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Stenzinger, A., Edsjö, A., Ploeger, C., Friedman, M., Fröhling, S., Wirta, V., . . . Rosenquist, R. (2022). Trailblazing precision medicine in Europe: A joint view by Genomic Medicine Sweden and the Centers for Personalized Medicine, ZPM, in Germany. Seminars in Cancer Biology, 84, 242-254
Open this publication in new window or tab >>Trailblazing precision medicine in Europe: A joint view by Genomic Medicine Sweden and the Centers for Personalized Medicine, ZPM, in Germany
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2022 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 84, p. 242-254Article in journal (Refereed) Published
Abstract [en]

Over the last decades, rapid technological and scientific advances have led to a merge of molecular sciences and clinical medicine, resulting in a better understanding of disease mechanisms and the development of novel therapies that exploit specific molecular lesions or profiles driving disease. Precision oncology is here used as an example, illustrating the potential of precision/personalized medicine that also holds great promise in other medical fields. Real-world implementation can only be achieved by dedicated healthcare connected centers which amass and build up interdisciplinary expertise reflecting the complexity of precision medicine. Networks of such centers are ideally suited for a nation-wide outreach offering access to precision medicine to patients independent of their place of residence. Two of these multicentric initiatives, Genomic Medicine Sweden (GMS) and the Centers for Personalized Medicine (ZPM) initiative in Germany have teamed up to present and share their views on core concepts, potentials, challenges, and future developments in precision medicine. Together with other initiatives worldwide, GMS and ZPM aim at providing a robust and sustainable framework, covering all components from technology development to clinical trials, ethical and legal aspects as well as involvement of all relevant stakeholders, including patients and policymakers in the field.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Cancer; Clinical trials; Molecular profiling; Personalized medicine; Precision medicine
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:liu:diva-192710 (URN)10.1016/j.semcancer.2021.05.026 (DOI)000830066100004 ()34033893 (PubMedID)2-s2.0-85111382323 (Scopus ID)
Funder
Vinnova
Available from: 2023-03-28 Created: 2023-03-28 Last updated: 2023-04-04Bibliographically approved
Richter, J., Haj-Hosseini, N., Milos, P., Hallbeck, M. & Wårdell, K. (2021). Optical Brain Biopsy with a Fluorescence and Vessel Tracing Probe. Operative Neurosurgery, 21(4), 217-224
Open this publication in new window or tab >>Optical Brain Biopsy with a Fluorescence and Vessel Tracing Probe
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2021 (English)In: Operative Neurosurgery, ISSN 2332-4252, E-ISSN 2332-4260, Vol. 21, no 4, p. 217-224Article in journal (Refereed) Published
Abstract [en]

BACKGROUND Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and tailoring of the therapy. Repetitive needle insertions enhance risks of brain lesioning, hemorrhage, and complications due to prolonged procedure.

OBJECTIVE To investigate clinical benefits of a combined 5-aminolaevulinic acid (5-ALA) fluorescence and laser Doppler flowmetry system for the detection of malignant brain tumor and blood vessels in stereotactic biopsies.

METHODS Planning of targets and trajectories was followed by optical measurements in 20 patients, using the Leksell Stereotactic System and a manual insertion device. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded each millimeter along the paths. Biopsies were taken at preplanned positions. The diagnoses were compared with the fluorescence signals. The recordings were plotted against measurement positions and compared. Sites indicating a risk of hemorrhage were counted as well as the time for the procedures.

RESULTS Signals were recorded along 28 trajectories, and 78 biopsies were collected. The final diagnosis showed 17 glioblastomas, 2 lymphomas, and 1 astrocytoma grade III. Fluorescence was seen along 23 of the paths with 4 having the peak of 5-ALA fluorescence 3 mm or more from the precalculated target. There was increased microcirculation in 40 of 905 measured positions. The measurement time for each trajectory was 5 to 10 min.

CONCLUSION The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target. The method can increase the precision and the safety of the biopsy procedure and reduce time.

Place, publisher, year, edition, pages
Oxford University Press, 2021
Keywords
Biopsy, Optical, Tumor, Fluorescence, Spectroscopy, Stereotactic navigation, 5-ALA
National Category
Other Medical Engineering Surgery
Identifiers
urn:nbn:se:liu:diva-179467 (URN)10.1093/ons/opab216 (DOI)000702156000006 ()34192763 (PubMedID)
Funder
Linköpings universitet, LiU Cancer Strategic Research GrantSwedish Childhood Cancer Foundation, MT 2013-0043Region Östergötland, ALF: LIO-599651Swedish Foundation for Strategic Research , RMX18-0056
Note

Funding: LiU Cancer Strategic Research Grant; Swedish Childhood Cancer FoundationEuropean Commission [MT 20130043]; ALF Grants Region Ostergotland; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [RMX18-0056]

Available from: 2021-09-21 Created: 2021-09-21 Last updated: 2023-03-28Bibliographically approved
Sackmann, C. & Hallbeck, M. (2020). Oligomeric amyloid-beta induces early and widespread changes to the proteome in human iPSC-derived neurons. Scientific Reports, 10(1), Article ID 6538.
Open this publication in new window or tab >>Oligomeric amyloid-beta induces early and widespread changes to the proteome in human iPSC-derived neurons
2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 6538Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease (AD) is the most common form of dementia globally and is characterized by aberrant accumulations of amyloid-beta (Aβ) and tau proteins. Oligomeric forms of these proteins are believed to be most relevant to disease progression, with oligomeric amyloid-β (oAβ) particularly implicated in AD. oAβ pathology spreads among interconnected brain regions, but how oAβ induces pathology in these previously unaffected neurons requires further study. Here, we use well characterized iPSC-derived human neurons to study the early changes to the proteome and phosphoproteome after 24 h exposure to oAβ 1-42. Using nLC-MS/MS and label-free quantification, we identified several proteins that are differentially regulated in response to acute oAβ challenge. At this early timepoint, oAβ induced the decrease of TDP-43, heterogeneous nuclear ribonucleoproteins (hnRNPs), and coatomer complex I (COPI) proteins. Conversely, increases were observed in 20 S proteasome subunits and vesicle associated proteins VAMP1/2, as well as the differential phosphorylation of tau at serine 208. These changes show that there are widespread alterations to the neuronal proteome within 24 h of oAβ uptake, including proteins previously not shown to be related to neurodegeneration. This study provides new targets for the further study of early mediators of AD pathogenesis.

Place, publisher, year, edition, pages
Nature Publishing Group, 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-169266 (URN)10.1038/s41598-020-63398-6 (DOI)000562145900023 ()32300132 (PubMedID)2-s2.0-85083477073 (Scopus ID)
Note

Funding Agencies|Swedish Research CouncilSwedish Research Council [MH: 523-2013-2735]; Swedish Alzheimer foundation; Swedish Brain Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Swedish Dementia Foundation; Linkoping University

Available from: 2020-09-12 Created: 2020-09-12 Last updated: 2022-09-15Bibliographically approved
Sackmann, C., Sackmann, V. & Hallbeck, M. (2020). TDP-43 Is Efficiently Transferred Between Neuron-Like Cells in a Manner Enhanced by Preservation of Its N-Terminus but Independent of Extracellular Vesicles. Frontiers in Neuroscience, 14, Article ID 540.
Open this publication in new window or tab >>TDP-43 Is Efficiently Transferred Between Neuron-Like Cells in a Manner Enhanced by Preservation of Its N-Terminus but Independent of Extracellular Vesicles
2020 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, FRONTIERS IN NEUROSCIENCE, Vol. 14, article id 540Article in journal (Refereed) Published
Abstract [en]

The misfolding of transactive response DNA-binding protein (TDP-43) is a major contributor to the pathogenesis of TDP-43 proteinopathies, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions, but also plays a role in other neurodegenerative diseases including Alzheimer disease. It is thought that different truncations at the N- and C-termini of TDP-43 contribute to its misfolding and aggregation in the brain, and that these aberrant TDP-43 fragments contribute to disease. Despite this, little is known about whether different truncation events influence the proteins transmissibility between cells and how this cell-to-cell transfer occurs. In this study, we use a well-established cellular model to study the efficiency by which full-length and truncated TDP-43 fragments are transferred between neuron-like cells. We demonstrate that preservation of the N-terminus of TDP-43 enhances its transmissibility between cells and that this protein transmission occurs in a manner exclusive of extracellular vesicles, instead requiring cellular proximity for efficient propagation. These data indicate that the N-terminus of TDP-43 might be a useful target in the generation of therapeutics to limit the spread of TDP-43 pathology.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2020
Keywords
TDP-43; extracellular vesicles; C-terminus; N-terminus; cell-to-cell; protein transfer; amyotrophic lateral sclerosis; frontotemporal lobar degeneration
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-167670 (URN)10.3389/fnins.2020.00540 (DOI)000543818500001 ()32595443 (PubMedID)2-s2.0-85087009216 (Scopus ID)
Note

Funding Agencies|Swedish Research CouncilSwedish Research Council [523-2013-2735]; Swedish Alzheimer Foundation; Swedish Brain Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Swedish Dementia Foundation

Available from: 2020-07-20 Created: 2020-07-20 Last updated: 2021-02-19Bibliographically approved
Haj-Hosseini, N., Richter, J., Milos, P., Hallbeck, M. & Wårdell, K. (2019). Optical guidance during stereotactic brain tumor biopsy. In: : . Paper presented at Medicinteknikdagarna 2019, 2-3 Okt., Linköping. Linköping
Open this publication in new window or tab >>Optical guidance during stereotactic brain tumor biopsy
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2019 (English)Conference paper, Oral presentation only (Other academic)
Place, publisher, year, edition, pages
Linköping: , 2019
Keywords
Biopsy procedures, biooptics, brain tumor, fluorescence, laser Doppler
National Category
Medical Engineering
Identifiers
urn:nbn:se:liu:diva-175394 (URN)
Conference
Medicinteknikdagarna 2019, 2-3 Okt., Linköping
Available from: 2021-09-20 Created: 2021-09-20 Last updated: 2021-11-10Bibliographically approved
Wårdell, K., Milos, P., Haj-Hosseini, N., Richter, J., Hallbeck, M. & Hillman, J. (2019). Optical measurements with 5-ALA during surgical resection of brain tumors in children. In: : . Paper presented at MTdagarna, Linköping, Oct. 2-3 2019.
Open this publication in new window or tab >>Optical measurements with 5-ALA during surgical resection of brain tumors in children
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2019 (English)Conference paper, Oral presentation only (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:liu:diva-174607 (URN)
Conference
MTdagarna, Linköping, Oct. 2-3 2019
Available from: 2021-03-25 Created: 2021-03-25 Last updated: 2021-03-30Bibliographically approved
Haj-Hosseini, N., Richter, J., Milos, P., Hallbeck, M. & Wårdell, K. (2018). 5-ALA fluorescence and laser Doppler flowmetry for guidance in a stereotactic brain tumor biopsy. Biomedical Optics Express, 9(5), 2284-2296
Open this publication in new window or tab >>5-ALA fluorescence and laser Doppler flowmetry for guidance in a stereotactic brain tumor biopsy
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2018 (English)In: Biomedical Optics Express, E-ISSN 2156-7085, Vol. 9, no 5, p. 2284-2296Article in journal (Refereed) Published
Abstract [en]

A fiber optic probe was developed for guidance during stereotactic brain biopsy procedures to target tumor tissue and reduce the risk of hemorrhage. The probe was connected to a setup for the measurement of 5-aminolevulinic acid (5-ALA) induced fluorescence and microvascular blood flow. Along three stereotactic trajectories, fluorescence (n = 109) and laser Doppler flowmetry (LDF) (n = 144) measurements were done in millimeter increments. The recorded signals were compared to histopathology and radiology images. The median ratio of protoporphyrin IX (PpIX) fluorescence and autofluorescence (AF) in the tumor was considerably higher than the marginal zone (17.3 vs 0.9). The blood flow showed two high spots (3%) in total. The proposed setup allows simultaneous and real-time detection of tumor tissue and microvascular blood flow for tracking the vessels.

Place, publisher, year, edition, pages
Optical Society of America, 2018
National Category
Medical Engineering
Identifiers
urn:nbn:se:liu:diva-147514 (URN)10.1364/BOE.9.002284 (DOI)000431181700022 ()29760987 (PubMedID)
Funder
Swedish Childhood Cancer Foundation, 2013-0043Linköpings universitet, LiU CancerRegion Östergötland, ALF LIO-599651
Note

Funding agencies: Linkoping University Cancer Organization; Swedish Childhood Cancer Organization [MT 2013-0043]; ALF Grants Region Ostergotland [LIO-599651]

Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2023-02-17Bibliographically approved
Bruhn, H., Strandeus, M., Milos, P., Hallbeck, M., Vrethem, M. & Lind, J. (2018). Improved survival of Swedish glioblastoma patients treated according to Stupp. Acta Neurologica Scandinavica, 138(4), 332-337
Open this publication in new window or tab >>Improved survival of Swedish glioblastoma patients treated according to Stupp
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2018 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 138, no 4, p. 332-337Article in journal (Refereed) Published
Abstract [en]

ObjectivesThe median survival in glioblastoma (GBM) patients used to be less than 1year. Surgical removal of the tumor with subsequent concomitant radiation/temozolomide (the Stupp regimen) has been shown to prolong survival. The Stupp protocol was implemented in the county of Jonkoping in 2006. The purpose of this study was to examine if the Stupp treatment has prolonged overall survival, in an unselected patient cohort with histologically verified GBM. Material and MethodThis study includes all patients from the county of Jonkoping, with a diagnosis of GBM from January 2001 to December 2012. Patients were divided into 2 cohorts, 2001-2005 and 2006-2012, that is before and after implementation of the Stupp regimen. By reviewing the medical case notes, the dates of the histological diagnosis and of death were identified. The median and mean overall survival and Kaplan-Meier survival analysis were calculated and compared between the 2 cohorts. ResultsThe mean survival was 110days longer in the cohort treated according to the Stupp regimen. Four patients in the 2006-2012 cohort and 1 patient in the 2001-2005 cohort are still alive. When comparing survival in patients with radical surgery vs biopsy, those that underwent radical surgery survived longer. The significance was slightly greater in the 2001-2005 cohort (mean 163 vs 344days, Pamp;lt;.001) than in the 2006-2012 cohort (mean 220 vs 397days, P=.02). ConclusionSurvival significantly improved after the implementation of the Stupp regimen in the study region of Sweden.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
glioblastoma; mortality; radiotherapy; Stupp treatment; survival; temozolomide
National Category
Surgery
Identifiers
urn:nbn:se:liu:diva-151465 (URN)10.1111/ane.12966 (DOI)000443931400010 ()29882211 (PubMedID)
Note

Funding Agencies|Gustav Lindholms Stiftelse for elakartade hjarntumorer; Futurum

Available from: 2018-09-24 Created: 2018-09-24 Last updated: 2023-12-28
Sardar Sinha, M., Villamil Giraldo, A. M., Öllinger, K., Hallbeck, M. & Civitelli, L. (2018). Lipid vesicles affect the aggregation of 4-hydroxy-2-nonenal-modified alpha-synuclein oligomers. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(9), 3060-3068
Open this publication in new window or tab >>Lipid vesicles affect the aggregation of 4-hydroxy-2-nonenal-modified alpha-synuclein oligomers
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2018 (English)In: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1864, no 9, p. 3060-3068Article in journal (Refereed) Published
Abstract [en]

Parkinsons disease (PD) and other synucleinopathies are characterized by accumulation of misfolded aggregates of alpha-synuclein (alpha-syn). The normal function of alpha-syn is still under investigation, but it has been generally linked to synaptic plasticity, neurotransmitter release and the maintenance of the synaptic pool. alpha-Syn localizes at synaptic terminals where it can bind to synaptic vesicles as well as to other cellular membranes. It has become clear that these interactions have an impact on both alpha-syn functional role and its propensity to aggregate. In this study, we investigated the aggregation process of alpha-syn covalently modified with 4-hydroxy-2-nonenal (HNE). HNE is a product of lipid peroxidation and has been implicated in the pathogenesis of different neurodegenerative diseases by modifying the kinetics of soluble toxic oligomers. Although HNE-modified alpha-syn has been reported to assemble into stable oligomers, we found that slightly acidic conditions promoted further protein aggregation. Lipid vesicles delayed the aggregation process in a concentration-dependent manner, an effect that was observed only when they were added at the beginning of the aggregation process. Co-aggregation of lipid vesicles with HNE-modified alpha-syn also induced cytotoxic effects on differentiated SHSY-SY cells. Under conditions in which the aggregation process was delayed cell viability was reduced. By exploring the behavior and potential cytotoxic effects of HNE-alpha-syn under acidic conditions in relation to protein-lipid interactions our study gives a framework to examine a possible pathway leading from a physiological setting to the pathological outcome of PD.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
alpha-Synuclein; Parkinsons disease; Lipids; Aggregation kinetics; Toxicity
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-151192 (URN)10.1016/j.bbadis.2018.06.020 (DOI)000442056200028 ()29960040 (PubMedID)
Note

Funding Agencies|Swedish Research Council [MH: 523-2013-2735]; Research Foundation of the Swedish Parkinsons Disease Association; Ostergotland Research Foundation for Parkinsons Disease; Parkinson Research Foundation; Swedish Alzheimer foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Konung Gustaf V och Drottning Victorias Frimurarestiftelse; Swedish Dementia Foundation; Linkoping University Neurobiology Centre; County Council of Ostergotland

Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2021-12-28
Gustafsson, G., Loov, C., Persson, E., Lazaro, D. F., Takeda, S., Bergstrom, J., . . . Ingelsson, M. (2018). Secretion and Uptake of -Synuclein Via Extracellular Vesicles in Cultured Cells. Cellular and molecular neurobiology, 38(8), 1539-1550
Open this publication in new window or tab >>Secretion and Uptake of -Synuclein Via Extracellular Vesicles in Cultured Cells
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2018 (English)In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, no 8, p. 1539-1550Article in journal (Refereed) Published
Abstract [en]

In Parkinsons disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular -synuclein (-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of -syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of -syn can influence the distribution and secretion of -syn in human neuroblastoma cells. Different -syn variants, including -syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted -syn, 0.1-2% was associated with vesicles. The major part of EV -syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For -syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT -syn. Moreover, such EV-associated -syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T -syn displayed an increased association with EVs. Taken together, our data suggest that -syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful -syn species and thereby contribute to the pathology in -synucleinopathies.

Place, publisher, year, edition, pages
SPRINGER/PLENUM PUBLISHERS, 2018
Keywords
Alpha-synuclein; Parkinsons disease; Alpha-synuclein oligomers; Human neuroblastoma; Extracellular vesicles; Exosomes
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-152810 (URN)10.1007/s10571-018-0622-5 (DOI)000449258300008 ()30288631 (PubMedID)
Note

Funding Agencies|U4 Ageing Brain Network; Swedish Research Council [2011-4519, 2012-2172, 2010-6745, 2013-2735]; Marianne and Marcus Wallenberg Foundation; Swedish Brain Foundation; Parkinson Research Foundation; Swedish Alzheimer Foundation; Swedish Parkinson Foundation; Swedish Society of Medicine; Hans-Gabriel and Alice Trolle Wachtmeisters Foundation for Medical Research; Lundbeck Foundation; Stohnes Foundation; Soderstrom-Konigska Foundation; Swedish Dementia Foundation; Bjorklunds Foundation for ALS research; Magnus Bergwall Foundation; Thore Nilsson Foundation; Old Servants Foundation; Ahlen Foundation; Loo and Hans Ostermans Foundation; Jeanssons Foundation; Larsson-Rosts Foundation; King Gustaf Vs and Queen Victorias Freemason Foundation; Goransson Sandvikens Foundation; NIH [NCI U19 CA179563]; DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB); Uppsala Berzelii Technology Center for Neurodiagnostics; Anna Maria Lundin Foundation; Goljes Foundation

Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2019-10-14
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6716-0314

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