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  • 151.
    Alhuseinalkhudhur, Ali
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jernling, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schiza, Aglaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Overall survival amongst patients with breast cancer brain metastasis: A cohort study based on Uppsala county cancer registryManuscript (preprint) (Other academic)
  • 152.
    Ali, Abir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 43-43Article in journal (Refereed)
  • 153.
    Ali, Abir Salwa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Federspiel, Birgitte
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Scoazec, Jean-Yves
    Inst Gustave Roussy, Villejuif, France.
    Hjortland, Geir Olav
    Univ Oslo, Oslo, Norway.
    Gronbaek, Henning
    Aarhus Univ Hosp, Aarhus, Denmark.
    Ladekarl, Morten
    Aarhus Univ Hosp, Aarhus, Denmark.
    Langer, Seppo W.
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, Lene Weber
    Odense Univ Hosp, Odense, Denmark.
    Arola, Johanna
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland.
    Osterlund, Pia
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland; Tampere Univ Hosp, Tampere, Finland.
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Bergen, Norway; Univ Bergen, Bergen, Norway.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology. Uppsala Univ, Sect Endocrine Oncol, Dept Med Sci, Uppsala, Sweden..
    Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187667Article in journal (Refereed)
    Abstract [en]

    Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

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  • 154.
    Ali, Abir Salwa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Langer, Seppo W.
    Federspiel, Birgitte
    Hjortland, Geir Olav
    Grønbæk, Henning
    Ladekarl, Morten
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Weber Vestermark, Lene
    Arola, Johanna
    Osterlund, Pia
    Knigge, Ulrich
    Sørbye, Halfdan
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    PD-L1 expression in gastroenteropancreatic neuroendocrine neoplasms grade 32020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 12, article id e0243900Article in journal (Refereed)
    Abstract [en]

    Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.

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  • 155.
    Ali, Abir Salwa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Perren, Aurel
    Univ Bern, Dept Pathol, Bern, Switzerland..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Candidate protein biomarkers in pancreatic neuroendocrine neoplasms grade 32020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 10639Article in journal (Refereed)
    Abstract [en]

    Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumours that compose 1-2% of all pancreatic tumours. Patients with metastatic grade 3 neoplasia are usually treated with chemotherapy but have a poor progression-free and overall survival. According to the WHO 2017 classification, they are divided into neuroendocrine tumours (NETs) G3 and neuroendocrine carcinomas (NECs). Despite the new classification, new diagnostic and prognostic biomarkers are needed to sub-categorise the patients and to help guide therapy decisions. Blood from 42 patients and 42 healthy controls were screened for the presence of 92 proteins with the Immuno-Oncology panel using the Proximity Extension Assay provided by Olink Biosciences. Immunohistochemical staining of FAS ligand (FASLG) was performed on 16 patient tumour specimens using a commercial antibody. Fifty-four out of 87 evaluable proteins differed significantly in concentration between blood from patients and blood from healthy controls. FASLG was the only protein for which the concentration in blood was significantly lower in patients compared to controls and the levels correlated negatively to Ki-67 index. Seven of 14 evaluable PanNEN G3 specimens showed FASLG immunoreactivity in the tumour cells while there was scattered immunoreactivity in immune cells. Positive FASLG immunoreactivity correlated to well-differentiated morphology. FASLG concentration in blood was significantly lower in patients with pancreatic NENs G3 compared to controls, and the expression in tumour tissue was variable. Furthermore, FASLG was negatively correlated to Ki-67 and was more frequently expressed in well-differentiated tumours. Taken together, these results may suggest a role of FASLG in PanNENs.

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  • 156.
    Ali, Arwa
    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, Cancer Immunotherapy.
    Gao, Menghan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Iskantar, Alexandros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wang, Hai
    Chinese Acad Sci, CAS Ctr Excellence Nanosci, Natl Ctr Nanosci & Technol, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing, Peoples R China.;Univ Chinese Acad Sci, Beijing, Peoples R China..
    Karlsson-Parra, Alex
    Mendus AB, Stockholm, Sweden..
    Yu, Di
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jin, Chuan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1146413Article in journal (Refereed)
    Abstract [en]

    As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic a4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of a4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFN?(+) CD8(+) T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T-RM) CD8(+) T cells (CD103(+)CD49a(+)CD69(+)). The combination treatment also led to increased infiltration of CD39(+)CD103(+) tumor-specific CD8(+) T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic a4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

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  • 157.
    Ali, Muhammad Akhtar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Understanding Cancer Mutations by Genome Editing2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mutational analyses of cancer genomes have identified novel candidate cancer genes with hitherto unknown function in cancer. To enable phenotyping of mutations in such genes, we have developed a scalable technology for gene knock-in and knock-out in human somatic cells based on recombination-mediated construct generation and a computational tool to design gene targeting constructs. Using this technology, we have generated somatic cell knock-outs of the putative cancer genes ZBED6 and DIP2C in human colorectal cancer cells. In ZBED6-/- cells complete loss of functional ZBED6 was validated and loss of ZBED6 induced the expression of IGF2. Whole transcriptome and ChIP-seq analyses revealed relative enrichment of ZBED6 binding sites at upregulated genes as compared to downregulated genes. The functional annotation of differentially expressed genes revealed enrichment of genes related to cell cycle and cell proliferation and the transcriptional modulator ZBED6 affected the cell growth and cell cycle of human colorectal cancer cells. In DIP2C-/-cells, transcriptome sequencing revealed 780 differentially expressed genes as compared to their parental cells including the tumour suppressor gene CDKN2A. The DIP2C regulated genes belonged to several cancer related processes such as angiogenesis, cell structure and motility. The DIP2C-/-cells were enlarged and grew slower than their parental cells. To be able to directly compare the phenotypes of mutant KRAS and BRAF in colorectal cancers, we have introduced a KRASG13D allele in RKO BRAFV600E/-/-/ cells. The expression of the mutant KRAS allele was confirmed and anchorage independent growth was restored in KRASG13D cells. The differentially expressed genes both in BRAF and KRAS mutant cells included ERBB, TGFB and histone modification pathways. Together, the isogenic model systems presented here can provide insights to known and novel cancer pathways and can be used for drug discovery.

    List of papers
    1. Computational and molecular tools for scalable rAAV mediated genome editing
    Open this publication in new window or tab >>Computational and molecular tools for scalable rAAV mediated genome editing
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The rapid discovery of potential driver mutations through large scale mutational analyses of human cancers generates a need to characterize their cellular phenotypes. Among the techniques for genome editing, recombinant adeno-associated virus (rAAV) mediated gene targeting is particularly suited to knock-in of single nucleotide substitutions. However, the generation of gene targeting constructs and the targeting process is time consuming and labor-intense. To facilitate rAAV mediated gene targeting, we developed the first software and complementary automation friendly vector tools to generate optimized targeting constructs for editing human protein encoding genes. By computational approaches, rAAV constructs for editing ~72% of bases in protein-coding exons were designed. Similarly, ~81% of genes were predicted to be targetable by rAAV mediated knock-out. A Gateway based cloning system for facile generation of rAAV constructs suitable for robotic automation was developed and used in successful generation of targeting constructs. Together, these tools enable automated rAAV targeting construct design, generation as well as enrichment and expansion of targeted cells with desired integrations.

    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-235563 (URN)
    Available from: 2014-11-05 Created: 2014-11-05 Last updated: 2018-01-11
    2. The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Open this publication in new window or tab >>The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-235564 (URN)
    Available from: 2014-11-05 Created: 2014-11-05 Last updated: 2018-01-11
    3. DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Open this publication in new window or tab >>DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized candidate

    breast and lung cancer gene. The gene contains a DMAP1 binding domain, pointing to

    potential involvement in DNMT1-dependent methylation. To study the role of DIP2C in

    tumor development, we engineered human DIP2C knockout cell systems by rAAV-mediated

    gene targeting. Homo- and heterozygous RKO DIP2C knockout cells displayed enlarged cells

    and growth retardation. This phenotype was most pronounced in DIP2C-/- knockouts, and

    these cells also displayed a significant decrease in DIP2C mRNA levels. RNA sequencing

    revealed 780 genes affected by the loss of DIP2C, including the cellular senescence marker

    P16INK4a. Functional annotation of the regulated genes shows enrichment of genes involved

    with cell death processes, cell structure and motility. Furthermore, KEGG pathway analysis

    shows association of 19 genes with pathways in cancer. In conclusion, the phenotypic data

    and expression changes induced by loss of DIP2C indicate that the gene function may be

    important for several biological processes implicated in cancer, and that loss of gene function

    may be a trigger of cellular senescence.

    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-235565 (URN)
    Available from: 2014-11-05 Created: 2014-11-05 Last updated: 2018-01-11
    4. Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    Open this publication in new window or tab >>Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    2012 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no Suppl.5, p. S118-S118Article in journal, Meeting abstract (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-194476 (URN)10.1016/S0959-8049(12)71162-0 (DOI)000313036501006 ()
    Conference
    22nd Biennial Congress of the European-Association-for-Cancer-Research, JUL 07-10, 2012, Barcelona, SPAIN
    Available from: 2013-02-15 Created: 2013-02-14 Last updated: 2017-12-06Bibliographically approved
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  • 158.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations2012In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no Suppl.5, p. S118-S118Article in journal (Refereed)
  • 159.
    Ali, Muhammad Akhtar
    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.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, 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, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, p. 7743-7748Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 160.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Younis, Shady
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Rajesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tobias Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cellsManuscript (preprint) (Other academic)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

  • 161.
    Ali, Zafar
    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. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Klar, Joakim
    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.
    Jameel, Mohammad
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Khan, Kamal
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Fatima, Ambrin
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Dahl, Niklas
    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.
    Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities2016In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 371, p. 105-111Article in journal (Refereed)
    Abstract [en]

    We describe eight subjects from two consanguineous families segregating with autosomal recessive childhood onset spastic ataxia, peripheral neuropathy and intellectual disability. The degree of intellectual disability varied from mild to severe and all four affected individuals in one family developed aggressive behavior and epilepsy. Using exome sequencing, we identified two novel truncating mutations (c.2656C>T (p.Gln886*)) and (c.4756_4760delAATCA (p.Asn1586Tyrfs*3)) in the SACS gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). MRI revealed typical cerebellar and pontine changes associated with ARSACS as well as multiple supratentorial changes in both families as likely contributing factors to the cognitive symptoms. Intellectual disability and behavioral abnormalities have been reported in some cases of ARSACS but are not a part of the characteristic triad of symptoms that includes cerebellar ataxia, spasticity and peripheral neuropathy. Our combined findings bring further knowledge to the phenotypic spectrum, neurodegenerative changes and genetic variability associated with the SACS gene of clinical and diagnostic importance.

  • 162.
    Ali, Zafar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    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.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ullah, Farid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Khan, Ayaz
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Abdullah, Uzma
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Dahl, Niklas
    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.
    Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features2017In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 18, no 1, article id 144Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.

    CASE PRESENTATION: We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.

    CONCLUSION: The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.

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  • 163.
    Al-Jebari, Yahia
    et al.
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Div Clin Epidemiol, Dept Med, Stockholm, Sweden.
    Nord, Carina Berglund
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Cohn-Cedermark, Gabriella
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Stahl, Olof
    Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Tandstad, Torgrim
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Fac Med & Hlth Sci, Trondheim, Norway;St Olavs Univ Hosp, Canc Clin, Trondheim, Norway.
    Jensen, Allan
    Danish Canc Soc Res Ctr, Virus Lifestyle & Genes, Copenhagen, Denmark.
    Haugnes, Hege Sagstuen
    Univ Hosp North Norway, Dept Oncol, Tromso, Norway;UiT Arctic Univ Norway, Inst Clin Med, Tromso, Norway.
    Daugaard, Gedske
    Rigshosp, Dept Oncol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Rylander, Lars
    Lund Univ, Div Occupat & Environm Med, Lund, Sweden.
    Giwercman, Aleksander
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 6, article id e1002816Article in journal (Refereed)
    Abstract [en]

    Background Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. Methods and findings In this nationwide register study, all singletons born in Sweden 1994-2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment-to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54-1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25-4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995-2000-both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. Conclusions No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

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  • 164.
    Al-Kass, Z.
    et al.
    Swedish Univ Agr Sci SLU, Clin Sci, SE-75007 Uppsala, Sweden.;Univ Mosul, Coll Vet Med, Dept Surg & Theriogenol, Mosul, Iraq..
    Guo, Y.
    Swedish Univ Agr Sci SLU, Clin Sci, SE-75007 Uppsala, Sweden..
    Vinnere, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Niazi, A.
    Swedish Univ Agr Sci, SLU Global Bioinformat Ctr, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Morrell, J. M.
    Swedish Univ Agr Sci SLU, Clin Sci, SE-75007 Uppsala, Sweden..
    Metagenomic analysis of bacteria in stallion semen2020In: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 221, article id 106568Article in journal (Refereed)
    Abstract [en]

    Bacteria colonize stallion semen during collection and processing which may cause disease in inseminated females or negatively affect sperm quality during storage prior to insemination. Antibiotics are added to semen extenders to control the growth of these bacteria but may induce antimicrobial resistance. Research into alternatives to antibiotics for this purpose requires knowledge of which bacteria are present in semen. Not all bacteria in semen, however, can be identified by conventional microbiological techniques. The objectives of the study were to: i) determine which bacteria are present in stallion semen using metagenomics; and ii) investigate individual differences in bacterial content in semen from all stallions on one premises. Bacterial DNA was extracted from ejaculates from seven stallions (one ejaculate per stallion) and bacteria were identified using 16S sequencing. In total, 83 bacterial genera were identified, varying from 25 to 52 among different individuals. There was a negative correlation (r = -0.81212; P < 0.05) between the presence of Treponema spp. and Advenella spp. In conclusion, most of the bacteria present in stallion semen could be identified to genus level by 16S sequencing even when present at a low frequency. This method of identification may help to clarify individual variation in bacterial content and its potential effects on fertility.

  • 165. Allanson, Judith E.
    et al.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Aoki, Yoki
    Armour, Christine M.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Cave, Helene
    Gripp, Karen W.
    Kerr, Bronwyn
    Nyström, Anna-Maja
    Sol-Church, Katia
    Verloes, Alain
    Zenker, Martin
    Cardio-Facio-Cutaneous Syndrome: Does Genotype Predict Phenotype?2011In: American Journal of Medical Genetics, Part C: Seminars in Medical Genetics, ISSN 1552-4868, Vol. 157C, no 2, p. 129-135Article in journal (Refereed)
    Abstract [en]

    Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10-30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype-phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (similar to 75%), while 46 (similar to 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413-427]. While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype-phenotype correlation, being more common in individuals with a BRAF mutation.

  • 166.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Andréasson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mitochondrial D-loop and coding sequence analysis using pyrosequencing2005In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 297, p. 179-196Article in journal (Refereed)
    Abstract [en]

    In forensic casework analysis, mitochondrial deoxyribonucleic acid (DNA) often is used when the evidence material contains scarce amounts of DNA. Here, a mitochondrial DNA typing system for D-loop and coding region analysis based on pyrosequencing is described. Pyrosequencing is a real-time, single-tube sequencing-by-synthesis method, in which a cascade of enzymatic reactions yields detectable light. This pyrosequencing system has a higher resolution than the D-loop analysis performed routinely today as it also covers informative positions in the mitochondrial coding region. The system is composed of 16 polymerase chain reaction (PCR) fragments and 24 pyrosequencing reactions with a turn around time for a 96-well plate of less than 3 h after PCR.

  • 167.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bjerke, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden..
    Edlund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    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.
    Westermark, Bengt
    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.
    Origin of the U87MG glioma cell line: Good news and bad news2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 354, article id 354re3Article in journal (Refereed)
    Abstract [en]

    Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.

  • 168.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology. 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 Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Universal tag arrays in forensic SNP analysis.2005In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 297, p. 141-154Article in journal (Refereed)
    Abstract [en]

    Microarray-based single nucleotide polymorphism (SNP) genotyping enables simultaneous and rapid detection of a large number of markers and is thus an attractive method for forensic individual acid identification. This assay relies on a one-color detection system and minisequencing in solution before hybridization to universal tag arrays. The minisequencing reaction is based on incorporation of a fluorescent dideoxynucleotide to a primer containing a tag-sequence flanking the position to be interrogated. This one-color system detects C and T polymorphisms in separate reactions on multiple polymerase chain reaction targets with the fluorophore TAMRA coupled to the respective dideoxynucleotide. After incorporation, tagged primer sequences are hybridized through their complementary sequence on the array, and positive signals are detected by a confocal laser-scanner.

  • 169.
    Allen, Marie
    et al.
    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.
    Calloway, Cassandra
    Erlich, Henry
    Author´s response:  2006In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 51, no 4, p. 937-938Article in journal (Other academic)
    Abstract [en]

    The mitochondrial hypervariable regions I and II have proven to be a useful target for analysis of forensic materials, in which the amount of DNA is limited or highly degraded. Conventional mitochondrial DNA (mtDNA) sequencing can be time-consuming and expensive, limitations that can be minimized using a faster and less expensive typing assay.We have evaluated the exclusion capacity of the linear array mtDNA HVI/HVII region-sequence typing assay (Roche Applied Science) in 16 forensic cases comprising 90 samples. Using the HVI/HVII mtDNA linear array, 56% of the samples were excluded and thus less than half of the samples require further sequencing due to a match or inconclusive results. Of all the samples that were excluded by sequence analysis, 79% could be excluded using the HVI/HVII linear array alone. Using the HVI/HVII mtDNA linear array assay, we demonstrate the potential to decrease sequencing efforts substantially and thereby reduce the cost and the turn-around time in casework analysis.

  • 170.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Engström, A-S.
    Meyers, S.
    Handt, O.
    Saldeen, Tom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    von Haeseler, A.
    Pääbo, S.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mitochondrial DNA sequencing of shed hairs and saliva on robbery caps: sensitivity and matching probabilities1998In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 43, no 3, p. 453-464Article in journal (Refereed)
    Abstract [en]

    Sequencing of mitochondrial DNA (mtDNA) has been used for human identification based on teeth and skeletal remains. Here, we describe an amplification system for the mtDNA control region (D-loop) suited for the analysis of shed hair, which constitutes the most common biological evidence material in forensic investigations. The success rate was over 90% when applied to evidence materials such as shed hair, saliva stains and saliva on stamps. The analysis of evidence materials collected from three similar robberies revealed the presence of mtDNA sequences identical to those of the suspects in the three crimes. The use of mtDNA control region sequences for individual identification was evaluated. The probability of identity by chance for the mtDNA types of the suspects in the robberies was found to vary between Pr = 0.017 - < 0.0017, depending on the reference population used, emphasizing the need for large population databases to obtain the appropriate estimate.

  • 171.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Eriksson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Liu, Limin
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    High resolution genetic typing of the class II HLA-DRB1 locus using group-specific amplification and SSO-hybridisation in microplates1998In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 129, no 2, p. 161-167Article in journal (Refereed)
    Abstract [en]

    The HLA-DRB1 locus is one of the most polymorphic HLA class II loci and rapid and accurate typing of this polymorphism is important both in bone-marrow transplantation, analysis of disease association and in forensic medicine. The allelic variation at DRB1 is characterized by combinations of a limited number of amino-acid motifs, reducing the resolution of a typing strategy based on a single PCR and subsequent analysis of polymorphic motifs. In the present paper we describe a strategy for typing of DRB1 based on eight allele-specific PCRs followed by sandwich hybridization to immobilized probes in a microplate format. The combined approach results in a rapid typing system with very high resolution. Using a rapid DNA extraction protocol, a complete HLA-DRB1 typing can be performed in less than a day.

  • 172.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Kalantari, M.
    Ylitalo, Natalie
    Pettersson, B.
    Hagmar, B.
    Scheibenflug, L.
    Johansson, B.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    HLA DQ-DR haplotype and susceptibility to cervical carcinoma: indications of increased risk for development of cervical carcinoma in individuals infected with HPV 181996In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 48, no 1, p. 32-37Article in journal (Refereed)
    Abstract [en]

    The association of HLA class II DQB1 and DRB1 alleles with the development of cervical carcinoma was studied in 150 Swedish patients using PCR-based HPV and HLA typing. The association of cervical carcinoma with alleles encoding the DQ3 antigen, previously found among German and Norwegian patients, was not observed in the Swedish patients. Five DQ-DR haplotypes were indicated to be positively associated with development of cervical carcinoma in the Swedish patients. Two of these HLA associations were specific for HPV 18 infected patients, suggesting that the ability of the oncogenic HPV 18 to cause more rapid-transit tumors than other high risk HPV types may be due to a deficiency in antigen presentation by the HLA molecules encoded by carried on these haplotypes.

  • 173.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Saldeen, Tom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Allele-specific HLA-DRB1 amplification of forensic evidence samples with mixed genotypes1995In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 19, no 3, p. 454-463Article in journal (Refereed)
    Abstract [en]

    A major problem in analyzing forensic casework samples is the presence of genetic material from more than one individual in the material evidence. For instance, in sexual assault cases the evidence (vaginal swabs) usually contains a majority of vaginal epithelial cells and varying amounts of sperm cells from the perpetrator. Samples with mixed genotypes are also common among other biological evidence materials such as nail scrapes and mixed bloodstains. We have developed an allele-specific amplification system for the highly polymorphic HLA class II DRB1 locus that permits the detection of individual alleles in a sample with mixed genotypes, independent of the initial frequency of the alleles. Using a set of eight allele-specific amplification primers and typing the amplified fragments with sequence-specific probes, most of the 60 DRB1 alleles can be resolved. The method is highly specific and sensitive, with the potential for amplifying 15 copies of a particular allele in a background of 3 x 10(5) copies of other alleles. The method was successfully applied to three forensic cases, where the material evidence consisted of sperm stains on panties, nail scrapes and bloodstains on skin. Thus the DRB1 allele-specific amplification system can be employed for the unambiguous determination of the presence of individual alleles in materials suspected to contain mixed genotypes, even when the alleles of interest constitute only a small fraction of the total DNA

  • 174.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Saldeen, Tom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    PCR-based DNA typing of saliva on stamps and envelopes1994In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 17, no 3, p. 546-552Article in journal (Refereed)
    Abstract [en]

    In forensic cases involving mail bombs, extortion, kidnapping or threatening letters, biological evidence such as the saliva used to attach the stamp and seal the envelope could be used for genetic analysis. We have developed a highly sensitive semi-nested PCR method for the HLA-DRB1 locus; suitable for the analyses of very limited amounts of DNA. When applied to a set of stamps and envelopes with saliva from control individuals, typing results were consistent with those obtained using hairs drawn from the same individuals. No interference was found due to DNA from the fingerprints of people handling the letters. The system was applied to three forensic cases with threatening letters. The first case resulted in an exclusion of the suspect. In the second case, the suspect could not be excluded (probability of identical genotype by chance > 0.01). These results demonstrate that biological evidence in cases with threatening letters is amenable to genetic typing.

  • 175.
    Al-Mashhadi, Ammar Nadhom Farman
    et al.
    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.
    Dukic, Milena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Engstrand Lilja, Helene
    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.
    Rhabdomyomatous mesenchymal hamartoma presenting in a child as a perineal mass2019In: Journal of Pediatric Surgery Case Reports, E-ISSN 2213-5766, Vol. 47, article id 101242Article in journal (Refereed)
    Abstract [en]

    Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare hamartomatous lesion in the dermis and subcutaneous tissue. It is mostly found in the face and neck region of children. We report a case of solitary RMH located in the perineum of an 8-month-old boy. Microscopic examination of specimen showed a disordered collection of mature adipose tissue, skeletal muscle, adnexal elements and nerve bundles, and immunohistochemistry confirmed a RMH. This case emphasizes the possibility of RMH in the perineum of the children. Even if RMH is a rare condition in the perineum it should be considered as a differential diagnosis of a perineal mass in children.

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  • 176.
    Almdalal, Tarik
    et al.
    Eskilstuna Country Hosp, Dept Surg & Urol, Eskilstuna, Sweden..
    Sundqvist, Pernilla
    Örebro Univ, Fac Med & Hlth, Dept Urol, Örebro, Sweden..
    Harmenberg, Ulrika
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden..
    Hellström, Mikael
    Department of Radiology, Sahlgrenska Academy/Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden..
    Lindskog, magli409
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindblad, Per
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden..
    Lundstam, Svan
    Department of Urology and Oncology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Ljungberg, Börje
    Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden..
    Clinical T1a Renal Cell Carcinoma, Not Always a Harmless Disease—A National Register Study2022In: European Urology Open Science, ISSN 2666-1691, E-ISSN 2666-1683, Vol. 39, p. 22-28Article in journal (Refereed)
    Abstract [en]

    Background: T1a renal cell carcinoma (RCC) is typically considered a curable disease, irrespective of the choice of local treatment modality.

    Objective: To identify factors associated with the risk of local and distant recurrence, and overall survival (OS) in patients with primary nonmetastatic clinical T1a RCC.

    Design setting and participants: A population-based nationwide register study of all 1935 patients with cT1a RCC, diagnosed during 2005-2012, identified through The National Swedish Kidney Cancer Register, was conducted.

    Outcome measurements and statistical analysis: Outcome variables were recurrence (local or distant) and OS. Possible explanatory variables included tumor size, RCC type, T stage, surgical technique, age, and gender. Associations with disease recurrence and OS were evaluated by multivariable regression and Cox multivariate analyses, respectively.

    Results and limitations: Among 1935 patients, 938 were treated with radical nephrectomy, 738 with partial nephrectomy, and 169 with ablative treatments, while 90 patients had no surgery. Seventy-eight (4%) patients were upstaged to pT3. Local or metastatic recurrences occurred in 145 (7.5%) patients, significantly more often after ablation (17.8%). The risk of recurrence was associated with tumor size, upstaging, and ablation. Larger tumor size, disease recurrence, and older age adversely affected OS, whereas partial nephrectomy and chromophobe RCC (chRCC) were associated with improved survival. Limitations include register design and a lack of comorbidity or performance status data.

    Conclusions: Upstaging and recurrence occurred, respectively, in 4.0% and 7.5% of patients with nonmetastatic RCCs ≤4 cm. Tumor size upstaging and ablation were associated with the risk for recurrence, while tumor size and recurrence were associated with decreased OS. Patients with chRCC and partial nephrectomy had prolonged OS in a real-world setting.

    Patient summary: We studied factors that may influence the risk of disease recurrence and overall survival, in a large nationwide patient cohort having nonmetastatic renal cell carcinoma ≤4 cm. Tumor size, tumor type, and treatment were associated with the risk of recurrence and overall death. Partial nephrectomy prolonged overall survival.

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  • 177. Almgren, J.
    et al.
    Lindvall, P.
    Englund,
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Safwenberg, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Comparison of Three Fully Automated Systems for Immunohematology with the Focus on Two Important Aspects of Capacity-Efficiency and Stress2014In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 54, p. 173A-174AArticle in journal (Other academic)
  • 178.
    Almhagen, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Techniques for the increased utilization of dose response variability in proton therapy2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Particle therapy is a form of radiation therapy in which protons and heavier ions are used, as opposed to photons in conventional radiation therapy. The biological effectiveness of particles compared to photons is often quantified as relative biological effectiveness (RBE). In clinical practice, protons are assumed to be 10% more efficient than photons, despite the fact that RBE is known to vary. On the other hand, variable RBE models can be used to describe the RBE at a given position as a function of a few parameters, such as the linear energy transfer (LET) of the beam. Questions of accuracy and validation have prevented the clinical introduction of variable RBE models. In this thesis, we tried to develop a variable RBE model for protons and carbon ions, and then apply it in a proton planning study.

    We started with developing a beam model for protons. It was based on measured data at the Skandion Clinic in Uppsala, Sweden. It is capable of describing the spatial, angular and energy distributions of a proton beam at a certain position in a treatment room. This, coupled with a particle transport engine, allows for accurate study of the physical properties of a clinical beam.

    Prior to developing our RBE model, we studied a number of publications containing proton in vitro cell survival data. It was found that the particle beams used included heavy secondary particle contamination and thus this need not be accounted for separately in a proton RBE model based on this data. Taking this into account, the subsequent RBE model did not provided increased accuracy compared to the considered proton RBE models. For carbon ions, accuracy was increased. Coupled with a treatment planning system, treatment plans taking into account RBE variability can thus be made with this RBE model.

    Finally, we applied the nanoCluE RBE model in a proton dose painting planning study, where the tumor target is given a heterogeneous dose based on an estimated radio sensitivity map of the tumor such that more resistant areas are given higher doses. Variable RBE was not beneficial in increasing the control probability of the tumor, but it did help in decreasing doses to nearby, healthy tissue.

    List of papers
    1. A beam model for focused proton pencil beams
    Open this publication in new window or tab >>A beam model for focused proton pencil beams
    2018 (English)In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 52, p. 27-32Article in journal (Refereed) Published
    Abstract [en]

    Introduction: We present a beam model for Monte Carlo simulations of the IBA pencil beam scanning dedicated nozzle installed at the Skandion Clinic. Within the nozzle, apart from entrance and exit windows and the two ion chambers, the beam traverses vacuum, allowing for a beam that is convergent downstream of the nozzle exit. Materials and methods: We model the angular, spatial and energy distributions of the beam phase space at the nozzle exit with single Gaussians, controlled by seven energy dependent parameters. The parameters were determined from measured profiles and depth dose distributions. Verification of the beam model was done by comparing measured and GATE acquired relative dose distributions, using plan specific log files from the machine to specify beam spot positions and energy. Results: GATE-based simulations with the acquired beam model could accurately reproduce the measured data. The gamma index analysis comparing simulated and measured dose distributions resulted in > 95% global gamma index pass rates (3%/2 mm) for all depths. Conclusion: The developed beam model was found to be sufficiently accurate for use with GATE e.g. for applications in quality assurance (QA) or patient motion studies with the IBA pencil beam scanning dedicated nozzles.

    Place, publisher, year, edition, pages
    Elsevier, 2018
    Keywords
    Proton therapy, Monte Carlo, Beam model
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-364002 (URN)10.1016/j.ejmp.2018.06.007 (DOI)000442110000004 ()30139606 (PubMedID)
    Funder
    Swedish Childhood Cancer FoundationSwedish Radiation Safety Authority
    Available from: 2018-10-30 Created: 2018-10-30 Last updated: 2022-04-18Bibliographically approved
    2. Handling of beam spectra in training and application of proton RBE models
    Open this publication in new window or tab >>Handling of beam spectra in training and application of proton RBE models
    2021 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 66, no 18, article id 185015Article in journal (Refereed) Published
    Abstract [en]

    Published data from cell survival experiments are frequently used as training data for models of proton relative biological effectiveness (RBE). The publications rarely provide full information about the primary particle spectrum of the used beam, or its content of heavy secondary particles. The purpose of this paper is to assess to what extent heavy secondary particles may have been present in published cell survival experiments, and to investigate the impact of non-primary protons for RBE calculations in treatment planning. We used the Monte Carlo code Geant4 to calculate the occurrence of non-primary protons and heavier secondary particles for clinical protons beams in water for four incident energies in the [100, 250] MeV interval. We used the resulting spectra together with a conservative RBE parameterization and an RBE model to map both the rise of RBE at the beam entry surface due to heavy secondary particle buildup, and the difference in estimated RBE if non-primary protons are included or not in the beam quality metric. If included, non-primary protons cause a difference of 2% of the RBE in the plateau region of an spread out Bragg peak and 1% in the Bragg peak. Including non-primary protons specifically for RBE calculations will consequently have a negligible impact and can be ignored. A buildup distance in water of one millimeter was sufficient to reach an equilibrium state of RBE for the four incident energies selected. For the investigated experimental data, 83 out of the 86 data points were found to have been determined with at least that amount of buildup material. Hence, RBE model training data should be interpreted to include the contribution of heavy secondaries.

    Place, publisher, year, edition, pages
    Institute of Physics Publishing (IOPP)IOP PUBLISHING LTD, 2021
    Keywords
    RBE, proton therapy, radiobiology, Monte Carlo
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-456485 (URN)10.1088/1361-6560/ac226a (DOI)000696368900001 ()34464939 (PubMedID)
    Available from: 2021-10-19 Created: 2021-10-19 Last updated: 2024-01-15Bibliographically approved
    3. Modelling tissue specific RBE for different radiation qualities based on a multiscale characterization of energy deposition
    Open this publication in new window or tab >>Modelling tissue specific RBE for different radiation qualities based on a multiscale characterization of energy deposition
    Show others...
    2023 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 182, article id 109539Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    We present the nanoCluE model, which uses nano- and microdosimetric quantities to model RBE for protons and carbon ions. Under the hypothesis that nano- and microdosimetric quantities correlates with the generation of complex DNA double strand breakes, we wish to investigate whether an improved accuracy in predicting LQ parameters may be achieved, compared to some of the published RBE models.

    Methods

    The model is based on experimental LQ data for protons and carbon ions. We generated a database of track structure data for a number of proton and carbon ion kinetic energies with the Geant4-DNA Monte Carlo code. These data were used to obtain both a nanodosimetric quantity and a set of microdosimetric quantities. The latter were tested with different parameterizations versus experimental LQ-data to select the variable and parametrization that yielded the best fit.

    Results

    For protons, the nanoCluE model yielded, for the ratio of the linear LQ term versus the test data, a root mean square error (RMSE) of 1.57 compared to 1.31 and 1.30 for two earlier other published proton models. For carbon ions the RMSE was 2.26 compared to 3.24 and 5.24 for earlier published carbon ion models.

    Conclusion

    These results demonstrate the feasibility of the nanoCluE RBE model for carbon ions and protons. The increased accuracy for carbon ions as compared to two other considered models warrants further investigation.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    RBE, Radiobiology, Proton therapy, Carbon ion therapy, Monte Carlo, Nanodosimetry, Microdosimetry
    National Category
    Cancer and Oncology Cancer and Oncology
    Research subject
    Medical Radiophysics
    Identifiers
    urn:nbn:se:uu:diva-472804 (URN)10.1016/j.radonc.2023.109539 (DOI)000954916600001 ()
    Funder
    Swedish Radiation Safety Authority
    Available from: 2022-04-18 Created: 2022-04-18 Last updated: 2023-04-18Bibliographically approved
    4. Plan robustness and RBE influence for proton dose painting by numbers for head and neck cancers
    Open this publication in new window or tab >>Plan robustness and RBE influence for proton dose painting by numbers for head and neck cancers
    Show others...
    2023 (English)In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 115, p. 103157-Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    To investigate the feasibility of dose painting by numbers (DPBN) with respect to robustness for proton therapy for head and neck cancers (HNC), and to study the influence of variable RBE on the TCP and OAR dose burden.

    Methods and materials

    Data for 19 patients who have been scanned pretreatment with PET-FDG and subsequently treated with photon therapy were used in the study. A dose response model developed for photon therapy was implemented in a TPS, allowing DPBN plans to be created. Conventional homogeneous dose and DPBN plans were created for each patient, optimized with either fixed RBE = 1.1 or a variable RBE model. Robust optimization was used to create clinically acceptable plans. To estimate the maximum potential loss in TCP due to actual SUV variations from the pre-treatment imaging, we applied a test case with randomized SUV distribution.

    Results

    Regardless of the use of variable RBE for optimization or evaluation, a statistically significant increase (p < 0.001) in TCP was found for DPBN plans as compared to homogeneous dose plans. Randomizing the SUV distribution decreased the TCP for all plans. A correlation between TCP increase and variance of the SUV distribution and target volume was also found.

    Conclusion

    DPBN for protons and HNC is feasible and could lead to a TCP gain. Risks associated with the temporal variation of SUV distributions could be mitigated by imposing minimum doses to targets. The correlation found between TCP increase and SUV variance and target volume may be used for patient selection.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    RBE, Radiobiology, Proton Therapy, Dose Painting, Head and Neck Cancer
    National Category
    Cancer and Oncology
    Research subject
    Medical Radiophysics
    Identifiers
    urn:nbn:se:uu:diva-472806 (URN)10.1016/j.ejmp.2023.103157 (DOI)001110333600001 ()
    Note

    Title in the list of papers of Erik Almhagen's thesis: RBE influence and plan robustness on proton dose painting by numbers for head and neck cancers

    Available from: 2022-04-18 Created: 2022-04-18 Last updated: 2023-12-22Bibliographically approved
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  • 179.
    Almhagen, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. The Skandion Clinic, Uppsala, Sweden.
    Boersma, David J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. ACMIT Gmbh, A-2700 Wiener Neustadt, Austria.
    Nyström, H.
    Skandion Clin, Uppsala, Sweden;DCPT, Aarhus, Denmark.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    A beam model for focused proton pencil beams2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 52, p. 27-32Article in journal (Refereed)
    Abstract [en]

    Introduction: We present a beam model for Monte Carlo simulations of the IBA pencil beam scanning dedicated nozzle installed at the Skandion Clinic. Within the nozzle, apart from entrance and exit windows and the two ion chambers, the beam traverses vacuum, allowing for a beam that is convergent downstream of the nozzle exit. Materials and methods: We model the angular, spatial and energy distributions of the beam phase space at the nozzle exit with single Gaussians, controlled by seven energy dependent parameters. The parameters were determined from measured profiles and depth dose distributions. Verification of the beam model was done by comparing measured and GATE acquired relative dose distributions, using plan specific log files from the machine to specify beam spot positions and energy. Results: GATE-based simulations with the acquired beam model could accurately reproduce the measured data. The gamma index analysis comparing simulated and measured dose distributions resulted in > 95% global gamma index pass rates (3%/2 mm) for all depths. Conclusion: The developed beam model was found to be sufficiently accurate for use with GATE e.g. for applications in quality assurance (QA) or patient motion studies with the IBA pencil beam scanning dedicated nozzles.

  • 180.
    Almhagen, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. The Skandion Clinic, Uppsala, Sweden.
    Dasu, Alexandru
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. The Skandion Clinic, Uppsala, Sweden.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Traneus, Erik
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Plan robustness and RBE influence for proton dose painting by numbers for head and neck cancers2023In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 115, p. 103157-Article in journal (Refereed)
    Abstract [en]

    Purpose

    To investigate the feasibility of dose painting by numbers (DPBN) with respect to robustness for proton therapy for head and neck cancers (HNC), and to study the influence of variable RBE on the TCP and OAR dose burden.

    Methods and materials

    Data for 19 patients who have been scanned pretreatment with PET-FDG and subsequently treated with photon therapy were used in the study. A dose response model developed for photon therapy was implemented in a TPS, allowing DPBN plans to be created. Conventional homogeneous dose and DPBN plans were created for each patient, optimized with either fixed RBE = 1.1 or a variable RBE model. Robust optimization was used to create clinically acceptable plans. To estimate the maximum potential loss in TCP due to actual SUV variations from the pre-treatment imaging, we applied a test case with randomized SUV distribution.

    Results

    Regardless of the use of variable RBE for optimization or evaluation, a statistically significant increase (p < 0.001) in TCP was found for DPBN plans as compared to homogeneous dose plans. Randomizing the SUV distribution decreased the TCP for all plans. A correlation between TCP increase and variance of the SUV distribution and target volume was also found.

    Conclusion

    DPBN for protons and HNC is feasible and could lead to a TCP gain. Risks associated with the temporal variation of SUV distributions could be mitigated by imposing minimum doses to targets. The correlation found between TCP increase and SUV variance and target volume may be used for patient selection.

    Download full text (pdf)
    fulltext
  • 181.
    Almhagen, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala Univ, Dept Immunol Genet & Pathol, Akad Sjukhuset, Med Radiat Sci, Uppsala, Sweden.;Skandion Clin, Uppsala, Sweden..
    Traneus, Erik
    RaySearch Labs, Stockholm, Sweden..
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Handling of beam spectra in training and application of proton RBE models2021In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 66, no 18, article id 185015Article in journal (Refereed)
    Abstract [en]

    Published data from cell survival experiments are frequently used as training data for models of proton relative biological effectiveness (RBE). The publications rarely provide full information about the primary particle spectrum of the used beam, or its content of heavy secondary particles. The purpose of this paper is to assess to what extent heavy secondary particles may have been present in published cell survival experiments, and to investigate the impact of non-primary protons for RBE calculations in treatment planning. We used the Monte Carlo code Geant4 to calculate the occurrence of non-primary protons and heavier secondary particles for clinical protons beams in water for four incident energies in the [100, 250] MeV interval. We used the resulting spectra together with a conservative RBE parameterization and an RBE model to map both the rise of RBE at the beam entry surface due to heavy secondary particle buildup, and the difference in estimated RBE if non-primary protons are included or not in the beam quality metric. If included, non-primary protons cause a difference of 2% of the RBE in the plateau region of an spread out Bragg peak and 1% in the Bragg peak. Including non-primary protons specifically for RBE calculations will consequently have a negligible impact and can be ignored. A buildup distance in water of one millimeter was sufficient to reach an equilibrium state of RBE for the four incident energies selected. For the investigated experimental data, 83 out of the 86 data points were found to have been determined with at least that amount of buildup material. Hence, RBE model training data should be interpreted to include the contribution of heavy secondaries.

  • 182.
    Almhagen, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. The Skandion Clinic, Uppsala, Sweden.
    Villegas, Fernanda
    Radiotherapy Physics and Engineering, Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
    Tilly, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Elekta Instrument AB, Box 7593, Stockholm SE-10393, Sweden.
    Glimelius, Lars
    RaySearch Laboratories, Stockholm, Sweden.
    Traneus, Erik
    RaySearch Laboratories, Stockholm, Sweden.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Modelling tissue specific RBE for different radiation qualities based on a multiscale characterization of energy deposition2023In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 182, article id 109539Article in journal (Refereed)
    Abstract [en]

    Purpose

    We present the nanoCluE model, which uses nano- and microdosimetric quantities to model RBE for protons and carbon ions. Under the hypothesis that nano- and microdosimetric quantities correlates with the generation of complex DNA double strand breakes, we wish to investigate whether an improved accuracy in predicting LQ parameters may be achieved, compared to some of the published RBE models.

    Methods

    The model is based on experimental LQ data for protons and carbon ions. We generated a database of track structure data for a number of proton and carbon ion kinetic energies with the Geant4-DNA Monte Carlo code. These data were used to obtain both a nanodosimetric quantity and a set of microdosimetric quantities. The latter were tested with different parameterizations versus experimental LQ-data to select the variable and parametrization that yielded the best fit.

    Results

    For protons, the nanoCluE model yielded, for the ratio of the linear LQ term versus the test data, a root mean square error (RMSE) of 1.57 compared to 1.31 and 1.30 for two earlier other published proton models. For carbon ions the RMSE was 2.26 compared to 3.24 and 5.24 for earlier published carbon ion models.

    Conclusion

    These results demonstrate the feasibility of the nanoCluE RBE model for carbon ions and protons. The increased accuracy for carbon ions as compared to two other considered models warrants further investigation.

    Download full text (pdf)
    fulltext
  • 183.
    Almstedt, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    New targeted therapies for malignant neural tumors: From systematic discovery to zebrafish models2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancers in the neural system presents a major health challenge. The most aggressive brain tumor in adults, glioblastoma, has a median survival of 15 months and few therapeutic options. High-risk neuroblastoma, a childhood tumor originating in the sympathetic nervous system, has a 5-year survival under 50%, despite extensive therapy. Molecular characterization of these tumors has had some, but so far limited, clinical impact. In neuroblastoma, patients with ALK mutated tumors can benefit from treatment with ALK inhibitors. In glioblastoma, molecular subgroups have not yet revealed any subgroup-specific gene dependencies due to tumor heterogeneity and plasticity. In this thesis, we identify novel treatment candidates for neuroblastoma and glioblastoma. 

    In paper I, we discover novel drug targets for high-risk neuroblastoma by integrating patient data, large-scale pharmacogenomic profiles, and drug-protein interaction maps. Using a novel algorithm, TargetTranslator, we identify more than 80 targets for this patient group. Activation of cannabinoid receptor 2 (CNR2) or inhibition of mitogen-activated protein kinase 8 (MAPK8) reduces tumor growth in zebrafish and mice models of neuroblastoma, establishing TargetTranslator as a useful tool for target discovery in cancer. 

    In paper II, we screen approximately 1500 compounds across 100 molecularly characterized cell lines from patients to uncover heterogeneous responses to drugs in glioblastoma. We identify several connections between pathway activities and drug response. Sensitivity to proteasome inhibition is linked to oxidative stress response and p53 activity in cells, and can be predicted using a gene signature. We also discover sigma receptors as novel drug targets for glioblastoma and find a synergistic vulnerability in targeting cholesterol homeostasis.

    In paper III, we systematically explore novel targets for glioblastoma using an siRNA screen. Downregulation of ZBTB16 decreases cell cycle-related proteins and transcripts in patient-derived glioblastoma cells. Using a zebrafish assay, we find that ZBTB16 promotes glioblastoma invasion in vivo

    In paper IV, we characterized the growth of seven patient-derived glioblastoma cell lines in orthotopic zebrafish xenografts. Using automated longitudinal imaging, we find that tumor engraftment strongly correlates with tumor initiation capacity in mice xenografts and that the heterogeneous response to proteasome inhibitors is maintained in vivo

    In summary, this thesis identifies novel targets for glioblastoma and neuroblastoma using systematic approaches. Treatment candidates are evaluated in novel zebrafish xenograft models that are developed for high-throughput glioblastoma and neuroblastoma drug evaluation. Together, this thesis provides promising evidence of new therapeutic options for malignant neural tumors.

    List of papers
    1. Integrative discovery of treatments for high-risk neuroblastoma
    Open this publication in new window or tab >>Integrative discovery of treatments for high-risk neuroblastoma
    Show others...
    2020 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 71Article in journal (Refereed) Published
    Abstract [en]

    Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

    National Category
    Cancer and Oncology Cell and Molecular Biology Bioinformatics (Computational Biology)
    Identifiers
    urn:nbn:se:uu:diva-402363 (URN)10.1038/s41467-019-13817-8 (DOI)000551406900001 ()31900415 (PubMedID)
    Funder
    Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilSwedish Foundation for Strategic Research
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2023-03-28Bibliographically approved
    2. A drug association map of glioblastoma informs precision targeting of p53-dependent metabolic states
    Open this publication in new window or tab >>A drug association map of glioblastoma informs precision targeting of p53-dependent metabolic states
    Show others...
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-402456 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-02-04Bibliographically approved
    3. ZBTB16 orchestrates growth and invasion in glioblastoma
    Open this publication in new window or tab >>ZBTB16 orchestrates growth and invasion in glioblastoma
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    ZBTB16/PLZF, glioblastoma, siRNA, targeted therapy
    National Category
    Cancer and Oncology Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-402522 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-18
    4. Real-time evaluation of glioblastoma growth in patient-specific zebrafish xenografts
    Open this publication in new window or tab >>Real-time evaluation of glioblastoma growth in patient-specific zebrafish xenografts
    Show others...
    2021 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 24, no 5, p. 726-738Article in journal (Refereed) Published
    Abstract [en]

    Background: Patient-derived xenograft (PDX) models of glioblastoma (GBM) are a central tool for neuro-oncology research and drug development, enabling the detection of patient-specific differences in growth, and in vivo drug response. However, existing PDX models are not well suited for large-scale or automated studies. Thus, here, we investigate if a fast zebrafish-based PDX model, supported by longitudinal, AI-driven image analysis, can recapitulate key aspects of glioblastoma growth and enable case-comparative drug testing.

    Methods: We engrafted 11 GFP-tagged patient-derived GBM IDH wild-type cell cultures (PDCs) into 1-day-old zebrafish embryos, and monitored fish with 96-well live microscopy and convolutional neural network analysis. Using light-sheet imaging of whole embryos, we analyzed further the invasive growth of tumor cells.

    Results: Our pipeline enables automatic and robust longitudinal observation of tumor growth and survival of individual fish. The 11 PDCs expressed growth, invasion and survival heterogeneity, and tumor initiation correlated strongly with matched mouse PDX counterparts (Spearman R = 0.89, p < 0.001). Three PDCs showed a high degree of association between grafted tumor cells and host blood vessels, suggesting a perivascular invasion phenotype. In vivo evaluation of the drug marizomib, currently in clinical trials for GBM, showed an effect on fish survival corresponding to PDC in vitro and in vivo marizomib sensitivity.

    Conclusions: Zebrafish xenografts of GBM, monitored by AI methods in an automated process, present a scalable alternative to mouse xenograft models for the study of glioblastoma tumor initiation, growth, and invasion, applicable to patient-specific drug evaluation.

    Place, publisher, year, edition, pages
    Oxford University PressOxford University Press (OUP), 2021
    National Category
    Cancer and Oncology Other Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-402416 (URN)10.1093/neuonc/noab264 (DOI)000764882800001 ()34919147 (PubMedID)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2024-01-15Bibliographically approved
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  • 184.
    Almstedt, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hekmati, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rosén, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Wärn, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Olsen, Thale Kristin
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Dyberg, Cecilia
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Doroszko, Milena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Larsson, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Arsenian Henriksson, Marie
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Påhlman, Sven
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Bexell, Daniel
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Department of Medicine, Integrated Cardio-Metabolic Centre Single Cell Facility, Karolinska Institutet, Stockholm, Sweden..
    Kogner, Per
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden..
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Integrative discovery of treatments for high-risk neuroblastoma2020In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 71Article in journal (Refereed)
    Abstract [en]

    Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

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  • 185.
    Almstedt, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rosén, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Gloger, Marleen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Rebecka, Stockard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hekmati, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Krona, Cecilia
    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.
    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.
    Real-time evaluation of glioblastoma growth in patient-specific zebrafish xenografts2021In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 24, no 5, p. 726-738Article in journal (Refereed)
    Abstract [en]

    Background: Patient-derived xenograft (PDX) models of glioblastoma (GBM) are a central tool for neuro-oncology research and drug development, enabling the detection of patient-specific differences in growth, and in vivo drug response. However, existing PDX models are not well suited for large-scale or automated studies. Thus, here, we investigate if a fast zebrafish-based PDX model, supported by longitudinal, AI-driven image analysis, can recapitulate key aspects of glioblastoma growth and enable case-comparative drug testing.

    Methods: We engrafted 11 GFP-tagged patient-derived GBM IDH wild-type cell cultures (PDCs) into 1-day-old zebrafish embryos, and monitored fish with 96-well live microscopy and convolutional neural network analysis. Using light-sheet imaging of whole embryos, we analyzed further the invasive growth of tumor cells.

    Results: Our pipeline enables automatic and robust longitudinal observation of tumor growth and survival of individual fish. The 11 PDCs expressed growth, invasion and survival heterogeneity, and tumor initiation correlated strongly with matched mouse PDX counterparts (Spearman R = 0.89, p < 0.001). Three PDCs showed a high degree of association between grafted tumor cells and host blood vessels, suggesting a perivascular invasion phenotype. In vivo evaluation of the drug marizomib, currently in clinical trials for GBM, showed an effect on fish survival corresponding to PDC in vitro and in vivo marizomib sensitivity.

    Conclusions: Zebrafish xenografts of GBM, monitored by AI methods in an automated process, present a scalable alternative to mouse xenograft models for the study of glioblastoma tumor initiation, growth, and invasion, applicable to patient-specific drug evaluation.

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  • 186.
    Al-Ramadan, Afkar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mortensen, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Analysis of radiation effects in two irradiated tumor spheroid models2018In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 15, no 3, p. 3008-3016Article in journal (Refereed)
    Abstract [en]

    Multicellular spheroids have proven suitable as three-dimensional in vivo-like models of non-vascularized micrometastases. Unlike monolayer-based models, spheroids mirror the cellular milieu and the pathophysiological gradients inside tumor nodules. However, there is limited knowledge of the radiation effects at the molecular level in spheroids of human origin. The present study is a presentation of selected cell biological processes that may easily be analyzed with methods available at routine pathology laboratories. Using gamma irradiated pancreatic neuroendocrine BON1 and colonic adenocarcinoma HCT116 spheroids as model systems, the present study assessed the radiobiological response in these models. Spheroid growth after irradiation was followed over time and molecular responses were subsequently assessed with immunohistochemistry (IHC) staining for descriptive analyses and semi-automatic grading of apoptosis, G(2)-phase and senescence in thin sections of the spheroids. Growth studies demonstrated the BON1 spheroids were slower growing and less sensitive to radiation compared with the HCT116 spheroids. IHC staining for G2-phase was primarily observed in the outer viable P-cell layers of the spheroids, with the 6 Gy irradiated HCT116 spheroids demonstrating a very clear increase in staining intensity compared with unirradiated spheroids. Apoptosis staining results indicated increased apoptosis with increasing radiation doses. No clear association between senescence and radiation exposure in the spheroids were observed. The present results demonstrate the feasibility of the use of multicellular spheroids of human origin in combination with IHC analyses to unravel radiobiological responses at a molecular level. The present findings inspire further investigations, including other relevant IHC-detectable molecular processes in time-and radiation dose-dependent settings.

  • 187.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Behare, Neha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Alsehli, Ahmed M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. King Abdulaziz Univ & Hosp, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia.
    Berkins, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Arora, Aadeya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Antoniou, Eirini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Moysiadou, Eleni I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Anantha-Krishnan, Sowmya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Cosmen, Patricia D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Vikner, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Moulin, Thiago C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Lund Univ, Fac Med, Dept Expt Med Sci, Solvegatan 19,BMC F10, S-22184 Lund, Sweden.
    Ammar, Nourhene
    Univ Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France..
    Boukhatmi, Hadi
    Univ Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France..
    Clemensson, Laura E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 22, article id 3528Article in journal (Refereed)
    Abstract [en]

    The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, C1C-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle C1C-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored C1C-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered C1C-a expression. Taken together, these results may indicate the potential role of C1C-a inhibition in statinassociated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.

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  • 188.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Nikpour, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Department of Medical Sciences, Uppsala University, BMC, Husargatan 3, 750 03, Uppsala, Sweden.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems: insights on its signalling pathway, linked disorders and theragnostic potential2022In: Cell & Bioscience, ISSN 2045-3701, Vol. 12, no 1, article id 151Article, review/survey (Refereed)
    Abstract [en]

    Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.

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  • 189.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Schulga, Alexey
    Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia.
    Deyev, Sergey
    Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia;Natl Res Tomsk Polytech Univ, Tomsk, Russia;Sechenov Univ, Ctr BioMed Engn, Moscow, Russia.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Natl Res Tomsk Polytech Univ, Tomsk, Russia.
    On the prevention of kidney uptake of radiolabeled DARPins2020In: EJNMMI Research, E-ISSN 2191-219X, Vol. 10, article id 7Article in journal (Refereed)
    Abstract [en]

    Background: Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14-18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation for targeted radionuclide therapy. A better understanding of the mechanisms behind the kidney uptake of DARPins could aid the development of strategies to reduce it. In this study, we have investigated whether the renal uptake of [Tc-99m]Tc(CO)(3)-G3 DARPin could be reduced by administration of compounds that act on various parts of the reabsorption system in the kidney.

    Results: Co-injection of lysine or Gelofusine was not effective for the reduction of kidney uptake of [Tc-99m]Tc(CO)(3)-G3. Administration of sodium maleate before the injection of [Tc-99m]Tc(CO)(3)-G3 reduced the kidney-associated activity by 60.4 +/- 10.3%, while administration of fructose reduced it by 46.9 +/- 7.6% compared with the control. The decrease in the kidney uptake provided by sodium maleate was also observed for [Tc-99m]Tc(CO)(3)-9_29 DARPin. Preinjection of colchicine, probenecid, mannitol, or furosemide had no effect on the kidney uptake of [Tc-99m]Tc(CO)(3)-G3. Kidney autoradiography showed mainly cortical accumulation of activity for all studied groups.

    Conclusion: Common clinical strategies were not effective for the reduction of kidney uptake of [Tc-99m]Tc(CO)(3)-G3. Both fructose and maleate lower the cellular ATP level in the proximal tubule cells and their reduction of the kidney reuptake indicates the involvement of an ATP-driven uptake mechanism. The decrease provided by maleate for both G3 and 9_29 DARPins indicates that their uptake proceeds through a mechanism independent of DARPin structure and binding site composition.

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  • 190.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Leitao, Charles Dahlsson
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Atterby, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs2018In: Cells, E-ISSN 2073-4409, Vol. 7, no 10, article id 164Article in journal (Refereed)
    Abstract [en]

    Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD 035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.

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  • 191.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, H.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, T.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Improving of molecular design of a novel Affibody-fused HER2-recognising anticancer toxin using radionuclide-based techniques2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S178-S178Article in journal (Refereed)
  • 192.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Ding, Haozhong
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Edqvist, Per-Henrik D
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjorn
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 288, p. 84-95Article in journal (Refereed)
    Abstract [en]

    Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, Z(HER2:2891), conjugated with the cytotoxic maytansine derivate MC-DM1, for targeted cancer therapy. Z(HER2:2891) was expressed as a monomer (Z(HER2:2891)), dimer ((Z(HER2:2891)) 2) and dimer with an albumin binding domain (ABD) for half-life extension ((Z(HER2:2891)) 2-ABD). All proteins had a unique C-terminal cysteine that could be used for efficient and site-specific conjugation with MC-DM1. The resulting affibody drug conjugates were potent cytotoxic molecules for human cells over-expressing HER2, with sub-nanomolar IC50-values similar to trastuzumab emtansine, and did not affect cells with low HER2 expression. A biodistribution study of a radiolabeled version of (Z(HER2:2891))(2)-ABD-MC-DM1, showed that it was taken up by the tumor. The major site of off-target uptake was the kidneys and to some extent the liver. (Z(HER2:2891)) 2-ABD-MC-DM1 was found to have a half-life in circulation of 14 h. The compound was tolerated well by mice at 8.5 mg/kg and was shown to extend survival of mice bearing HER2 over-expressing tumors. The findings in this study show that affibody molecules are a promising class of engineered affinity proteins to specifically deliver small molecular drugs to cancer cells and that such conjugates are potential candidates for clinical evaluation on HER2-overexpressing cancers.

  • 193.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016In: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 49, no 3, p. 1185-1194Article in journal (Refereed)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 194.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Membreno, Rosemery
    CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA.;CUNY, Grad Ctr, PhD Program Chem, New York, NY USA.;Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Cook, Brendon
    CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA.;CUNY, Grad Ctr, PhD Program Chem, New York, NY USA.;Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Zeglis, Brian M.
    CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA.;CUNY, Grad Ctr, PhD Program Chem, New York, NY USA.;Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Pretargeted Imaging and Therapy2017In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no 10, p. 1553-1559Article in journal (Refereed)
    Abstract [en]

    In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.

  • 195.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Perols, Anna
    Tsourma, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Robillard, Marc
    Rossin, Raffaella
    Ten Hoeve, Wolter
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Feasibility of affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting2016In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 3, p. 431-436Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal re-absorption of affibody molecules prevents the use of residualizing radiometals, including a number of promising low energy beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys.

    Methods:

    TCO was conjugated to the anti-HER2 affibody molecule Z2395. DOTA-tetrazine was labeled with indium-111 and lutetium-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts.

    Results:

    125I-Z2395-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45±16 pM. 111In-tetrazine bound specifically and selectively to Z2395-TCO pre-treated cells. In vivo studies demonstrated HER2-specific 125I-Z2395-TCO accumulation in xenografts. TCO-mediated 111In-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z2395-TCO. At 1 h post injection, the tumor uptake of 111In-tetrazine and 177Lu-tetrazine was ca. 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of 111In in comparison with direct targeting.

    Conclusion:

    The feasibility of affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pretargeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.

  • 196.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tsourma, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Preclin PET Platform, Uppsala, Sweden..
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Perols, A.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Robillard, M.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    Rossin, R.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    ten Hoeve, W.
    Syncom BV, Groningen, Netherlands..
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Karlstrom, A. Eriksson
    KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting: proof-of-principle2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, no S1, p. S246-S246Article in journal (Other academic)
  • 197.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Karlström, Amelie Eriksson
    Westerlund, Kristina
    Preparation of Conjugates for Affibody-Based PNA-Mediated Pretargeting.2020In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 2105, p. 283-304Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are small engineered scaffold proteins suitable for in vivo tumor targeting. Radionuclide molecular imaging using directly radiolabelled affibody molecules provides excellent imaging. However, affibody molecules have a high renal reabsorption, which complicates their use for radionuclide therapy. The high renal reabsorption is a common problem for the use of engineered scaffold proteins for radionuclide therapy. Affibody-based PNA-mediated pretargeting reduces dramatically the absorbed dose to the kidneys and makes affibody-based radionuclide therapy possible. This methodology might, hopefully, solve the problem of high renal reabsorption for radionuclide therapy mediated by other engineered scaffold proteins.

  • 198.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Westerlund, K.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Velletta, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Eriksson-Karlström, A.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Comparative evaluation of Lu-177-HP2 and In-111-HP2, secondary agents for affibody-based PNA-mediated radionuclide pretargeting2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S237-S237Article in journal (Refereed)
  • 199.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Westerlund, Kristina
    KTH Royal Inst Technol, Div Prot Technol, Sch Biotechnol, Stockholm, Sweden..
    Velletta, Justin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Eriksson Karlström, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting: Development of an optimized conjugation protocol and 177Lu labeling2017In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 54, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Introduction: We have previously developed a pretargeting approach for affibody-mediated cancer therapy based on PNA-PNA hybridization. In this article we have further developed this approach by optimizing the production of the primary agent, Z(HER2.342)-SR-HP1, and labeling the secondary agent, HP2, with the therapeutic radionuclide Lu-177. We also studied the biodistribution profile of Lu-177-HP2 in mice, and evaluated pretargeting with Lu-177-HP2 in vitro and in vivo.

    Methods: The biodistribution profile of Lu-177-HP2 was evaluated in NMRI mice and compared to the previously studied In-111-HP2. Pretargeting using Lu-177-HP2 was studied in vitro using the HER2-expressing cell lines BT-474 and SKOV-3, and in vivo in mice bearing SKOV-3 xenografts.

    Results and conclusion: Using an optimized production protocol for Z(HER2:342)-SR-HP1 the ligation time was reduced from 15 h to 30 min, and the yield increased from 45% to 70%. Lu-177-labeled HP2 binds specifically in vitro to BT474 and SKOV-3 cells pre-treated with Z(HER2:342)-SR-HP1.Lu-177-HP2 was shown to have a more rapid blood clearance compared to In-111-HP2 in NMRI mice, and the measured radioactivity in blood was 0.22 +/- 0.1 and 0.68 +/- 0.07%ID/g for Lu-177- and In-111-HP2, respectively, at 1 h p.i. In contrast, no significant difference in kidney uptake was observed (4.47 +/- 1.17 and 3.94 +/- 0.58%ID/g for Lu-177- and In-111-HP2, respectively, at I h p.i.). Co-injection with either Gelofusine or lysine significantly reduced the kidney uptake for Lu-177-HP2 (1.0 +/- 0.1 and 1.6 +/- 0.2, respectively, vs. 2.97 +/- 0.87%ID/g in controls at 4 h p.i.). Lu-177-HP2 accumulated in SKOV-3 xenografts in BALB/C nu/nu mice when administered after injection of Z(HER2:342)-SR-HP1. Without pre-injection of Z(HER2:342)-SR-HP1, the uptake of Lu-177-HP2 was about 90-fold lower in tumor (0.23 +/- 0.08 vs. 20.7 +/- 3.5%ID/g). The tumor-to-kidney radioactivity accumulation ratio was almost 5-fold higher in the group of mice pre-injected with Z(HER2:342)-SR-HP1. In conclusion, (177)LuHP2 was shown to be a promising secondary agent for affibody-mediated tumor pretargeting in vivo.

  • 200.
    Altena, Renske
    et al.
    Karolinska Inst, Inst Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Karolinska Comprehens Canc Ctr, Med Unit Breast Endocrine Tumors & Sarcoma, Theme Canc, Solna, Sweden..
    Tzortzakakis, Antonios
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Radiol, Stockholm, Sweden.;Karolinska Univ Hosp, Funct Unit Nucl Med, Med Radiat Phys & Nucl Med, Huddinge, Sweden..
    Buren, Siri Af
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Radiol, Stockholm, Sweden.;Karolinska Univ Hosp, Funct Unit Nucl Med, Med Radiat Phys & Nucl Med, Huddinge, Sweden..
    Tran, Thuy A.
    Karolinska Univ Hosp, Karolinska Comprehens Canc Ctr, Med Unit Breast Endocrine Tumors & Sarcoma, Theme Canc, Solna, Sweden.;Karolinska Univ Hosp, Dept Radiopharm, Solna, Sweden..
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Affibody AB, Solna, Sweden..
    Bergh, Jonas
    Karolinska Inst, Inst Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Karolinska Comprehens Canc Ctr, Med Unit Breast Endocrine Tumors & Sarcoma, Theme Canc, Solna, Sweden..
    Axelsson, Rimma
    Karolinska Univ Hosp, Funct Unit Nucl Med, Med Radiat Phys & Nucl Med, Huddinge, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Current status of contemporary diagnostic radiotracers in the management of breast cancer: first steps toward theranostic applications2023In: EJNMMI Research, E-ISSN 2191-219X, Vol. 13, no 1, article id 43Article, review/survey (Refereed)
    Abstract [en]

    BackgroundExpanding therapeutic possibilities have improved disease-related prospects for breast cancer patients. Pathological analysis on a tumor biopsy is the current reference standard biomarker used to select for treatment with targeted anticancer drugs. This method has, however, several limitations, related to intra- and intertumoral as well as spatial heterogeneity in receptor expression as well as the need to perform invasive procedures that are not always technically feasible.Main bodyIn this narrative review, we focus on the current role of molecular imaging with contemporary radiotracers for positron emission tomography (PET) in breast cancer. We provide an overview of diagnostic radiotracers that represent treatment targets, such as programmed death ligand 1, human epidermal growth factor receptor 2, polyadenosine diphosphate-ribose polymerase and estrogen receptor, and discuss developments in therapeutic radionuclides for breast cancer management.ConclusionImaging of treatment targets with PET tracers may provide a more reliable precision medicine tool to find the right treatment for the right patient at the right time. In addition to visualization of the target of treatment, theranostic trials with alpha- or beta-emitting isotopes provide a future treatment option for patients with metastatic breast cancer.

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