Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Refine search result
1 - 47 of 47
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ Hosp, Dept Pathol, S-75185 Uppsala, Sweden..
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala Univ Hosp, Dept Pathol, S-75185 Uppsala, Sweden..
    Ageing-Related Neurodegeneration and Cognitive Decline2024In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 7, article id 4065Article in journal (Refereed)
    Abstract [en]

    Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to the morgue of Uppsala University Hospital during a 15-year-long period. Among the 1630 subjects, 1610 were ≥ 41 years of age (range 41 to 102 years). Overall, hyperphosphorylated (HP) τ was observed in the brains of 98% of the 1610 subjects, and amyloid β-protein (Aβ) in the brains of 64%. The most common alteration observed was Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) in 26% of the subjects. In 16% of the subjects, HPτ was limited to the locus coeruleus. In 14 subjects (<1%), no altered proteins were observed. In 3 subjects, only Aβ was observed, and in 17, HPτ was observed in a distribution other than that seen in ADNC/PART. The transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant age-related TDP encephalopathy (LATE) was observed in 565 (35%) subjects and α-synuclein (αS) pathology, i.e., Lewy body disease (LBD) or multi system atrophy (MSA) was observed in the brains of 21% of the subjects. A total of 39% of subjects with ADNC, 59% of subjects with PART, and 81% of subjects with HPτ limited to the locus coeruleus lacked concomitant pathologies, i.e., LATE-NC or LBD-NC. Of the 293 (18% of the 1610 subjects) subjects with dementia, 81% exhibited a high or intermediate level of ADNC. In 84% of all individuals with dementia, various degrees of concomitant alterations were observed; i.e., MIXED-NC was a common cause of dementia. A high or intermediate level of PART was observed in 10 subjects with dementia (3%), i.e., tangle-predominant dementia. No subjects exhibited only vascular NC (VNC), but in 17 subjects, severe VNC might have contributed to cognitive decline. Age-related tau astrogliopathy (ARTAG) was observed in 37% of the 1610 subjects and in 53% of those with dementia.

    Download full text (pdf)
    FULLTEXT01
  • 2.
    Babacic, Haris
    et al.
    Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Stockholm, Sweden..
    Galardi, Silvia
    Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy..
    Umer, Husen M.
    Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Stockholm, Sweden..
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Maturi, Nagaprathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Cardinali, Deborah
    Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy..
    Pellegatta, Serena
    Fdn IRCCS, Inst Neurol Carlo Besta, Dept Mol Neurooncol, Unit Immunotherapy Brain Tumors, Milan, Italy..
    Michienzi, Alessandro
    Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy..
    Trevisi, Gianluca
    G D Annunzio Univ, Hosp Spirito St, Neurosurg Unit, Chieti, Pescara, Italy..
    Mangiola, Annunziato
    G D Annunzio Univ, Hosp Spirito St, Neurosurg Unit, Chieti, Pescara, Italy..
    Lehtiö, Janne
    Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Stockholm, Sweden..
    Ciafré, Silvia Anna
    Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy.;Univ Rome TorVergata, Dept Biomedicineand Prevent, Via Montpellier 1, I-00133 Rome, Italy..
    Pernemalm, Maria
    Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Tomtebodavagen 23, S-17165 Stockholm, Sweden..
    Glioblastoma stem cells express non-canonical proteins and exclusive mesenchymal-like or non-mesenchymal-like protein signatures2023In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 17, no 2, p. 238-260Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) cancer stem cells (GSCs) contribute to GBM's origin, recurrence, and resistance to treatment. However, the understanding of how mRNA expression patterns of GBM subtypes are reflected at global proteome level in GSCs is limited. To characterize protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry. We quantified > 10 000 proteins in two independent GSC panels and propose a GSC-associated proteomic signature characterizing two distinct phenotypic conditions; one defined by proteins upregulated in proneural and classical GSCs (GPC-like), and another by proteins upregulated in mesenchymal GSCs (GM-like). The GM-like protein set in GBM tissue was associated with necrosis, recurrence, and worse overall survival. Through proteogenomics, we discovered 252 non-canonical peptides in the GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered non-protein-coding, including variants of the heterogeneous ribonucleoproteins implicated in RNA splicing. In summary, GSCs express two protein sets that have an inverse association with clinical outcomes in GBM. The discovery of non-canonical protein sequences questions existing gene models and pinpoints new protein targets for research in GBM.

    Download full text (pdf)
    fulltext
  • 3.
    Bendahl, Par-Ola
    et al.
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Gezelius, Emelie
    Lund Univ, Dept Clin Sci, Div Oncol, Barngatan 4, SE-22185 Lund, Sweden.;Lund Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Longitudinal Assessment of Circulating Tumor Cells and Outcome in Small Cell Lung Cancer: A Sub-Study of RASTEN-A Randomized Trial with Low Molecular Weight Heparin2023In: Cancers, ISSN 2072-6694, Vol. 15, no 12, article id 3176Article in journal (Refereed)
    Abstract [en]

    Simple Summary Small cell lung cancer (SCLC) is an aggressive lung cancer subtype associated with an overall poor prognosis but a variable response rate to chemotherapy. The measurement of circulating tumor cells (CTCs) offers a non-invasive method to monitor the disease and may provide prognostic information as potential guidance to clinicians in the management of SCLC. However, the value of CTCs during and after chemotherapy appears inconclusive. Here, we show that the detection of CTCs at baseline correlates to overall survival in SCLC, and that persistently detectable CTCs after completion of treatment adds further prognostic value. This suggests that repetitive analysis of CTCs during and after the course of treatment may have a role in the management of SCLC, warranting further studies. Circulating tumor cells (CTCs) may provide a liquid biopsy approach to disease monitoring in small cell lung cancer (SCLC), a particularly aggressive tumor subtype. Yet, the prognostic role of CTCs during and after treatment in relation to baseline remains ill-defined. Here, we assessed the value of longitudinal CTC analysis and the potential of low-molecular-weight heparin (LMWH) to reduce CTC abundance in SCLC patients from a randomized trial (RASTEN). Blood samples were collected at baseline, before chemotherapy Cycle 3, and at 2-month follow-up from 42 patients in total, and CTCs were quantified using the FDA-approved CellSearch system. We found a gradual decline in CTC count during and after treatment, independently of the addition of LMWH to standard therapy. Detectable CTCs at baseline correlated significantly to reduced survival compared to undetectable CTCs (unadjusted hazard ratio (HR) of 2.75 (95% CI 1.05-7.20; p = 0.040)). Furthermore, a persistent CTC count at 2-month follow-up was associated with a HR of 4.22 (95% CI 1.20-14.91; p = 0.025). Our findings indicate that persistently detectable CTCs during and after completion of therapy offer further prognostic information in addition to baseline CTC, suggesting a role for CTC in the individualized management of SCLC.

    Download full text (pdf)
    FULLTEXT01
  • 4.
    Boot, James
    et al.
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Rosser, Gabriel
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Kancheva, Dailya
    Vrije Univ Brussel, Lab Mol & Cellular Therapy, Brussels, Belgium..
    Vinel, Claire
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Lim, Yau Mun
    Univ Coll London Hosp NHS Fdn Trust, Natl Hosp Neurol & Neurosurg, Div Neuropathol, London, England.;UCL, Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London, England..
    Pomella, Nicola
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Zhang, Xinyu
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Guglielmi, Loredana
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Sheer, Denise
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Barnes, Michael
    Queen Mary Univ London, William Harvey Res Inst, Ctr Translat Bioinformat, Barts & London Sch Med & Dent, London, England..
    Brandner, Sebastian
    Univ Coll London Hosp NHS Fdn Trust, Natl Hosp Neurol & Neurosurg, Div Neuropathol, London, England.;UCL, Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London, England..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Movahedi, Kiavash
    Vrije Univ Brussel, Lab Mol & Cellular Therapy, Brussels, Belgium..
    Marino, Silvia
    Queen Mary Univ, Blizard Inst, Barts & London Sch Med & Dent, London, England..
    Global hypo-methylation in a proportion of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape2022In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e77335Article in journal (Refereed)
    Abstract [en]

    We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.

    Download full text (pdf)
    FULLTEXT01
  • 5.
    Borgenvik, Anna
    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, Neurooncology and neurodegeneration.
    Holmberg, Karl O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bolin, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Hutter, Sonja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Garancher, Alexandra
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Rahmanto, Aldwin Suryo
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Olsen, Thale Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mainwaring, Oliver
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Sattanino, Damiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Verbaan, Annemieke D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rusert, Jessica M.
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Sundström, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Ballester Bravo, Mar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dang, Yonglong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wenz, Amelie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Richardson, Stacey
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Fotaki, Grammatiki
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hill, Rebecca M.
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Dubuc, Adrian M.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Kalushkova, Antonia
    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 precision medicine.
    Remke, Marc
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Čančer, Matko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    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 precision medicine.
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Chen, Xingqi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Taylor, Michael D.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Sangfelt, Olle
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Clifford, Steven C.
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Schueller, Ulrich
    Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany.;Univ Med Ctr Hamburg Eppendorf, Dept Paediat Hematol & Oncol, Hamburg, Germany.;Res Inst Childrens Canc Ctr Hamburg, Hamburg, Germany..
    Wechsler-Reya, Robert J.
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Weishaupt, Holger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma2022In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 82, no 24, p. 4586-4603Article in journal (Refereed)
    Abstract [en]

    Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.

    Download full text (pdf)
    fulltext
  • 6.
    Borota, Ljubisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Latini, Francesco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurovetenskap. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Complete functional recovery in a child after endovascular treatment of basilar artery occlusion caused by spontaneous dissection: a case report2022In: Child's Nervous System, ISSN 0256-7040, E-ISSN 1433-0350, Vol. 38, no 8, p. 1605-1612Article in journal (Refereed)
    Abstract [en]

    Stroke caused by dissection of arteries of the vertebrobasilar system in children is still poorly investigated in terms of etiology, means of treatment, course of disease, and prognosis. The aim of this report was to describe the unusual course of a spontaneous dissection of the basilar artery (BA) in a child treated with endovascular techniques and to point out that the plasticity of the brain stem can fully compensate for structural damage caused by stroke. We report the case of a 15-year-old boy who suffered a wake-up stroke with BA occlusion caused by spontaneous dissection. A blood clot was aspirated from the false lumen and the true lumen re-opened, but the patient deteriorated a few hours later, and repeated angiography revealed that the intimal flap was detached, occluding the BA again. The lumen of BA was then reconstructed by a stent. Despite a large pons infarction, the patient was completely recovered 11 months after the onset. The case was analyzed with angiograms and magnetic resonance imaging, macroscopic and microscopic pathological analysis, computed tomographic angiography, magnetic resonance-based angiography, and diffusion tensor imaging. This case illustrates that applied endovascular techniques and intensive care measures can alter the course of potentially fatal brain stem infarction. Our multimodal analysis gives new insight into the anatomical basis for the plasticity mechanism of the brain stem.

    Download full text (pdf)
    fulltext
    Download (pdf)
    errata
  • 7.
    Buxbaum, Joel N.
    et al.
    Scripps Res Inst, Dept Mol Med, Protego Biopharm San Diego, La Jolla, CA USA..
    Dispenzieri, Angela
    Mayo Clin, Div Hematol, Rochester, MN USA..
    Eisenberg, David S.
    Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA USA..
    Fändrich, Marcus
    Ulm Univ, Inst Prot Biochem, Ulm, Germany..
    Merlini, Giampaolo
    Fdn IRCCS Policlin San Matteo, Amyloid Res & Treatment Ctr, Pavia, Italy.;Univ Pavia, Pavia, Italy..
    Saraiva, Maria J. M.
    Univ Porto, Inst Mol & Cellular Biol, Mol Neurobiol, Porto, Portugal..
    Sekijima, Yoshiki
    Shinshu Univ, Dept Med Neurol & Rheumatol, Sch Med, Matsumoto, Japan..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee2022In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, no 4, p. 213-219Article in journal (Refereed)
    Abstract [en]

    The Nomenclature Committee of the International Society of Amyloidosis met at the XVIII International Symposium on Amyloidosis in September and virtually in October 2022 with discussions resulting in this upgraded nomenclature recommendation. The nomenclature principles remain unchanged but there is an ongoing discussion regarding the importance and varying nature of intracellular protein aggregates, particularly those associated with neurodegenerative diseases. Six novel proteins were added to the list of human amyloid fibril proteins. Of these, three are polypeptide hormones and two currently utilised peptide drugs, making the number of known iatrogenic amyloid forms four, all appearing as subcutaneous nodules at the injection site. The sixth novel amyloid fibril protein is the transmembrane 106B protein, forming intracellular amyloid fibrils in disorders associated with frontotemporal dementia. The number of known human amyloid fibril proteins is now 42.

  • 8.
    Castell, Alina
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Yan, Qinzi
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Fawkner, Karin
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Bazzar, Wesam
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Zhang, Fan
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Wickström, Malin
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Alzrigat, Mohammad
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Franco, Marcela
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Cameron, Donald P.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Dyberg, Cecilia
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Olsen, Thale Kristin
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Verschut, Vasiliki
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Schmidt, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lim, Sheryl Y.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mahmoud, Loay
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Hydbring, Per
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Lehmann, Sören
    Karolinska Univ Hosp, Dept Med, Huddinge, Sweden..
    Baranello, Laura
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Johnsen, John Inge
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Lars-Gunnar
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    MYCMI-7: A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner2022In: Cancer Research Communications, E-ISSN 2767-9764, Vol. 2, no 3, p. 182-201Article in journal (Refereed)
    Abstract [en]

    Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered "undruggable," and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells be- come G1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregu- lates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer.Significance: Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby ham- pering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells.

    Download full text (pdf)
    fulltext
  • 9.
    Cerezo-Magana, Myriam
    et al.
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden..
    Bång-Rudenstam, Anna
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden..
    Proteoglycans: a common portal for SARS-CoV-2 and extracellular vesicle uptake2023In: American Journal of Physiology - Cell Physiology, ISSN 0363-6143, E-ISSN 1522-1563, Vol. 324, no 1, p. C76-C84Article, review/survey (Refereed)
    Abstract [en]

    As structural components of the glycocalyx, heparan sulfate proteoglycans (HSPGs) are involved in multiple pathophysiological processes at the apex of cell signaling cascades, and as endocytosis receptors for particle structures, such as lipoproteins, extracellular vesicles, and enveloped viruses, including SARS-CoV-2. Given their diversity and complex biogenesis regulation, HSPGs remain understudied. Here we compile some of the latest studies focusing on HSPGs as internalizing receptors of extracellular vesicles ("endogenous virus") and SARS-CoV-2 lipid-enclosed particles and highlight similarities in their biophysical and structural characteristics. Specifically, the similarities in their biogenesis, size, and lipid composition may explain a common dependence on HSPGs for efficient cell-surface attachment and uptake. We further discuss the relative complexity of extracellular vesicle composition and the viral mechanisms that evolve towards increased infectivity that complicate therapeutic strategies addressing blockade of their uptake.

  • 10.
    Damhofer, Helene
    et al.
    Inst Canc Res, Div Canc Biol, London, England.;Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Tatar, Tülin
    Inst Canc Res, Div Canc Biol, London, England.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Southgate, Benjamin
    Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Scotland..
    Scarneo, Scott
    Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA.;EydisBio Inc, Durham, NC USA..
    Agger, Karl
    Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Shlyueva, Daria
    Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Morrison, Gillian M.
    Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Scotland..
    Hughes, Philip F.
    Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA.;EydisBio Inc, Durham, NC USA..
    Haystead, Timothy
    Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA.;EydisBio Inc, Durham, NC USA..
    Pollard, Steven M.
    Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Scotland..
    Helin, Kristian
    Inst Canc Res, Div Canc Biol, London, England.;Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers2024In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 15, article id 273Article in journal (Refereed)
    Abstract [en]

    Poor survival and lack of treatment response in glioblastoma (GBM) is attributed to the persistence of glioma stem cells (GSCs). To identify novel therapeutic approaches, we performed CRISPR/Cas9 knockout screens and discovered TGFβ activated kinase (TAK1) as a selective survival factor in a significant fraction of GSCs. Loss of TAK1 kinase activity results in RIPK1-dependent apoptosis via Caspase-8/FADD complex activation, dependent on autocrine TNFα ligand production and constitutive TNFR signaling. We identify a transcriptional signature associated with immune activation and the mesenchymal GBM subtype to be a characteristic of cancer cells sensitive to TAK1 perturbation and employ this signature to accurately predict sensitivity to the TAK1 kinase inhibitor HS-276. In addition, exposure to pro-inflammatory cytokines IFN gamma and TNFα can sensitize resistant GSCs to TAK1 inhibition. Our findings reveal dependency on TAK1 kinase activity as a novel vulnerability in immune-activated cancers, including mesenchymal GBMs that can be exploited therapeutically.

    Download full text (pdf)
    FULLTEXT01
  • 11.
    Damjanovic Vesterlund, Justina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden..
    Ihse, Elisabet
    Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden.;Uppsala Univ, Dept Genet Immunol & Pathol, Uppsala, Sweden..
    Thelander, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden..
    Zancanaro, Alice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden..
    Tissue-based diagnosis of systemic amyloidosis: Experience of the informal diagnostic center at Uppsala University Hospital2022In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 127, no 1, article id e8913Article in journal (Refereed)
    Abstract [en]

    Diagnosis of systemic amyloidosis is a clinical challenge and usually relies on a tissue biopsy. We have developed diagnostic methods based on the presence of amyloid deposits in abdominal subcutaneous fat tissue. This tissue is also used to determine the biochemical type of amyloidosis, performed by western blot and immunohistochemical analyses with the aid of in-house developed rabbit antisera and mouse monoclonal antibodies. Mass spectrometric methods are under development for selected cases. The diagnostic outcome for 2018-2020 was studied. During this period, we obtained 1,562 biopsies, of which 1,397 were unfixed subcutaneous fat tissue with varying degrees of suspicion of systemic amyloidosis. Of these, 440 contained amyloid deposits. The biochemical nature of the amyloid was determined by western blot analysis in 319 specimens and by immunohistochemistry in further 51 cases.

    Download full text (pdf)
    FULLTEXT01
  • 12.
    de Oliveira, Kelin Goncalves
    et al.
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Bång-Rudenstam, Anna
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Beyer, Sarah
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Boukredine, Axel
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Talbot, Hugo
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Governa, Valeria
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Johansson, Maria C.
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Månsson, Ann-Sofie
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Forsberg Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Univ Nottingham, Biodiscovery Inst, Div Canc & Stem Cells, Nottingham, England..
    Bengzon, Johan
    Lund Univ, Dept Clin Sci, Sect Neurosurg, Lund, Sweden..
    Malmström, Johan
    Lund Univ, Dept Clin Sci, Div Infect Med, Lund, Sweden..
    Welinder, Charlotte
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden..
    Belting, Mattias
    Lund Univ, Dept Clin Sci, Sect Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden..
    Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche2024In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, article id 35Article in journal (Refereed)
    Abstract [en]

    Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM.

    Download full text (pdf)
    FULLTEXT01
  • 13.
    Doloczki, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kern, Christoph
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Holmberg, Karl O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Streuff, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Dyrager, Christine
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    An Indolin-3-imine Photobase and pH Sensitive Fluorophore2023In: ChemPhotoChem, E-ISSN 2367-0932, article id e202300171Article in journal (Refereed)
    Abstract [en]

    This work presents the pH sensing ability of a fluorescent indolin-3-imine derivative. Protonation of the weakly basic imine (pKa = 8.3 of its conjugate acid) results in a significant redshift of the absorption band. The fluorophore acts as a photobase, with a basicity increase of approximately 6 units upon photoexcitation. This behavior promotes excited state proton transfer from weak acids such as protic solvents. The characteristics of the fluorophore enable sensing of water fractions in organic solvents and differentiation between methanol, ethanol, and longer chain alcohols. Initial cell studies indicated the future potential of indolin-3-imines as fluorophores for bioimaging applications.

  • 14.
    Ehinger, Erik
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden.;Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Kopecky, Jan
    Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Darabi, Anna
    Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Visse, Edward
    Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Edvardsson, Charlotte
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden..
    Tomasevic, Gregor
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden..
    Cederberg, David
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Skåne Univ Hosp, Dept Clin Sci, Oncol, Lund, Sweden; Skåne Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Bengzon, Johan
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden.;Lund Univ, Lund Stem Cell Ctr, Dept Clin Sci, Lund, Sweden..
    Siesjö, Peter
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Neurosurg, Lund, Sweden.;Lund Univ, Dept Clin Sci, Glioma Immunotherapy Grp, Neurosurg, Lund, Sweden..
    Antisecretory factor is safe to use as add-on treatment in newly diagnosed glioblastoma2023In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 76Article in journal (Refereed)
    Abstract [en]

    Purpose

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite the best available treatment, prognosis remains poor. Current standard therapy consists of surgical removal of the tumor followed by radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Experimental studies suggest that antisecretory factor (AF), an endogenous protein with proposed antisecretory and anti-inflammatory properties, may potentiate the effect of TMZ and alleviate cerebral edema. Salovum is an egg yolk powder enriched for AF and is classified as a medical food in the European Union. In this pilot study, we evaluate the safety and feasibility of add-on Salovum in GBM patients.

    Methods

    Eight patients with newly diagnosed, histologically confirmed GBM were prescribed Salovum during concomitant radiochemotherapy. Safety was determined by the number of treatment-related adverse events. Feasibility was determined by the number of patients who completed the full prescribed Salovum treatment.

    Results

    No serious treatment-related adverse events were observed. Out of 8 included patients, 2 did not complete the full treatment. Only one of the dropouts was due to issues directly related to Salovum, which were nausea and loss of appetite. Median survival was 23 months.

    Conclusions

    We conclude that Salovum is safe to use as an add-on treatment for GBM. In terms of feasibility, adherence to the treatment regimen requires a determined and independent patient as the large doses prescribed may cause nausea and loss of appetite.

    Download full text (pdf)
    FULLTEXT01
  • 15.
    Eltom, Khalid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Mothes, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Department of Pathology, Uppsala University Hospital, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. University Health Network, Krembil Brain Institute, Toronto, Ontario, Canada. Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment2024In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 34Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD. 

    Download full text (pdf)
    fulltext
  • 16.
    Gezelius, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Precision Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enblad, Anna Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Precision Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Lundmark, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Precision Medicine.
    Åberg, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ Hosp, Dept Clin Chem & Pharmacol, S-75185 Uppsala, Sweden..
    Blom, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ Hosp, Dept Clin Chem & Pharmacol, S-75185 Uppsala, Sweden..
    Rudfeldt, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ Hosp, Dept Clin Chem & Pharmacol, S-75185 Uppsala, Sweden..
    Raine, Amanda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Harila-Saari, Arja H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Rendo, Verónica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Heinaniemi, Merja
    Univ Eastern Finland, Sch Med, Kuopio 70210, Finland..
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ Hosp, Dept Clin Chem & Pharmacol, S-75185 Uppsala, Sweden..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Precision Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comparison of high-throughput single-cell RNA-seq methods for ex vivo drug screening2024In: NAR Genomics and Bioinformatics, E-ISSN 2631-9268, Vol. 6, no 1, article id lqae001Article in journal (Refereed)
    Abstract [en]

    Functional precision medicine (FPM) aims to optimize patient-specific drug selection based on the unique characteristics of their cancer cells. Recent advancements in high throughput ex vivo drug profiling have accelerated interest in FPM. Here, we present a proof-of-concept study for an integrated experimental system that incorporates ex vivo treatment response with a single-cell gene expression output enabling barcoding of several drug conditions in one single-cell sequencing experiment. We demonstrate this through a proof-of-concept investigation focusing on the glucocorticoid-resistant acute lymphoblastic leukemia (ALL) E/R+ Reh cell line. Three different single-cell transcriptome sequencing (scRNA-seq) approaches were evaluated, each exhibiting high cell recovery and accurate tagging of distinct drug conditions. Notably, our comprehensive analysis revealed variations in library complexity, sensitivity (gene detection), and differential gene expression detection across the methods. Despite these differences, we identified a substantial transcriptional response to fludarabine, a highly relevant drug for treating high-risk ALL, which was consistently recapitulated by all three methods. These findings highlight the potential of our integrated approach for studying drug responses at the single-cell level and emphasize the importance of method selection in scRNA-seq studies. Finally, our data encompassing 27 327 cells are freely available to extend to future scRNA-seq methodological comparisons.

    Download full text (pdf)
    fulltext
  • 17.
    Godina, Christopher
    et al.
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Skane, Sweden..
    Vallon-Christersson, Johan
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Isaksson, Karolin
    Lund Univ, Dept Clin Sci Lund Surg, Kristianstad, Sweden.;Kristianstad Hosp, Kristianstad, Sweden..
    Bosch, Ana
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Skane, Sweden..
    Jernström, Helena
    Lund Univ, Dept Clin Sci Lund Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Caveolin-1 gene expression provides additional prognostic information combined with PAM50 risk of recurrence (ROR) score in breast cancer2024In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, article id 6675Article in journal (Refereed)
    Abstract [en]

    Combining information from the tumor microenvironment (TME) with PAM50 Risk of Recurrence (ROR) score could improve breast cancer prognostication. Caveolin-1 (CAV1) is a marker of an active TME. CAV1 is a membrane protein involved in cell signaling, extracellular matrix organization, and tumor-stroma interactions. We sought to investigate CAV1 gene expression in relation to PAM50 subtypes, ROR score, and their joint prognostic impact. CAV1 expression was compared between PAM50 subtypes and ROR categories in two cohorts (SCAN-B, n = 5326 and METABRIC, n = 1980). CAV1 expression was assessed in relation to clinical outcomes using Cox regression and adjusted for clinicopathological predictors. Effect modifications between CAV1 expression and ROR categories on clinical outcome were investigated using multiplicative and additive two-way interaction analyses. Differential gene expression and gene set enrichment analyses were applied to compare high and low expressing CAV1 tumors. All samples expressed CAV1 with the highest expression in the Normal-like subtype. Gene modules consistent with epithelial-mesenchymal transition (EMT), hypoxia, and stromal activation were associated with high CAV1 expression. CAV1 expression was inversely associated with ROR category. Interactions between CAV1 expression and ROR categories were observed in both cohorts. High expressing CAV1 tumors conferred worse prognosis only within the group classified as ROR high. ROR gave markedly different prognostic information depending on the underlying CAV1 expression. CAV1, a potential mediator between the malignant cells and TME, could be a useful biomarker that enhances and further refines PAM50 ROR risk stratification in patients with ROR high tumors and a potential therapeutic target.

    Download full text (pdf)
    FULLTEXT01
  • 18.
    Godina, Christopher
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Tryggvadottir, Helga
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmö, Sweden..
    Bosch, Ana
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmö, Sweden..
    Borgquist, Signe
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden.;Aarhus Univ, Dept Oncol, Aarhus, Denmark.;Aarhus Univ Hosp, Aarhus, Denmark..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund and Malmö, Sweden.
    Isaksson, Karolin
    Lund Univ, Dept Clin Sci Lund, Div Surg, Lund, Sweden.;Kristianstad Hosp, Kristianstad, Sweden..
    Jernström, Helena
    Lund Univ, Dept Clin Sci Lund, Div Oncol, Barngatan 4, S-22185 Lund, Sweden.;Skane Univ Hosp, Barngatan 4, S-22185 Lund, Sweden..
    Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer2023In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 199, no 2, p. 335-347Article in journal (Refereed)
    Abstract [en]

    Purpose

    Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer.

    Methods

    A cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments).

    Results

    Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome.

    Conclusion

    CAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.

    Download full text (pdf)
    FULLTEXT01
  • 19.
    Gupta, Rajesh Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, Flemingsberg Campus, Huddinge, Sweden..
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Tumor-specific migration routes of xenotransplanted human glioblastoma cells in mouse brain2024In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, article id 864Article in journal (Refereed)
    Abstract [en]

    The migration of neural progenitor cells (NPCs) to their final destination during development follows well-defined pathways, such as along blood vessels. Cells originating from the highly malignant tumor glioblastoma (GBM) seem to exploit similar routes for infiltrating the brain parenchyma. In this report, we have examined the migration of GBM cells using three-dimensional high-resolution confocal microscopy in brain tumors derived from eight different human GBM cell lines xenografted into immunodeficient mice. The primary invasion routes identified were long-distance migration along white matter tracts and local migration along blood vessels. We found that GBM cells in the majority of tumors (6 out of 8) did not exhibit association with blood vessels. These tumors, derived from low lamin A/C expressing GBM cells, were comparatively highly diffusive and invasive. Conversely, in 2 out of 8 tumors, we noted perivascular invasion and displacement of astrocyte end-feet. These tumors exhibited less diffusive migration, grew as solid tumors, and were distinguished by elevated expression of lamin A/C. We conclude that the migration pattern of glioblastoma is distinctly tumor cell-specific. Furthermore, the ability to invade the confined spaces within white matter tracts may necessitate low expression of lamin A/C, contributing to increased nuclear plasticity. This study highlights the role of GBM heterogeneity in driving the aggressive growth of glioblastoma.

    Download full text (pdf)
    FULLTEXT01
  • 20.
    Holmberg Olausson, Karl O.
    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, Neurooncology and neurodegeneration.
    Borgenvik, Anna
    Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giraud, Géraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects. Uppsala Univ, Dept Pediat Hematol & Oncol, Childrens Hosp, S-75185 Uppsala, Sweden..
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies2024In: Cancers, ISSN 2072-6694, Vol. 16, no 9, article id 1752Article, review/survey (Refereed)
    Abstract [en]

    Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

    Download full text (pdf)
    FULLTEXT01
  • 21.
    Ilkhanizadeh, Shirin
    et al.
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Gracias, Aileen
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Aslund, Andreas K. O.
    Linköping Univ, Dept Chem, IFM, S-58183 Linköping, Sweden..
    Back, Marcus
    Linköping Univ, Dept Chem, IFM, S-58183 Linköping, Sweden..
    Simon, Rozalyn
    Linköping Univ, Dept Chem, IFM, S-58183 Linköping, Sweden..
    Kavanagh, Edel
    Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden..
    Migliori, Bianca
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Neofytou, Christina
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Forsberg Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Konradsson, Peter
    Linköping Univ, Dept Chem, IFM, S-58183 Linköping, Sweden..
    Teixeira, Ana I.
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Uhlen, Per
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Joseph, Bertrand
    Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden..
    Hermanson, Ola
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Nilsson, K. Peter R.
    Linköping Univ, Dept Chem, IFM, S-58183 Linköping, Sweden..
    Live Detection of Neural Progenitors and Glioblastoma Cells by an Oligothiophene Derivative2023In: ACS Applied Bio Materials, E-ISSN 2576-6422, Vol. 6, no 9, p. 3790-3797Article in journal (Refereed)
    Abstract [en]

    There is an urgent need for simple and non-invasive identification of live neural stem/progenitor cells (NSPCs) in the developing and adult brain as well as in disease, such as in brain tumors, due to the potential clinical importance in prognosis, diagnosis, and treatment of diseases of the nervous system. Here, we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) stem cell-like cells and NSPCs. While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSPCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same cell population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of neural and glioma stem and progenitor cells.

    Download full text (pdf)
    fulltext
  • 22.
    Jujic, Amra
    et al.
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden.;Skane Univ Hosp, Dept Cardiol, Malmö, Sweden.;Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ, Clin Res Ctr, Box 50332, S-20213 Malmö, Sweden..
    Godina, Christopher
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Melander, Olle
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden..
    Holst, Jens Juul
    Panum Inst, Dept Biomed Sci, Copenhagen, Denmark.;NNF Ctr Basal Metab Res, Panum Inst, Copenhagen, Denmark.;Univ Copenhagen, NNF Ctr Basal Metab Res, Copenhagen, Denmark..
    Ahlqvist, Emma
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden..
    Gomez, Maria F.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmö, Sweden..
    Nilsson, Peter M.
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden..
    Jernström, Helena
    Lund Univ, Dept Clin Sci Lund, Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Magnusson, Martin
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden.;Skane Univ Hosp, Dept Cardiol, Malmö, Sweden.;Lund Univ, Wallenberg Ctr Mol Med, Malmö, Sweden.;Northwest Univ Potchefstroom, Hypertens Afr Res Team HART, Potchefstroom, South Africa..
    Endogenous incretin levels and risk of first incident cancer: a prospective cohort study2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, article id 382Article in journal (Refereed)
    Abstract [en]

    Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmo Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 +/- 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82-0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

    Download full text (pdf)
    FULLTEXT01
  • 23.
    Krynina, Olha
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Díaz de Ståhl, Teresita
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Jylhä, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet & Genom, Stockholm, Sweden..
    Arthur, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet & Genom, Stockholm, Sweden..
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Akademiska University Hospital, Uppsala, Sweden.
    Nyman, Per
    Linköping Univ Hosp, Crown Princess Victor Childrens Hosp, Dept Hlth, Linköping, Sweden.;Linköping Univ, Dept Med & Caring Sci, Linköping, Sweden.;Linköping Univ, Ctr Med Image Sci & Visualizat CMIV, Linköping, Sweden..
    Fritzberg, Anders
    Clin Pediat Falun Hosp, Daycare Unit Oncol & Hematol, Dalarna, Dalarna Region, Sweden..
    Sandgren, Johanna
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Tham, Emma
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet & Genom, Stockholm, Sweden..
    Sandvik, Ulrika
    Karolinska Inst, Dept Clin Neurosci, Div Neurosurg, Stockholm, Sweden..
    The potential of liquid biopsy for detection of the KIAA1549-BRAF fusion in circulating tumor DNA from children with pilocytic astrocytoma2024In: Neuro-Oncology Advances, E-ISSN 2632-2498, Vol. 6, no 1, article id vdae008Article in journal (Refereed)
    Abstract [en]

    Background

    Low-grade gliomas (LGGs) represent children’s most prevalent central nervous system tumor, necessitating molecular profiling to diagnose and determine the most suitable treatment. Developing highly sensitive screening techniques for liquid biopsy samples is particularly beneficial, as it enables the early detection and molecular characterization of tumors with minimally invasive samples.

    Methods

    We examined CSF and plasma samples from patients with pilocytic astrocytoma (PA) using custom multiplexed droplet digital polymerase chain reaction (ddPCR) assays based on whole genome sequencing data. These assays included a screening test to analyze BRAF duplication and a targeted assay for the detection of patient-specific KIAA1549::BRAF fusion junction sequences or single nucleotide variants.

    Results

    Our findings revealed that 5 out of 13 individual cerebrospinal fluid (CSF) samples tested positive for circulating tumor DNA (ctDNA). Among these cases, 3 exhibited the KIAA1549::BRAF fusion, which was detected through copy number variation (CNV) analysis (n = 1) or a fusion-specific probe (n = 2), while 1 case each displayed the BRAF V600E mutation and the FGFR1 N577K mutation. Additionally, a quantitative analysis of cell-free DNA (cfDNA) concentrations in PA CSF samples showed that most cases had low cfDNA levels, below the limit of detection of our assay (<1.9 ng).

    Conclusions

    While CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the BRAF V600 test, to provide important insights into the molecular characteristics of LGGs.

    Download full text (pdf)
    fulltext
  • 24.
    Larsson, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Integrative modeling of intratumoral heterogeneity, plasticity and regulation in nervous system cancers2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The adult brain tumor glioblastoma (GBM) is characterized by short survival and a lack of efficient treatments. Median survival is 15 months from time of diagnosis and the 5-year survival rate is only 7 %. There is an urgent need for more efficient treatment against GBM, but there are many challenges, including the high extent of heterogeneity of GBM. The tumoral heterogeneity of GBM ranges from interpatient to intratumoral. The aim of this thesis has been to address unanswered questions relating to the intratumoral heterogeneity of GBM, with three specific focuses; (1) the organization of GBM cell state transitions (paper I and III), (2) the regulation of cell states and cell state transitions (paper II), and (3) targeted interventions against cell states (paper II and IV).

    In paper I, we develop an experimental-computational method to measure and quantify cell state transitions. We find that GBM cell states organize hierarchically, with a clear “source state” feeding cells downwards in the hierarchy towards a “sink state” with negative growth rate, but with multi-directional transitions between intermediate states. 

    In paper II, we address the lack of computational methods to identify regulators of intratumoral heterogeneity by developing an algorithm called scRegClust that uses scRNA-seq data to estimate regulatory programs. Through an integrative study of the regulatory landscape of neuro-oncology we find two potential regulators of the macrophage-induced mesenchymal transition in GBM.

    In paper III, we explore the energy-concept as a way of measuring differentiation potential of single cells, instead of relying on gene markers or gene signatures of stemness. We fit a model called the Ising model from statistical mechanics to scRNA-seq data and show both on synthetic and real data that the estimated Ising energy is a good measure of a cell’s differentiation potential, where high Ising energy indicate a high degree of stemness.

    Finally, in paper IV, another experimental-computational method is developed to investigate drug-induced effects on both inter- and intratumoral heterogeneity. 

    In summary, the high extent of intratumoral heterogeneity in nervous system cancer is a major caveat for the development of more efficient treatments. In this thesis we have taken a systems biology approach to understand how this heterogeneity is structured and how we can exploit that knowledge for therapeutic purposes. 

    List of papers
    1. Modeling glioblastoma heterogeneity as a dynamic network of cell states
    Open this publication in new window or tab >>Modeling glioblastoma heterogeneity as a dynamic network of cell states
    Show others...
    2021 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 17, no 9, article id e10105Article in journal (Refereed) Published
    Abstract [en]

    Tumor cell heterogeneity is a crucial characteristic of malignant brain tumors and underpins phenomena such as therapy resistance and tumor recurrence. Advances in single-cell analysis have enabled the delineation of distinct cellular states of brain tumor cells, but the time-dependent changes in such states remain poorly understood. Here, we construct quantitative models of the time-dependent transcriptional variation of patient-derived glioblastoma (GBM) cells. We build the models by sampling and profiling barcoded GBM cells and their progeny over the course of 3 weeks and by fitting a mathematical model to estimate changes in GBM cell states and their growth rates. Our model suggests a hierarchical yet plastic organization of GBM, where the rates and patterns of cell state switching are partly patient-specific. Therapeutic interventions produce complex dynamic effects, including inhibition of specific states and altered differentiation. Our method provides a general strategy to uncover time-dependent changes in cancer cells and offers a way to evaluate and predict how therapy affects cell state composition.

    Place, publisher, year, edition, pages
    John Wiley & SonsWILEY, 2021
    Keywords
    cell state, cellular barcoding, patient-derived brain tumor cells, single-cell lineage tracing, time-dependent computational models
    National Category
    Cell Biology Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-495138 (URN)
    Funder
    Swedish Cancer SocietySwedish Research CouncilSwedish Foundation for Strategic Research
    Available from: 2023-01-24 Created: 2023-01-24 Last updated: 2024-01-15
    2. Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers
    Open this publication in new window or tab >>Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Nervous system cancers contain a large spectrum of transcriptional cell states, reflecting processes active during normal development, injury response and growth. However, we lack a good understanding of these states' regulation and pharmacological importance. Here, we describe the integrated reconstruction of such cellular regulatory programs and their therapeutic targets from extensive collections of single-cell RNA sequencing data (scRNA-seq) from both tumors and developing tissues. Our method, termed single-cell Regulatory-driven Clustering (scRegClust), predicts essential kinases and transcription factors in little computational time thanks to a new efficient optimization strategy. Using this method, we analyze scRNA-seq data from both adult and childhood brain cancers to identify transcription factors and kinases that regulate distinct tumor cell states.  In adult glioblastoma, our model predicts that blocking the activity of PDGFRA, DDR1, ERBB3 or SOX6, or increasing YBX1-activity, would potentiate temozolomide treatment. We further perform an integrative study of scRNA-seq data from both cancer and the developing brain to uncover the regulation of emerging meta-modules. We find a meta-module regulated by the transcription factors SPI1 and IRF8 and link it to an immune-mediated mesenchymal-like state. Our algorithm is available as an easy-to-use R package and companion visualization tool that help uncover the regulatory programs underlying cell plasticity in cancer and other diseases.

    Keywords
    regulatory programs, regulatory-driven clustering, cell state, phenotypic plasticity
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-498235 (URN)10.1101/2023.03.10.532041 (DOI)
    Available from: 2023-03-12 Created: 2023-03-12 Last updated: 2023-03-23
    3. Estimating the differentiation potential and plasticity of cancer cells using statistical mechanics
    Open this publication in new window or tab >>Estimating the differentiation potential and plasticity of cancer cells using statistical mechanics
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Cell differentiation is a crucial property of both normal and cancerous cells, that is driven by complex underlying processes. A number of computational methods can score the differentiation potential of individual cells based on their RNA expression. However, we lack a unifying model to explain how differentiation arises from underlying gene regulation and external perturbations. Here, we show that an adaptation of the Ising model, commonly used in statistical mechanics, can bridge this gap, thereby offering a way to identify normal and cancer stem cells. Our new model states that every cell updates its gene expression pattern according to a Boltzmann distribution, influenced by the gene-gene network and an external perturbation field. We first show that this model can be fitted to scRNAseq data sets. We apply the model to a range of data sets to demonstrate its efficacy in separating cells with varying differentiation potential and creating a pseudo-temporal ordering of cells in a GBM data set. Additionally, we explore other aspects of the model to identify known chromosomal aberrations of GBM from single cells and predict therapeutic interventions. This framework has potential applications in many cancer types and can be used to identify CSCs and measure differentiation potential without relying on stemness signatures or marker genes. 

    Keywords
    differentiation potential, plasticity, single-cell profiling, the ising model, computational modeling, gene perturbations
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Oncology; Oncology; Oncology
    Identifiers
    urn:nbn:se:uu:diva-498237 (URN)
    Available from: 2023-03-12 Created: 2023-03-12 Last updated: 2023-03-23
    4. Using drug-induced cell states to build therapeutic combinations against nervous system cancers
    Open this publication in new window or tab >>Using drug-induced cell states to build therapeutic combinations against nervous system cancers
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Evidence is amounting that nervous system cancers are heterogeneous at the single cell level, yet data are currently scarce on how therapeutic agents affect this heterogeneity. Here, we describe a new, data-driven strategy to identify drugs that modulate the intratumoral heterogeneity of nervous system cancers. First, we demonstrate that drugs elicit structured changes in pathway activation in patient-derived cells from glioblastomas, neuroblastomas and medulloblastomas.  Second, we present a mathematical model to estimate how drugs induce changes in tumor heterogeneity, as defined by single cell RNA sequencing atlases of each disease. Finally, as an evaluation of our method we use it to identify candidate synergistic drug pairs based on the drugs' effects on intratumoral heterogeneity.

    Keywords
    Glioblastoma, Neuroblastoma, Medulloblastoma, DRUG-Seq
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-498238 (URN)
    Available from: 2023-03-12 Created: 2023-03-12 Last updated: 2023-03-23
    Download full text (pdf)
    UUThesis_I-Larsson-2023
    Download (jpg)
    preview image
  • 25.
    Lazarczyk, Marzena
    et al.
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, PL-05552 Jastrzebiec, Poland..
    Kurzejamska, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Mickael, Michel-Edwar
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, PL-05552 Jastrzebiec, Poland..
    Poznanski, Piotr
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, PL-05552 Jastrzebiec, Poland..
    Skiba, Dominik
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, PL-05552 Jastrzebiec, Poland..
    Sacharczuk, Mariusz
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, PL-05552 Jastrzebiec, Poland.;Med Univ Warsaw, Ctr Preclin Res & Technol, Dept Pharmacodynam, PL-02091 Warsaw, Poland..
    Gaciong, Zbigniew
    Med Univ Warsaw, Dept Internal Med Hypertens & Vasc Dis, PL-02091 Warsaw, Poland..
    Religa, Piotr
    Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Mouse CCL9 Chemokine Acts as Tumor Suppressor in a Murine Model of Colon Cancer2023In: Current Issues in Molecular Biology, ISSN 1467-3037, E-ISSN 1467-3045, Vol. 45, no 4, p. 3446-3461Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer is the third most frequently diagnosed cancer in the world. Despite extensive studies and apparent progress in modern strategies for disease control, the treatment options are still not sufficient and effective, mostly due to frequently encountered resistance to immunotherapy of colon cancer patients in common clinical practice. In our study, we aimed to uncover the CCL9 chemokine action employing the murine model of colon cancer to seek new, potential molecular targets that could be promising in the development of colon cancer therapy. Mouse CT26.CL25 colon cancer cell line was used for introducing lentivirus-mediated CCL9 overexpression. The blank control cell line contained an empty vector, while the cell line marked as CCL9+ carried the CCL9-overexpressing vector. Next, cancer cells with empty vector (control) or CCL9-overexpressing cells were injected subcutaneously, and the growing tumors were measured within 2 weeks. Surprisingly, CCL9 contributed to a decline in tumor growth in vivo but had no effect on CT26.CL25 cell proliferation or migration in vitro. Microarray analysis of the collected tumor tissues revealed upregulation of the immune system-related genes in the CCL9 group. Obtained results suggest that CCL9 reveals its anti-proliferative functions by interplay with host immune cells and mediators that were absent in the isolated, in vitro system. Under specific study conditions, we determined unknown features of the murine CCL9 that have so far bee reported to be predominantly pro-oncogenic.

    Download full text (pdf)
    FULLTEXT01
  • 26.
    Lazarczyk, Marzena
    et al.
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Garbatka, Poland..
    Mickael, Michel Edwar
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Garbatka, Poland..
    Skiba, Dominik
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Garbatka, Poland..
    Kurzejamska, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Karolinska Inst, Dept Lab Med, Div Pathol, SE-14186 Stockholm, Sweden.
    Lawinski, Michal
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Garbatka, Poland.;Med Univ Warsaw, Dept Gen Surg Gastroenterol & Oncol, PL-02091 Warsaw, Poland..
    Horbanczuk, Jaroslaw Olav
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Postepu 36A, PL-05552 Garbatka, Poland..
    Radziszewski, Jakub
    Siedlce Univ Nat Sci & Humanities, Fac Med & Hlth Sci, Stanislawa Konarskiego 2, PL-08110 Siedlce, Poland.;Jan Pawel II Mem Prov Mazov Hosp, Dept Oncol Surg, 26, Ksiec Jozefa Poniatowskiego, PL-08110 Siedlce, Poland..
    Fraczek, Karolina
    Med Univ Warsaw, Fac Pharm, Dept Pharmacodynam, Banacha 1B, PL-02091 Warsaw, Poland..
    Wolinska, Renata
    Med Univ Warsaw, Fac Pharm, Dept Pharmacodynam, Banacha 1B, PL-02091 Warsaw, Poland..
    Paszkiewicz, Justyna
    John Paul II Univ Appl Sci Biala Podlaska, Dept Hlth, Sidorska 95-97, PL-21500 Biala Podlaska, Poland..
    Religa, Piotr
    Karolinska Inst, Dept Med, SE-17177 Solna, Sweden..
    Sacharczuk, Mariusz
    Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Garbatka, Poland.;Med Univ Warsaw, Fac Pharm, Dept Pharmacodynam, Banacha 1B, PL-02091 Warsaw, Poland..
    The Journey of Cancer Cells to the Brain: Challenges and Opportunities2023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 4, article id 3854Article, review/survey (Refereed)
    Abstract [en]

    Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.

    Download full text (pdf)
    FULLTEXT01
  • 27.
    Libard, Sylwia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala Univ Hosp, Dept Surg Pathol, Uppsala, Sweden..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada.;Univ Toronto, Dept Med, Toronto, ON, Canada.;Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada..
    Alafuzoff, Irina
    Uppsala Univ Hosp, Dept Surg Pathol, Uppsala, Sweden..
    Mixed Pathologies in a Subject with a Novel PSEN1 G206R Mutation2022In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 90, no 4, p. 1601-1614Article in journal (Refereed)
    Abstract [en]

    Background: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed.

    Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer's disease (sAD).

    Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations.

    Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations.

    Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.

    Download full text (pdf)
    fulltext
  • 28.
    Lu, Xi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Zhong, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Sichuan, China.
    Lindell, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Veanes, Margus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Guo, Jing
    Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore.
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Salehi, Maede
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Chen, Xingqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Zhang, Xiaonan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells2023In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 14, no 10, article id 676Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.

    Download full text (pdf)
    fulltext
  • 29. Mashausi, Dhahiri Saidi
    et al.
    Roy, Debmalya
    Mangukiya, Hitesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Merugu, Siva Bharath
    Raza, Ghulam
    Yunus, Fakhar-Un-Nisa
    Liu, Guo-Song
    Negi, Hema
    Li, Dawei
    A high efficient FVIII variant corrects bleeding in hemophilia A mouse model2022In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 637, p. 358-364Article in journal (Refereed)
    Abstract [en]

    Hemophilia A is a bleeding disorder caused by quantitative or qualitative deficiencies in coagulation factor VIII (FVIII). Low FVIII expression due to its unstable mRNA and binding with immunoglobulin-binding protein (BiP) compromises gene therapy endeavors in hemophilia A. Site-directed mutagenesis have demonstrated an improvement in the expression of FVIII proteins. In this study, a targeted point mutation of Pro at position 290 to Thr (P290T) enhances the in vitro specific activity of B-domain-deleted factor VIII (BDD-FVIII). Hydrodynamic gene delivery of P290T cDNA into FVIII-deficient (FVIII-/-) mice corrected bleeding symptoms. P290T variant resulted in high plasma FVIII coagulant activity 24 h post-gene delivery. Furthermore, bleeding time and average blood loss was significantly reduced in FVIII-/- mice injected with P290T variant, whereas BDD-FVIII and PBS-injected mice experienced prolonged bleeding and excessive blood loss. Histological analysis of the liver biopsies revealed no apparent signs of liver damage. No signs of potential toxicity were seen in mice following mice bodyweights assessment. Altogether, our results demonstrate that the introduction of P290T mutation increases both in vitro and in vivo FVIII coagulant activity, supporting ongoing efforts to develop more effective replacement therapy for hemophilia A.

  • 30.
    Mothes, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Konstantinidis, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eltom, Khalid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Streubel-Gallasch, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Dept Med, Toronto, ON, Canada.
    Rostami, Jinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology2023In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 97Article in journal (Refereed)
    Abstract [en]

    Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

    Download full text (pdf)
    FULLTEXT01
  • 31.
    Neves, Inês
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lu, Xi
    Maturi, Nagaprathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Dang, Yonglong
    Latini, Francesco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Yildirim, Irem
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Jokinen, Veera
    Xing, Pengwei
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Ryttlefors, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Chen, Xingqi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Paired glioblastoma cell cultures of the fluorescent bulk tumor and non-fluorescent tumor margin display differential phenotypes and cell states across patientsManuscript (preprint) (Other academic)
    Abstract [en]

    Glioblastoma is an aggressive and therapy-resistant primary brain tumor with a dismal prognosis. The inevitable recurrence is in almost all patients in contact with the resection cavity, suggesting the local peritumoral area as its origin. Glioblastoma cells of this region have seldom been studied and few authenticated models exist. We have explanted matched tissue samples from the bulk tumor and local tumor edge of 13 glioblastoma patients of which 7 were sustainable beyond passage 6. Each edge culture was more invasive and less self-renewing and tumorigenic compared to its paired bulk culture. Three pairs of edge and bulk cultures were profiled with a combined single nucleus (sn) RNA- and ATAC-sequencing. Transcriptome analysis displayed for all patients a shift towards AC-MES cell states in the edge cultures. Chromatin-accessibility profiles uncovered differential regulatory networks with edge cells being enriched for transcription factor (TF) motifs of invasion, neurons, and immune cells. We propose that edge cells have been epigenetically reprogrammed by their unique interactions with various cell types in the peritumoral region. The fact that glioblastoma edge cells display distinct epigenetic regulation compared to their bulk tumor cells has implications for therapy development that should be targeted to and tested on the relapse-causing glioblastoma edge cells.

  • 32.
    Pocas, Juliana
    et al.
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal..
    Marques, Catarina
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal..
    Gomes, Catarina
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Otake, Andreia Hanada
    Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Inst Canc Estado Sao Paulo, BR-01246000 Sao Paulo, Brazil.;Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Pinto, Filipe
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Ferreira, Mariana
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Silva, Tiago
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Faria-Ramos, Isabel
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Matos, Rita
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Ribeiro, Ana Raquel
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal..
    Senra, Emanuel
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal..
    Cavadas, Bruno
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal..
    Batista, Silvia
    Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Maia, Joana
    Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Macedo, Joana A.
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal..
    Lima, Luis
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Afonso, Luis Pedro
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Ferreira, José Alexandre
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Santos, Lúcio Lara
    Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP RISE CI IPOP, Hlth Res Network, Expt Pathol & Therapeut Grp, P-4200072 Porto, Portugal..
    Polónia, António
    Osório, Hugo
    Univ Porto, FMUP Fac Med, P-4200319 Porto, Portugal..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci, Sect Oncol, S-22184 Lund, Sweden; Skane Univ Hosp, S-22185 Lund, Sweden.
    Reis, Celso A.
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal.;Univ Porto, FMUP Fac Med, P-4200319 Porto, Portugal..
    Costa-Silva, Bruno
    Champalimaud Fdn, Champalimaud Physiol & Canc Programme, P-1400038 Lisbon, Portugal..
    Magalhães, Ana
    Univ Porto, i3S Inst Invest & Inovacao Saude, P-4200135 Porto, Portugal.;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, P-4200465 Porto, Portugal.;Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto, Portugal..
    Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival2023In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 20, article id e2214853120Article in journal (Refereed)
    Abstract [en]

    Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane pro-teoglycan, is highly expressed in intestinal subtype gastric tumors and that this sig -nature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

    Download full text (pdf)
    fulltext
  • 33.
    Rosén, Emil
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mangukiya, Hitesh
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Elfineh, Lioudmila
    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 Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Stockgard, Rebecka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Krona, Cecilia
    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 Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Gerlee, Philip
    Chalmers Univ Technol, Math Sci, Gothenburg, Sweden.;Univ Gothenburg, Math Sci, Gothenburg, Sweden..
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Inference of glioblastoma migration and proliferation rates using single time-point images2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 402Article in journal (Refereed)
    Abstract [en]

    Cancer cell migration is a driving mechanism of invasion in solid malignant tumors. Anti-migratory treatments provide an alternative approach for managing disease progression. However, we currently lack scalable screening methods for identifying novel anti-migratory drugs. To this end, we develop a method that can estimate cell motility from single end-point images in vitro by estimating differences in the spatial distribution of cells and inferring proliferation and diffusion parameters using agent-based modeling and approximate Bayesian computation. To test the power of our method, we use it to investigate drug responses in a collection of 41 patient-derived glioblastoma cell cultures, identifying migration-associated pathways and drugs with potent anti-migratory effects. We validate our method and result in both in silico and in vitro using time-lapse imaging. Our proposed method applies to standard drug screen experiments, with no change needed, and emerges as a scalable approach to screen for anti-migratory drugs. The spatial positioning of cultured glioblastoma cells is used to estimate cell motility and drug effects from single end-point images in vitro.

    Download full text (pdf)
    FULLTEXT01
  • 34.
    Secilmis, Deniz
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, S-17121 Solna, Sweden..
    Hillerton, Thomas
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, S-17121 Solna, Sweden..
    Tjärnberg, Andreas
    NYU, Ctr Dev Genet, New York, NY USA..
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Nordling, Torbjörn E. M.
    Natl Cheng Kung Univ, Dept Mech Engn, Tainan 701, Taiwan.;Umeå Univ, Dept Appl Phys & Elect, S-90187 Umeå, Sweden..
    Sonnhammer, Erik L. L.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, S-17121 Solna, Sweden..
    Knowledge of the perturbation design is essential for accurate gene regulatory network inference2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 16531Article in journal (Refereed)
    Abstract [en]

    The gene regulatory network (GRN) of a cell executes genetic programs in response to environmental and internal cues. Two distinct classes of methods are used to infer regulatory interactions from gene expression: those that only use observed changes in gene expression, and those that use both the observed changes and the perturbation design, i.e. the targets used to cause the changes in gene expression. Considering that the GRN by definition converts input cues to changes in gene expression, it may be conjectured that the latter methods would yield more accurate inferences but this has not previously been investigated. To address this question, we evaluated a number of popular GRN inference methods that either use the perturbation design or not. For the evaluation we used targeted perturbation knockdown gene expression datasets with varying noise levels generated by two different packages, GeneNetWeaver and GeneSpider. The accuracy was evaluated on each dataset using a variety of measures. The results show that on all datasets, methods using the perturbation design matrix consistently and significantly outperform methods not using it. This was also found to be the case on a smaller experimental dataset from E. coli. Targeted gene perturbations combined with inference methods that use the perturbation design are indispensable for accurate GRN inference.

    Download full text (pdf)
    FULLTEXT01
  • 35.
    Secilmis, Deniz
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden..
    Sonnhammer, Erik L. L.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Optimal Sparsity Selection Based on an Information Criterion for Accurate Gene Regulatory Network Inference2022In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 13, article id 855770Article in journal (Refereed)
    Abstract [en]

    Accurate inference of gene regulatory networks (GRNs) is important to unravel unknown regulatory mechanisms and processes, which can lead to the identification of treatment targets for genetic diseases. A variety of GRN inference methods have been proposed that, under suitable data conditions, perform well in benchmarks that consider the entire spectrum of false-positives and -negatives. However, it is very challenging to predict which single network sparsity gives the most accurate GRN. Lacking criteria for sparsity selection, a simplistic solution is to pick the GRN that has a certain number of links per gene, which is guessed to be reasonable. However, this does not guarantee finding the GRN that has the correct sparsity or is the most accurate one. In this study, we provide a general approach for identifying the most accurate and sparsity-wise relevant GRN within the entire space of possible GRNs. The algorithm, called SPA, applies a "GRN information criterion " (GRNIC) that is inspired by two commonly used model selection criteria, Akaike and Bayesian Information Criterion (AIC and BIC) but adapted to GRN inference. The results show that the approach can, in most cases, find the GRN whose sparsity is close to the true sparsity and close to as accurate as possible with the given GRN inference method and data.

    Download full text (pdf)
    FULLTEXT01
  • 36.
    Slipsager, Anna
    et al.
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.;Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark.;Dept Oncol, Hobrovej 18-22, DK-9000 Aalborg, Denmark..
    Henrichsen, Sofie N.
    Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Falkmer, Ursula G.
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.;Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Dybkaer, Karen
    Aalborg Univ, Dept Clin Med, Aalborg, Denmark.;Aalborg Univ Hosp, Dept Hematol, Aalborg, Denmark..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Lund Univ, Dept Clin Sci, Lund, Sweden.
    Poulsen, Laurids Ø.
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.;Aalborg Univ Hosp, Clin Canc Res Ctr, Aalborg, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Predictive biomarkers in radioresistant rectal cancer: A systematic review2023In: Critical reviews in oncology/hematology, ISSN 1040-8428, E-ISSN 1879-0461, Vol. 186, article id 103991Article, review/survey (Refereed)
    Abstract [en]

    Background and aims

    The treatment of locally advanced rectal cancer often consists of neoadjuvant chemoradiotherapy followed by surgery. However, approximately 15% of patients show no response to this neoadjuvant chemoradiotherapy. This systematic review aimed to identify biomarkers of innate radioresistant rectal cancer.

    Method

    Through a systematic literature search, 125 papers were included and analyzed using ROBINS-I, a Cochrane risk of bias tool for non-randomized studies of interventions. Both statistically significant and nonsignificant biomarkers were identified. Biomarkers mentioned more than once in the results or biomarkers with a low or moderate risk of bias were included as the final results.

    Results

    Thirteen unique biomarkers, three genetic signatures, one specific pathway, and two combinations of two or four biomarkers were identified. In particular, the connection between HMGCS2, COASY, and PI3K-pathway seems promising. Future scientific research should focus on further validating these genetic resistance markers.

    Download full text (pdf)
    fulltext
  • 37.
    Sonavane, Sumalata
    et al.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Rising, Anna
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Neo, Huddinge, Sweden..
    Holm, Lena
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Regionalization of cell types in silk glands of Larinioides sclopetarius suggest that spider silk fibers are complex layered structures2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, article id 22273Article in journal (Refereed)
    Abstract [en]

    In order to produce artificial silk fibers with properties that match the native spider silk we likely need to closely mimic the spinning process as well as fiber architecture and composition. To increase our understanding of the structure and function of the different silk glands of the orb weaver Larinioides sclopetarius, we used resin sections for detailed morphology, paraffin embedded sections for a variety of different histological stainings, and a histochemical method for localization of carbonic anhydrase activity. Our results show that all silk glands, except the tubuliform glands, are composed of two or more columnar epithelial cell types, some of which have not been described previously. We observed distinct regionalization of the cell types indicating sequential addition of secretory products during silk formation. This means that the major ampullate, minor ampullate, aciniform type II, and piriform silk fibers most likely are layered and that each layer has a specific composition. Furthermore, a substance that stains positive for polysaccharides may be added to the silk in all glands except in the type I aciniform glands. Active carbonic anhydrase was found in all silk glands and/or ducts except in the type I aciniform and tubuliform glands, with the strongest staining in aggregate glands and their ductal nodules. Carbonic anhydrase plays an important role in the generation of a pH gradient in the major ampullate glands, and our results suggest that some other glands may also harbor pH gradients.

    Download full text (pdf)
    FULLTEXT01
  • 38.
    Stigenberg, Mathilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Predicting tumour growth-driving interactions from transcriptomic data using machine learning2023Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The mortality rate is high for cancer patients and treatments are only efficient in a fraction of patients. To be able to cure more patients, new treatments need to be invented. Immunotherapy activates the immune system to fight against cancer and one treatment targets immune checkpoints. If more targets are found, more patients can be treated successfully. In this project, interactions between immune and cancer cells that drive tumour growth were investigated in an attempt to find new potential targets. This was achieved by creating a machine learning model that finds genes expressed in cells involved in tumour-driving interactions.

    Single-cell RNA sequencing and spatial transcriptomic data from breast cancer patients were utilised as well as single-cell RNA sequencing data from healthy patients. The tumour rate was based on the cumulative expression of G2/M genes. The G2/M related genes were excluded from the analysis since these were assumed to be cell cycle genes. The machine learning model was based on a supervised variational autoencoder architecture. By using this kind of architecture, it was possible to compress the input into a low dimensional space of genes, called a latent space, which was able to explain the tumour rate. Optuna hyperparameter optimizer framework was utilised to find the best combination of hyperparameters for the model. The model had a R2 score of 0.93, which indicated that the latent space was able to explain the growth rate 93% accurately.

    The latent space consisted of 20 variables. To find out which genes that were in this latent space, the correlation between each latent variable and each gene was calculated. The genes that were positively correlated or negatively correlated were assumed to be in the latent space and therefore involved in explaining tumour growth. Furthermore, the correlation between each latent variable and the growth rate was calculated. The up- and downregulated genes in each latent variable were kept and used for finding out the pathways for the different latent variables. Five of these latent variables were involved in immune responses and therefore these were further investigated. The genes in these five latent variables were mapped to cell types. One of these latent variables had upregulated immune response for positively correlated growth, indicating that immune cells were involved in promoting cancer progression. Another latent variable had downregulated immune response for negatively correlated growth. This indicated that if these genes would be upregulated instead, the tumour would be thriving. The genes found in these latent variables were analysed further. CD80, CSF1, CSF1R, IL26, IL7, IL34 and the protein NF-kappa-B were interesting finds and are known immune-modulators. These could possibly be used as markers for pro-tumour immunity. Furthermore, CSF1, CSF1R, IL26, IL34 and the protein NF-kappa-B could potentially be targeted in immunotherapy.

    Download full text (pdf)
    fulltext
  • 39. Tesi, Bianca
    et al.
    Lagerstedt Robinson, Kristina
    Abel, Frida
    Díaz de Ståhl, Teresita
    Orrsjö, Sara
    Poluha, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
    Hellberg, Maria
    Wessman, Sandra
    Samuelsson, Sofie
    Frisk, Tony
    Vogt, Hartmut
    Henning, Karin
    Sabel, Magnus
    Ek, Torben
    Pal, Niklas
    Nyman, Per
    Giraud, Géraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects. Pediatric Oncology, Uppsala University Children’s Hospital, Uppsala, Sweden.
    Wille, Joakim
    Pronk, Cornelis Jan
    Norén-Nyström, Ulrika
    Borssén, Magnus
    Fili, Maria
    Stålhammar, Gustav
    Herold, Nikolas
    Tettamanti, Giorgio
    Maya-Gonzalez, Carolina
    Arvidsson, Linda
    Rosén, Anna
    Ekholm, Katja
    Kuchinskaya, Ekaterina
    Hallbeck, Anna-Lotta
    Nordling, Margareta
    Palmebäck, Pia
    Kogner, Per
    Kanter Smoler, Gunilla
    Lähteenmäki, Päivi
    Fransson, Susanne
    Martinsson, Tommy
    Shamik, Alia
    Mertens, Fredrik
    Rosenquist, Richard
    Wirta, Valtteri
    Tham, Emma
    Grillner, Pernilla
    Sandgren, Johanna
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects. Pediatric Oncology, Uppsala University Children’s Hospital, Uppsala, Sweden.
    Gisselsson, David
    Taylan, Fulya
    Nordgren, Ann
    Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors: a nationwide, prospective Swedish study2024In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 39, article id 100881Article in journal (Refereed)
    Abstract [en]

    Background

    Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.

    Methods

    gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.

    Findings

    The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).

    Interpretation

    Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.

    Download full text (pdf)
    fulltext
  • 40.
    Vesterlund Damjanovic, Justina
    et al.
    Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden.;Uppsala Univ, Dept Genet Immunol & Pathol, Uppsala, Sweden..
    Ihse, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden.;Uppsala Univ, Dept Genet Immunol & Pathol, Uppsala, Sweden..
    Thelander, Ulrika
    Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden.;Uppsala Univ, Dept Genet Immunol & Pathol, Uppsala, Sweden..
    Zancanaro, Alice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research. Uppsala Univ, Dept Genet Immunol & Pathol, Uppsala, Sweden..
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Med Cell Biol, Uppsala, Sweden..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala Univ Hosp, Clin Pathol, Uppsala, Sweden.;Uppsala Univ, Dept Genet Immunol & Pathol, Uppsala, Sweden..
    Tissue-based diagnosis of systemic amyloidosis: Experience of the informal diagnostic center at Uppsala University Hospital2022In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 127, no 1, article id e8913Article in journal (Refereed)
    Abstract [en]

    Diagnosis of systemic amyloidosis is a clinical challenge and usually relies on a tissue biopsy. We have developed diagnostic methods based on the presence of amyloid deposits in abdominal subcutaneous fat tissue. This tissue is also used to determine the biochemical type of amyloidosis, performed by western blot and immunohistochemical analyses with the aid of in-house developed rabbit antisera and mouse monoclonal antibodies. Mass spectrometric methods are under development for selected cases. The diagnostic outcome for 2018-2020 was studied. During this period, we obtained 1,562 biopsies, of which 1,397 were unfixed subcutaneous fat tissue with varying degrees of suspicion of systemic amyloidosis. Of these, 440 contained amyloid deposits. The biochemical nature of the amyloid was determined by western blot analysis in 319 specimens and by immunohistochemistry in further 51 cases.

    Download full text (pdf)
    FULLTEXT01
  • 41.
    Wang, Mengqi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lu, Xi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Sinha, Tanay Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Wu, Di
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Surface protein profiles of extracellular vesicles reveal SARS-CoV-2 infectionManuscript (preprint) (Other academic)
  • 42.
    Weishaupt, Holger
    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, Neurooncology and neurodegeneration.
    Čančer, Matko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Holmberg, Karl O.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Häggqvist, Susana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jiang, Yiwen
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sreedharan, Smitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Becher, Oren J.
    Northwestern Univ, Dept Pediat, Chicago, IL 60611 USA.;Northwestern Univ, Dept Biochem & Mol Genet, Chicago, IL 60611 USA.;Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA..
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas2023In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 25, no 1, p. 97-107Article in journal (Refereed)
    Abstract [en]

    Background Malignant gliomas, the most common malignant brain tumors in adults, represent a heterogeneous group of diseases with poor prognosis. Retroviruses can cause permanent genetic alterations that modify genes close to the viral integration site. Methods Here we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next-generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies. Results A large fraction of common integration sites contained genes that have been dysregulated or misexpressed in glioma. Others overlapped with loci identified in previous glioma-related forward genetic screens, but several novel putative cancer-causing genes were also found. Integrating retroviral tagging and clinical data, Ppfibp1 was highlighted as a frequently tagged novel glioma-causing gene. Retroviral integrations into the locus resulted in Ppfibp1 upregulation, and Ppfibp1-tagged cells generated tumors with shorter latency on orthotopic transplantation. In human gliomas, increased PPFIBP1 expression was significantly linked to poor prognosis and PDGF treatment resistance. Conclusions Altogether, the current study has demonstrated a novel approach to tagging glioma genes via forward genetics, validating previous results, and identifying PPFIBP1 as a putative oncogene in gliomagenesis.

    Download full text (pdf)
    fulltext
  • 43.
    Wærn, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Karolinska Institutet.
    Identifying cell type-specific proliferation signatures in spatial transcriptomics data and inferring interactions driving tumour growth2023Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Cancer is a dangerous disease caused by mutations in the host's genome that makes the cells proliferateuncontrollably and disrupts bodily functions. The immune system tries to prevent this, but tumours have methods ofdisrupting the immune system's ability to combat the cancer. These immunosuppression events can for examplehappen when the immune system interacts with the tumour to recognise it or try and destroy it. The tumours can bychanging their displayed proteins on the cell surface avoid detection or by excreting proteins, they can neutralisedangerous immune cells. This happens within the tumour microenvironment (TME), the immediate surrounding of atumour where there is a plethora of different cells both aiding and suppressing the tumour. Some of these cells arenot cancer cells but can still aid the tumour due to how the tumour has influenced them. For example, throughangiogenesis, where new blood vessels are formed which feeds the tumour.

    The interactions in the TME can be used as a target for immunotherapy, a field of treatments which improves theimmune system's own ability at defending against cancer. Immunotherapy can for example help the immune systemby guiding immune cells towards the tumour. It is therefore essential to understand the complex system ofinteractions within the TME to be able to create new methods of immunotherapy and thus treat cancers moreefficiently. Concurrently new methods of mapping what happens in a tissue have been developed in recent years,namely spatial transcriptomics (ST). It allows for the retrieval of transcriptomic information of cells throughsequencing while still retaining spatial information. However, the ST methods which capture the wholetranscriptome of the cells and reveal the cell-to-cell interactions are not of single-cell resolution yet. They capturemultiple cells in each spot, creating a mix of cells in the sequencing. This mix of cells can be detangled, and theproportions of each cell type revealed through the process of deconvolution. Deconvolution works by mapping thesingle cell expression profile of different cell types onto the ST data and figuring out what proportions of expressioneach cell type produces the expression of the mix. This reveals the cellular composition of the microenvironment.But since the interactions in the TME depend on the cells current expression we need to deconvolute according tophenotype and not just cell type.

    In this project we were able to create a tool which automatically finds phenotypes in the single-cell data and usesthose phenotypes to deconvolute ST data. Phenotypes are found using dimensionality reduction methods todifferentiate cells according to their contribution to the variability in the data. The resulting deconvoluted data wasthen used as the foundation for describing the growth of a cancer as a system of phenotype proportions in the tumourmicroenvironment. From this system a mathematical model was created which predicts the growth and couldprovide insight into how the phenotypes interact. The tool created worked as intended and the model explains thegrowth of a tumour in the TME with not just cancer cells phenotypes but other cell phenotypes as well. However, nonew interaction could be discovered by the final model and no phenotype found could provide us with new insightsto the structure of the TME. But our analysis was able to identify structures we expect to see in a tumour, eventhough they might not be so obvious, so an improved version of our tools might be able to find even more detailsand perhaps new, more subtle interactions.

    Download full text (pdf)
    fulltext
  • 44.
    Xie, Yuan
    et al.
    Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China..
    He, Liqun
    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.
    Zhang, Yanyu
    Fourth Mil Med Univ, Dept Neurosurg, Xijing Hosp, Xian 710032, Peoples R China..
    Huang, Hua
    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.
    Yang, Fan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Tianjin Med Univ Gen Hosp, Dept Neurosurg, Tianjin Neurol Inst, Key Lab Postneuroinjury Neurorepair & Regenerat Ce, Tianjin 300052, Peoples R China..
    Chao, Min
    Fourth Mil Med Univ, Dept Neurosurg, Tangdu Hosp, 569 Xinsi Rd, Xian 710038, Peoples R China..
    Cao, Haiyan
    Fourth Mil Med Univ, Dept Neurosurg, Tangdu Hosp, 569 Xinsi Rd, Xian 710038, Peoples R China..
    Wang, Jianhao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Tianjin Med Univ Gen Hosp, Dept Neurosurg, Tianjin Neurol Inst, Key Lab Postneuroinjury Neurorepair & Regenerat Ce, Tianjin 300052, Peoples R China..
    Li, Yaling
    Xian Fourth Hosp, Dept Obstet & Gynaecol, Xian Peoples Hosp, Xian 710005, Peoples R China..
    Zhang, Lingxue
    Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China..
    Xin, Lele
    Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China..
    Xiao, Bing
    Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China..
    Shi, Xinxin
    Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China..
    Zhang, Xue
    Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China..
    Tang, Jiefu
    Hunan Univ Med, Trauma Ctr, Affiliated Hosp, Huaihua 418000, Peoples R China..
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Dimberg, Anna
    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.
    Wang, Liang
    Fourth Mil Med Univ, Dept Neurosurg, Tangdu Hosp, 569 Xinsi Rd, Xian 710038, Peoples R China.;Fourth Mil Med Univ, Dept Neurosurg, Tangdu Hosp, Xian, Peoples R China..
    Zhang, Lei
    Shaanxi Normal Univ, China Sweden Int Joint Res Ctr Brain Dis, Key Lab, Minist Educ Med Plant Resource & Nat Pharmaceut Ch, Xian 710119, Peoples R China.;Shaanxi Normal Univ, Coll Life Sci, Xian 710119, Peoples R China..
    Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma2023In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 25, no 6, p. 1073-1084Article in journal (Refereed)
    Abstract [en]

    Background: Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed.

    Methods: Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms.

    Results: We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice.

    Conclusions: These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.

  • 45.
    Zhang, Hanzhao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Role of MYCN in retinoblastoma: From carcinogenesis to tumor progression2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Retinoblastoma, a pediatric malignancy of the retina, is primarily driven by the bi-allelic inactivation of the RB1gene. However, a subset of cases are characterized by proficient RB1 functions but with MYCN copy number mutations, suggesting an alternative oncogenic mechanism in the absence of RB1 mutations. The aim of this thesis is to investigate the intricate molecular and cellular pathways implicated in retinoblastoma, with a particular focus on the role of MYCN expression and its interplay with the cell cycle and apoptotic pathways.

    In Paper I, we explored the regulatory mechanisms underpinning MYCN-induced retinoblastoma using aRB1-proficient MYCN-overexpressing in vivo model in embryonic chicken retina and MYCN-transformed cells in culture. Our findings revealed that MYCN overexpression led to a significant upregulation of E2F levels, thereby dysregulating the cell cycle and mimicking the mechanistic phenotype of RB1-deficient tumors. Inhibition on E2f DNA-binding activity efficiently normalized growth and apoptosis in MYCN-transformed cells in culture. Despite RB1 proficiency, the elevated E2F levels induced a neoplastic behavior in retinal cells, indicating a novel mechanism of retinoblastoma carcinogenesis independent of RB1 inactivation.

    Paper II employed single-cell RNA sequencing to dissect the cellular composition of MYCN-driven retinoblastoma in chicken in vivo model, revealing a predominant origin in cone photoreceptor progenitors. This finding suggested a cell-type-specific vulnerability to MYCN-induced transformation. The research further identifies a notable heterogeneity within the MYCN-transformed cells, with a subset of cells exhibiting non-cone photoreceptor features but features of other neurons like ganglion cells. A cluster was also identified withelevated expression of genes related to malignancy and tumor progression, including UBE2C and TOP2A. This suggested a link between MYCN overexpression and tumor development, potentially mediated through the E2F pathway.

    In Paper III, the focus shifted to the interplay between MYCN expression, E2f activity, and the p53 pathway in human retinoblastoma cell lines exhibiting both RB1 deficiency and MYCN amplification. By modulating E2f and p53 pathway activities using chemical inhibitors, we demonstrated the essential role of MYCN expression level in mediating p53-driven growth inhibition and highlighted the independent effects of E2f inhibition and p53 activation by a Mdm2 inhibitor.

    Together, these studies illuminate the intricate molecular pathways involved in MYCN-amplified retinoblastoma, emphasizing the pivotal role of MYCN in disrupting cell cycle regulation and promoting tumorigenesis. These insights not only advance our understanding of retinoblastoma pathogenesis but also provide potential therapeutic targets within the MYCN-E2F axis, offering novel treatment strategies in MYCN-amplified retinoblastoma.

    List of papers
    1. Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour.
    Open this publication in new window or tab >>Inhibition of high level E2F in a RB1 proficient MYCN overexpressing chicken retinoblastoma model normalizes neoplastic behaviour.
    Show others...
    2023 (English)In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    PURPOSE: Retinoblastoma, a childhood cancer, is most frequently caused by bi-allelic inactivation of RB1 gene. However, other oncogenic mutations such as MYCN amplification can induce retinoblastoma with proficient RB1. Previously, we established RB1-proficient MYCN-overexpressing retinoblastoma models both in human organoids and chicken. Here, we investigate the regulatory events in MYCN-induced retinoblastoma carcinogenesis based on the model in chicken.

    METHODS: MYCN transformed retinal cells in culture were obtained from in vivo MYCN electroporated chicken embryo retina. The expression profiles were analysed by RNA sequencing. Chemical treatments, qRT-PCR, flow cytometry, immunohisto- and immunocytochemistry and western blot were applied to study the properties and function of these cells.

    RESULTS: The expression profile of MYCN-transformed retinal cells in culture showed cone photoreceptor progenitor signature and robustly increased levels of E2Fs. This expression profile was consistently observed in long-term culture. Chemical treatments confirmed RB1 proficiency in these cells. The cells were insensitive to p53 activation but inhibition of E2f efficiently induced cell cycle arrest followed by apoptosis.

    CONCLUSION: In conclusion, with proficient RB1, MYCN-induced high level of E2F expression dysregulates the cell cycle and contributes to retinoblastoma carcinogenesis. The increased level of E2f renders the cells to adopt a similar mechanistic phenotype to a RB1-deficient tumour.

    Keywords
    Animal model, Chicken, E2F, Intraocular cancer, MYCN, RB1 proficient, Retinoblastoma
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-522867 (URN)10.1007/s13402-023-00863-0 (DOI)37606819 (PubMedID)
    Available from: 2024-02-12 Created: 2024-02-12 Last updated: 2024-02-21
    2. Single-cell RNA sequencing reveals cellular properties and carcinogenesis of a RB1-proficient MYCN-overexpressing retinoblastoma model from embryonic chicken retina
    Open this publication in new window or tab >>Single-cell RNA sequencing reveals cellular properties and carcinogenesis of a RB1-proficient MYCN-overexpressing retinoblastoma model from embryonic chicken retina
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-523113 (URN)
    Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-02-21
    3. Characterization of MYCN amplified retinoblastoma lines with respect to effects of E2f and p53 activity
    Open this publication in new window or tab >>Characterization of MYCN amplified retinoblastoma lines with respect to effects of E2f and p53 activity
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-523107 (URN)
    Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-02-21
    Download full text (pdf)
    UUThesis_H-Zhang-2024
    Download (jpg)
    preview image
  • 46.
    Zhang, Hanzhao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Konjusha, Dardan
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tararuk, Tatsiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Single-cell RNA sequencing reveals cellular properties and carcinogenesis of a RB1-proficient MYCN-overexpressing retinoblastoma model from embryonic chicken retinaManuscript (preprint) (Other academic)
  • 47.
    Zhang, Hanzhao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Tararuk, Tatsiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Characterization of MYCN amplified retinoblastoma lines with respect to effects of E2f and p53 activityManuscript (preprint) (Other academic)
1 - 47 of 47
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf