systemic mastocytosis describe the time between symptom onset and receiving diagnosis
- 2022
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Ingår i: Primary Health Care Research and Development. - : Cambridge University Press. - 1463-4236 .- 1477-1128. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of the study was to explore how persons with systemic mastocytosis (SM) described the time between the onset of symptoms and signs and getting the diagnosis.Background: SM is a rare disease caused by the accumulation of clonal mast cells with abnormal function. The symptoms and signs of the disease are varied, often diffuse and affect individuals differently. Due to this complexity, a multi-disciplinary diagnostic approach is required, in which general practitioners play an important part in identifying and referring patients relevant for such investigations.Methods: Sixteen persons with SM were interviewed about their experiences of the time before the diagnosis was received. Systematic text condensation was used in the analysis process.Findings: The time between symptom and signs onset and diagnosis was perceived as difficult. SM often had a complex and unpredictable effect on a person’s daily life, long before diagnosis. In the analysis, three themes were found. Having symptoms and signs with an unknown cause included the participants’ descriptions of numerous symptoms and signs, often years before diagnosis. These could be severe and result in worries for both participants and their next-of-kin. Dealing with the symptoms and signs encompassed the different ways in which the participants coped with the symptoms and signs, and sought relief. Being a patient without a diagnosis underlined the lack of information and knowledge within healthcare, often resulting in a delayed or incorrect diagnosis. The study highlighted the importance of a person-centred approach and the need to increase knowledge of the disease within primary care, to shorten this stressful and vulnerable time.
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| 5. |
- Kumar, Jagarlamudi Kiran, et al.
(författare)
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AroCell TK 210 ELISA for determination of TK1 protein : age-related reference ranges and comparison with other TK1 assays
- 2020
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Ingår i: BioTechniques. - : FUTURE SCI LTD. - 0736-6205 .- 1940-9818. ; 68:6, s. 335-342
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Tidskriftsartikel (refereegranskat)abstract
- Thymidine kinase 1 (TK1) is an enzyme involved in DNA precursor synthesis that has been used as a biomarker for prognosis and monitoring of different malignancies. In this study, we compared two immunoassays for measuring TK1 protein concentrations: the TK 210 ELISA (AroCell AB) and TK1 ELISA from Abcam. Overall, the TK 210 ELISA showed higher sensitivity than the Abcam TK1 ELISA for differentiating hematological malignancies (sensitivity of 0.77 vs 0.45) as well as for distinguishing sera of patients with solid tumors from those of apparently healthy individuals (0.61 vs 0.20). There was no significant difference in the TK1 protein levels determined with the TK 210 ELISA between different age groups from apparently healthy individuals. These results strongly indicate that the AroCell TK 210 ELISA is accurate and sensitive enough to be a valuable tool in cancer management. METHOD SUMMARY Thymidine kinase 1 (TK1) is an enzyme that leaks from S phase cells as a result of high cell turnover. Commercially available TK activity assays have certain limitations; to overcome these, we developed a dual monoclonal antibody-based ELISA, the AroCell TK 210 ELISA, which is commercially available. The ELISA includes a preincubation procedure with a special buffer that reduces high molecular weight complexes of serum TK1 and exposes the TK1 epitope to facilitate antibody binding. This provides a robust and convenient assay for the determination of TK1 protein concentrations in sera from patients with different malignancies.
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| 6. |
- Lampinen, Maria, et al.
(författare)
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Mefloquine causes selective mast cell apoptosis in cutaneous mastocytosis lesions by a secretory granule-mediated pathway
- 2022
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Ingår i: Experimental dermatology. - : John Wiley & Sons. - 0906-6705 .- 1600-0625. ; 31:11, s. 1729-1740
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Tidskriftsartikel (refereegranskat)abstract
- Mastocytosis is a KIT-related myeloproliferative disease characterised by abnormal expansion of neoplastic mast cells (MC) in the skin or virtually any other organ system. The cutaneous form of adult-onset mastocytosis is almost invariably combined with indolent systemic involvement for which curative therapy is yet not available. Here we evaluated a concept of depleting cutaneous MCs in mastocytosis lesions ex vivo by targeting their secretory granules. Skin biopsies from mastocytosis patients were incubated with or without mefloquine, an antimalarial drug known to penetrate into acidic organelles such as MC secretory granules. Mefloquine reduced the number of dermal MCs without affecting keratinocyte proliferation or epidermal gross morphology at drug concentrations up to 40 mu M. Flow cytometric analysis of purified dermal MCs showed that mefloquine-induced cell death was mainly due to apoptosis and accompanied by caspase-3 activation. However, caspase inhibition provided only partial protection against mefloquine-induced cell death, indicating predominantly caspase-independent apoptosis. Further assessments revealed that mefloquine caused an elevation of granule pH and a corresponding decrease in cytosolic pH, suggesting drug-induced granule permeabilisation. Extensive damage to the MC secretory granules was confirmed by transmission electron microscopy analysis. Further, blockade of granule acidification or serine protease activity prior to mefloquine treatment protected MCs from apoptosis, indicating that granule acidity and granule-localised serine proteases play major roles in the execution of mefloquine-induced cell death. Altogether, these findings reveal that mefloquine induces selective apoptosis of MCs by targeting their secretory granules and suggest that the drug may potentially extend its range of medical applications.
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| 7. |
- Levedahl, Kerstin, et al.
(författare)
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Living with systemic mastocytosis: balancing between vulnerability and resilience: A qualitative study
- 2022
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Ingår i: European Journal of Oncology Nursing. - : Elsevier. - 1462-3889 .- 1532-2122. ; 60
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Systemic mastocytosis (SM) is a rare group of hematological malignancies with heterogeneous symptoms from various organs, and overall survival ranges from normal for indolent SM (ISM) to 2–4 years for advanced SM subtypes (Adv SM). There is limited knowledge about the experience of living with SM. Thus, the purpose of this study was to describe the experiences of everyday life among persons diagnosed with ISM or Adv SM. Methods In this descriptive qualitative study, data were collected through purposive sampling and semi-structured interviews with 16 participants diagnosed with ISM (n = 9) or Adv SM (n = 7). Data were subsequently analysed with content analysis. Results Three main categories were identified. The persistent presence of the disease includes findings of how the symptoms affected the participants, how they handled its limitations, and the adaptions and medication management required. Struggling against ignorance illustrates contact with both healthcare professionals and strangers. The participants described being forced to be experts on SM due to a general lack of knowledge. An illness or wellness perspective encompasses the participants’ feelings of vulnerability and alienation, but also how various strategies were used to gain emotional control.Conclusions The disease has a considerable impact on everyday life, with constant efforts required to manage symptoms and medication side effects. The complexity and rarity of the disease complicated relationships with healthcare professionals and contributed to feelings of marginalisation and alienation. The participants described feeling vulnerable but used a multitude of strategies in their striving for resilience. Trusting relationships with healthcare professionals, family members and friends promoted a wellness perspective.
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| 8. |
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| 9. |
- Oerlemans, Simone, et al.
(författare)
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International validation of the EORTC QLQ-CLL17 questionnaire for assessment of health-related quality of life for patients with chronic lymphocytic leukaemia
- 2022
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 197:4, s. 431-441
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Tidskriftsartikel (refereegranskat)abstract
- Selecting the most appropriate chronic lymphocytic leukaemia (CLL) treatment is challenging. Patient-reported health-related quality of life (HRQoL) is therefore a critical aspect to consider. This international study by the European Organization for Research and Treatment of Cancer (EORTC) tested the psychometric properties of a newly developed measure for CLL patients: the EORTC QLQ-CLL17 to supplement the core questionnaire (EORTC QLQ-C30). Patients with CLL (n = 341) from 12 countries completed the QLQ-C30, QLQ-CLL17 and a debriefing questionnaire. Sociodemographic and clinical data were recorded from medical records. A high percentage (30%-66%) reported symptoms and/or worries (e.g. aches/pains in muscles, lack of energy and worry/fears about health). Confirmatory factor analysis showed an acceptable to good fit of the 17 items on the three scales (i.e. symptom burden, physical condition/fatigue and worries/fears about health and functioning). Completion took on average 8 min. Test-retest and convergent validity was demonstrated. The QLQ-CLL17 differentiated between patients with an Eastern Cooperative Oncology group (ECOG) performance of 0 versus 1-3 (p's < 0.01 and clinically relevant). The newly developed EORTC QLQ-CLL17 will increase sensitivity of HRQoL assessment in patients with CLL. Implementation of this questionnaire both in clinical research and practice will help to generate unique clinically relevant data to better inform CLL treatment decision-making.
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| 10. |
- Struyf, Nona, et al.
(författare)
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Delineating functional and molecular impact of ex vivo sample handling in precision medicine
- 2024
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Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.
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