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  • 1.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alexsson, Andrei
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ladenvall, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mansouri, Larry
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Berglund, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Cavelier, Lucia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    PD-L1 and IDO1 are potential targets for treatment in patients with primary diffuse large B-cell lymphoma of the CNS2021Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 60, nr 4, s. 531-538Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL).

    Material and methods

    Tissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases. Immunohistochemical stainings for PD-1, PD-L1/paired box protein 5 (PAX-5), PD-L2/PAX-5 and IDO1, and Epstein-Barr virus encoding RNA (EBER) in situ hybridization were analyzed.

    Results

    High proportions of PD-L1 and PD-L2 positive tumor cells were observed in 11% and 9% of cases, respectively. High proportions of PD-L1 and PD-L2 positive leukocytes were observed in 55% and 51% of cases, respectively. RNA sequencing revealed that gene expression of IDO1 was high in patients with high proportion of PD-L1 positive leukocytes (p = .01). Protein expression of IDO1 in leukocytes was detected in 14/45 cases, in 79% of these cases a high proportion of PD-L1 positive leukocytes was observed. Gene expression of IDO1 was high in EBER-positive cases (p = .0009) and protein expression of IDO1 was detected in five of six EBER-positive cases.

    Conclusion

    Our study shows a significant association between gene and protein expression of IDO1 and protein expression of PD-L1 in the tumor microenvironment of PCNSL, possibly of importance for prediction of response to immunotherapies.

    Fulltekst (pdf)
    fulltext
  • 2.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Hosp, Uppsala, Sweden..
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Univ Hosp, Uppsala, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Univ Hosp, Uppsala, Sweden..
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Hosp, Uppsala, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Saft, Leonie
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Hosp, Uppsala, Sweden..
    Outcome in PCNSL patients and its association with PD-L1+leukocytes in the tumor microenvironment2022Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 61, nr 7, s. 824-829Artikkel i tidsskrift (Fagfellevurdert)
  • 3.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Expression of IDO1 and PD-L2 in Patients with Benign Lymphadenopathies and Association with Autoimmune Diseases2023Inngår i: Biomolecules, E-ISSN 2218-273X, Vol. 13, nr 2, artikkel-id 240Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The expression patterns of IDO1 and PD-L2 have not been thoroughly investigated in benign lymphadenopathies. The aim with this study was to elucidate how IDO1 and PD-L2 are expressed in benign lymphadenopathies in patients with autoimmune diseases (AD) compared to patients without AD. Formalin-fixed paraffin-embedded lymph nodes from 22 patients with AD and 57 patients without AD were immunohistochemically stained to detect IDO1 and PD-L2. The material was previously stained with EBER in situ hybridization to detect cells harboring the Epstein-Barr virus (EBV). IDO1 and PD-L2 were generally expressed by leukocytes to low degrees, while follicular IDO1+ cells were very rare. IDO1+ cells in single germinal centers were detected in five patients, and there was a high co-occurrence of follicular EBV+ cells in these cases (three of five patients). There were also significant correlations between interfollicular EBV+ cells and interfollicular IDO1+ cells (Spearman rho = 0.32, p = 0.004) and follicular IDO1+ cells (Spearman rho = 0.34, p = 0.004). High or low amounts of IDO1+ or PD-L2+ cells were not statistically significantly associated with patients with AD. However, the lymphadenopathy with the highest amount of interfollicular IDO1+ cells, which was also the only lymphadenopathy in which endothelial cells expressed IDO1, was in a patient with sarcoidosis. This study further supports that the EBV induces the expression of IDO1 and our findings should be recognized by future studies on IDO1 and PD-L2 in inflammatory and malignant conditions.

    Fulltekst (pdf)
    FULLTEXT01
  • 4.
    Adhikari, Subash
    et al.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia..
    Nice, Edouard C.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia.;Monash Univ, Dept Biochem & Mol Biol, Fac Med Nursing & Hlth Sci, Melbourne, Vic 3800, Australia..
    Deutsch, Eric W.
    Inst Syst Biol, 401 Terry Ave North, Seattle, WA 98109 USA..
    Lane, Lydie
    Univ Geneva, SIB Swiss Inst Bioinformat, Fac Med, CMU, Michel Servet 1, CH-1211 Geneva, Switzerland.;Univ Geneva, Dept Microbiol & Mol Med, Fac Med, CMU, Michel Servet 1, CH-1211 Geneva, Switzerland..
    Omenn, Gilbert S.
    Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Pennington, Stephen R.
    Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, Sch Med, Dublin, Ireland..
    Paik, Young-Ki
    Yonsei Proteome Res Ctr, Sudaemoon Ku, 50 Yonsei ro, Seoul 120749, South Korea..
    Overall, Christopher M.
    Univ British Columbia, Fac Dent, Vancouver, BC, Canada..
    Corrales, Fernando J.
    Ctr Nacl Biotecnol CSIC, Funct Prote Lab, Proteored ISCIII, Madrid 28049, Spain..
    Cristea, Ileana M.
    Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA..
    Van Eyk, Jennifer E.
    Smidt Heart Inst, Cedars Sinai Med Ctr, Adv Clin Biosyst Res Inst, Los Angeles, CA 90048 USA..
    Uhlen, Mathias
    KTH Royal Inst Technol, Sch Engn Sci Chem, Sci Life Lab Biotechnol & Hlth, S-17121 Solna, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Chan, Daniel W.
    Johns Hopkins Univ, Dept Pathol & Oncol, Sch Med, Baltimore, MD 21224 USA..
    Bairoch, Amos
    Arizona State Univ, Biodesign Inst, Tempe, AZ USA..
    Waddington, James C.
    Justice, Joshua L.
    Arizona State Univ, Biodesign Inst, Tempe, AZ USA..
    LaBaer, Joshua
    Rodriguez, Henry
    NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA..
    He, Fuchu
    Beijing Inst Life, Beijing Proteome Res Ctr, Natl Ctr Prot Sci Beijing, State Key Lab Prote, Beijing 102206, Peoples R China..
    Kostrzewa, Markus
    Bruker Daltonik GmbH, Microbiol & Diagnost, Fahrenheitstr, D-428359 Bremen, Germany..
    Ping, Peipei
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Cardiac Prote & Signaling Lab, Los Angeles, CA USA..
    Gundry, Rebekah L.
    Univ Nebraska Med Ctr, Div Cardiovasc Med, Cardiom Program, Ctr Heart & Vasc Res, Omaha, NE 68198 USA.;Univ Nebraska Med Ctr, Dept Cellular & Integrat Physiol, Cardiom Program, Ctr Heart & Vasc Res, Omaha, NE 68198 USA..
    Stewart, Peter
    Royal Prince Alfred Hosp, Dept Chem Pathol, Camperdown, NSW, Australia..
    Srivastava, Sanjeeva
    Indian Inst Technol, Powai 400076, Maharashtra, India..
    Srivastava, Sudhir
    Natl Canc Inst, Natl Inst Hlth, Canc Biomarkers Res Branch, Med Ctr Dr, Suite 5E136, Rockville, MD 20852 USA.;Fed Univ Rio Janeiro, Inst Chem, Lab Prote, Athos da Silveria Ramos,149, BR-21941909 Rio De Janeiro, RJ, Brazil..
    Nogueira, Fabio C. S.
    Fed Univ Rio Janeiro, Inst Chem, Prote Unit, Athos da Silveria Ramos,149, BR-21941909 Rio De Janeiro, RJ, Brazil.;Univ Grenoble Alpes, INSERM, CEA, IRIG BGE,U1038, F-38000 Grenoble, France..
    Domont, Gilberto B.
    Univ Grenoble Alpes, INSERM, CEA, IRIG BGE,U1038, F-38000 Grenoble, France..
    Vandenbrouck, Yves
    Univ Colorado, Dept Med Cardiol, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Biochem, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Mol Genet, Anschutz Med Campus, Aurora, CO USA..
    Lam, Maggie P. Y.
    Univ Colorado, Dept Med, Div Cardiol, Anschutz Med Campus, Aurora, CO USA.;European Bioinformat Inst, Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England..
    Wennersten, Sara
    Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia..
    Vizcaino, Juan Antonio
    Univ Calif San Diego, Dept Comp Sci & Engn, 9500 Gilman Dr,Mail Code 0404, San Diego, CA 92093 USA..
    Wilkins, Marc
    Lund Univ, Dept Biomed Engn, Lund, Sweden..
    Schwenk, Jochen M.
    Lundberg, Emma
    Bandeira, Nuno
    Univ Texas Hlth Sci Ctr San Antonio, UT Hlth, Dept Biochem & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA..
    Marko-Varga, Gyorgy
    Univ Rennes, INSERM, EHESP, IREST,UMR S 1085, F-35042 Rennes, France..
    Weintraub, Susan T.
    Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands..
    Pineau, Charles
    Stanford Sch Med, Dept Genet, Stanford, CA 94305 USA..
    Kusebauch, Ulrike
    Moritz, Robert L.
    Ahn, Seong Beom
    Palmblad, Magnus
    Univ Rennes, INSERM, EHESP, IREST,UMR S 1085, F-35042 Rennes, France..
    Snyder, Michael P.
    Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands..
    Aebersold, Ruedi
    Stanford Sch Med, Dept Genet, Stanford, CA 94305 USA..
    Baker, Mark S.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia.;Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands.;Univ Zurich, Fac Sci, Zurich, Switzerland..
    A high-stringency blueprint of the human proteome2020Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1, artikkel-id 5301Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP's tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases. The Human Proteome Project (HPP) was launched in 2010 to enhance accurate annotation of the genome-encoded proteome. Ten years later, the HPP releases its first blueprint of the human proteome, annotating 90% of all known proteins at high-stringency and discussing the implications of proteomics for precision medicine.

    Fulltekst (pdf)
    FULLTEXT01
  • 5.
    Ali, Abir Salwa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Perren, Aurel
    Univ Bern, Dept Pathol, Bern, Switzerland..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Candidate protein biomarkers in pancreatic neuroendocrine neoplasms grade 32020Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikkel-id 10639Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
    FULLTEXT01
  • 6.
    Ambroise, Gorbatchev
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Yu, Ting-ting
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden.;Nanjing Med Univ, Sch Basic Med Sci, Dept Med Genet, Nanjing 211166, Jiangsu, Peoples R China..
    Zhang, Boxi
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Kacal, Merve
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Hao, Yuqing
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Queiroz, Andre L.
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Ouchida, Amanda T.
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Norberg, Erik
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Vakifahmetoglu-Norberg, Helin
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Systematic analysis reveals a functional role for STAMBPL1 in the epithelial-mesenchymal transition process across multiple carcinomas2020Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 123, nr 7, s. 1164-1177Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Deubiquitinating enzymes (DUBs) are linked to cancer progression and dissemination, yet less is known about their regulation and impact on epithelial-mesenchymal transition (EMT). Methods An integrative translational approach combining systematic computational analyses of The Cancer Genome Atlas cancer cohorts with CRISPR genetics, biochemistry and immunohistochemistry methodologies to identify and assess the role of human DUBs in EMT. Results We identify a previously undiscovered biological function of STAM-binding protein like 1 (STAMBPL1) deubiquitinase in the EMT process in lung and breast carcinomas. We show that STAMBPL1 expression can be regulated by mutant p53 and that its catalytic activity is required to affect the transcription factor SNAI1. Accordingly, genetic depletion and CRISPR-mediated gene knockout of STAMBPL1 leads to marked recovery of epithelial markers, SNAI1 destabilisation and impaired migratory capacity of cancer cells. Reversely, STAMBPL1 expression reprogrammes cells towards a mesenchymal phenotype. A significant STAMBPL1-SNAI1 co-signature was observed across multiple tumour types. Importantly, STAMBPL1 is highly expressed in metastatic tissues compared to matched primary tumour of the same lung cancer patient and its expression predicts poor prognosis. Conclusions Our study provides a novel concept of oncogenic regulation of a DUB and presents a new role and predictive value of STAMBPL1 in the EMT process across multiple carcinomas.

  • 7.
    Backman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kurppa, Pinja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Elfving, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Division of Pathology, Lund University Skåne University Hospital Lund Sweden.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindberg, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pontén, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Eltahir, Mohamed
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mangsbo, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Isaksson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Respiratory Medicine Gävle Hospital Gävle Sweden.
    Jirström, Karin
    Division of Oncology and Therapeutic Pathology Department of Clinical Sciences Lund, Lund, Sweden.
    Kärre, Klas
    Department of Microbiology, Cell and Tumor Biology Karolinska Institutet, Stockholm, Sweden.
    Leandersson, Karin
    Cancer Immunology, Department of Translational Medicine, Lund University Skånes University Hospital, Malmö, Sweden.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer2021Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 255, nr 3, s. 243-256Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

    Fulltekst (pdf)
    fulltext
  • 8.
    Backman, Max
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    La Fleur, Linnea
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Kurppa, Pinja
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Djureinovic, Dijana
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Elfving, Hedvig
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Brunnström, Hans
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Mattsson, Johanna Sofia Margareta
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Victor
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Eltahir, Mohamed
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Mangsbo, Sara
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Isaksson, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Dept. of Respiratory Medicine, Gävle Hospital, Gävle, Sweden..
    Jirström, Karin
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Kärre, Klas
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden..
    Carbone, Ennio
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden; Tumor Immunology and Immunopathology Laboratory, Dept. of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy..
    Leandersson, Karin
    Cancer Immunology, Dept. of Translational Medicine, Lund University, Skånes University Hospital, Malmö, Sweden.
    Mezheyeuski, Artur
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lindskog, Cecilia
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Extending the immune phenotypes of lung cancer: Oasis in the desertManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. 

    Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. 

    Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. 

    Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy. 

  • 9. Birgersson, Madeleine
    et al.
    Katona, Borbala
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Pontén, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Williams, Cecilia
    Antibody Validation for Estrogen Receptor Beta2022Inngår i: Estrogen Receptors. Methods in Molecular Biology / [ed] Eyster, K.M, Springer Nature, 2022, s. 1-23Kapittel i bok, del av antologi (Fagfellevurdert)
  • 10. Björling, Erik
    et al.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Oksvold, Per
    Linné, Jerker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kampf, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hober, Sophia
    Uhlén, Mathias
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A web-based tool for in silico biomarker discovery based on tissue-specific protein profiles in normal and cancer tissues2008Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 7, nr 5, s. 825-844Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Here we report the development of a publicly available Web-based analysis tool for exploring proteins expressed in a tissue- or cancer-specific manner. The search queries are based on the human tissue profiles in normal and cancer cells in the Human Protein Atlas portal and rely on the individual annotation performed by pathologists of images representing immunohistochemically stained tissue sections. Approximately 1.8 million images representing more than 3000 antibodies directed toward human proteins were used in the study. The search tool allows for the systematic exploration of the protein atlas to discover potential protein biomarkers. Such biomarkers include tissue-specific markers, cell type-specific markers, tumor type-specific markers, markers of malignancy, and prognostic or predictive markers of cancers. Here we show examples of database queries to generate sets of candidate biomarker proteins for several of these different categories. Expression profiles of candidate proteins can then subsequently be validated by examination of the underlying high resolution images. The present study shows examples of search strategies revealing several potential protein biomarkers, including proteins specifically expressed in normal cells and in cancer cells from specified tumor types. The lists of candidate proteins can be used as a starting point for further validation in larger patient cohorts using both immunological approaches and technologies utilizing more classical proteomics tools.

  • 11.
    Carapito, Christine
    et al.
    Univ Strasbourg, Lab Spectrometrie Masse BioOrgan LSMBO, IPHC, CNRS,UMR7178, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Duek, Paula
    SIB, CALIPHO Grp, CMU, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland..
    Macron, Charlotte
    Univ Strasbourg, Lab Spectrometrie Masse BioOrgan LSMBO, IPHC, CNRS,UMR7178, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Seffals, Marine
    Univ Rennes 1, UMS BioSit, Core Facil H2P2, F-35040 Rennes, France..
    Rondel, Karine
    Irset, INSERM, U1085, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Delalande, Francois
    Univ Strasbourg, Lab Spectrometrie Masse BioOrgan LSMBO, IPHC, CNRS,UMR7178, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Freour, Thomas
    CHU Nantes, Serv Med Reprod, 38 Blvd Jean Monnet, F-44093 Nantes, France.;INSERM, UMR1064, F-44093 Nantes, France..
    Vandenbrouck, Yves
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;INSERM, U1038, F-38054 Grenoble, France.;Grenoble Alpes Univ, F-38054 Grenoble, France..
    Lane, Lydie
    SIB, CALIPHO Grp, CMU, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.;Univ Geneva, Fac Med, Dept Human Prot Sci, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland..
    Pineau, Charles
    Irset, INSERM, U1085, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Validating Missing Proteins in Human Sperm Cells by Targeted Mass-Spectrometry- and Antibody-based Methods2017Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 16, nr 12, s. 4340-4351Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study is a contribution to the "neXt50 challenge", a coordinated effort across C-HPP teams to identify the SO most tractable missing proteins (MPs) on each chromosome. We report the targeted search of 38 theoretically detectable MPs from chromosomes 2 and 14 in Triton X-100 soluble and insoluble sperm fractions from a total of 15 healthy donors. A targeted mass spectrometry-based strategy consisting of the development of LC-PRM assays (with heavy labeled synthetic peptides) targeting 92 proteotypic peptides of the 38 selected MPs was used. Out of the 38 selected MPs, 12 were identified with two or more peptides and 3 with one peptide after extensive SDS-PAGE fractionation of the two samples and with overall low-intensity signals. The PRM data are available via ProteomeXchange in PASSEL (PASS01013). Further validation by immunohistochemistry on human testes sections and cytochemistry on sperm smears was performed for eight MPs with antibodies available from the Human Protein Atlas. Deep analysis of human sperm still allows the validation of MPs and therefore contributes to the C-HPP worldwide effort. We anticipate that our results will be of interest to the reproductive biology community because an in-depth analysis of these MPs may identify potential new candidates in the context of human idiopathic infertilities.

  • 12.
    Carreras-Puigvert, Jordi
    et al.
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Zitnik, Marinka
    Univ Ljubljana, Fac Comp & Informat Sci, SI-1000 Ljubljana, Slovenia.; Stanford Univ, Dept Comp Sci, Palo Alto, CA 94305 USA.
    Jemth, Ann-Sofie
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Carter, Megan
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Unterlass, Judith E
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Hallström, Björn
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Loseva, Olga
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Karem, Zhir
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Calderón-Montaño, José Manuel
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik D
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Matuszewski, Damian J.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ait Blal, Hammou
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Berntsson, Ronnie P A
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Häggblad, Maria
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Martens, Ulf
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Studham, Matthew
    Stockholm Univ, Dept Biochem & Biophys, Stockholm Bioinformat Ctr, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Lundgren, Bo
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Wählby, Carolina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Sonnhammer, Erik L L
    Stockholm Univ, Dept Biochem & Biophys, Stockholm Bioinformat Ctr, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Lundberg, Emma
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Stenmark, Pål
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Zupan, Blaz
    Univ Ljubljana, Fac Comp & Informat Sci, SI-1000 Ljubljana, Slovenia.; Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family2017Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 8, nr 1, artikkel-id 1541Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

    Fulltekst (pdf)
    fulltext
  • 13.
    Cheung, Pierre
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Translationell avbildning med PET.
    Persson, Jonas
    Zhang, Bo
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Translationell avbildning med PET.
    Khalil, Amina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Translationell avbildning med PET. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Huang, Zhijun
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Ståhl, Stefan
    Löfblom, John
    Eriksson, Olof
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Translationell avbildning med PET.
    Lead compound identification from first-in-class high affinity Affibody molecules binders towards DGCR2Manuskript (preprint) (Annet vitenskapelig)
  • 14.
    Corell, Alba
    et al.
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Vecchio, Tomas Gomez
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Vega, Sandra Ferreyra
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Denes, Anna
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Neimantaite, Alice
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Hagerius, Alexander
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Barcheus, Hanna
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Solheim, Ole
    Norwegian Univ Sci & Technol, Dept Neuromed & Movement Sci, Trondheim, Norway.;St Olavs Univ Hosp, Dept Neurosurg, Trondheim, Norway..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bontell, Thomas Olsson
    Sahlgrens Univ Hosp, Dept Clin Pathol & Cytol, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Physiol, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Caren, Helena
    Univ Gothenburg, Sahlgrenska Acad, Sahlgrenska Ctr Canc Res, Inst Biomed,Dept Lab Med, Gothenburg, Sweden..
    Jakola, Asgeir S.
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden.;Norwegian Univ Sci & Technol, Dept Neuromed & Movement Sci, Trondheim, Norway..
    Smits, Anja
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden..
    Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma: an exploratory study2022Inngår i: Neuro-Oncology Advances, E-ISSN 2632-2498, Vol. 4, nr 1, artikkel-id vdac074Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied. Methods We included 188 patients >= 18 years with IDH-mutated dLGG (WHO grades 2-3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P < .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P < .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42). Conclusions We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.

    Fulltekst (pdf)
    fulltext
  • 15.
    Dalmo, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Rosén, Gabriela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Niklasson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bergström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Miletic, Hrvoje
    University of Bergen, Department of Biomedicine; Haukeland University Hospital, Department of Pathology.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Forsberg Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Swartling, Fredrik J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Targeting SOX2 in glioblastoma cells reveals heterogeneity in SOX2 dependencyManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Glioblastoma (GBM) is a lethal disease with no curative treatment. SOX2 is a stem cell transcription factor which is widely expressed across human GBM tumors. Downregulation of SOX2 inhibits tumor formation and its depletion leads to a complete stop of cell proliferation. Despite its known important role in GBM, there is a lack of SOX2 overexpression studies in human GBM cells cultured under stem cell conditions. Previous work in our lab suggests that SOX2 levels need to be precisely maintained for GBM cells to thrive. In this project, we have investigated how altered SOX2 expression affects primary human GBM lines. We found that elevated SOX2 expression inhibited proliferation in a dose-dependent manner in three out of four GBM cell lines. Global gene expression in the resistant line was shifted towards that of the proliferation-inhibited lines upon SOX2 induction. However, SOX2 induction also led to an increase in a GBM stem cell injury response phenotype, which was not present in proliferation-inhibited lines. Furthermore, CRISPR/Cas9-mediated SOX2 knockout revealed a SOX2 independence in the resistant cell line, where SOX2-negative cells could be propagated both in vitro and in vivo.

  • 16.
    Danielsson, Angelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Schwenk, Jochen M.
    Uhlen, Mathias
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindskog, Cecilia Bergström
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The Human Pancreas Proteome Defined by Transcriptomics and Antibody-Based Profiling2014Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 12, s. e115421-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the molecular constituents with elevated expression in the human pancreas, we employed a genome-wide RNA sequencing analysis of the human transcriptome to identify genes with elevated expression in the human pancreas. This quantitative transcriptomics data was combined with immunohistochemistry-based protein profiling to allow mapping of the corresponding proteins to different compartments and specific cell types within the pancreas down to the single cell level. Analysis of whole pancreas identified 146 genes with elevated expression levels, of which 47 revealed a particular higher expression as compared to the other analyzed tissue types, thus termed pancreas enriched. Extended analysis of in vitro isolated endocrine islets identified an additional set of 42 genes with elevated expression in these specialized cells. Although only 0.7% of all genes showed an elevated expression level in the pancreas, this fraction of transcripts, in most cases encoding secreted proteins, constituted 68% of the total mRNA in pancreas. This demonstrates the extreme specialization of the pancreas for production of secreted proteins. Among the elevated expression profiles, several previously not described proteins were identified, both in endocrine cells (CFC1, FAM159B, RBPJL and RGS9) and exocrine glandular cells (AQP12A, DPEP1, GATM and ERP27). In summary, we provide a global analysis of the pancreas transcriptome and proteome with a comprehensive list of genes and proteins with elevated expression in pancreas. This list represents an important starting point for further studies of the molecular repertoire of pancreatic cells and their relation to disease states or treatment effects.

    Fulltekst (pdf)
    fulltext
  • 17.
    Denes, Anna
    et al.
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Clin Neurosci, Gothenburg, Sweden..
    Bontell, Thomas Olsson
    Sahlgrens Univ Hosp, Dept Clin Pathol, Gothenburg, Sweden.;Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Physiol, Gothenburg, Sweden..
    Barcheus, Hanna
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Clin Neurosci, Gothenburg, Sweden..
    Vega, Sandra Ferreyra
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Clin Neurosci, Gothenburg, Sweden.;Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Sahlgrenska Ctr Canc Res,Dept Med Biochem & Cell B, Gothenburg, Sweden..
    Caren, Helena
    Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Sahlgrenska Ctr Canc Res,Dept Med Biochem & Cell B, Gothenburg, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Jakola, Asgeir S.
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Clin Neurosci, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden..
    Smits, Anja
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Dept Clin Neurosci, Gothenburg, Sweden..
    The clinical value of proneural, classical and mesenchymal protein signatures in WHO 2021 adult-type diffuse lower-grade gliomas2023Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 18, nr 5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ObjectivesAccumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the tumor phenotype over time, has not been studied. Most efforts to correlate proneural, classical or mesenchymal phenotype with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype predicted survival and tumor recurrence in a clinical cohort of dLGGs, re-classified according to the 2021 WHO criteria. MethodsUsing a TMA-based approach with five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2), we investigated 183 primary and 49 recurrent tumors derived from patients with previously diagnosed dLGG. Of the 49 relapses, nine tumors recurred a second time, and one a third time. ResultsIn total, 71.0% of all tumors could be subtyped. Proneural was most dominant in IDH-mut tumors (78.5%), mesenchymal more common among IDH-wt tumors (63.6%). There was a significant difference in survival between classical, proneural and mesenchymal phenotypes in the total cohort (p<0.001), but not after molecular stratification (IDH-mut: p = 0.220, IDH-wt: p = 0.623). Upon recurrence, proneural was retained in 66.7% of the proneural IDH-mut dLGGs (n = 21), whereas IDH-wt tumors (n = 10) mainly retained or gained mesenchymal phenotype. No significant difference in survival was found between IDH-mut gliomas remaining proneural and those shifting to mesenchymal phenotype (p = 0.347). ConclusionSubtyping into classical, proneural and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but protein signatures did not correlate with patient survival in our WHO2021-stratified cohort. At recurrence, IDH-mut tumors mainly retained proneural, while IDH-wt tumors mostly retained or gained mesenchymal signatures. This phenotypic shift, associated with increased aggressiveness in glioblastoma, did not affect survival. Group sizes were, however, too small to draw any firm conclusions.

    Fulltekst (pdf)
    fulltext
  • 18.
    Digre, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    The Human Protein Atlas - Spatial localization of the human proteome in health and disease2021Inngår i: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 30, nr 1, s. 218-233Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    For a complete understanding of a system's processes and each protein's role in health and disease, it is essential to study protein expression with a spatial resolution, as the exact location of proteins at tissue, cellular, or subcellular levels is tightly linked to protein function. The Human Protein Atlas (HPA) project is a large-scale initiative aiming at mapping the entire human proteome using antibody-based proteomics and integration of various other omics technologies. The publicly available knowledge resource www.proteinatlas.org is one of the world's most visited biological databases and has been extensively updated during the last few years. The current version is divided into six main sections, each focusing on particular aspects of the human proteome: (a) the Tissue Atlas showing the distribution of proteins across all major tissues and organs in the human body; (b) the Cell Atlas showing the subcellular localization of proteins in single cells; (c) the Pathology Atlas showing the impact of protein levels on survival of patients with cancer; (d) the Blood Atlas showing the expression profiles of blood cells and actively secreted proteins; (e) the Brain Atlas showing the distribution of proteins in human, mouse, and pig brain; and (f) the Metabolic Atlas showing the involvement of proteins in human metabolism. The HPA constitutes an important resource for further understanding of human biology, and the publicly available datasets hold much promise for integration with other emerging efforts focusing on single cell analyses, both at transcriptomic and proteomic level.

  • 19.
    Digre, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    The human protein atlas-Integrated omics for single cell mapping of the human proteome2023Inngår i: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 32, nr 2, artikkel-id e4562Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studying the spatial distribution of proteins provides the basis for understanding the biology, molecular repertoire, and architecture of every human cell. The Human Protein Atlas (HPA) has grown into one of the world's largest biological databases, and in the most recent version, a major update of the structure of the database was performed. The data has now been organized into 10 different comprehensive sections, each summarizing different aspects of the human proteome and the protein-coding genes. In particular, large datasets with information on the single cell type level have been integrated, refining the tissue and cell type specificity and detailing the expression in cell states with an increased resolution. The multi-modal data constitute an important resource for both basic and translational science, and hold promise for integration with novel emerging technologies at the protein and RNA level.

    Fulltekst (pdf)
    fulltext
  • 20.
    Djureinovic, Dijana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fagerberg, L.
    Hallstrom, B.
    Danielsson, A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindskog Bergström, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhlen, M.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The human testis-specific proteome defined by transcriptomics and antibody-based profiling2014Inngår i: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 20, nr 6, s. 476-488Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The testis' function is to produce haploid germ cells necessary for reproduction. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to characterize the molecular components of the testis. Deep sequencing (RNA-Seq) of normal human testicular tissue from seven individuals was performed and compared with 26 other normal human tissue types. All 20 050 putative human genes were classified into categories based on expression patterns. The analysis shows that testis is the tissue with the most tissue-specific genes by far. More than 1000 genes show a testis-enriched expression pattern in testis when compared with all other analyzed tissues. Highly testis enriched genes were further characterized with respect to protein localization within the testis, such as spermatogonia, spermatocytes, spermatids, sperm, Sertoli cells and Leydig cells. Here we present an immunohistochemistry-based analysis, showing the localization of corresponding proteins in different cell types and various stages of spermatogenesis, for 62 genes expressed at > 50-fold higher levels in testis when compared with other tissues. A large fraction of these genes were unexpectedly expressed in early stages of spermatogenesis. In conclusion, we have applied a genome-wide analysis to identify the human testis-specific proteome using transcriptomics and antibody-based protein profiling, providing lists of genes expressed in a tissue-enriched manner in the testis. The majority of these genes and proteins were previously poorly characterised in terms of localization and function, and our list provides an important starting point to increase our molecular understanding of human reproductive biology and disease.

  • 21.
    Djureinovic, Dijana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hallström, Bjorn M.
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Horie, Masafumi
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Brunnström, Hans
    Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Madjar, Katrin
    Tech Univ Dortmund, Dept Stat, Dortmund, Germany..
    Rahnenfuehrer, Joerg
    Tech Univ Dortmund, Dept Stat, Dortmund, Germany..
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ståhle, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Edlund, Karolina
    Tech Univ Dortmund, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Hengstler, Jan G.
    Tech Univ Dortmund, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Lambe, Mats
    Univ Uppsala Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Profiling cancer testis antigens in non-small-cell lung cancer2016Inngår i: JCI INSIGHT, ISSN 2379-3708, Vol. 1, nr 10, artikkel-id e86837Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

  • 22.
    Djureinovic, Dijana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hallström, Björn
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Fagerberg, Linn
    Brunnström, Hans
    Lund Univ, Div Pathol, Lund, Sweden..
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ståhle, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Koyi, Hirsh
    Gavle Cent Hosp, Dept Pneumol, S-80187 Gavle, Sweden..
    Lambe, Mats
    Reg Canc Ctr Uppsala Orebro, Uppsala, Sweden..
    Branden, Eva
    Gavle Cent Hosp, Dept Pneumol, S-80187 Gavle, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Uhlen, Mathias
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The Identification of Therapeutic Targets in Lung Cancer Based on Transcriptomic and Proteomic Characterization of Cancer-Testis Antigens2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S256-S256Artikkel i tidsskrift (Fagfellevurdert)
  • 23.
    Edfors, Fredrik
    et al.
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Hober, Andreas
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Linderbäck, Klas
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Maddalo, Gianluca
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Azimi, Alireza
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, SE-17177 Stockholm, Sweden.
    Sivertsson, Åsa
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Tegel, Hanna
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Szigyarto, Cristina Al-Khalili
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Oksvold, Per
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Forsström, Björn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden;Tech Univ Denmark, Novo Nordisk Fdn Ctr Biosustainabil, DK-2970 Horsholm, Denmark.
    Enhanced validation of antibodies for research applications2018Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 9, artikkel-id 4130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is a need for standardized validation methods for antibody specificity and selectivity. Recently, five alternative validation pillars were proposed to explore the specificity of research antibodies using methods with no need for prior knowledge about the protein target. Here, we show that these principles can be used in a streamlined manner for enhanced validation of research antibodies in Western blot applications. More than 6,000 antibodies were validated with at least one of these strategies involving orthogonal methods, genetic knockdown, recombinant expression, independent antibodies, and capture mass spectrometry analysis. The results show a path forward for efforts to validate antibodies in an application-specific manner suitable for both providers and users.

    Fulltekst (pdf)
    FULLTEXT01
  • 24.
    Edlund, Karolina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Saito, Akira
    Berglund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Göransson-Kultima, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Isaksson, Anders
    Jirström, Karin
    Planck-Sturegård, Maria
    Johansson, Leif
    Lambe, Mats
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Nyberg, Fredrik
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Landelius, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Lamberg, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Östman, Arne
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    CD99 is a novel prognostic stromal marker in non-small cell lung cancer2012Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, nr 10, s. 2264-2273Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC, VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p=0.037) and multivariate (p=0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells, and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p=0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.

  • 25.
    Edlund, Karolina
    et al.
    TU Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Madjar, Katrin
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.
    Jirström, Karin
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rahnenführer, Jörg
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hengstler, Jan G
    TU Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC2019Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 14, nr 4, s. 628-640, artikkel-id S1556-0864(19)30009-7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.

    Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.

    Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.

    Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.

    Fulltekst (pdf)
    fulltext
  • 26.
    Egevad, Lars
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol & Pathol, Radiumhemmet P1 02, S-17176 Stockholm, Sweden.
    Delahunt, Brett
    Univ Otago, Wellington Sch Med & Hlth Sci, Dept Pathol & Mol Med, Wellington, New Zealand.
    Samaratunga, Hemamali
    Aquesta Uropathol, Brisbane, Qld, Australia; Univ Queensland, Brisbane, Qld, Australia.
    Tsuzuki, Toyonori
    AichiMed Univ, Sch Med, Dept Surg Pathol, Nagoya, Aichi, Japan.
    Olsson, Henrik
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Ström, Peter
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Häkkinen, Tomi
    Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland; Tampere Univ Hosp, Tays Canc Ctr, Tampere, Finland.
    Kartasalo, Kimmo
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden; Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland.
    Eklund, Martin
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Ruusuvuori, Pekka
    Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland; Univ Turku, Inst Biomed, Turku, Finland.
    Interobserver reproducibility of perineural invasion of prostatic adenocarcinoma in needle biopsies2021Inngår i: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 478, nr 6, s. 1109-1116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Numerous studies have shown a correlation between perineural invasion (PNI) in prostate biopsies and outcome. The reporting of PNI varies widely in the literature. While the interobserver variability of prostate cancer grading has been studied extensively, less is known regarding the reproducibility of PNI. A total of 212 biopsy cores from a population-based screening trial were included in this study (106 with and 106 without PNI according to the original pathology reports). The glass slides were scanned and circulated among four pathologists with a special interest in urological pathology for assessment of PNI. Discordant cases were stained by immunohistochemistry for S-100 protein. PNI was diagnosed by all four observers in 34.0% of cases, while 41.5% were considered to be negative for PNI. In 24.5% of cases, there was a disagreement between the observers. The kappa for interobserver variability was 0.67-0.75 (mean 0.73). The observations from one participant were compared with data from the original reports, and a kappa for intraobserver variability of 0.87 was achieved. Based on immunohistochemical findings among discordant cases, 88.6% had PNI while 11.4% did not. The most common diagnostic pitfall was the presence of bundles of stroma or smooth muscle. It was noted in a few cases that collagenous micronodules could be mistaken for a nerve. The distance between cancer and nerve was another cause of disagreement. Although the results suggest that the reproducibility of PNI may be greater than that of prostate cancer grading, there is still a need for improvement and standardization.

    Fulltekst (pdf)
    FULLTEXT01
  • 27.
    Ehrstedt, Christoffer
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Ahlsten, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Strömberg, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood2020Inngår i: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 76, s. 123-130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age.

    Method: 37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics.

    Results: Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n=4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found.

    Conclusions: Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.

  • 28.
    Elfving, Hedvig
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Menzel, Uwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Programmed Cell Death Ligand 1 Immunohistochemistry: A Concordance Study Between Surgical Specimen, Biopsy, and Tissue Microarray2019Inngår i: Clinical Lung Cancer, ISSN 1525-7304, E-ISSN 1938-0690, Vol. 20, nr 4, s. 258-262.e1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Programmed cell death ligand 1 (PD-L1) expression within the same lung cancer tissue is variable. In this study we evaluated if the PD-L1 expression on small biopsy specimens represent the PD-L1 status of the corresponding resection specimen. Our results indicate a relative good agreement between biopsy and surgical specimens, with a discordance in approximately 10% of the cases. Background: The immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissue of non-small-cell lung cancer patients has now been integrated in the diagnostic workup. Analysis is commonly done on small tissue biopsy samples representing a minimal fraction of the whole tumor. The aim of the study was to evaluate the correlation of PD-L1 expression on biopsy specimens with corresponding resection specimens. Materials and Methods: In total, 58 consecutive cases with preoperative biopsy and resected tumor specimens were selected. From each resection specimen 2 tumor cores were compiled into a tissue microarray (TMA). Immunohistochemical staining with the antibody SP263 was performed on biopsy specimens, resection specimens (whole sections), as well as on the TMA. Results: The proportion of PD-L1-positive stainings were comparable between the resection specimens (48% and 19%), the biopsies (43% and 17%), and the TMAs (47% and 14%), using cutoffs of 1% and 50%, respectively (P > .39 all comparisons). When the resection specimens were considered as reference, PD-L1 status differed in 16%/5% for biopsies and in 9%/9% for TMAs (1%/50% cutoff). The sensitivity of the biopsy analysis was 79%/82% and the specificity was 90%/98% at the 1%/50% cutoff. The Cohens kappa value for the agreement between biopsy and tumor. was 0.70 at the 1% cutoff and 0.83 at the 50% cutoff. Conclusion: The results indicate a moderate concordance between the analysis of biopsy and whole tumor tissue, resulting in misclassification of samples in particular when the lower 1% cutoff was used. Clinicians should be aware of this uncertainty when interpreting PD-L1 reports for treatment decisions.

  • 29.
    Eriksson, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Engholm, Ebbe
    Univ Copenhagen, Chem Biol, Dept Chem, DK-1871 Frederiksberg C, Denmark.
    Blixt, Ola
    Univ Copenhagen, Chem Biol, Dept Chem, DK-1871 Frederiksberg C, Denmark.
    Waldenstrom, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, SE-39231 Kalmar, Sweden.
    Munster, Vincent
    NIAID, Lab Virol, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA.
    Lundkvist, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Olsen, Bjorn
    Uppsala Univ, Zoonosis Sci Ctr, Dept Med Sci, SE-75123 Uppsala, Sweden.
    Jourdain, Elsa
    INRA, EPIA, VetAgro Sup, UMR0346, FR-63122 St Genes Champanelle, France.
    Ellstrom, Patrik
    Uppsala Univ, Zoonosis Sci Ctr, Dept Med Sci, SE-75123 Uppsala, Sweden.
    Characterization of avian influenza virus attachment patterns to human and pig tissues2018Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 8, artikkel-id 12215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Wild birds of Anseriformes and Charadriiformes are natural reservoirs of influenza A viruses (IAVs). Occasionally, IAVs transmit and adapt to mammalian hosts, and are maintained as epidemic strains in their new hosts. Viral adaptions to mammalian hosts include altered receptor preference of host epithelial sialylated oligosaccharides from terminal alpha 2,3-linked sialic acid (SA) towards alpha 2,6-linked SA. However, alpha 2,3-linked SA has been found in human respiratory tract epithelium, and human infections by avian IAVs (AIVs) have been reported. To further explore the attachment properties of AIVs, four AIVs of different subtypes were investigated on human and pig tissues using virus histochemistry. Additionally, glycan array analysis was performed for further characterization of IAVs' receptor structure tropism. Generally, AIV attachment was more abundant to human tissues than to pig tissues. The attachment pattern was very strong to human conjunctiva and upper respiratory tract, but variable to the lower respiratory tract. AIVs mainly attached to alpha 2,3-linked SA, but also to combinations of alpha 2,3-and alpha 2,6-linked SA. The low attachment of these AIV isolates to pig tissues, but high attachment to human tissues, addresses the question whether AIVs in general require passage through pigs to obtain adaptions towards mammalian receptor structures.

    Fulltekst (pdf)
    fulltext
  • 30.
    Eriksson, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lorente-Leal, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.
    González-Acuna, Daniel
    Univ Concepcion, Fac Ciencias Vet, Chillan, Chile.
    Järhult, Josef D.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionsmedicin.
    Lundkvist, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Olsen, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionsmedicin.
    Jourdain, Elsa
    INRA, UMR0346 EPIA, VetAgro Sup, St Genes Champanelle, France.
    Ellström, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionsmedicin.
    Attachment Patterns of Human and Avian Influenza Viruses to Trachea and Colon of 26 Bird Species: Support for the Community Concept2019Inngår i: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 10, artikkel-id 815Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Avian influenza A viruses (AIVs) have a broad host range, but are most intimately associated with waterfowl (Anseriformes) and, in the case of the H13 and H16 subtypes, gulls (Charadriiformes). Host associations are multifactorial, but a key factor is the ability of the virus to bind host cell receptors and thereby initiate infection. The current study aims at investigating the tissue attachment pattern of a panel of AIVs, comprising H3N2, H6N1, H12N5, and H16N3, to avian trachea and colon tissue samples obtained from host species of different orders. Virus attachment was not restricted to the bird species or order from which the virus was isolated. Instead, extensive virus attachment was observed to several distantly related avian species. In general, more virus attachment and receptor expression were observed in trachea than in colon samples. Additionally, a human seasonal H3N2 virus was studied. Unlike the studied AIVs, this virus mainly attached to tracheae from Charadriiformes and a very limited set of avian cola. In conclusion, the reported results highlight the importance of AIV attachment to trachea in many avian species. Finally, the importance of chickens and mallards in AIVs dynamics was illustrated by the abundant AIV attachment observed.

    Fulltekst (pdf)
    FULLTEXT01
  • 31. Fagerberg, Linn
    et al.
    Hallström, Björn M
    Oksvold, Per
    Kampf, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Odeberg, Jacob
    Habuka, Masato
    Tahmasebpoor, Simin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Danielsson, Angelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Asplund, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sjöstedt, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Lundberg, Emma
    Szigyarto, Cristina Al-Khalili
    Skogs, Marie
    Takanen, Jenny Ottosson
    Berling, Holger
    Tegel, Hanna
    Mulder, Jan
    Nilsson, Peter
    Schwenk, Jochen M
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Danielsson, Frida
    Mardinoglu, Adil
    Sivertsson, Asa
    von Feilitzen, Kalle
    Forsberg, Mattias
    Zwahlen, Martin
    Olsson, IngMarie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Navani, Sanjay
    Huss, Mikael
    Nielsen, Jens
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Uhlén, Mathias
    Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics2014Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 13, nr 2, s. 397-406Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biology and disease. Here, we used a quantitative transcriptomics analysis (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this analysis with antibody-based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to ∼80% of the human protein-coding genes with access to the primary data for both the RNA and the protein analysis on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the molecular constituents of the human body.

  • 32.
    Garcia-Alonso, Luz
    et al.
    Wellcome Sanger Inst, Cambridge, England..
    Handfield, Louis-Francois
    Wellcome Sanger Inst, Cambridge, England..
    Roberts, Kenny
    Wellcome Sanger Inst, Cambridge, England..
    Nikolakopoulou, Konstantina
    Univ Cambridge, Ctr Trophoblast Res, Cambridge, England.;Univ Cambridge, Dept Pathol, Cambridge, England..
    Fernando, Ridma C.
    Univ Cambridge, Ctr Trophoblast Res, Cambridge, England.;Univ Cambridge, Dept Pathol, Cambridge, England..
    Gardner, Lucy
    Univ Cambridge, Ctr Trophoblast Res, Cambridge, England.;Univ Cambridge, Dept Pathol, Cambridge, England..
    Woodhams, Benjamin
    Wellcome Sanger Inst, Cambridge, England.;Wellcome Genome Campus, EMBL EBI, Hinxton, England..
    Arutyunyan, Anna
    Wellcome Sanger Inst, Cambridge, England.;Univ Cambridge, Ctr Trophoblast Res, Cambridge, England..
    Polanski, Krzysztof
    Wellcome Sanger Inst, Cambridge, England..
    Hoo, Regina
    Wellcome Sanger Inst, Cambridge, England.;Univ Cambridge, Ctr Trophoblast Res, Cambridge, England..
    Sancho-Serra, Carmen
    Wellcome Sanger Inst, Cambridge, England..
    Li, Tong
    Wellcome Sanger Inst, Cambridge, England..
    Kwakwa, Kwasi
    Wellcome Genome Campus, EMBL EBI, Hinxton, England..
    Tuck, Elizabeth
    Wellcome Sanger Inst, Cambridge, England..
    Lorenzi, Valentina
    Wellcome Sanger Inst, Cambridge, England..
    Massalha, Hassan
    Wellcome Sanger Inst, Cambridge, England.;Univ Cambridge, Cavendish Lab, Theory Condensed Matter Grp, Cambridge, England..
    Prete, Martin
    Wellcome Sanger Inst, Cambridge, England..
    Kleshchevnikov, Vitalii
    Wellcome Sanger Inst, Cambridge, England..
    Tarkowska, Aleksandra
    Wellcome Sanger Inst, Cambridge, England..
    Porter, Tarryn
    Wellcome Sanger Inst, Cambridge, England..
    Mazzeo, Cecilia Icoresi
    Wellcome Sanger Inst, Cambridge, England..
    van Dongen, Stijn
    Wellcome Sanger Inst, Cambridge, England..
    Dabrowska, Monika
    Wellcome Sanger Inst, Cambridge, England..
    Vaskivskyi, Vasyl
    Wellcome Sanger Inst, Cambridge, England..
    Mahbubani, Krishnaa T.
    Univ Cambridge, Dept Haematol, Cambridge, England.;NIHR Cambridge Biomed Res Ctr, Cambridge Biorepository Translat Med CBTM, Cambridge, England..
    Park, Jong-Eun
    Wellcome Sanger Inst, Cambridge, England..
    Jimenez-Linan, Mercedes
    Cambridge Univ Hosp NHS Fdn Trust, Dept Pathol, Cambridge, England..
    Campos, Lia
    Wellcome Sanger Inst, Cambridge, England..
    Kiselev, Vladimir Yu.
    Wellcome Sanger Inst, Cambridge, England..
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ayuk, Paul
    Newcastle Upon Tyne Hosp NHS Fdn Trust, Dept Womens Serv, Newcastle Upon Tyne, Tyne & Wear, England..
    Prigmore, Elena
    Wellcome Sanger Inst, Cambridge, England..
    Stratton, Michael R.
    Wellcome Sanger Inst, Cambridge, England..
    Saeb-Parsy, Kourosh
    NIHR Cambridge Biomed Res Ctr, Cambridge Biorepository Translat Med CBTM, Cambridge, England.;Univ Cambridge, Dept Surg, Cambridge, England..
    Moffett, Ashley
    Univ Cambridge, Ctr Trophoblast Res, Cambridge, England.;Univ Cambridge, Dept Pathol, Cambridge, England..
    Moore, Luiza
    Wellcome Sanger Inst, Cambridge, England..
    Bayraktar, Omer A.
    Wellcome Sanger Inst, Cambridge, England..
    Teichmann, Sarah A.
    Wellcome Sanger Inst, Cambridge, England..
    Turco, Margherita Y.
    Univ Cambridge, Ctr Trophoblast Res, Cambridge, England.;Univ Cambridge, Dept Pathol, Cambridge, England.;Friedrich Miescher Inst Biomed Res, Basel, Switzerland..
    Vento-Tormo, Roser
    Wellcome Sanger Inst, Cambridge, England.;Univ Cambridge, Ctr Trophoblast Res, Cambridge, England..
    Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro2021Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 53, nr 12, s. 1698-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively.

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  • 33. Ghoshal, Biraja
    et al.
    Hikmet, Feria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Pineau, Charles
    Tucker, Allan
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    DeepHistoClass: A Novel Strategy for Confident Classification of Immunohistochemistry Images Using Deep Learning2021Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 20, artikkel-id 100140Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A multitude of efforts worldwide aim to create a single-cell reference map of the human body, for fundamental understanding of human health, molecular medicine, and targeted treatment. Antibody-based proteomics using immunohistochemistry (IHC) has proven to be an excellent technology for integration with large-scale single-cell transcriptomics datasets. The golden standard for evaluation of IHC staining patterns is manual annotation, which is expensive and may lead to subjective errors. Artificial intelligence holds much promise for efficient and accurate pattern recognition, but confidence in prediction needs to be addressed. Here, the aim was to present a reliable and comprehensive framework for automated annotation of IHC images. We developed a multilabel classification of 7848 complex IHC images of human testis corresponding to 2794 unique proteins, generated as part of the Human Protein Atlas (HPA) project. Manual annotation data for eight different cell types was generated as a basis for training and testing a proposed Hybrid Bayesian Neural Network. By combining the deep learning model with a novel uncertainty metric, DeepHistoClass (DHC) Confidence Score, the average diagnostic performance improved from 86.9% to 96.3%. This metric not only reveals which images are reliably classified by the model, but can also be utilized for identification of manual annotation errors. The proposed streamlined workflow can be developed further for other tissue types in health and disease and has important implications for digital pathology initiatives or large-scale protein mapping efforts such as the HPA project.

    Fulltekst (pdf)
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  • 34.
    Ghoshal, Biraja
    et al.
    Brunel Univ London, Uxbridge UB8 3PH, Middx, England..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Tucker, Allan
    Brunel Univ London, Uxbridge UB8 3PH, Middx, England..
    Estimating Uncertainty in Deep Learning for Reporting Confidence: An Application on Cell Type Prediction in Testes Based on Proteomics2020Inngår i: Advances In Intelligent Data Analysis XVIII, IDA 2020 / [ed] Berthold, MR; Feelders, A; Krempl, G, Springer Nature , 2020, Vol. 12080, s. 223-234Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Multi-label classification in deep learning is a practical yet challenging task, because class overlaps in the feature space means that each instance is associated with multiple class labels. This requires a prediction of more than one class category for each input instance. To the best of our knowledge, this is the first deep learning study which quantifies uncertainty and model interpretability in multi-label classification; as well as applying it to the problem of recognising proteins expressed in cell types in testes based on immunohistochemically stained images. Multi-label classification is achieved by thresholding the class probabilities, with the optimal thresholds adaptively determined by a grid search scheme based on Matthews correlation coefficients. We adopt MC-Dropweights to approximate Bayesian Inference in multi-label classification to evaluate the usefulness of estimating uncertainty with predictive score to avoid overconfident, incorrect predictions in decision making. Our experimental results show that the MC-Dropweights visibly improve the performance to estimate uncertainty compared to state of the art approaches.

    Fulltekst (pdf)
    FULLTEXT01
  • 35.
    Guo, Jingtao
    et al.
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA;Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA.
    Grow, Edward J.
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    Mlcochova, Hana
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Maher, Geoffrey J.
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nie, Xichen
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    Guo, Yixuan
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    Takei, Yodai
    CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
    Yun, Jina
    CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
    Cai, Long
    CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
    Kim, Robin
    Univ Utah, Sch Med, Dept Surg, Sect Transplantat, Salt Lake City, UT 84132 USA.
    Carrell, Douglas T.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA.
    Goriely, Anne
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Hotaling, James M.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA.
    Cairns, Bradley R.
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    The adult human testis transcriptional cell atlas2018Inngår i: Cell Research, ISSN 1001-0602, E-ISSN 1748-7838, Vol. 28, s. 1141-1157Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human adult spermatogenesis balances spermatogonial stem cell (SSC) self-renewal and differentiation, alongside complex germ cell-niche interactions, to ensure long-term fertility and faithful genome propagation. Here, we performed single-cell RNA sequencing of similar to 6500 testicular cells from young adults. We found five niche/somatic cell types (Leydig, myoid, Sertoli, endothelial, macrophage), and observed germline-niche interactions and key human-mouse differences. Spermatogenesis, including meiosis, was reconstructed computationally, revealing sequential coding, non-coding, and repeat-element transcriptional signatures. Interestingly, we identified five discrete transcriptional/developmental spermatogonial states, including a novel early SSC state, termed State 0. Epigenetic features and nascent transcription analyses suggested developmental plasticity within spermatogonial States. To understand the origin of State 0, we profiled testicular cells from infants, and identified distinct similarities between adult State 0 and infant SSCs. Overall, our datasets describe key transcriptional and epigenetic signatures of the normal adult human testis, and provide new insights into germ cell developmental transitions and plasticity.

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  • 36.
    Guo, Jingtao
    et al.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Grow, Edward J.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Yi, Chongil
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Mlcochova, Hana
    Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England..
    Maher, Geoffrey J.
    Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England..
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Murphy, Patrick J.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Wike, Candice L.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Carrell, Douglas T.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA..
    Goriely, Anne
    Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England..
    Hotaling, James M.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA..
    Cairns, Bradley R.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Chromatin and Single-Cell RNA- Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development2017Inngår i: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 21, nr 4, s. 533-546Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human adult spermatogonial stem cells (hSSCs) must balance self-renewal and differentiation. To understand how this is achieved, we profiled DNA methylation and open chromatin (ATAC-seq) in SSEA4(+) hSSCs, analyzed bulk and single-cell RNA transcriptomes (RNA-seq) in SSEA4+ hSSCs and differentiating c-KIT+ spermatogonia, and performed validation studies via immunofluorescence. First, DNA hypomethylation at embryonic developmental genes supports their epigenetic "poising'' in hSSCs for future/embryonic expression, while core pluripotency genes (OCT4 and NANOG) were transcriptionally and epigenetically repressed. Interestingly, open chromatin in hSSCs was strikingly enriched in binding sites for pioneer factors (NFYA/B, DMRT1, and hormone receptors). Remarkably, single-cell RNA-seq clustering analysis identified four cellular/developmental states during hSSC differentiation, involving major transitions in cell-cycle and transcriptional regulators, splicing and signaling factors, and glucose/mitochondria regulators. Overall, our results outline the dynamic chromatin/transcription landscape operating in hSSCs and identify crucial molecular pathways that accompany the transition from quiescence to proliferation and differentiation.

  • 37.
    Guo, Jingtao
    et al.
    Univ Utah, Howard Hughes Med Inst, Dept Oncol Sci, Sch Med, Salt Lake City, UT 84112 USA;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA;Univ Utah, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Androl Lab,Hlth Sci Ctr, Salt Lake City, UT 84112 USA.
    Nie, Xichen
    Univ Utah, Howard Hughes Med Inst, Dept Oncol Sci, Sch Med, Salt Lake City, UT 84112 USA;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA.
    Giebler, Maria
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Mlcochova, Hana
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Wang, Yueqi
    Columbia Univ, Dept Comp Sci, New York, NY 10027 USA.
    Grow, Edward J.
    Univ Utah, Howard Hughes Med Inst, Dept Oncol Sci, Sch Med, Salt Lake City, UT 84112 USA;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA.
    Kim, Robin
    Univ Utah, Dept Surg, Sect Transplantat, Sch Med, Salt Lake City, UT 84132 USA.
    Tharmalingam, Melissa
    Univ Edinburgh, MRC Ctr Reprod Hlth, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland;Royal Hosp Children & Young People, Edinburgh EH9 1LF, Midlothian, Scotland.
    Matilionyte, Gabriele
    Univ Edinburgh, MRC Ctr Reprod Hlth, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland;Royal Hosp Children & Young People, Edinburgh EH9 1LF, Midlothian, Scotland.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Carrell, Douglas T.
    Univ Utah, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Androl Lab,Hlth Sci Ctr, Salt Lake City, UT 84112 USA.
    Mitchell, Rod T.
    Univ Edinburgh, MRC Ctr Reprod Hlth, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland;Royal Hosp Children & Young People, Edinburgh EH9 1LF, Midlothian, Scotland.
    Goriely, Anne
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Hotaling, James M.
    Univ Utah, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Androl Lab,Hlth Sci Ctr, Salt Lake City, UT 84112 USA.
    Cairns, Bradley R.
    Univ Utah, Howard Hughes Med Inst, Dept Oncol Sci, Sch Med, Salt Lake City, UT 84112 USA;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA.
    The Dynamic Transcriptional Cell Atlas of Testis Development during Human Puberty2020Inngår i: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 26, nr 2, s. 262-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of similar to 10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.

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  • 38. Haggmark, Anna
    et al.
    Hamsten, Carl
    Wiklundh, Emil
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mattsson, Cecilia
    Andersson, Eni
    Lundberg, Ingrid E.
    Gronlund, Hans
    Schwenk, Jochen M.
    Eklund, Anders
    Grunewald, Johan
    Nilsson, Peter
    Proteomic Profiling Reveals Autoimmune Targets in Sarcoidosis2015Inngår i: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 191, nr 5, s. 574-583Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rationale: There is a need to further characterize the antibody repertoire in relation to sarcoidosis and potentially related autoantigens. Objectives: We investigated bronchoalveolar lavage (BAL) and serum samples from patients with sarcoidosis and healthy and diseased control subjects to discover sarcoidosis-associated autoantigens. Methods: Antigen microarrays built on 3,072 protein fragments were used to screen for IgG reactivity in 73 BAL samples from subjects with sarcoidosis, subjects with asthma, and healthy subjects. A set of 131 targets were selected for subsequent verification on suspension bead arrays using 272 additional BAL samples and 141 paired sera. Reactivity to four antigens was furthermore analyzed in 22 unprocessed BAL samples from patients with fibrosis and 269 plasma samples from patients diagnosed with myositis. Measurements and Main Results: Reactivity toward zinc finger protein 688 and mitochondrial ribosomal protein L43 were discovered with higher frequencies in patients with sarcoidosis, for mitochondrial ribosomal protein L43 especially in patients with non-Lofgren syndrome. Increased reactivity toward nuclear receptor coactivator 2 was also observed in patients with non-Lofgren syndrome as compared with patients with Lofgren syndrome. The antigen representing adenosine diphosphate-ribosylation factor GTPase activating protein 1 revealed high reactivity frequency in all sample groups but with significantly higher level of IgG reactivities in patients with sarcoidosis. Conclusions: Autoantigen reactivity was present in most BAL and serum samples analyzed, and the results revealed high interindividual heterogeneity, with most of the reactivities observed in single individuals only. Four proteins are here proposed as sarcoidosis-associated autoimmune targets and of interest for further validation in independent cohorts.

  • 39.
    Hamsten, C.
    et al.
    Immunology and Allergy Unit; Department of Medicine Solna; Karolinska Institutet; and Karolinska University Hospital;Center for Inflammatory Diseases; Karolinska Institutet; Stockholm Sweden.
    Häggmark, A.
    Affinity Proteomics; SciLifeLab; School of Biotechnology; KTH-Royal Institute of Technology; Stockholm Sweden.
    Grundström, J.
    Immunology and Allergy Unit; Department of Medicine Solna; Karolinska Institutet; and Karolinska University Hospital.
    Mikus, M.
    Affinity Proteomics; SciLifeLab; School of Biotechnology; KTH-Royal Institute of Technology; Stockholm Sweden.
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin. SciLifeLab; Department of Immunology; Genetics and Pathology; Uppsala University; Uppsala Sweden.
    Konradsen, J. R.
    Astrid Lindgren Children's Hospital; Karolinska University Hospital; Stockholm Sweden;Department of Women's and Children's Health; Karolinska Institutet; Stockholm Sweden.
    Eklund, A.
    Respiratory Medicine Unit; Department of Medicine Solna and CMM; Karolinska Institutet and Karolinska University Hospital; Stockholm Sweden.
    Pershagen, G.
    Institute of Environmental Medicine; Karolinska Institutet; Stockholm Sweden.
    Wickman, M.
    Institute of Environmental Medicine; Karolinska Institutet; Stockholm Sweden;Sachs’ Children and Youth Hospital; Södersjukhuset; Stockholm Sweden.
    Grunewald, J.
    Respiratory Medicine Unit; Department of Medicine Solna and CMM; Karolinska Institutet and Karolinska University Hospital; Stockholm Sweden.
    Melén, E.
    Institute of Environmental Medicine; Karolinska Institutet; Stockholm Sweden;Sachs’ Children and Youth Hospital; Södersjukhuset; Stockholm Sweden.
    Hedlin, G.
    Astrid Lindgren Children's Hospital; Karolinska University Hospital; Stockholm Sweden;Department of Women's and Children's Health; Karolinska Institutet; Stockholm Sweden.
    Nilsson, P.
    Affinity Proteomics; SciLifeLab; School of Biotechnology; KTH-Royal Institute of Technology; Stockholm Sweden.
    van Hage, M.
    Immunology and Allergy Unit; Department of Medicine Solna; Karolinska Institutet; and Karolinska University Hospital.
    Protein profiles of CCL5, HPGDS, and NPSR1 in plasma reveal association with childhood asthma2016Inngår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 71, nr 9, s. 1357-1361Artikkel i tidsskrift (Fagfellevurdert)
  • 40.
    Hikmet Noraddin, Feria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Rassy, Marc
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Méar, Loren
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Yale Univ, Sch Med, Dept Med Med Oncol, New Haven, CT USA..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer2023Inngår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 17, nr 12, s. 2603-2617Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.

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  • 41.
    Huang, Dan
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Damdimopoulos, Anastasios
    Karolinska Inst, Dept Biosci & Nutr, Bioinformat & Express Core Facil, SE-14183 Huddinge, Sweden..
    Antonson, Per
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Okret, Sam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma-Possible Estrogen Effects2023Inngår i: Cancers, ISSN 2072-6694, Vol. 15, nr 4, artikkel-id 1298Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Simple Summary Females show a favorable sex difference in incidence as well as in survival for many cancer types, so also in lymphoma. The reasons for this are unknown. We have therefore analyzed global gene expression in a large cohort of the most common lymphoma type, diffuse large B-cell lymphoma. We show that many genes are differentially expressed between males and females. Furthermore, the results demonstrate sex-dependent differences in gene expression between DLBCL subtypes. In addition, gene expression differs in pre- vs. postmenopausal women suggesting that estrogen regulation of genes is involved. Thus, estrogens may contribute to the sex and female age differences in incidence and prognosis observed. For most lymphomas, including diffuse large B-cell lymphoma (DLBCL), the male incidence is higher, and the prognosis is worse compared to females. The reasons are unclear; however, epidemiological and experimental data suggest that estrogens are involved. With this in mind, we analyzed gene expression data from a publicly available cohort (EGAD00001003600) of 746 DLBCL samples based on RNA sequencing. We found 1293 genes to be differentially expressed between males and females (adj. p-value < 0.05). Few autosomal genes and pathways showed common sex-regulated expression between germinal center B-cell (GCB) and activated B-cell lymphoma (ABC) DLBCL. Analysis of differentially expressed genes between pre- vs. postmenopausal females identified 208 GCB and 345 ABC genes, with only 5 being shared. When combining the differentially expressed genes between females vs. males and pre- vs. postmenopausal females, nine putative estrogen-regulated genes were identified in ABC DLBCL. Two of them, NR4A2 and MUC5B, showed induced and repressed expression, respectively. Interestingly, NR4A2 has been reported as a tumor suppressor in lymphoma. We show that ABC DLBCL females with a high NR4A2 expression showed better survival. Inversely, MUC5B expression causes a more malignant phenotype in several cancers. NR4A2 and MUC5B were confirmed to be estrogen-regulated when the ABC cell line U2932 was grafted to mice. The results demonstrate sex- and female reproductive age-dependent differences in gene expression between DLBCL subtypes, likely due to estrogens. This may contribute to the sex differences in incidence and prognosis.

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  • 42.
    Jain, Yashvardhan
    et al.
    Indiana Univ, Luddy Sch Informat Comp & Engn, Dept Intelligent Syst Engn, Bloomington, IN 47408 USA..
    Godwin, Leah L.
    Indiana Univ, Luddy Sch Informat Comp & Engn, Dept Intelligent Syst Engn, Bloomington, IN 47408 USA..
    Joshi, Sripad
    Indiana Univ, Luddy Sch Informat Comp & Engn, Dept Intelligent Syst Engn, Bloomington, IN 47408 USA..
    Mandarapu, Shriya
    Indiana Univ, Luddy Sch Informat Comp & Engn, Dept Intelligent Syst Engn, Bloomington, IN 47408 USA..
    Le, Trang
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Stockholm, Sweden.;Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Lundberg, Emma
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Stockholm, Sweden.;Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.;Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.;Chan Zuckerberg Biohub, San Francisco, CA 94305 USA..
    Börner, Katy
    Indiana Univ, Luddy Sch Informat Comp & Engn, Dept Intelligent Syst Engn, Bloomington, IN 47408 USA..
    Segmenting functional tissue units across human organs using community-driven development of generalizable machine learning algorithms2023Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, artikkel-id 4656Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Constructing the human reference atlas requires integration and analysis of massive amounts of data. Here the authors report the setup and results of the Hacking the Human Body machine learning algorithm development competition hosted by the Human Biomolecular Atlas and the Human Protein Atlas teams. The development of a reference atlas of the healthy human body requires automated image segmentation of major anatomical structures across multiple organs based on spatial bioimages generated from various sources with differences in sample preparation. We present the setup and results of the Hacking the Human Body machine learning algorithm development competition hosted by the Human Biomolecular Atlas (HuBMAP) and the Human Protein Atlas (HPA) teams on the Kaggle platform. We create a dataset containing 880 histology images with 12,901 segmented structures, engaging 1175 teams from 78 countries in community-driven, open-science development of machine learning models. Tissue variations in the dataset pose a major challenge to the teams which they overcome by using color normalization techniques and combining vision transformers with convolutional models. The best model will be productized in the HuBMAP portal to process tissue image datasets at scale in support of Human Reference Atlas construction.

    Fulltekst (pdf)
    FULLTEXT01
  • 43.
    Jamin, Soazik P.
    et al.
    Univ Rennes, INSERM, EHESP, Irset Inst Rech Sante Environm & Travail,UMR S, Rennes, France..
    Hikmet, Feria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mathieu, Romain
    Univ Rennes, INSERM, EHESP, Irset Inst Rech Sante Environm & Travail,UMR S, Rennes, France.;Univ Hosp, Dept Urol, Rennes, France..
    Jégou, Bernard
    Univ Rennes, INSERM, EHESP, Irset Inst Rech Sante Environm & Travail,UMR S, Rennes, France..
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Chalmel, Frédéric
    Univ Rennes, INSERM, EHESP, Irset Inst Rech Sante Environm & Travail,UMR S, Rennes, France..
    Primig, Michael
    Univ Rennes, INSERM, EHESP, Irset Inst Rech Sante Environm & Travail,UMR S, Rennes, France..
    Combined RNA/tissue profiling identifies novel Cancer/testis genes2021Inngår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 15, nr 11, s. 3003-3023Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer/Testis (CT) genes are induced in germ cells, repressed in somatic cells, and derepressed in somatic tumors, where these genes can contribute to cancer progression. CT gene identification requires data obtained using standardized protocols and technologies. This is a challenge because data for germ cells, gonads, normal somatic tissues, and a wide range of cancer samples stem from multiple sources and were generated over substantial periods of time. We carried out a GeneChip-based RNA profiling analysis using our own data for testis and enriched germ cells, data for somatic cancers from the Expression Project for Oncology, and data for normal somatic tissues from the Gene Omnibus Repository. We identified 478 candidate loci that include known CT genes, numerous genes associated with oncogenic processes, and novel candidates that are not referenced in the Cancer/Testis Database (). We complemented RNA expression data at the protein level for SPESP1, GALNTL5, PDCL2, and C11orf42 using cancer tissue microarrays covering malignant tumors of breast, uterus, thyroid, and kidney, as well as published RNA profiling and immunohistochemical data provided by the Human Protein Atlas (). We report that combined RNA/tissue profiling identifies novel CT genes that may be of clinical interest as therapeutical targets or biomarkers. Our findings also highlight the challenges of detecting truly germ cell-specific mRNAs and the proteins they encode in highly heterogenous testicular, somatic, and tumor tissues.

    Fulltekst (pdf)
    fulltext
  • 44.
    Karlsson, Max
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Sjöstedt, Evelina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Oksvold, Per
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Sivertsson, Asa
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Huang, Jinrong
    BGI Shenzhen, Shenzhen, Peoples R China.;BGI Qingdao, Qingdao Europe Adv Inst Life Sci, Lars Bolund Inst Regenerat Med, Qingdao, Peoples R China.;Aarhus Univ, Dept Biomed, Aarhus, Denmark..
    Alvez, Maria Bueno
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Arif, Muhammad
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Li, Xiangyu
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Lin, Lin
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.;Aarhus Univ Hosp, Steno Diabet Ctr Aarhus, Aarhus, Denmark..
    Yu, Jiaying
    BGI Shenzhen, Shenzhen, Peoples R China.;BGI Qingdao, Qingdao Europe Adv Inst Life Sci, Lars Bolund Inst Regenerat Med, Qingdao, Peoples R China..
    Ma, Tao
    BGI Shenzhen, MGI, Shenzhen, Peoples R China..
    Xu, Fengping
    BGI Shenzhen, Shenzhen, Peoples R China.;BGI Qingdao, Qingdao Europe Adv Inst Life Sci, Lars Bolund Inst Regenerat Med, Qingdao, Peoples R China..
    Han, Peng
    BGI Qingdao, Qingdao Europe Adv Inst Life Sci, Lars Bolund Inst Regenerat Med, Qingdao, Peoples R China..
    Jiang, Hui
    BGI Shenzhen, MGI, Shenzhen, Peoples R China..
    Mardinoglu, Adil
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Zhang, Cheng
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Xu, Xun
    BGI Shenzhen, Shenzhen, Peoples R China..
    Wang, Jian
    BGI Shenzhen, Shenzhen, Peoples R China..
    Yang, Huanming
    BGI Shenzhen, Shenzhen, Peoples R China..
    Bolund, Lars
    BGI Shenzhen, Shenzhen, Peoples R China.;BGI Qingdao, Qingdao Europe Adv Inst Life Sci, Lars Bolund Inst Regenerat Med, Qingdao, Peoples R China.;Aarhus Univ, Dept Biomed, Aarhus, Denmark..
    Zhong, Wen
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Fagerberg, Linn
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pontén, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Luo, Yonglun
    BGI Shenzhen, Shenzhen, Peoples R China.;BGI Qingdao, Qingdao Europe Adv Inst Life Sci, Lars Bolund Inst Regenerat Med, Qingdao, Peoples R China.;Aarhus Univ, Dept Biomed, Aarhus, Denmark.;Aarhus Univ Hosp, Steno Diabet Ctr Aarhus, Aarhus, Denmark..
    Uhlen, Mathias
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Genome-wide annotation of protein-coding genes in pig2022Inngår i: BMC Biology, E-ISSN 1741-7007, Vol. 20, nr 1, artikkel-id 25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There is a need for functional genome-wide annotation of the protein-coding genes to get a deeper understanding of mammalian biology. Here, a new annotation strategy is introduced based on dimensionality reduction and density-based clustering of whole-body co-expression patterns. This strategy has been used to explore the gene expression landscape in pig, and we present a whole-body map of all protein-coding genes in all major pig tissues and organs. Results: An open-access pig expression map (www.rnaatlas.org ) is presented based on the expression of 350 samples across 98 well-defined pig tissues divided into 44 tissue groups. A new UMAP-based classification scheme is introduced, in which all protein-coding genes are stratified into tissue expression clusters based on body-wide expression profiles. The distribution and tissue specificity of all 22,342 protein-coding pig genes are presented. Conclusions: Here, we present a new genome-wide annotation strategy based on dimensionality reduction and density-based clustering. A genome-wide resource of the transcriptome map across all major tissues and organs in pig is presented, and the data is available as an open-access resource (www.rnaatlas.org), including a comparison to the expression of human orthologs.

    Fulltekst (pdf)
    FULLTEXT01
  • 45.
    Karlsson, Max
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Zhang, Cheng
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Méar, Loren
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Zhong, Wen
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Digre, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Katona, Borbala
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sjöstedt, Evelina
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Butler, Lynn
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Karolinska Univ Lab, Clin Chem, Stockholm, Sweden.;Arctic Univ Norway, Dept Clin Med, Tromso, Norway..
    Odeberg, Jacob
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden.;Arctic Univ Norway, Dept Clin Med, Tromso, Norway..
    Dusart, Philip
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden.;Arctic Univ Norway, Dept Clin Med, Tromso, Norway..
    Edfors, Fredrik
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Oksvold, Per
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Zwahlen, Martin
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Arif, Muhammad
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Altay, Ozlem
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Li, Xiangyu
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Ozcan, Mehmet
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Mardonoglu, Adil
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Fagerberg, Linn
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden..
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Luo, Yonglun
    BGI Qingdao, BGI Shenzhen, Lars Bolund Inst Regenerat Med & Qingdao Europe A, Qingdao, Peoples R China.;Aarhus Univ, Dept Biomed, Aarhus, Denmark..
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Uhlen, Mathias
    KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    A single-cell type transcriptomics map of human tissues2021Inngår i: Science Advances, E-ISSN 2375-2548, Vol. 7, nr 31, artikkel-id eabh2169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Advances in molecular profiling have opened up the possibility to map the expression of genes in cells, tissues, and organs in the human body. Here, we combined single-cell transcriptomics analysis with spatial antibody-based protein profiling to create a high-resolution single-cell type map of human tissues. An open access atlas has been launched to allow researchers to explore the expression of human protein-coding genes in 192 individual cell type clusters. An expression specificity classification was performed to determine the number of genes elevated in each cell type, allowing comparisons with bulk transcriptomics data. The analysis highlights distinct expression clusters corresponding to cell types sharing similar functions, both within the same organs and between organs.

    Fulltekst (pdf)
    fulltext
  • 46.
    Katona, Borbala
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    The Human Protein Atlas and Antibody-Based Tissue Profiling in Clinical Proteomics2022Inngår i: Clinical Proteomics: Methods and protocols / [ed] Corrales, Fernando J; Paradela, Alberto; Marcilla, Miguel, Humana Press, 2022, s. 191-206Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Immunohistochemistry (IHC) is a standard method for spatial proteomics and allows for exploration of protein expression at single-cell resolution within the intact tissue environment. Stringent procedures and proper antibody validation strategies are however needed to ensure reliability of results. Application-specific strategies have been proposed by the scientific community to ensure high quality despite variations in sample preparation between different antibody-based methods. Here, the entire workflow utilized within the Human Protein Atlas, from sample preparation to annotation of the IHC staining patterns is described in detail, with important notes on various factors that can affect the outcome of IHC. Methods include tissue microarray (TMA) production, tissue sectioning, IHC, annotation, and validation. Also, building on previously suggested validation strategies, IHC-specific orthogonal and independent validation methods are outlined.

  • 47.
    Keller, Magdalena
    et al.
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Rohlf, Katharina
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Glotzbach, Annika
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Leonhardt, Gregor
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Lueke, Simon
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Derksen, Katharina
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Demirci, Özlem
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Göcener, Defne
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    AlWahsh, Mohammad
    Leibniz Inst Analyt Wissensch ISAS EV, Dortmund, Germany.;Heidelberg Univ, Inst Pathol, Mannheim, Germany.;Heidelberg Univ, Univ Med Ctr Mannheim, Med Res Ctr ZMF, Mannheim, Germany.;AlZaytoonah Univ Jordan, Dept Pharm, Amman, Jordan..
    Lambert, Jörg
    Leibniz Inst Analyt Wissensch ISAS EV, Dortmund, Germany..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Schmidt, Marcus
    Univ Med Ctr Mainz, Dept Obstet & Gynecol, Mainz, Germany..
    Brenner, Walburgis
    Univ Med Ctr Mainz, Dept Obstet & Gynecol, Mainz, Germany..
    Baumann, Matthias
    Lead Discovery Ctr, Pharmacol Dept, Dortmund, Germany..
    Zent, Eldar
    Lead Discovery Ctr, Pharmacol Dept, Dortmund, Germany..
    Zischinsky, Mia-Lisa
    Lead Discovery Ctr, Pharmacol Dept, Dortmund, Germany..
    Hellwig, Birte
    TU Dortmund Univ, Dept Stat, Dortmund, Germany..
    Madjar, Katrin
    TU Dortmund Univ, Dept Stat, Dortmund, Germany..
    Rahnenführer, Jörg
    TU Dortmund Univ, Dept Stat, Dortmund, Germany..
    Overbeck, Nina
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Reinders, Jörg
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Cadenas, Cristina
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Hengstler, Jan. G. G.
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Edlund, Karolina
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Marchan, Rosemarie
    TU Dortmund IfADo, Leibniz Res Ctr Working Environm & Human Factors, Ardeystr 67, D-44139 Dortmund, Germany..
    Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth2023Inngår i: Journal of Experimental & Clinical Cancer Research, E-ISSN 1756-9966, Vol. 42, artikkel-id 25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Intrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored.

    Methods: EDI3 mRNA and protein expression in human breast cancer tissue were investigated using publicly-available Affymetrix gene expression microarray datasets (n = 540) and with immunohistochemistry on a tissue microarray (n = 265), respectively. A panel of breast cancer cell lines of different molecular subtypes were used to investigate expression and activity of EDI3 in vitro. To determine whether EDI3 expression is regulated by HER2 signalling, the effect of pharmacological inhibition and siRNA silencing of HER2, as well as the influence of inhibiting key components of signalling cascades downstream of HER2 were studied. Finally, the influence of silencing and pharmacologically inhibiting EDI3 on viability was investigated in vitro and on tumour growth in vivo.

    Results: In the present study, we show that EDI3 expression is highest in ER-HER2 + human breast tumours, and both expression and activity were also highest in ER-HER2 + breast cancer cell lines. Silencing HER2 using siRNA, as well as inhibiting HER2 signalling with lapatinib decreased EDI3 expression. Pathways downstream of PI3K/Akt/mTOR and GSK3 beta, and transcription factors, including HIF1 alpha, CREB and STAT3 were identified as relevant in regulating EDI3 expression. Silencing EDI3 preferentially decreased cell viability in the ER-HER2 + cells. Furthermore, silencing or pharmacologically inhibiting EDI3 using dipyridamole in ER-HER2 + cells resistant to HER2-targeted therapy decreased cell viability in vitro and tumour growth in vivo.

    Conclusions: Our results indicate that EDI3 may be a potential novel therapeutic target in patients with HER2-targeted therapy-resistant ER-HER2 + breast cancer that should be further explored.

    Fulltekst (pdf)
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  • 48. Larsson, K.
    et al.
    Hofstrom, C.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Hansson, M.
    Angelidou, P.
    Hokfelt, T.
    Uhlen, M.
    Wernerus, H.
    Graslund, T.
    Hober, S.
    Novel antigen design for the generation of antibodies to G-protein-coupled receptors2011Inngår i: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 370, nr 1-2, s. 14-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Antibodies are important tools for the study of G-protein-coupled receptors, key proteins in cellular signaling. Due to their large hydrophobic membrane spanning regions and often very short loops exposed on the surface of the cells, generation of antibodies able to recognize the receptors in the endogenous environment has been difficult. Here, we describe an antigen-design method where the extracellular loops and N-terminus are combined to a single antigen for generation of antibodies specific to three selected GPCRs: NPY5R, B2ARN and GLP1R. The design strategy enabled straightforward antigen production and antibody generation. Binding of the antibodies to intact receptors was analyzed using flow cytometry and immunofluorescence based confocal microscopy on A-431 cells overexpressing the respective GPCR. The antibody-antigen interactions were characterized using epitope mapping, and the antibodies were applied in immunohistochemical staining of human tissues. Most of the antibodies showed specific binding to their respective overexpressing cell line but not to the non-transfected cells, thus indicating binding to their respective target receptor. The epitope mapping showed that sub-populations within the purified antibody pool recognized different regions of the antigen. Hence, the genetic combination of several different epitopes enables efficient generation of specific antibodies with potential use in several applications for the study of endogenous receptors.

  • 49.
    Lesage, Adrien
    et al.
    Nantes Univ, Inst Thorax, CNRS, Inserm, Nantes, France..
    Lorenzini, Maxime
    Nantes Univ, Inst Thorax, CNRS, Inserm, Nantes, France..
    Burel, Sophie
    Nantes Univ, Inst Thorax, CNRS, Inserm, Nantes, France..
    Sarlandie, Marine
    Nantes Univ, Inst Thorax, CNRS, Inserm, Nantes, France..
    Bibault, Floriane
    Nantes Univ, Inst Thorax, CNRS, Inserm, Nantes, France..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Maloney, Daniel
    Bioinformat Solut Inc, Waterloo, ON, Canada..
    Silva, Jonathan R.
    Washington Univ, Dept Biomed Engn, St Louis, MO USA..
    Townsend, R. Reid
    Washington Univ, Dept Cell Biol & Physiol, Med Sch, St Louis, MO USA.;Washington Univ, Dept Med, Med Sch, St Louis, MO USA..
    Nerbonne, Jeanne M.
    Washington Univ, Dept Biomed Engn, St Louis, MO USA.;Washington Univ, Dept Med, Med Sch, St Louis, MO USA.;Washington Univ, Dept Dev Biol, Med Sch, St Louis, MO USA..
    Marionneau, Celine
    Nantes Univ, Inst Thorax, CNRS, Inserm, Nantes, France..
    Determinants of iFGF13-mediated regulation of myocardial voltage-gated sodium (NaV) channels in mouse2023Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 155, nr 9, artikkel-id e202213293Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Posttranslational regulation of cardiac Na(V)1.5 channels is critical in modulating channel expression and function, yet their regulation by phosphorylation of accessory proteins has gone largely unexplored. Using phosphoproteomic analysis of Na-V channel complexes from adult mouse left ventricles, we identified nine phosphorylation sites on intracellular fibroblast growth factor 13 (iFGF13). To explore the potential roles of these phosphosites in regulating cardiac NaV currents, we abolished expression of iFGF13 in neonatal and adult mouse ventricular myocytes and rescued it with wild-type (WT), phosphosilent, or phosphomimetic iFGF13-VY. While the increased rate of closed-state inactivation of NaV channels induced by Fgf13 knockout in adult cardiomyocytes was completely restored by adenoviral-mediated expression of WT iFGF13-VY, only partial rescue was observed in neonatal cardiomyocytes after knockdown. The knockdown of iFGF13 in neonatal ventricular myocytes also shifted the voltage dependence of channel activation toward hyperpolarized potentials, a shift that was not reversed by WT iFGF13-VY expression. Additionally, we found that iFGF13-VY is the predominant isoform in adult ventricular myocytes, whereas both iFGF13-VY and iFGF13-S are expressed comparably in neonatal ventricular myocytes. Similar to WT iFGF13-VY, each of the iFGF13-VY phosphomutants studied restored NaV channel inactivation properties in both models. Lastly, Fgf13 knockout also increased the late Na+ current in adult cardiomyocytes, and this effect was restored with expression of WT and phosphosilent iFGF13-VY. Together, our results demonstrate that iFGF13 is highly phosphorylated and displays differential isoform expression in neonatal and adult ventricular myocytes. While we found no roles for iFGF13 phosphorylation, our results demonstrate differential effects of iFGF13 on neonatal and adult mouse ventricular NaV channels.

  • 50.
    Lindskog Bergström, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Tissue Microarrays for Analysis of Expression Patterns2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Proteins are essential building blocks in every living cell, and since the complete human genome was sequenced in 2004, researchers have attempted to map the human proteome, which is the functional representation of the genome. One such initiative is the Human Protein Atlas programme (HPA), which generates monospecific antibodies towards all human proteins and uses these for high-throughput tissue profiling on tissue microarrays (TMAs). The results are publically available at the website www.proteinatlas.org.

    In this thesis, TMAs were used for analysis of expression patterns in various research areas. Different search queries in the HPA were tested and evaluated, and a number of potential biomarkers were identified, e.g. proteins exclusively expressed in islets of Langerhans, but not in exocrine glandular cells or other abdominal organs close to pancreas. The identified candidates were further analyzed on TMAs with pancreatic tissues from normal and diabetic individuals, and colocalization studies with insulin and glucagon revealed that several of the investigated proteins (DGCR2, GBF1, GPR44 and SerpinB10) appeared to be beta cell specific. Moreover, a set of proteins differentially expressed in lung cancer stroma was further analyzed on a clinical lung cancer cohort in the TMA format, and one protein (CD99) was significantly associated with survival. In addition, TMAs with tissue samples from different species were generated, e.g. for mapping of influenza virus attachment in various human and avian tissues. The results showed that the gull influenza virus H16N3 attached to human respiratory tract and eye, suggesting possible transmission of the virus between gull and human. TMAs were also used for analysis of protein expression differences between humans and other primates, and two proteins (TCF3 and SATB2) proved to be significantly differentially expressed on the human lineage at both the protein level and the RNA level.  

    In conclusion, this thesis exemplifies the potential of the TMA technology, which can be used for analysis of expression patterns in a large variety of research fields, such as biomarker discovery, influenza virus research or further understanding of human evolution.

    Delarbeid
    1. A web-based tool for in silico biomarker discovery based on tissue-specific protein profiles in normal and cancer tissues
    Åpne denne publikasjonen i ny fane eller vindu >>A web-based tool for in silico biomarker discovery based on tissue-specific protein profiles in normal and cancer tissues
    Vise andre…
    2008 (engelsk)Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 7, nr 5, s. 825-844Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Here we report the development of a publicly available Web-based analysis tool for exploring proteins expressed in a tissue- or cancer-specific manner. The search queries are based on the human tissue profiles in normal and cancer cells in the Human Protein Atlas portal and rely on the individual annotation performed by pathologists of images representing immunohistochemically stained tissue sections. Approximately 1.8 million images representing more than 3000 antibodies directed toward human proteins were used in the study. The search tool allows for the systematic exploration of the protein atlas to discover potential protein biomarkers. Such biomarkers include tissue-specific markers, cell type-specific markers, tumor type-specific markers, markers of malignancy, and prognostic or predictive markers of cancers. Here we show examples of database queries to generate sets of candidate biomarker proteins for several of these different categories. Expression profiles of candidate proteins can then subsequently be validated by examination of the underlying high resolution images. The present study shows examples of search strategies revealing several potential protein biomarkers, including proteins specifically expressed in normal cells and in cancer cells from specified tumor types. The lists of candidate proteins can be used as a starting point for further validation in larger patient cohorts using both immunological approaches and technologies utilizing more classical proteomics tools.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-103798 (URN)10.1074/mcp.M700411-MCP200 (DOI)000255830200001 ()17913849 (PubMedID)
    Tilgjengelig fra: 2009-05-20 Laget: 2009-05-20 Sist oppdatert: 2017-12-13
    2. Antibody-based proteomics for discovery and exploration of proteins expressed in pancreatic islets
    Åpne denne publikasjonen i ny fane eller vindu >>Antibody-based proteomics for discovery and exploration of proteins expressed in pancreatic islets
    Vise andre…
    2010 (engelsk)Inngår i: Discovery Medicine, ISSN 1539-6509, E-ISSN 1944-7930, Vol. 9, nr 49, s. 565-578Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Abnormal glucose tolerance and deviant blood glucose levels are late stage clinical parameters that signify diabetes mellitus. To be able to diagnose the disease at an earlier stage and develop new tools for beta cell imaging, new molecular markers are needed. In the present study, five proteins highly expressed in pancreatic islets with no expression in the surrounding exocrine glandular cells of pancreas, and one protein with the opposite expression pattern, were identified by searches in the Human Protein Atlas (www.proteinatlas.org). The proteins were analyzed immunohistochemically on a specially designed tissue microarray, containing isolated human islets and pancreatic tissues with different characteristics, and compared to the expression of previously known markers of endocrine and exocrine pancreatic cells. Of the five novel endocrine markers, tetraspanin-7 was identified as a membrane-bound protein with exclusive positivity in islet cells. Also beta-2-microglobulin and ubiquitin carboxyl-terminal hydrolase isozyme L1 were expressed in a majority of islet cells, whereas sad1/unc-84 domain-containing protein 1 and beta-1,3-glucuronyltransferase 1 were positive in a smaller subset of islet cells. The potential exocrine marker galectin-2 was expressed in both exocrine acinary cells and pancreatic ductal cells, with no or low positivity in islet cells. In conclusion, antibody-based proteomics and specially designed tissue microarrays enable identification and exploration of novel proteins with differential expression in pancreatic islets. Here we describe 5 candidate proteins for further investigation of their physiological role and potential involvement in the pathogenesis of diabetes. One of these proteins, tetraspanin-7, is expressed on the cell membrane and could thus be a potential candidate for future development of tracers for beta cell imaging.

    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-153099 (URN)000208638200011 ()20587347 (PubMedID)
    Tilgjengelig fra: 2011-05-05 Laget: 2011-05-05 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    3. Novel pancreatic beta cell-specific proteins: Antibody-based proteomics for identification of new biomarker candidates
    Åpne denne publikasjonen i ny fane eller vindu >>Novel pancreatic beta cell-specific proteins: Antibody-based proteomics for identification of new biomarker candidates
    Vise andre…
    2012 (engelsk)Inngår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, nr 9, s. 2611-2620Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Beta cell-specific surface targets are required for non-invasive monitoring of beta cell mass, which could be used for evaluation of new diabetes treatments as well as to help unravel pathogenic mechanisms underlying beta cell dysfunction. By antibody-based proteomics, we have identified and explored a set of islet cell-specific proteins. A search algorithm in the Human Protein Atlas was set up for identification of islet-specific proteins that yielded 27 hits, of which twelve showed a clear membranous expression pattern or had predicted transmembrane regions. The specificity of the identified proteins was investigated by immunohistochemical staining of pancreas sections from diabetic and non-diabetic subjects. No expression of these antigens could be detected in the exocrine pancreas. Colocalization with insulin and glucagon was further determined by confocal microscopy using isolated human islets. All antibodies specifically stained human islets and colocalization analysis revealed that four proteins were exclusively expressed in beta cells. Importantly, these antibodies were negative in sections from subjects with long-standing type 1 diabetes. In the present study, we present four proteins; DGCR2, GBF1, GPR44 and SerpinB10, the expression of which has not previously been described in beta cells.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-175948 (URN)10.1016/j.jprot.2012.03.008 (DOI)000304634000009 ()22465717 (PubMedID)
    Tilgjengelig fra: 2012-06-14 Laget: 2012-06-14 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    4. CD99 is a novel prognostic stromal marker in non-small cell lung cancer
    Åpne denne publikasjonen i ny fane eller vindu >>CD99 is a novel prognostic stromal marker in non-small cell lung cancer
    Vise andre…
    2012 (engelsk)Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, nr 10, s. 2264-2273Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC, VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p=0.037) and multivariate (p=0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells, and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p=0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.

    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-170991 (URN)10.1002/ijc.27518 (DOI)000309185300007 ()22392539 (PubMedID)
    Merknad

    Karolina Edlund and Cecilia Lindskog are shared first authors.

    Tilgjengelig fra: 2012-03-14 Laget: 2012-03-14 Sist oppdatert: 2022-01-28
    5. H16 Gull Influenza Virus Attaches to the Human Respiratory Tract and Eye
    Åpne denne publikasjonen i ny fane eller vindu >>H16 Gull Influenza Virus Attaches to the Human Respiratory Tract and Eye
    Vise andre…
    (engelsk)Inngår i: Emerging Infectious Diseases, ISSN 1080-6059Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-186270 (URN)
    Tilgjengelig fra: 2012-11-28 Laget: 2012-11-28 Sist oppdatert: 2015-10-29
    6. Analysis of Candidate Genes for Lineage-Specific Expression Changes in Humans and Primates
    Åpne denne publikasjonen i ny fane eller vindu >>Analysis of Candidate Genes for Lineage-Specific Expression Changes in Humans and Primates
    Vise andre…
    2014 (engelsk)Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, nr 8, s. 3596-3606Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    RUNX2, a gene involved in skeletal development, has previously been shown to be potentially affected by positive selection during recent human evolution. Here we have used antibody-based proteomics to characterize potential differences in expression patterns of RUNX2 interacting partners during primate evolution. Tissue microarrays consisting of a large set of normal tissues from human and macaque were used for protein profiling of 50 RUNX2 partners with immunohistochemistry. Eleven proteins (AR, CREBBP, EP300, FGF2, HDAC3, JUN, PRKD3, RUNX1, SATB2, TCF3, and YAP1) showed differences in expression between humans and macaques. These proteins were further profiled in tissues from chimpanzee, gorilla, and orangutan, and the corresponding genes were analyzed with regard to genomic features. Moreover, protein expression data were compared with previously obtained RNA sequencing data from six different organs. One gene (TCF3) showed significant expression differences between human and macaque at both the protein and RNA level, with higher expression in a subset of germ cells in human testis compared with macaque. In conclusion, normal tissues from macaque and human showed differences in expression of some RUNX2 partners that could be mapped to various defined cell types. The applied strategy appears advantageous to characterize the consequences of altered genes selected during evolution.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-186271 (URN)10.1021/pr500045f (DOI)000339983600010 ()
    Tilgjengelig fra: 2012-11-28 Laget: 2012-11-28 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    Fulltekst (pdf)
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