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  • 3801.
    Niinivirta, Marjut
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ullenhag, Gustav J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib2017In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 143, no 6, p. 961-970Article in journal (Refereed)
    Abstract [en]

    Purpose Tyrosine kinase inhibitors like sunitinib and sorafenib are commonly used to treat metastatic renal cell cancer patients. Cubilin is a membrane protein expressed in the proximal renal tubule. Cubilin and megalin function together as endocytic receptors mediating uptake of many proteins. There is no established predictive marker for metastatic renal cell cancer patients and the purpose of the present study was to assess if cubilin can predict response to treatment with tyrosine kinase inhibitors.

    Methods Cubilin protein expression was analyzsed in tumor tissue from a cohort of patients with metastatic renal cell cancer (n = 139) using immunohistochemistry. One hundred and thirty six of the patients were treated with sunitinib or sorafenib in the first- or second-line setting. Thirty of these were censored because of toxicity leading to the termination of treatment and the remaining (n = 106) were selected for the current study.

    Results Fifty-three (50%) of the tumors expressed cubilin in the membrane. The median progression-free survival was 8 months in patients with cubilin expressing tumors and 4 months in the cubilin negative group. In addition, the overall survival was better for patients with cubilin positive tumors. We also found that the fraction of cubilin negative patients was significantly higher in the non-responding group (PFS ≤3 months) compared to responding patients (PFS >3 months).

    Conclusions We show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib.

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  • 3802.
    Niinivirta, Marjut
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Surgical Pathology, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.
    Tumoral pyruvate kinase L/R as a predictive marker for the treatment of renal cancer patients with sunitinib and sorafenib2019In: Journal of Cancer, E-ISSN 1837-9664, Vol. 10, no 14, p. 3224-3231Article in journal (Other academic)
    Abstract [en]

    Background and aims: Treatment with tyrosine kinase inhibitors (TKI) like sunitinib and sorafenib has improved the prognosis of patients with metastatic renal cell cancer (mRCC). No predictive marker is available to select patients who will gain from these treatments. Tumoral pyruvate kinase L/R (PKLR) is a membrane protein with highly specific expression in the renal tubule. We have previously shown that the tumoral expression of cubilin (CUBN) is associated with progression free survival (PFS) in mRCC patients treated with sunitinib and sorafenib. The aim of the present study was to investigate if PKLR can predict response in these patients, alone and/or in combination with CUBN.

    Methods: A tissue microarray (TMA) was constructed of tumor samples from 139 mRCC patients. One hundred and thirty-six of these patients had been treated with sunitinib or sorafenib in the first or second-line setting. Thirty patients suffered from early severe toxicity leading to the termination of treatment. The remaining patients (n=106) were selected for the current study.

    Results: Fifty-five (52%) of the tumors expressed membranous PKLR. Patients with PKLR tumor expression experienced a significantly longer PFS compared to patients with no expression (eight versus five months, p = 0.019). Overall survival (OS) was also significantly better for patients with PKLR expression. In addition, the combined expression of PKLR and CUBN resulted in a higher predictive value than either marker alone.

    Conclusions: In this real world study we show that tumoral PKLR membrane expression is a positive predictive biomarker for sunitinib and sorafenib treatment in patients suffering from mRCC. Our results also indicate that the combined expression with cubilin more accurately than PKLR alone can select patients with no benefit from treatment.

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  • 3803.
    Niinivirta, Marjut
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Georganaki, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib2020In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 20, article id 339Article in journal (Refereed)
    Abstract [en]

    Background: Patients with metastatic renal cell cancer (mRCC) are commonly treated with the tyrosine kinase inhibitor sunitinib, which blocks signalling from vascular endothelial growth factor (VEGF) - and platelet-derived growth factor-receptors, inhibiting development of new blood vessels. There are currently no predictive markers available to select patients who will gain from this treatment. Epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is up-regulated in tumor endothelial cells in many types of cancer and may be a putative predictive biomarker due to its association with ongoing angiogenesis.

    Methods: ELTD1, CD34 and VEGF receptor 2 (VEGFR2) expressions were analysed in tumor vessels of renal cancer tissues from 139 patients with mRCC using immunohistochemistry. Ninety-nine patients were treated with sunitinib as the first or second-line therapy. Early toxicity, leading to the termination of the treatment, eliminated 22 patients from the analyses. The remaining (n = 77) patients were included in the current study. In an additional analysis, 53 sorafenib treated patients were evaluated.

    Results: Patients with high ELTD1 expression in the tumor vasculature experienced a significantly better progression free survival (PFS) with sunitinib treatment as compared to patients with low ELTD1 expression (8 versus 5.5 months, respectively). The expression level of CD34 and VEGFR2 showed no correlation to sunitinib response. In sorafenib treated patients, no association with ELTD1 expression and PFS/OS was found.

    Conclusions: Our results identify tumor vessel ELTD1 expression as a positive predictive marker for sunitinib-treatment in patients suffering from mRCC. The negative results in the sorafenib treated group supports ELTD1 being a pure predictive and not a prognostic marker for sunitinib therapy.

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  • 3804.
    Niittykoski, Minna
    et al.
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Biotechnol & Mol Med, Kuopio, Finland..
    zu Fraunberg, Mikael von und
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Martikainen, Miika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rauramaa, Tuomas
    Univ Eastern Finland, Inst Clin Med, Pathol, Kuopio, Finland.;Kuopio Univ Hosp, Dept Pathol, Kuopio, Finland..
    Immonen, Arto
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Koponen, Susanna
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland..
    Leinonen, Ville
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Vaha-Koskela, Markus
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Zhang, Qiwei
    Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Kuhnel, Florian
    Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany..
    Mei, Ya-Fang
    Umea Univ, Dept Clin Microbiol, Umea, Sweden..
    Yla-Herttuala, Seppo
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Biotechnol & Mol Med, Kuopio, Finland..
    Jaaskelainen, Juha E.
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Hinkkanen, Ari
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Biotechnol & Mol Med, Kuopio, Finland..
    Immunohistochemical Characterization and Sensitivity to Human Adenovirus Serotypes 3, 5, and 11p of New Cell Lines Derived from Human Diffuse Grade II to IV Gliomas2017In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, no 5, p. 772-779Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Oncolytic adenoviruses show promise in targeting gliomas because they do not replicate in normal brain cells. However, clinical responses occur only in a subset of patients. One explanation could be the heterogenic expression level of virus receptors. Another contributing factor could be variable activity of tumor antiviral defenses in different glioma subtypes.

    METHODS:

    We established a collection of primary low-passage cell lines from different glioma subtypes (3 glioblastomas, 3 oligoastrocytomas, and 2 oligodendrogliomas) and assessed them for receptor expression and sensitivity to human adenovirus (HAd) serotypes 3, 5, and 11p. To gauge the impact of antiviral defenses, we also compared the infectivity of the oncolytic adenoviruses in interferon (IFN)-pretreated cells with IFN-sensitive Semliki Forest virus (SFV).

    RESULTS:

    Immunostaining revealed generally low expression of HAd5 receptor CAR in both primary tumors and derived cell lines. HAd11p receptor CD46 levels were maintained at moderate levels in both primary tumor samples and derived cell lines. HAd3 receptor DSG-2 was reduced in the cell lines compared to the tumors. Yet, at equal multiplicities of infection, the oncolytic potency of HAd5 in vitro in tumor-derived cells was comparable to HAd11p, whereas HAd3 lysed fewer cells than either of the other two HAd serotypes in 72 hours. IFN blocked replication of SFV, while HAds were rather unaffected.

    CONCLUSIONS:

    Adenovirus receptor levels on glioma-derived cell lines did not correlate with infection efficacy and may not be a relevant indicator of clinical oncolytic potency. Adenovirus receptor analysis should be preferentially performed on biopsies obtained perioperatively.

  • 3805. Nik, Ali Moussavi
    et al.
    Reyahi, Azadeh
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Carlsson, Peter
    Foxf2 in Intestinal Fibroblasts Reduces Numbers of Lgr5(+) Stem Cells and Adenoma Formation by Inhibiting Wnt Signaling2013In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 144, no 5, p. 1001-1011Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: The stem cell niche at the base of the intestinal crypts, as well as stemness and high clonogenicity in colon cancer cells, depend on Wnt signaling to beta-catenin. Fibroblasts modulate the Wnt pathway in normal and neoplastic epithelial cells via unclear mechanisms. We investigated how in intestinal fibroblasts the forkhead transcription factor Foxf2 controls Wnt signaling to affect numbers of stem cells and formation and growth of adenomas in mice. METHODS: We created mice with different copy numbers of Foxf2 by generating Foxf2(-/+) mice and a transgenic strain, Tg(FOXF2). Adenoma formation was investigated in Apc(Min/+) mice, stem cells were counted in mice with the Lgr5-enhanced green fluorescent protein knock-in allele, proliferation was measured by incorporation of bromodeoxyuridine, Foxf2 and Sfrp1 were localized by immunohistochemistry, and signaling pathways were analyzed by quantitative polymerase chain reaction and immunoblot assays. RESULTS: Epithelial beta-catenin was stabilized in Foxf2(-/+) mice, resulting in increased number and size of adenomas. Tg(FOXF2) mice, however, were partially resistant to intestinal neoplasia and developed fewer and smaller adenomas; Foxf2(-/+) mice developed 24-fold more tumors than Tg(FOXF2) mice. Epithelial cells of Foxf2(-/+) mice also had higher numbers of Lgr5(+) stem cells and greater amounts of crypt cell proliferation and expression of Myc (a target of Wnt signaling) than Tg(FOXF2) mice. Expression of Sfrp1, which encodes an extracellular inhibitor of Wnt, in fibroblasts increased with copy number of Foxf2. CONCLUSIONS: Foxf2 is a fibroblast factor that inhibits paracrine Wnt signaling and restricts the crypt stem cell niche in intestines of mice. Loss of Foxf2 promotes adenoma formation and growth.

  • 3806.
    Nikberg, Maziar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Chabok, Abbas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Letocha, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Kindler, Csaba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedh, Kennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Lymphovascular and perineural invasion in stage II rectal cancer: a report from the Swedish colorectal cancer registry2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 12, p. 1418-1424Article in journal (Refereed)
    Abstract [en]

    Background: Adjuvant chemotherapy for stage II and III rectal cancer patients is a matter of discussion. The aim of the present study was to evaluate the prognostic value of lymphovascular (LVI) and perineural (PNI) invasion in stage II rectal cancer on a national level. Materials and methods: Clinico-pathological factors associated with disease-free survival (DFS) and time to recurrence in stage II rectal cancer patients were analyzed from patient data registered in the Swedish Colorectal Cancer Registry between 2006 and 2012. Results: Of 2649 patients with TNM stage II disease, 1395 (53%) received preoperative radiotherapy and 456 (17%) preoperative chemoradiotherapy. LVI and PNI were detected in 387 (15%) and 269 (10%) patients, respectively. Adjuvant chemotherapy was planned in 14%, but more often if LVI or PNI was detected (25% and 31%, respectively, p < .001 for both). The three-year DFS and time to recurrence were 78% and 17%, respectively. Both LVI and PNI indicated worse outcome. In patients not receiving postoperative chemotherapy, the risks of recurrence after three years were 20% if LVI was seen and 22% if PNI was detected (p < .001 for both). In the absence of LVI and PNI, it was 13% and 12%, respectively. In a multivariate Cox regression analysis, patients with LVI (hazard ratio 1.44, 95% CI 1.09-1.90; p = .011) and PNI (hazard ratio 1.80, 95% CI 1.34-2.43, p < .001) had significantly increased risks of recurrence. Conclusions: Stage II rectal cancer patients with LVI and PNI have an increased risk of recurrence which emphasizes the need to properly evaluate the role of adjuvant chemotherapy particularly in these subgroups.

  • 3807. Nikitenko, Leonid L
    et al.
    Shimosawa, Tatsuo
    Henderson, Stephen
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Shimosawa, Hiromi
    Qureshi, Uzma
    Pedley, R Barbara
    Rees, Margaret C P
    Fujita, Toshiro
    Boshoff, Chris
    Adrenomedullin haploinsufficiency predisposes to secondary lymphedema.2013In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 133, no 7Article in journal (Refereed)
    Abstract [en]

    Secondary lymphedema is a debilitating condition, and genetic factors predisposing to its development remain largely unknown. Adrenomedullin (AM) is peptide encoded, together with proadrenomedullin N-terminal peptide (PAMP), by the Adm gene (adrenomedullin gene). AM and its putative receptor calcitonin receptor-like receptor (CLR) are implicated in angiogenesis and lymphangiogenesis during embryogenesis and wound healing, suggesting their possible involvement in secondary lymphedema. To investigate whether AM deficiency predisposes to secondary lymphedema, we used heterozygous adult mice with Adm gene-knockin stop mutation, which selectively abrogated AM, but preserved PAMP, expression (Adm(AM+/Δ) animals). After hind limb skin incision, Adm messenger RNA expression was upregulated in wounded tissue of both Adm(AM+/+) and Adm(AM+/Δ) mice. However, only Adm(AM+/Δ) animals developed limb swelling and histopathological lymphedematous changes, including epidermal thickening, elevated collagen fiber density, and increased microvessel diameter. Secondary lymphedema was prevented when circulating AM levels in Adm(AM+/Δ) mice were restored by systemic peptide delivery. In human skin, CLR was expressed in tissue components affected by lymphedema, including epidermis, lymphatics, and blood vessels. Our study identified a previously unrecognized role for endogenous AM as a key factor in secondary lymphedema pathogenesis and provided experimental in vivo evidence of an underlying germ-line genetic predisposition to developing this disorder.

  • 3808.
    Nikkarinen, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Lokhande, Lavanya
    Lund Univ, Dept Immunotechnol, Lund, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Jerkeman, Mats
    Lund Univ, Dept Clin Sci Oncol & Pathol, Lund, Sweden..
    Porwit, Anna
    Lund Univ, Dept Clin Sci Oncol & Pathol, Lund, Sweden..
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Kolstad, Arne
    Innlandet Hosp Trust Div Gjovik, Dept Oncol, Lillehammer, Norway..
    Raety, Riikka
    Helsinki Univ Hosp, Comprehens Canc Ctr, Dept Hematol, Helsinki, Finland..
    Hutchings, Martin
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Weibull, Caroline E.
    Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden..
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Ek, Sara
    Lund Univ, Dept Immunotechnol, Lund, Sweden..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden..
    Soluble CD163 predicts outcome in both chemoimmunotherapy and targeted therapy-treated mantle cell lymphoma2023In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 7, no 18, p. 5304-5313Article in journal (Refereed)
    Abstract [en]

    The outcome for patients with mantle cell lymphoma (MCL) has drastically improved with new treatments directed toward the tumor immune microenvironment, where macrophages play an important role. In MCL, the presence of M2 macrophages defined by CD163 expression in diagnostic biopsies has been associated with a worse prognosis. An alternative way to assess the abundance of M2 macrophages is by measuring the level of soluble CD163 in serum (sCD163). We aimed to investigate the prognostic value of sCD163 in 131 patients with MCL. We found that high sCD163 at diagnosis was associated with shorter progression-free survival (PFS) and shorter overall survival (OS) in 81 patients who were newly diagnosed and subsequently treated with chemoimmunotherapy. The same was seen in a cohort of 50 patients with relapsed MCL that were mainly treated within the phase 2 Philemon-trial with rituximab, ibrutinib, and lenalidomide. In patients who were newly diagnosed and had low levels of sCD163, 5-year survival was 97%. There was a moderate correlation between sCD163 and tissue CD163. The association with a poor prognosis was independent of MCL international prognostic index, Ki67, p53 status, and blastoid morphology, as assessed in a multivariable Cox proportional hazards model. In this study, high sCD163 was associated with both shorter PFS and shorter OS, showing that high levels of the M2 macrophage marker sCD163 is an independent negative prognostic factor in MCL, both in the chemoimmunotherapy and ibrutinib/lenalidomide era. In addition, low sCD163 levels identify patients with MCL with a very good prognosis.

  • 3809.
    Niklasson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nyberg, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Segerman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Natl Vet Inst, Dept Microbiol, Uppsala, Sweden.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, Uppsala, Sweden;Uppsala Univ, Uppsala Univ Hosp, Dept Med Sci Canc Pharmacol & Computat Med, Uppsala, Sweden.
    Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 249, no 3, p. 295-307Article in journal (Refereed)
    Abstract [en]

    Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma-initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy-resistant MES-like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single-cell level and strongly correlated with our previously defined therapy-resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy-resistant MES-like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long-term exposure to the proinflammatory cytokine interleukin 1 beta (IL1 beta). IL1 beta induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive-astrocyte-like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called 'reactive GICs'. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor-promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment-resistant relapse-driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 3810.
    Niklasson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dalmo, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    BMP4 induction of a senescence-like phenotype in human glioblastoma cells is dependent on p21Manuscript (preprint) (Other academic)
    Abstract [en]

    Glioblastoma (GBM) is a lethal disease and curative treatment is still lacking. BMP4 was initially suggested as a differentiation treatment of GBM, since it has been shown to induce astrocytic differentiation, but other reports have demonstrated that the response is reversible, variable among patient samples, and heterogeneous within the same cell line. To further interrogate the nature of the BMP4 proliferation-inhibitory response, we focused on cellular growth and senescence. BMP4 was found to induce a senescence-like phenotype in a SMAD-dependent manner in a subpopulation of GBM cells, demonstrated by induction of senescence-associated (SA)-β-gal, downregulation of lamin B1, as well as increased lysosomal mass, cell size and granularity, paralleled by an increase in p21 levels. To zoom in on the heterogeneity in BMP4 response within a cell culture, we used a therapy-sensitive/proneural-like (SENS/PN) clone and a therapy-resistant/mesenchymal-like (RES/MES) clone from the same tumor and saw a more prominent induction of a senescence-like phenotype in the RES/MES clone. Since the RES/MES clone showed higher basal levels of p21 and lower lamin B1 than the SENS/PN clone, we suggest that the expression of senescence markers is a component of the mesenchymal profile. Senolytic treatment ablated the SA-β-gal positive cells and normalized the p21 levels, and this enabled us to couple p21 upregulation to the senescence-like phenotype. In p21 knockout cells, BMP4-induced cell growth and SA-β-gal were abolished and lamin B1 was not down-regulated. SOX2, which in part mediates the inhibition of proliferation by BMP4, was down-regulated but still BMP4-treated p21 knockout cells proliferated faster than BMP4-treated wild-type cells. Altogether, this demonstrates that p21 signaling is crucial for BMP4-mediated induction of a senescence-like phenotype in GBM.

  • 3811.
    Niklasson, Mia
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Maddalo, Gianluca
    Sramkova, Zuzana
    Mutlu, Ercan
    Wee, Shimei
    Sekyrova, Petra
    Schmidt, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fritz, Nicolas
    Dehnisch, Ivar
    Kyriatzis, Gregorios
    Krafcikova, Michaela
    Carson, Brittany B
    Feenstra, Jennifer M
    Marinescu, Voichita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haraldsson, Martin
    Gustavsson, Anna-Lena
    Hammarström, Lars G J
    Jenmalm Jensen, Annika
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Altelaar, A F Maarten
    Linnarsson, Sten
    Uhlén, Per
    Trantirek, Lukas
    Vincent, C Theresa
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enger, Per Øyvind
    Andäng, Michael
    Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 7, p. 1741-1752Article in journal (Refereed)
    Abstract [en]

    Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca(2+) and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na(+), which compromised Na(+)-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.

  • 3812.
    Nilchian, Azadeh
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Johansson, Joel
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden;Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland.
    Ghalali, Aram
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden;Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA.
    Asanin, Sandra T.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Santiago, Ana
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Rosencrantz, Oskar
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Sollerbrant, Kerstin
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Univ Hosp, Stockholm, Sweden.
    Vincent, C. Theresa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden;Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA.
    Sund, Malin
    Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden.
    Stenius, Ulla
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Fuxe, Jonas
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 1, p. 47-60Article in journal (Refereed)
    Abstract [en]

    Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here, we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyperactivation of AKT and sensitized cells to TGF beta 1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer.

    Significance: The tight junction protein CXADR controls epithelial-mesenchymal plasticity in breast cancer by stabilizing the AKT regulators PTEN and PHLPP2.

  • 3813. Nilsson, A.
    et al.
    Lundkvist, J.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Time and value of chemotherapy administration burden in a Swedish hospital2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76Article in journal (Other academic)
  • 3814.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl N., Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden.
    Manell, Elin
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, Uppsala, Sweden.
    Biglarnia, Alireza
    Skane Univ Hosp, Dept Transplantat, Malmo, Sweden.
    Jensen-Waern, Marianne
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, Uppsala, Sweden.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Tokyo, Dept Bioengn, Tokyo, Japan.
    A protective role of complement regulators linked to a PEG phospholipid construct in reducing ischemic reperfusion injury in transplantation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 208-208Article in journal (Other academic)
  • 3815.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Complement Diagnostics: Concepts, Indications, and Practical Guidelines2012In: Clinical & Developmental Immunology, ISSN 1740-2522, E-ISSN 1740-2530, p. 962702-Article, review/survey (Refereed)
    Abstract [en]

    Aberrations in the complement system have been shown to be direct or indirect pathophysiological mechanisms in a number of diseases and pathological conditions such as autoimmune disease, infections, cancer, allogeneic and xenogeneic transplantation, and inflammation. Complement analyses have been performed on these conditions in both prospective and retrospective studies and significant differences have been found between groups of patients, but in many diseases, it has not been possible to make predictions for individual patients because of the lack of sensitivity and specificity of many of the assays used. The basic indications for serological diagnostic complement analysis today may be divided into three major categories: (a) acquired and inherited complement deficiencies; (b) disorders with complement activation; (c) inherited and acquired C1INH deficiencies. Here, we summarize indications, techniques, and interpretations for basic complement analyses and present an algorithm, which we follow in our routine laboratory.

  • 3816.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The tick-over theory revisited: Is C3 a contact-activated protein?2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1106-1110Article, review/survey (Refereed)
    Abstract [en]

    The tick-over theory was first introduced in the 1970s to explain the presence of the initial C3b molecules, which are able to trigger complement activation by the alternative pathway in human plasma under physiological conditions. After the identification of the thioester, the predominant hypothesis has been that this bond is hydrolyzed at a slow but constant rate by nucleophilic attack by H2O, leading to the generation of C3(H2O). Here we put forward the hypothesis that the rate of hydrolysis of C3 to C3(H2O) may be greatly accelerated by the interaction between C3 and a number of biological and artificial interfaces, including gas bubbles, biomaterial surfaces and different lipid surfaces and complexes. We therefore propose that C3 should preferentially be regarded as a contact activated protein rather than a target for passive, random hydrolysis in the fluid phase.

  • 3817.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kemper, Claudia
    Mollnes, Tom Eirik
    Preface: Special Issue 15th European Meeting on Complement in Human Disease 2015, Uppsala, Sweden2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 1-2Article in journal (Other academic)
  • 3818.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Plasma concentrations of C3 and C4 are linked to cardiovascular risk factors and to the metabolic syndrome2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3 SI, p. 252-252Article in journal (Other academic)
  • 3819.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eriksson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Persson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    How COVID-19 and other pathological conditions and medical treatments activate our intravascular innate immune system2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 1030627Article in journal (Refereed)
    Abstract [en]

    COVID-19 has been shown to have a multifaceted impact on the immune system. In a recently published article in Front Immunol, we show that the intravascular innate immune system (IIIS) is strongly activated in severe COVID-19 with ARDS and appears to be one of the causes leading to severe COVID-19. In this article, we describe the IIIS and its physiological function, but also the strong pro-inflammatory effects that are observed in COVID-19 and in various other pathological conditions and treatments such as during ischemia reperfusion injury and in treatments where biomaterials come in direct contact with blood in, e.g., extracorporeal and intravasal treatments. In the present article, we describe how the IIIS, a complex network of plasma proteins and blood cells, constitute the acute innate immune response of the blood and discuss the effects that the IIIS induces in pathological disorders and treatments in modern medicine.

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  • 3820.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hänni, Arvo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    C3 And C4 Are Strongly Related To Adipose Tissue Variables And Cardiovascular Risk Factors2014In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 44, no 6, p. 587-596Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In several reports C3 and C4 have been linked to diabetes and cardiovascular disease (CVD). Here we investigate this link and the degree of C3 activation in elderly individuals.

    METHODS: In the present study, C3 and C4 and the activation fragment C3a-desArg were analyzed in 1016 subjects aged 70, in which blood pressure, lipid variables and fasting blood glucose were assessed.

    RESULTS: C3 levels were related to all the investigated classical cardiovascular risk factors and the metabolic syndrome (BMI, waist circumference, fat distribution, blood pressure, blood glucose levels, TG) except total cholesterol and LDL-cholesterol in a highly significant fashion (Spearman up to 0,5; p<0.0001). C4 and C3a-desArg were associated in the same fashion but less significantly, while the ratios C4/C3 or C3a-desArg/C3 were not, indicating that the association was not directly related to complement activation. The levels C3 and to a lesser degree C4 and C3a-desArg, were associated particularly to CRP, but also to E-selectin and ICAM-1. In addition, C3 and C4 levels were shown to decline significantly in 15 female subjects enrolled in a weight-reduction program over 4 months.

    CONCLUSION: A strong relation between C3, C4 and C3a-desArg levels, adipose tissue and risk factors of CVD was established. The data support that the adipose tissue produces complement components and generates initiators of inflammation, such as C3a and C5a, able to trigger a cyto/chemokine response, in proportion to the amount of adipose tissue. This corroborates the concept that complement contributes to the low-grade inflammation associated with obesity. This article is protected by copyright. All rights reserved.

  • 3821.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kozarcanin, Huda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lood, Christian
    Munthe-Fog, Lea
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bengtsson, Anders
    Skjodt, Mikkel-Ole
    Garred, Peter
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The lectin complement pathway serine proteases (MASPs) represent the crossroad between activation of the coagulation and complement systems2014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 218-219Article in journal (Other academic)
  • 3822.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment2011In: Current Opinion in Organ Transplantation, ISSN 1087-2418, E-ISSN 1531-7013, Vol. 16, no 6, p. 620-626Article in journal (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW:

    Transplantation of islets of Langerhans is an emerging treatment procedure for patients with severe type 1 diabetes, but despite recent progress the procedure is associated with massive tissue loss caused by an inflammatory reaction termed instant blood-mediated inflammatory reaction (IBMIR). This reaction involves activation of the complement and coagulation cascades, ultimately resulting in clot formation and infiltration of leukocytes into the islets, which leads to disruption of islet integrity and islet destruction.

    RECENT FINDINGS:

    In this review we discuss basic mechanisms underlying the IBMIR and emerging strategies for therapeutic regulation of the IBMIR. These include the use of selective inhibitors of the coagulation and complement systems, different procedures to coat the surface of the islets as well as the development of composite islet-endothelial cell grafts.

    SUMMARY:

    The IBMIR is a major cause of tissue loss in clinical islet transplantation, and most likely in other cell therapies in which cells are exposed to blood. Thus, it is an obvious target for therapeutic intervention. Due to its complexity, it is necessary to use different strategies to control the IBMIR.

  • 3823.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Persson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Hedenstierna laboratory.
    Huber-Lang, Markus
    Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany..
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    How the Innate Immune System of the Blood Contributes to Systemic Pathology in COVID-19-Induced ARDS and Provides Potential Targets for Treatment2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 840137Article, review/survey (Refereed)
    Abstract [en]

    Most SARS-CoV-2 infected patients experience influenza-like symptoms of low or moderate severity. But, already in 2020 early during the pandemic it became obvious that many patients had a high incidence of thrombotic complications, which prompted treatment with high doses of low-molecular-weight heparin (LMWH; typically 150-300IU/kg) to prevent thrombosis. In some patients, the disease aggravated after approximately 10 days and turned into a full-blown acute respiratory distress syndrome (ARDS)-like pulmonary inflammation with endothelialitis, thrombosis and vascular angiogenesis, which often lead to intensive care treatment with ventilator support. This stage of the disease is characterized by dysregulation of cytokines and chemokines, in particular with high IL-6 levels, and also by reduced oxygen saturation, high risk of thrombosis, and signs of severe pulmonary damage with ground glass opacities. The direct link between SARS-CoV-2 and the COVID-19-associated lung injury is not clear. Indirect evidence speaks in favor of a thromboinflammatory reaction, which may be initiated by the virus itself and by infected damaged and/or apoptotic cells. We and others have demonstrated that life-threatening COVID-19 ARDS is associated with a strong activation of the intravascular innate immune system (IIIS). In support of this notion is that activation of the complement and kallikrein/kinin (KK) systems predict survival, the necessity for usage of mechanical ventilation, acute kidney injury and, in the case of MBL, also coagulation system activation with thromboembolism. The general properties of the IIIS can easily be translated into mechanisms of COVID-19 pathophysiology. The prognostic value of complement and KKsystem biomarkers demonstrate that pharmaceuticals, which are licensed or have passed the phase I trial stage are promising candidate drugs for treatment of COVID-19. Examples of such compounds include complement inhibitors AMY-101 and eculizumab (targeting C3 and C5, respectively) as well as kallikrein inhibitors ecallantide and lanadelumab and the bradykinin receptor (BKR) 2 antagonist icatibant. In this conceptual review we discuss the activation, crosstalk and the therapeutic options that are available for regulation of the IIIS.

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  • 3824.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies2014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 185-190Article, review/survey (Refereed)
    Abstract [en]

    Cell therapies in which the cells come into direct contact with blood and other body fluids are emerging treatment procedures for patients with various diseases, such as diabetes mellitus, liver insufficiency, and graft-versus-host disease. However, despite recent progress, these procedures are associated with tissue loss caused by thromboinflammatory reactions. These deleterious reactions involve the activation of the complement and coagulation cascades and platelet and leukocyte activation, ultimately resulting in clot formation and damage to the implanted cells. In this concept review, we discuss the basic mechanisms underlying the thrombininflammatory process, with special reference to the engagement of complement and emerging strategies for the therapeutic regulation of these reactions that include the use of selective systemic inhibitors and various procedures to coat the surfaces of the cells. The coating procedures may also be applied to other treatment modalities in which similar mechanisms are involved, including whole organ transplantation, treatment with biomaterials in contact with blood, and extracorporeal procedures.

  • 3825.
    Nilsson, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Ida
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund.
    Ahlin, Cecilia
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Thorstenson, Sten
    Department of Pathology, Linköping University Hospital, Linköping, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Holmqvist, Marit
    Uppsala-Örebro Regional Oncologic Center, Uppsala, Sweden .
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hedenfalk, Ingrid
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 1, p. 102-109Article in journal (Refereed)
    Abstract [en]

    Background.

    Male breast cancer (MBC) is an uncommon disease and there is limited information on the prognostic impact of routinely used clinicopathological parameters.

    Material and methods.

    In a retrospective setting, we reviewed 197 MBC patients with accessible paraffin-embedded tumor tissue and clinicopathological data. Immunohistochemical (IHC) stainings were performed on tissue microarrays and histological grading on conventional slides. Cox proportional regression models were applied for uni- and multivariate analyses using breast cancer death as the event.

    Results.

    Estrogen receptor (ER) and progesterone receptor positivity were demonstrated in 93% and 77% of patients, respectively. Nottingham histologic grade (NHG) III was seen in 41% and HER2 positivity in 11%. Classification into molecular subtypes using IHC markers according to three alternative definitions revealed luminal A and luminal B in 81% vs. 11%; 48% vs. 44% and 41% vs. 42% of cases. Two cases of basal-like were identified, but no cases of HER2-like. Factors associated with an increased risk of breast cancer death were node positivity (HR 4.5; 95% CI 1.8-11.1), tumor size > 20 mm (HR 3.3; 95% CI 1.4-7.9) and ER negativity (HR 10.9; 95% CI 3.2-37.9). No difference in breast cancer death between the luminal subgroups was demonstrated, regardless of definition.

    Conclusion.

    MBC tumors were more often of high grade, whereas HER2 overexpression was as frequent as in FBC. Lymph nodes, tumor size and ER status were independent predictors of breast cancer death. The prognostic impact of molecular subtyping in MBC seems to differ from that previously established in FBC.

  • 3826.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Davoodpour, Padideh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ekstrand-Hammarström, Barbro
    Division of CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bucht, Anders
    Division of CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden;Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Mohlin, Camilla
    Linnæus Centre for Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
    Seisenbaeva, Gulaim
    Department of Chemistry and Biotechnology, BioCenter, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Kessler, Vadim
    Department of Chemistry and Biotechnology, BioCenter, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles.2018In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 14, no 3, p. 735-744Article in journal (Refereed)
    Abstract [en]

    Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. alpha-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine alpha-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The alpha-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikrein activation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.

  • 3827.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Evaluation of the blood compatibility of materials, cells and tissues: Basic concepts, test models and practical guidelines2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 735, p. 257-270Article in journal (Refereed)
    Abstract [en]

    Medicine today uses a wide range of biomaterials, most of which make contact with blood permanently or transiently upon implantation. Contact between blood and nonbiological materials or cells or tissue of nonhematologic origin initiates activation of the cascade systems (complement, contact activation/coagulation) of the blood, which induces platelet and leukocyte activation.

    Although substantial progress regarding biocompatibility has been made, many materials and medical treatment procedures are still associated with severe side effects. Therefore, there is a great need for adequate models and guidelines for evaluating the blood compatibility of biomaterials. Due to the substantial amount of cross talk between the different cascade systems and cell populations in the blood, it is advisable to use an intact system for evaluation.

    Here, we describe three such in vitro models for the evaluation of the biocompatibility of materials and therapeutic cells and tissues. The use of different anticoagulants and specific inhibitors in order to be able to dissect interactions between the different cascade systems and cells of the blood is discussed. In addition, we describe two clinically relevant medical treatment modalities, the integration of titanium implants and transplantation of islets of Langerhans to patients with type 1 diabetes, whose mechanisms of action we have addressed using these in vitro models.

  • 3828.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lambris, John
    University of Pennsylvania.
    Elwing, Hans
    Götebors universitet.
    Ricklin, Daniel
    University of Pennsylvania.
    Nilsson, Per H.
    Linneuniversitetet.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nicholls, Ian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategie2011In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 63, no 12, p. 1042-1050Article, review/survey (Refereed)
    Abstract [en]

    When an artificial biomaterial (e.g., a stent or implantable pump) is exposed to blood, plasma proteins immediately adhere to the surface, creating a new interface between the biomaterial and the blood. The recognition proteins within the complement and contact activation/coagulation cascade systems of the blood will be bound to, or inserted into, this protein film and generate different mediators that will activate polymorphonuclear leukocytes and monocytes, as well as platelets. Under clinical conditions, the ultimate outcome of these processes may be thrombotic and inflammatory reactions, and consequently the composition and conformation of the proteins in the initial layer formed on the surface will to a large extent determine the outcome of a treatment involving the biomaterial, affecting both the functionality of the material and the patient's life quality. This review presents models of biomaterial-induced activation processes and describes various strategies to attenuate potential adverse reactions by conjugating bioactive molecules to surfaces or by introducing nanostructures.

  • 3829.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden.
    Mohlin, Camilla
    Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden.
    Adler, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Åman, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Manivel, Vivek Anand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sandholm, Kerstin
    Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Is generation of C3(H2O) necessary for activation of the alternative pathway in real life?2019In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 114, p. 353-361Article in journal (Refereed)
    Abstract [en]

    In the alternative pathway (AP) an amplification loop is formed, which is strictly controlled by various fluid-phase and cell-bound regulators resulting in a state of homeostasis. Generation of the “C3b-like” C3(H2O) has been described as essential for AP activation, since it conveniently explains how the initial fluid-phase AP convertase of the amplification loop is generated. Also, the AP has a status of being an unspecific pathway despite thorough regulation at different surfaces.

    During complement attack in pathological conditions and inflammation, large amounts of C3b are formed by the classical/lectin pathway (CP/LP) convertases. After the discovery of LP's recognition molecules and its tight interaction with the AP, it is increasingly likely that the AP acts in vivo mainly as a powerful amplification mechanism of complement activation that is triggered by previously generated C3b molecules initiated by the binding of specific recognition molecules.

    Also in many pathological conditions caused by a dysregulated AP amplification loop such as paroxysmal nocturnal hemoglobulinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), C3b is available due to minute LP and CP activation and/or generated by non-complement proteases. Therefore, C3(H2O) generation in vivo may be less important for AP activation during specific attack or dysregulated homeostasis, but may be an important ligand for C3 receptors in cell-cell interactions and a source of C3 for the intracellular complement reservoir.

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  • 3830.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Persson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mohlin, Camilla
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Sandholm, Kerstin
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Skattum, Lillemor
    Lund Univ, Dept Lab Med Clin Immunol & Transfus Med, Sect Microbiol Immunol & Glycobiol, Lund, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Interpretation of Serological Complement Biomarkers in Disease2018In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 2237Article, review/survey (Refereed)
    Abstract [en]

    Complement systemaberrations have been identified as pathophysiological mechanisms in a number of diseases and pathological conditions either directly or indirectly. Examples of such conditions include infections, inflammation, autoimmune disease, as well as allogeneic and xenogenic transplantation. Both prospective and retrospective studies have demonstrated significant complement-related differences between patient groups and controls. However, due to the low degree of specificity and sensitivity of some of the assays used, it is not always possible to make predictions regarding the complement status of individual patients. Today, there are three main indications for determination of a patient's complement status: (1) complement deficiencies (acquired or inherited); (2) disorders with aberrant complement activation; and (3) C1 inhibitor deficiencies (acquired or inherited). An additional indication is to monitor patients on complement-regulating drugs, an indication which may be expected to increase in the near future since there is now a number of such drugs either under development, already in clinical trials or in clinical use. Available techniques to study complement include quantification of: (1) individual components; (2) activation products, (3) function, and (4) autoantibodies to complement proteins. In this review, we summarize the appropriate indications, techniques, and interpretations of basic serological complement analyses, exemplified by a number of clinical disorders.

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  • 3831.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jonsson, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Thromboinflammation in Therapeutic Medicine2015In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 865, p. 3-17Article, review/survey (Refereed)
    Abstract [en]

    Thromboinflammation is primarily triggered by the humoral innate immune system, which mainly consists of the cascade systems of the blood, i.e., the complement, contact/coagulation and fibrinolytic systems. Activation of these systems subsequently induces activation of endothelial cells, leukocytes and platelets, finally resulting in thrombotic and inflammatory reactions. Such reactions are triggered by a number of medical procedures, e.g., treatment with biomaterials or drug delivery devices as well as in transplantation with cells, cell clusters or whole vascularized organs. Here, we (1) describe basic mechanisms for thromboinflammation; (2) review thromboinflammatory reactions in therapeutic medicine; and (3) discuss emerging strategies to dampen thromboinflammation.

  • 3832.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, Tokyo, Japan.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dührkop, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafson, Elisabet K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kozarcanin, Huda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Huber-Lang, Markus
    Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University of Ulm, Ulm, Germany.
    Garred, Peter
    Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation2016In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 274, no 1, p. 245-269Article in journal (Refereed)
    Abstract [en]

    Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.

  • 3833.
    Nilsson, Greger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Gavle Cent Hosp, Dept Oncol, Gavle, Sweden.;Visby Hosp, Sect Oncol, Visby, Sweden..
    Nyström, Petra Witt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garmo, Hans
    Kings Coll London, Fac Life Sci & Med, Div Canc Studies, Guys Campus, London, England.;Uppsala Univ, Univ Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Duvernoy, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sjögren, Iwar
    Falun Cent Hosp, Dept Cardiol, Falun, Sweden..
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, Div Canc Studies, Guys Campus, London, England..
    Blomqvist, Carl
    Univ Orebro, Univ Hosp, Dept Oncol, Orebro, Sweden..
    Radiation dose distribution in coronary arteries in breast cancer radiotherapy2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 8, p. 959-963Article in journal (Refereed)
    Abstract [en]

    Background: Women irradiated for left-sided breast cancer (BC) have an increased risk of coronary artery disease compared to women with right-sided BC. We describe the distribution of radiation dose in segments of coronary arteries in women receiving adjuvant radiotherapy (RT) for left- or right-sided BC.Material and methods: Fifteen women with BC, seven left-sided and eight right-sided, who had received three-dimensional conformal radiotherapy (3DCRT), constituted the study base. The heart and the segments of the coronary arteries were defined as separate organs at risk (OAR), and the mean and maximum radiation doses were calculated for each OAR.Results: In women with left-sided BC, irrespective of if regional lymph node RT was given or not, maximum dose in mid and distal left anterior descending artery (mdLAD) was approximately 50Gy in 6/7 patients, whereas women with right-sided BC mainly received low doses of radiation. In women with left-sided BC, 6/7 patients had substantially higher mean dose to the distal LAD than to the heart, ranging from 30 to 55Gy and 3 to13Gy, respectively.Conclusion: We found a pronounced difference of radiation dose distribution in the coronary arteries between women with left- and right-sided BC. Women with left-sided BC had almost full treatment dose in parts of mdLAD, regardless of if regional lymph node irradiation was given or not, while women with right-sided BC mainly received low doses to the coronary arteries.

  • 3834.
    Nilsson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Umea Univ Hosp, Dept Radiat Sci & Oncol, Umea, Sweden; Gavle Cent Hosp, Dept Radiol, SE-80187 Gavle, Sweden..
    Axelsson, Bertil
    Umea Univ Hosp, Dept Radiat Sci & Oncol, Umea, Sweden; Umea Univ, Unit Clin Res Ctr Ostersund, Dept Radiat Sci, Umea, Sweden..
    Holgersson, Georg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ, Dept Immunol Genet & Pathol IGP, Uppsala, Sweden..
    Carlsson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Umea Univ Hosp, Dept Radiat Sci & Oncol, Umea, Sweden; Gavle Cent Hosp, Dept Oncol, Gavle, Sweden..
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Umea Univ Hosp, Dept Radiat Sci & Oncol, Umea, Sweden..
    Geographical Differences in Likelihood of Home Death Among Palliative Cancer Patients: A National Population-based Register Study2020In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 40, no 7, p. 3897-3903Article in journal (Refereed)
    Abstract [en]

    Background/Aim: Previous studies have shown discrepancies between patient's desired and actual death place. As planning of family support and involvement of palliative home care teams seem to improve the chance to meet patients preferences, geographical availability of specialized palliative home care could influence place of death. Patients and Methods: Data of patients diagnosed and deceased between January 2011 until December 2014 with lung, brain, colorectal, breast and prostate cancer was collected from Swedish national registers and multiple regression analyses were performed. Results: Patients with lung, brain, colorectal, and prostate cancer who resided in rural municipalities had a higher likelihood of dying at home than dying in hospital settings, compared to those who lived in urban areas. Conclusion: Patients in Sweden, with the exception of breast cancer patients, have a higher likelihood of home death than inpatient hospital death when residing in rural areas compared to when residing in urban areas.

  • 3835.
    Nilsson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Umeå Univ Hosp, Dept Radiat Sci, Umeå, Sweden.;Gävle Cent Hosp, Dept Radiol, Gävle, Sweden..
    Holgersson, Georg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Holmgren, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Gävle Cent Hosp, Dept Oncol, Gävle, Sweden..
    Axelsson, Bertil
    Umeå Univ Hosp, Dept Radiat Sci, Umeå, Sweden.;Unit Clin Res Ctr, Östersund, Sweden..
    Carlsson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Umeå Univ Hosp, Dept Radiat Sci, Umeå, Sweden.;Gävle Cent Hosp, Dept Oncol, Gävle, Sweden..
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Umeå Univ Hosp, Dept Radiat Sci, Umeå, Sweden.;Gävle Cent Hosp, Dept Oncol, Gävle, Sweden..
    Socioeconomy as a prognostic factor for location of death in Swedish palliative cancer patients2021In: BMC Palliative Care, E-ISSN 1472-684X, Vol. 20, article id 43Article in journal (Refereed)
    Abstract [en]

    Background: An important aspect of end-of-life care is the place of death. A majority of cancer patients prefer home death to hospital death. At the same time, the actual location of death is often against patient's last-known wish. The aim of this study was to analyze whether socioeconomic factors influence if Swedish palliative cancer patients die at home or at a hospital. There is no previous study on location of death encompassing several years in Swedish cancer patients.

    Methods: Data was collected from the Swedish Register of Palliative Care for patients diagnosed with brain tumor, lung, colorectal, prostate or breast cancer recorded between 2011 and 2014. The data was linked to the Swedish Cancer Register, the Cause of Death Register and the Longitudinal Integration Database for health-insurance and labor-market studies. A total of 8990 patients were included.

    Results: We found that marital status was the factor that seemed to affect the place of death. Lack of a partner, compared to being married, was associated with a higher likelihood of dying at a hospital.

    Conclusion: Our findings are in line with similar earlier studies encompassing only 1 year and based on patients in other countries. Whether inequalities at least partly explain the differences remains to be investigated. Patients dying of cancer in Sweden, who do not have a life partner, may not have the option of dying at home due to lack of informal support. Perhaps the need of extensive community support services to enable home death have to improve, and further studies are warranted to answer this question.

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  • 3836.
    Nilsson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Umea Univ, Dept Radiat Sci & Oncol, Umea, Sweden;Gavle Cent Hosp, Dept Radiol, Gavle, Sweden.
    Jaras, Jacob
    Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden.
    Henriksson, Roger
    Umea Univ, Dept Radiat Sci & Oncol, Umea, Sweden;Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden.
    Holgersson, Georg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Cent Hosp, Dept Oncol, Gavle, Sweden.
    Estenberg, Jimmy
    Swedish Radiat Safety Author, Stockholm, Sweden.
    Augustsson, Torsten
    Swedish Radiat Safety Author, Stockholm, Sweden.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Umea Univ, Dept Radiat Sci & Oncol, Umea, Sweden;Gavle Cent Hosp, Dept Oncol, Gavle, Sweden.
    No Evidence for Increased Brain Tumour Incidence in the Swedish National Cancer Register Between Years 1980-20122019In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 39, no 2, p. 791-796Article in journal (Refereed)
    Abstract [en]

    Background/Aim: The main objective of this study was to evaluate if there was an increased incidence of brain tumours between years 1980-2012, a time period when mobile phone usage has increased substantially.

    Materials and Methods: From the Swedish Cancer Registry, cases of meningiomas, low-grade gliomas (LGG) and high-grade gliomas (HGG) were identified in patients between 1980-2012. Direct age-standardised incidence rates were used to calculate incidence trends over time.

    Results: A total of 13,441 cases of meningiomas, 12,259 cases of high-grade gliomas and 4,555 cases of LGG were reported to the register during the study period. The results suggest that there may be a negative development in the trend for LGG of -0,016 cases per 100,000 and year, corresponding to a mean reduction of approximately 1% per year.

    Conclusion: The present study was not able to demonstrate an increased incidence of glioma during the past 30 years in Sweden.

  • 3837.
    Nilsson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Univ Hosp, Ctr Res & Dev, Gavle, Sweden.;Gavle Univ Hosp, Dept Radiol, Gavle, Sweden.;Umea Univ Hosp, Dept Radiat Sci & Oncol, Umea, Sweden..
    Kallman, Mikael
    Gavle Univ Hosp, Dept Oncol, Gavle, Sweden..
    Ostlund, Ulrika
    Gavle Univ Hosp, Ctr Res & Dev, Gavle, Sweden..
    Holgersson, Georg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Gavle Univ Hosp, Ctr Res & Dev, Gavle, Sweden.;Gavle Univ Hosp, Dept Oncol, Gavle, Sweden..
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Univ Hosp, Ctr Res & Dev, Gavle, Sweden.;Gavle Univ Hosp, Dept Oncol, Gavle, Sweden.;Umea Univ Hosp, Dept Radiat Sci & Oncol, Umea, Sweden..
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Univ Hosp, Ctr Res & Dev, Gavle, Sweden.;Gavle Univ Hosp, Dept Oncol, Gavle, Sweden..
    The Use of Complementary and Alternative Medicine in Scandinavia2016In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 36, no 7, p. 3243-3251Article, review/survey (Refereed)
    Abstract [en]

    Background: Complementary alternative medicine (CAM) is widely used among patients with cancer. This usage may have potentially harmful effects, especially when combined with anticancer drugs. However, some complementary methods may benefit patients. This review investigated the prevalence of CAM use among patients with cancer in Scandinavia and secondly studied the educational levels of CAM users compared to non-users. Materials and Methods: A systematic search of the PubMed library was carried out to locate articles published between January 2000 and October 2015 that investigated prevalence of CAM use among Scandinavian patients with cancer. Results: Twenty-two articles were found, of which nine were included in the review. The prevalence of CAM use was 7.9% to 53%, with an average of 36.0% across all studies. Conclusion: Use of CAM is widespread among patients with cancer. Knowledge about CAM should be disseminated to both patients and staff in order to optimise discussions about CAM in clinical practice.

  • 3838.
    Nilsson, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wollmer, P
    Pulmonary clearance of 99mTc--DTPA and 99mTc-albumin in rabbits with surfactant dysfunction and lung injury.1992In: Clinical Physiology, ISSN 0144-5979, E-ISSN 1365-2281, Vol. 12, no 5, p. 587-94Article in journal (Refereed)
    Abstract [en]

    We measured the pulmonary clearance of inhaled 99mTc-DTPA and 99mTc-albumin in rabbits with surfactant dysfunction induced by dioctyl sodium sulphosuccinate and in rabbits with lung injury induced by oleic acid. The animals were tracheotomized and mechanically ventilated. After inhalation of 99mTc-albumin in ten animals, clearance of the tracer from the lungs was monitored for 90 min. The first 30 min was a control period. Dioctyl sodium sulphosuccinate was then administered in aerosol and after another 30 min oleic acid was injected intravenously. Ten other rabbits were given 99mTc-DTPA, and clearance was externally recorded for 60 min. Five animals inhaled detergent aerosol and five animals were given oleic acid intravenously after 30 min. Airway pressures, tidal volume, and arterial blood gases were measured before and after each intervention. The half-life of 99mTc-albumin in the lung was 442 +/- 123 min during the control period, 363 +/- 52 min after detergent administration, and 134 +/- 18 min after oleic acid administration (P less than 0.05 compared to control and P less than 0.01 compared to the period after detergent). The half-life of 99mTc-DTPA was 94 +/- 16 min before and 10 +/- 0.6 min (P less than 0.01) after detergent administration and 75 +/- 12 min before and 18 +/- 1.8 min (P less than 0.01) after oleic acid administration. Gas exchange was not affected by administration of dioctyl sodium sulphosuccinate but markedly impaired after injection of oleic acid. Compliance of the respiratory system remained unaffected by detergent but decreased after injection of oleic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 3839.
    Nilsson, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wollmer, P
    Pulmonary clearance of tracers with different lipid and water solubility in experimental surfactant dysfunction.1993In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 6, no 4, p. 505-8Article in journal (Refereed)
    Abstract [en]

    We measured the pulmonary clearance of inhaled 99mTc-diethylenetriamine penta-acetic acid (DTPA), 99mTc-sestamibi and 99mTc-dimethyliminodiacetic acid (HIDA) in normal rabbits, and rabbits with surfactant dysfunction induced by the detergent dioctyl sodium sulfosuccinate. The tracers differ widely in lipid/water partition coefficients, but have similar molecular radius and weight. Five animals in each group received the detergent in aerosol, and the other five a vehicle aerosol, before the administration of the tracer. Pulmonary clearance of the tracers was measured with a gamma camera. The half-life of 99mTc-DTPA was 94 +/- 16 min in normal lungs, and 10 +/- 1 min after detergent administration (p < 0.001). The half-life for 99mTc-sestamibi was 45 +/- 4 min and 39 +/- 4 min, respectively, (p < 0.05). There was no significant difference between the half-life of 99mTc-HIDA in normal lungs and in lungs with surfactant dysfunction. The half-life was 20 +/- 3 min and 17 +/- 2 min, respectively. The results indicate that the clearance rate limiting factors for the alveolocapillary transfer of water and lipid soluble substances are not the same. Surfactant dysfunction affects the transfer of water soluble substances (99mTc-DTPA) but not of substances with high lipid solubility (99mTc-HIDA).

  • 3840.
    Nilsson, Martin P.
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Undseth, Christine
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Albertsson, Per
    Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Region Vastra G, Sweden.;Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Oncol, Gothenburg, Sweden..
    Eidem, Monika
    Trondheim Reg & Univ Hosp, St Olavs Hosp, Canc Clin, Trondheim, Norway..
    Havelund, Birgitte Mayland
    Lillebaelt Hosp, Univ Hosp Southern Denmark, Dept Oncol, Vejle, Denmark..
    Johannsson, Jakob
    Landspitali Univ Hosp, Dept Radiat Oncol, Reykjavik, Iceland..
    Johnsson, Anders
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Radu, Calin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Serup-Hansen, Eva
    Copenhagen Univ Hosp Herlev & Gentofte, Dept Oncol, Copenhagen, Denmark..
    Spindler, Karen-Lise
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark..
    Zakrisson, Bjoern
    Umeå Univ, Dept Radiat Sci Oncol, Umeå, Sweden..
    Guren, Marianne G.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Kronborg, Camilla
    Aarhus Univ Hosp, Ctr Particle Therapy, Danish, Aarhus, Denmark.;Aarhus Univ, Dept Clin Med, Aarhus, Denmark..
    Nordic anal cancer (NOAC) group consensus guidelines for risk-adapted delineation of the elective clinical target volume in anal cancer2023In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 62, no 8, p. 897-906Article in journal (Refereed)
    Abstract [en]

    Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer.Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus.Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk.Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.

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  • 3841.
    Nilsson, Martina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Andreasson-Jansson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ingman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Evaluation of mitochondrial DNA coding region assays for increased discrimination in forensic analysis2008In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 2, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    There is an increasing trend to use mitochondrial DNA (mtDNA) analysis in criminal investigations where only limited amounts of DNA are available. However, analysis of the mtDNA control region has the drawback of low discrimination power, due to the lack of recombination that results from uniparental (maternal) inheritance. As a strategy to increase discrimination, a number of typing assays detecting variation in the mitochondrial coding region have been developed. In this study, several of these assays are evaluated for their discriminatory capacity using data obtained from 495 complete Caucasian mtDNA sequences. In order to add a local geographic perspective to this evaluation, we have also sequenced and analysed the entire mtDNA from 20 individuals of Swedish origin. We find that the coding region assays are very useful for resolving sequences with identical HVI/HVII regions. The best-performing coding region assay was able to discriminate 46% of the resolvable sequences, compared to 20–30% for the other coding region assays we evaluated.

  • 3842.
    Nilsson, Martina
    et al.
    Swedish Police Author, Forens Sect, Div Investigat, Stockholm Police Reg, S-10675 Stockholm, Sweden..
    de Maeyer, Hanne
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Evaluation of Different Cleaning Strategies for Removal of Contaminating DNA Molecules2022In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 13, no 1, article id 162Article in journal (Refereed)
    Abstract [en]

    Decontamination strategies and their efficiencies are crucial when performing routine forensic analysis, and many factors influence the choice of agent to use. In this study, the effects of ten different cleaning strategies were evaluated to compare their ability to remove contaminating DNA molecules. Cell-free DNA or blood was deposited on three surfaces (plastic, metal, and wood) and decontaminated with various treatments. The quantities of recovered DNA, obtained by swabbing the surfaces after cleaning using the different strategies, was analyzed by real-time PCR. Large differences in the DNA removal efficiencies were observed between different cleaning strategies, as well as between different surfaces. The most efficient cleaning strategies for cell-free DNA were the different sodium hypochlorite solutions and Trigene(R), for which a maximum of 0.3% DNA was recovered on all three surfaces. For blood, a maximum of 0.8% of the deposited DNA was recovered after using Virkon(R) for decontamination. The recoveries after using these cleaning strategies correspond to DNA from only a few cells, out of 60 ng of cell-free DNA or thousands of deposited blood cells.

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  • 3843.
    Nilsson, Martina
    et al.
    Swedish Police Author, Div Invest, Forens Sect, S-10675 Stockholm, Sweden..
    Grånemo, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Bus, Magdalena M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Havsjö, Mikael
    AlphaHelix Technol AB, Penarp 1150, S-26491 Klippan, Sweden..
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Comparison of DNA polymerases for improved forensic analysis of challenging samples2016In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 24, p. 55-59Article in journal (Refereed)
    Abstract [en]

    Inhibitors of polymerase chain reaction (PCR) amplification often present a challenge in forensic investigations of e.g., terrorism, missing persons, sexual assaults and other criminal cases. Such inhibitors may be counteracted by dilution of the DNA extract, using different additives, and selecting an inhibitory resistant DNA polymerase. Additionally, DNA in forensic samples is often present in limited amounts and degraded, requiring special analyses of short nuclear targets or mitochondrial DNA. The present study evaluated the enzymes AmpliTaq Gold, HotStarTaq Plus, KAPA3G Plant, and KAPA2G Robust, with regard to their ability to overcome inhibitory effects. Our data showed that diluting the extracts and adding bovine serum albumin may increase the yield of the PCR product. However, the largest impact was observed when alternative enzymes were utilized, instead of the commonly used AmpliTaq Gold. KAPA2G Robust presented the highest amplification efficiency in the presence of the inhibitor ammonium nitrate. Moreover, the KAPA3G Plant enzyme had the highest efficiency in amplifying degraded DNA from old buried bone material. KAPA3G Plant and KAPA2G Robust may thus be useful for counteracting inhibitors and improving the analysis of challenging samples.

  • 3844. Nilsson, Martina
    et al.
    Norlin, Stina
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Sequencing of mtDNA in Shed Hairs: A Retrospective Analysis of Material from Forensic Cases and a Pre-Screening Method2012In: Open Forensic Science Journal, ISSN 1874-4028, Vol. 5, p. 13-22Article in journal (Refereed)
    Abstract [en]

    In crime scene investigations, shed hairs are one of the most frequently found types of biological evidence material. DNA analysis of hair can be of great significance in forensic investigations, and the sequencing of the hypervariable regions I(HVI) and II (HVII) of the mitochondrial genome has become a useful tool in this field. This paper describes a retrospective evaluation of the potential of sequence analysis of mitochondrial DNA. We examined evidentiary hair and reference samples obtained from 25 criminal investigations conducted over a ten year period and determined the number of matches and exclusions between samples in the investigation. In total, the study includes the results of 129 samples obtained between 1999 and 2008. Analysis resulted in high quality sequence data from most of the evidentiary hairs, allowing comparison to reference samples. On the basis of matches between mitochondrial DNA sequences from evidentiary hairs and those from reference samples, inclusions were obtained in 16 of the 25 cases (64%). Thus, sequencing of mitochondrial DNA was informative in many cases in this data set. In addition, we conducted an initial evaluation of a strategy for estimating the mitochondrial DNA and nuclear DNA contents of plucked and shed hair samples. The strategy is based on staining both the nuclear DNA and the mitochondria, and may be useful when trying to identify an optimal DNA profiling approach for a given hair sample.

  • 3845.
    Nilsson, Martina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Edlund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Budowle, Bruce
    Kjellström, Anna
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Analysis of the putative remains of a European patron saint--St. Birgitta2010In: PLoS ONE, ISSN 1932-6203, Vol. 5, no 2, p. e8986-Article in journal (Refereed)
    Abstract [en]

    Saint Birgitta (Saint Bridget of Sweden) lived between 1303 and 1373 and was designated one of Europe's six patron saints by the Pope in 1999. According to legend, the skulls of St. Birgitta and her daughter Katarina are maintained in a relic shrine in Vadstena abbey, mid Sweden. The origin of the two skulls was assessed first by analysis of mitochondrial DNA (mtDNA) to confirm a maternal relationship. The results of this analysis displayed several differences between the two individuals, thus supporting an interpretation of the two skulls not being individuals that are maternally related. Because the efficiency of PCR amplification and quantity of DNA suggested a different amount of degradation and possibly a very different age for each of the skulls, an orthogonal procedure, radiocarbon dating, was performed. The radiocarbon dating results suggest an age difference of at least 200 years and neither of the dating results coincides with the period St. Birgitta or her daughter Katarina lived. The relic, thought to originate from St. Birgitta, has an age corresponding to the 13(th) century (1215-1270 cal AD, 2sigma confidence), which is older than expected. Thus, the two different analyses are consistent in questioning the authenticity of either of the human skulls maintained in the Vadstena relic shrine being that of St. Birgitta. Of course there are limitations when interpreting the data of any ancient biological materials and these must be considered for a final decision on the authenticity of the remains.

  • 3846.
    Nilsson, Martina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Styrman, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andreasson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Divne, Anna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sensitive forensic analysis using the Pyrosequencing technology2006In: Progress in Forensic Genetics, no 1288, p. 625-627Article in journal (Refereed)
    Abstract [en]

    In forensic casework analysis, rapid and flexible systems for detection of variation found in nuclear or mitochondrial genomes are valuable. We have developed several different typing systems based on the Pyrosequencing technology to allow sensitive analysis of mtDNA as well as autosomal and Y-chromosome SNPs or STRs in short amplicons.

  • 3847.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Point of care mutation detection2010In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 31, no 2, p. v-Article in journal (Refereed)
  • 3848.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Unraveling the Transcriptional Heterogeneity in Human Colon Cancer: Potential New Insights regarding Pathobiology and Treatment2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 6, p. 966-967Article in journal (Other academic)
  • 3849. Nilsson, Per H.
    et al.
    N. Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Qu, Hongchang
    Iwata, Hiroo
    Ricklin, Daniel
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lambris, John D.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 4, p. 985-994Article in journal (Refereed)
    Abstract [en]

    Activation of the thrombotic and complement systems is the main recognition and effector mechanisms in the multiple adverse biological responses triggered when biomaterials or therapeutic cells come into blood contact. We have created a surface which is auto-protective to human innate immunity by combining three fundamentally different strategies, all developed by us previously, which have been shown to induce substantial, but incomplete hemocompatibility when used separately. In summary, we have conjugated a factor H-binding peptide; and an ADP-degrading enzyme; using a PEG linker on both material and cellular surfaces. When exposed to human whole blood, factor H was specifically recruited to the modified surfaces and inhibited complement attack. In addition, activation of platelets and coagulation was efficiently attenuated, by degrading ADP. Thus, by inhibiting thromboinflammation using a multicomponent approach, we have created a hybrid surface with the potential to greatly reduce incompatibility reactions involving biomaterials and transplantation.

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  • 3850.
    Nilsson, Per J.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    van Etten, Boudewijn
    Univ Med Ctr Groningen, Groningen, Netherlands..
    Hospers, Geke A. P.
    Univ Med Ctr Groningen, Groningen, Netherlands..
    Marijnen, Corrie A. M.
    Netherlands Canc Inst Antoni van Leeuwenhoek, Amsterdam, Netherlands..
    Meershoek-Klein Kranenberg, Elma
    Leiden Univ, Med Ctr, Leiden, Netherlands..
    Roodvoets, Annet G. H.
    Leiden Univ, Med Ctr, Leiden, Netherlands..
    van de Velde, Cornelis J. H.
    Leiden Univ, Med Ctr, Leiden, Netherlands..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Comment on the RAPIDO Trial Point-Counterpoint Debate2024In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 67, no 2, article id E126Article in journal (Other academic)
74757677787980 3801 - 3850 of 5902
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