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  • 201.
    Posautz, Annika
    et al.
    Univ Vet Med, Austria..
    Kuebber-Heiss, Anna
    Univ Vet Med, Austria..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Different population - different prevalence or, what is going on in the European brown hare (Lepus europaeus)2017Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, s. 142-143Artikkel i tidsskrift (Annet vitenskapelig)
  • 202.
    Posautz, Annika
    et al.
    Univ Vet Med Vienna, Res Inst Wildlife Ecol, Vienna, Austria.
    Loncaric, Igor
    Univ Vet Med Vienna, Inst Microbiol, Vienna, Austria.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Is there a connection between the microbiome and AA amyloidosis?: First hints from the European brown hare (Lepus europaeus)2019Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, nr Suppl. 1, s. 119-120Artikkel i tidsskrift (Fagfellevurdert)
  • 203.
    Posautz, Annika
    et al.
    Univ Vet Med, Res Inst Wildlife Ecol, Vienna, Austria.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Experimental transmission of AA amyloidosis in the European brown hare (Lepus europaeus) - first results2019Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, nr Suppl. 1, s. 121-122Artikkel i tidsskrift (Fagfellevurdert)
  • 204.
    Pouliou, Evi
    et al.
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece.;Univ Athens, Sch Med, Dept Pathol, Athens, Greece..
    Xochelli, Aliki
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Kanellis, George
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Stalika, Evangelia
    Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, Lesley-Ann
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Navarro, Alba
    Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain.;Univ Barcelona, Inst Biomed Res August Pi i Sunyer, Barcelona, Spain..
    Agathangelidis, Andreas
    Ist Sci San Raffaele, IRCCS, Div Mol Oncol, Milan, Italy.;Ist Sci San Raffaele, IRCCS, Dept Oncohematol, Milan, Italy.;Univ Vita Salutte San Raffaele, Milan, Italy..
    Dimosthenous, Kypros
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematopoiet Cell Transplantat Unit, Thessaloniki, Greece..
    Patsouris, Efstratios
    Univ Athens, Sch Med, Dept Pathol, Athens, Greece..
    Korkolopoulou, Penelope
    Univ Athens, Sch Med, Dept Pathol, Athens, Greece..
    Sundström, Christer
    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.
    Ghia, Paolo
    Ist Sci San Raffaele, IRCCS, Div Mol Oncol, Milan, Italy.;Ist Sci San Raffaele, IRCCS, Dept Oncohematol, Milan, Italy.;Univ Vita Salutte San Raffaele, Milan, Italy..
    Ponzoni, Maurilio
    Ist Sci San Raffaele, Milan, Italy..
    Sander, Birgitta
    Karolinska Inst, Dept Lab Med, Div Pathol, Huddinge, Sweden.;Karolinska Univ Hosp, Huddinge, Sweden..
    Campo, Elias
    Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain.;Univ Barcelona, Inst Biomed Res August Pi i Sunyer, Barcelona, Spain..
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Hadzidimitriou, Anastasia
    Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematopoiet Cell Transplantat Unit, Thessaloniki, Greece..
    Papadaki, Theodora
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Numerous Ontogenetic Roads to Mantle Cell Lymphoma: Immunogenetic and Immunohistochemical Evidence2017Inngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, nr 7, s. 1454-1458Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To obtain insight into the ontogeny of mantle cell lymphoma (MCL), we assessed 206 patients from a morphological, immunohistochemical, and immunogenetic perspective. Our series included nodal (n = 151), extranodal. (n = 28), and primary splenic (n = 27) MCL cases. Skewing of the immunoglobulin heavy variable (IGHV) gene repertoire was noted, with only four IGHV genes accounting for 46% of cases and approximately 70% of cases (107/154) bearing an imprint of somatic hypermutation (SHM) ranging from minimalto pronounced. Interestingly, a distinctive immunophenotypic and immunogenetic profile was identified for primary splenic MCL, which was enriched for DBA.44-positive cases (P < 0.001) and used the IGHV1-8 gene more frequently (P = 0.02) compared to nodal or extranodal cases, alluding to distinct immunopathogenetic and antigen selection processes. Expression of CD27 (considered a marker of activated B cells) was generally dissociated from SHM and was more prevalent in cases with no or minimal/borderline SHM. These findings support the idea that antigen drive is relevant for most MCL cases, although the specific antigens and the precise location of affinity maturation remain to be elucidated. Moreover, they raise the intriguing hypothesis of multiple cellular origins for MCL.

  • 205.
    Pozniak, Yair
    et al.
    Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-6997801 Tel Aviv, Israel..
    Balint-Lahat, Nora
    Inst Pathol, Sheba Med Ctr, IL-5265601 Tel Hashomer, Israel..
    Rudolph, Jan Daniel
    Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-6997801 Tel Aviv, Israel.;Tel Aviv Univ, Sch Comp Sci, IL-6997801 Tel Aviv, Israel..
    Lindskog, Cecilia
    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.
    Katzir, Rotem
    Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA.;Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA..
    Avivi, Camilla
    Inst Pathol, Sheba Med Ctr, IL-5265601 Tel Hashomer, Israel..
    Ponten, Fredrik
    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.
    Ruppin, Eytan
    Tel Aviv Univ, Sch Comp Sci, IL-6997801 Tel Aviv, Israel.;Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA.;Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA.;Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-6997801 Tel Aviv, Israel..
    Barshack, Iris
    Inst Pathol, Sheba Med Ctr, IL-5265601 Tel Hashomer, Israel.;Tel Aviv Univ, Sackler Fac Med, Dept Pathol, IL-6997801 Tel Aviv, Israel..
    Geiger, Tamar
    Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-6997801 Tel Aviv, Israel..
    System-wide Clinical Proteomics of Breast Cancer Reveals Global Remodeling of Tissue Homeostasis2016Inngår i: CELL SYSTEMS, ISSN 2405-4712, Vol. 2, nr 3, s. 172-184Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genomic and transcriptomic landscapes of breast cancer have been extensively studied, but the proteomes of breast tumors are far less characterized. Here, we use high-resolution, high-accuracy mass spectrometry to perform a deep analysis of luminal-type breast cancer progression using clinical breast samples from primary tumors, matched lymph node metastases, and healthy breast epithelia. We used a super-SILAC mix to quantify over 10,000 proteins with high accuracy, enabling us to identify key proteins and pathways associated with tumorigenesis and metastatic spread. We found high expression levels of proteins associated with protein synthesis and degradation in cancer tissues, accompanied by metabolic alterations that may facilitate energy production in cancer cells within their natural environment. In addition, we found proteomic differences between breast cancer stages and minor differences between primary tumors and their matched lymph node metastases. These results highlight the potential of proteomic technology in the elucidation of clinically relevant cancer signatures.

  • 206.
    Pyykko, Okko T.
    et al.
    Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland.
    Nerg, Ossi
    Kuopio Univ Hosp, Neurol NeuroCtr, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland.
    Niskasaari, Hanna-Mari
    Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland.
    Niskasaari, Timo
    Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland.
    Koivisto, Anne M.
    Kuopio Univ Hosp, Neurol NeuroCtr, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland.
    Hiltunen, Mikko
    Univ Eastern Finland, Inst Biomed, Dept Neurol, Kuopio Univ Hosp, Kuopio, Finland.
    Pihlajamaki, Jussi
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Dept Clin Nutr, Kuopio, Finland;Kuopio Univ Hosp, Clin Nutr & Obes Ctr, Kuopio, Finland.
    Rauramaa, Tuomas
    Kuopio Univ Hosp, Dept Pathol, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med Pathol, Kuopio, Finland.
    Kojoukhova, Maria
    Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Soininen, Hilkka
    Kuopio Univ Hosp, Neurol NeuroCtr, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland.
    Jaaskelainen, Juha E.
    Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland.
    Leinonen, Ville
    Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland.
    Incidence, Comorbidities, and Mortality in Idiopathic Normal Pressure Hydrocephalus2018Inngår i: World Neurosurgery, ISSN 1878-8750, E-ISSN 1878-8769, Vol. 112, s. E624-E631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECT: To investigate the incidence, comorbidities, mortality, and causes of death in idiopathic normal pressure hydrocephalus (iNPH). METHODS: A cohort of 536 patients with possible NPH from a defined population with a median follow-up time of 5.1 years, (range 0.04-19.9 years) was included in the study. Patients were evaluated by brain imaging and intraventricular pressure monitoring, with a brain biopsy specimen immunostained against amyloid-beta and hyper-phosphorylated tau. Hospital records were reviewed for vascular diseases and type 2 diabetes mellitus (T2DM). Death certificates and yearly population of the catchment area were obtained from national registries. RESULTS: A total of 283 patients had a clinical diagnosis of iNPH, leading to a median annual incidence of 1.58 iNPH patients per 100,000 inhabitants (range, 0.8-4.5). Alzeimer disease-related brain biopsy findings were less frequent in iNPH patients than in non-iNPH patients (P < 0.05). An overrepresentation of hypertension (52% vs. 33%, P < 0.001) and T2DM (23% vs. 13%, P = 0.002) was noted in iNPH patients. Age (hazard ratio [HR] 1.04/year, 95% confidence interval [CI] 1.03-1.06, P< 0.001) and T2DM (HR 1.63, 95% CI 1.23-2.16, P < 0.001) increased the risk of death in the iNPH patients and in the total population. iNPH was associated with decreased risk of death (HR 0.63, 95% CI 0.50-0.78, P < 0.001). The most frequent causes of death were cardiovascular and cerebrovascular disease. Dementia as a cause of death was more common in non-iNPH patients (27% vs. 10%, P < 0.001). CONCLUSIONS: Hypertension and T2DM are common in iNPH and the latter causes excess mortality in the affected patients.

  • 207.
    Quentmeier, Hilmar
    et al.
    Leibniz Inst DSMZ German Collect Microorganisms &, Dept Human & Anim Cell Lines, Braunschweig, Germany..
    Drexler, Hans G.
    Leibniz Inst DSMZ German Collect Microorganisms &, Dept Human & Anim Cell Lines, Braunschweig, Germany..
    Hauer, Vivien
    Leibniz Inst DSMZ German Collect Microorganisms &, Dept Human & Anim Cell Lines, Braunschweig, Germany..
    MacLeod, Roderick A. F.
    Leibniz Inst DSMZ German Collect Microorganisms &, Dept Human & Anim Cell Lines, Braunschweig, Germany..
    Pommerenke, Claudia
    Leibniz Inst DSMZ German Collect Microorganisms &, Dept Human & Anim Cell Lines, Braunschweig, Germany..
    Uphoff, Cord C.
    Leibniz Inst DSMZ German Collect Microorganisms &, Dept Human & Anim Cell Lines, Braunschweig, Germany..
    Zaborski, Margarete
    Leibniz Inst DSMZ German Collect Microorganisms &, Dept Human & Anim Cell Lines, Braunschweig, Germany..
    Berglund, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, Uppsala, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Diffuse Large B Cell Lymphoma Cell Line U2946: Model for MCL1 Inhibitor Testing2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 12, artikkel-id e0167599Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma worldwide. We describe the establishment and molecular characteristics of the DLBCL cell line U-2946. This cell line was derived from a 52-year-old male with DLBCL. U-2946 cells carried the chromosomal translocation t(8; 14) and strongly expressed MYC, but not the mature B-cell lymphoma associated oncogenes BCL2 and BCL6. Instead, U-2946 cells expressed the antiapoptotic BCL2 family member MCL1 which was highly amplified genomically (14n). MCL1 amplification is recurrent in DLBCL, especially in the activated B cell (ABC) variant. Results of microarray expression cluster analysis placed U-2946 together with ABC-, but apart from germinal center (GC)-type DLBCL cell lines. The 1q21.3 region including MCL1 was focally coamplified with a short region of 17p11.2 (also present at 14n). The MCL1 inhibitor A-1210477 triggered apoptosis in U-2946 (MCL1(pos)/BCL2(neg)) cells. In contrast to BCL2(pos) DLBCL cell lines, U-2946 did not respond to the BCL2 inhibitor ABT-263. In conclusion, the novel characteristics of cell line U-2946 renders it a unique model system to test the function of small molecule inhibitors, especially when constructing a panel of DLBCL cell lines expressing broad combinations of antiapoptotic BCL2-family members.

  • 208.
    Rao, Shuan
    et al.
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Sigl, Verena
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Wimmer, Reiner Alois
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Novatchkova, Maria
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Jais, Alexander
    Med Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria.;Max Planck Inst Metab Res, Dept Neuronal Control Metab, D-50931 Cologne, Germany..
    Wagner, Gabriel
    Med Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria..
    Handschuh, Stephan
    Univ Vet Med, VetCore Facil Res, A-1220 Vienna, Austria..
    Uribesalgo, Iris
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Hagelkruys, Astrid
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Kozieradzki, Ivona
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Tortola, Luigi
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Nitsch, Roberto
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Cronin, Shane J.
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Orthofer, Michael
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Branstetter, Daniel
    Amgen Inc, Dept Pathol, Seattle, WA 98119 USA..
    Canon, Jude
    Amgen Inc, Dept Oncol Res, Seattle, WA 98119 USA..
    Rossi, John
    Amgen Inc, Dept Mol Sci, Seattle, WA 98119 USA..
    D'Arcangelo, Manolo
    Univ Colorado, Ctr Canc, Aurora, CO 80045 USA..
    Botling, Johan
    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.
    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.
    Edlund, Karolina
    Leibniz Res Ctr Working Environm & Human Factors, D-44139 Dortmund, Germany..
    Bergqvist, Michael
    Gavle Cent Hosp, Dept Oncol, S-80187 Gavle, Sweden..
    Ekman, Simon
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden..
    Lendl, Thomas
    Gregor Mendel Inst Mol Plant Biol GMI, A-1030 Vienna, Austria..
    Popper, Helmut
    Med Univ Graz, Inst Pathol, Res Unit Mol Lung & Pleura Pathol, A-8036 Graz, Austria..
    Takayanagi, Hiroshi
    Univ Tokyo, Dept Immunol, Tokyo 1088639, Japan..
    Kenner, Lukas
    Med Univ Vienna, Dept Clin Pathol, A-1090 Vienna, Austria.;Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria.;Univ Vet Med Vienna, Unit Pathol Lab Anim, A-1220 Vienna, Austria..
    Hirsch, Fred R.
    Univ Colorado, Ctr Canc, Aurora, CO 80045 USA..
    Dougall, William
    Amgen Inc, Dept Oncol Res, Seattle, WA 98119 USA.;QIMR, Berghofer Med Res Inst, Dept Immunol Canc & Infect, Brisbane, Qld 4006, Australia..
    Penninger, Josef
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer2017Inngår i: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, nr 20, s. 2099-2112Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D)-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.

  • 209.
    Rauramaa, Tuomas
    et al.
    Univ Eastern Finland, Inst Clin Med, Unit Pathol, Kuopio, Finland;Kuopio Univ Hosp, Dept Pathol, POB 1777, FIN-70211 Kuopio, Finland.
    Saxlin, Anna
    Tampere Univ Hosp, Dept Pathol, Fimlab Labs, Tampere, Finland.
    Lohvansuu, Kaisa
    Univ Jyvaskyla, Ctr Interdisciplinary Brain Res, Jyvaskyla, Finland;Univ Jyvaskyla, Dept Psychol, Jyvaskyla, Finland.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pitkanen, Asla
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland.
    Soininen, Hilkka
    Univ Eastern Finland, Sch Med, Dept Neurol, Kuopio, Finland.
    Epilepsy in neuropathologically verified Alzheimer's disease2018Inngår i: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 58, s. 9-12Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Subjects with Alzheimer's disease (AD) have been shown to be at a higher risk for epilepsy. The vast majority of the previous studies have not included a full neuropathological examination. Methods: The objective of this study was to assess the prevalence of epilepsy and clinicopathological characteristics in a well-defined study group of 64 subjects with AD. We evaluated the clinicopathological findings in 64 subjects (mean age at death 85 +/- 8.6 years) from a longitudi-nal study cohort of patients with dementia. Results: Eleven out of the 64 subjects (17%) had a history of epilepsy, which is comparable to previous studies. The subjects with AD and epilepsy were significantly younger at the time of AD diagnosis and at the time of hospitalisation. In addition, their duration of AD was longer. Concomitant neuropathology in addition to AD was common in both groups and the ApoE genotypes did not differ significantly between the groups. Conclusion: The strength of this study is a thorough neuropathological examination of all study subjects. Our findings support the previous literature regarding the prevalence of epilepsy in subjects with AD. We have shown that the subjects with AD and epilepsy differ significantly from the subjects without epilepsy.

  • 210.
    Rinne, Juha O.
    et al.
    Univ Turku, Turku PET Ctr, Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland;Turku Univ Hosp, Div Clin Neurosci, Turku, Finland.
    Suotunen, Timo
    Univ Turku, Turku PET Ctr, Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland.
    Rummukainen, Jaana
    Kuopio Univ Hosp, Dept Clin Pathol, Kuopio, Finland.
    Herukka, Sanna-Kaisa
    Kuopio Univ Hosp, Neurol NeuroCtr, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med, Neurol, Kuopio, Finland.
    Nerg, Ossi
    Kuopio Univ Hosp, Neurol NeuroCtr, Kuopio, Finland.
    Koivisto, Anne M.
    Kuopio Univ Hosp, Neurol NeuroCtr, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med, Neurol, Kuopio, Finland.
    Rauramaa, Tuomas
    Kuopio Univ Hosp, Dept Clin Pathol, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med, Pathol, Kuopio, Finland.
    Någren, Kjell
    Odense Univ Hosp, PET & Cyclotron Unit, Dept Nucl Med, Odense, Denmark.
    Hiltunen, Mikko
    Univ Eastern Finland, Inst Biomed, Kuopio, Finland.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rinne, Jaakko
    Turku Univ Hosp, Dept Neurosurg, Clin Neurosci, Turku, Finland.
    Jääskeläinen, Juha E.
    Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland;Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland.
    Soininen, Hilkka
    Univ Eastern Finland, Inst Clin Med, Neurol, Kuopio, Finland.
    Leinonen, Ville
    Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland;Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland;Univ Oulu, Unit Clin Neurosci, Neurosurg, Oulu, Finland;Oulu Univ Hosp, Med Res Ctr, Oulu, Finland.
    [C-11]PIB PET Is Associated with the Brain Biopsy Amyloid-beta Load in Subjects Examined for Normal Pressure Hydrocephalus2019Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, nr 4, s. 1343-1351Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-beta (A beta) pathology. Objective: To compare the [C-11]PIB PET uptake in the patients with suspected iNPH to A beta and hyperphosphorylated-tau (HP tau) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) A beta, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD). Methods: Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for A beta and HP tau in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [C-1(1)]PIB PET. A beta, total tau, and P tau(181) were measured by ELISA from the ventricular (n= 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3 +/- 2.4 years, range 3-1). Results: [C-11]PIB uptake in the right frontal cortex (rho = 0.60, p < 0.01) and the combined neocortical [C-11]PIB uptake score (rho = 0.61, p < 0.01) were associated with a higher A beta load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [C-11]PIB uptake was also associated with the ventricular CSF A beta (rho = -0.58, p = 0.03). Conclusions: The findings show that [C-11]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of A beta pathology in the patients with iNPH might also warrant treatment with current AD drugs.

  • 211.
    Rising, Anna
    et al.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75007 Uppsala, Sweden.;Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, S-14157 Huddinge, Sweden..
    Cederlund, Ella
    Karolinska Inst, Dept Med Biochem & Biophys MBB, S-17177 Stockholm, Sweden..
    Palmberg, Carina
    Karolinska Inst, Ctr Prote Karolinska PKKI, S-17177 Stockholm, Sweden..
    Uhlhorn, Henrik
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, S-75189 Uppsala, Sweden..
    Gaunitz, Stefan
    Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, S-14157 Huddinge, Sweden..
    Nordling, Kerstin
    Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, S-14157 Huddinge, Sweden..
    Agren, Erik
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, S-75189 Uppsala, Sweden..
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Westermark, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tjernberg, Lars
    Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, S-14157 Huddinge, Sweden..
    Jornvall, Hans
    Karolinska Inst, Dept Med Biochem & Biophys MBB, S-17177 Stockholm, Sweden..
    Johansson, Jan
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75007 Uppsala, Sweden.;Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, S-14157 Huddinge, Sweden..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Systemic AA amyloidosis in the red fox (Vulpes vulpes)2017Inngår i: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 26, nr 11, s. 2312-2318Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid A (AA) amyloidosis occurs spontaneously in many mammals and birds, but the prevalence varies considerably among different species, and even among subgroups of the same species. The Blue fox and the Gray fox seem to be resistant to the development of AA amyloidosis, while Island foxes have a high prevalence of the disease. Herein, we report on the identification of AA amyloidosis in the Red fox (Vulpes vulpes). Edman degradation and tandem MS analysis of proteolyzed amyloid protein revealed that the amyloid partly was composed of full-length SAA. Its amino acid sequence was determined and found to consist of 111 amino acid residues. Based on inter-species sequence comparisons we found four residue exchanges (Ser31, Lys63, Leu71, Lys72) between the Red and Blue fox SAAs. Lys63 seems unique to the Red fox SAA. We found no obvious explanation to how these exchanges might correlate with the reported differences in SAA amyloidogenicity. Furthermore, in contrast to fibrils from many other mammalian species, the isolated amyloid fibrils from Red fox did not seed AA amyloidosis in a mouse model.

  • 212.
    Rostami, Elham
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nyström, Petra Witt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Skandionkliniken, Uppsala, Sweden.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Gudjonsson, Olafur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy.2017Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, nr 11, s. 2217-2221Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.

  • 213.
    Roy, Ananya
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Weishaupt, Holger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Gustavsson, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Johansson, Fredrik K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Tchougounova, Elena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Mast Cell Infiltration in Human Brain Metastases Modulates the Microenvironment and Contributes to the Metastatic Potential2017Inngår i: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 7, artikkel-id 115Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metastatic brain tumors continue to be a clinical problem, despite new therapeutic advances in cancer treatment. Brain metastases (BMs) are among the most common mass lesions in the brain that are resistant to chemotherapies, have a very poor prognosis, and currently lack any efficient diagnostic tests. Predictions estimate that about 40% of lung and breast cancer patients will develop BM. Despite this, very little is known about the immunological and genetic aberrations that drive tumorigenesis in BM. In this study, we demonstrate the infiltration of mast cells (MCs) in a large cohort of human BM samples with different tissues of origin for primary cancer. We applied patient-derived BM cell models to the study of BM cell-MC interactions. BM cells when cocultured with MCs demonstrate enhanced growth and self-renewal capacity. Gene set enrichment analyses indicate increased expression of signal transduction and transmembrane proteins related genes in the cocultured BM cells. MCs exert their effect by release of mediators such as IL-8, IL-10, matrix metalloprotease 2, and vascular endothelial growth factor, thereby permitting metastasis. In conclusion, we provide evidence for a role of MCs in BM. Our findings indicate MCs' capability of modulating gene expression in BM cells and suggest that MCs can serve as a new target for drug development against metastases in the brain.

  • 214.
    Saito, Akira
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Horie, Masafumi
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Southern Calif, Keck Sch Med, Dept Med, Hastings Ctr Pulm Res,Div Pulm Crit Care & Sleep, Los Angeles, CA 90033 USA.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    The Role of TGF- Signaling in Lung Cancer Associated with Idiopathic Pulmonary Fibrosis2018Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, nr 11, artikkel-id 3611Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and dismal prognosis. IPF patients are known to have an increased risk of lung cancer and careful decision-making is required for the treatment of lung cancer associated with IPF. Transforming growth factor (TGF)- signaling plays a central role in tissue fibrosis and tumorigenesis. TGF--mediated pathological changes that occur in IPF lung tissue may promote the process of field cancerization and provide the microenvironment favorable to cancer initiation and progression. This review summarizes the current knowledge related to IPF pathogenesis and explores the molecular mechanisms that underlie the occurrence of lung cancer in the background of IPF, with an emphasis on the multifaceted effects of TGF- signaling.

  • 215.
    Salanova, R.
    et al.
    Hosp Gastroenterol Dr Carlos Bonorino Udaonda, Buenos Aires, DF, Argentina.
    Dietel, M.
    Charite Univ Med Berlin, Inst Pathol, Berlin, Germany.
    Savelov, N.
    Moscow Oncol Hosp, Moscow, Russia.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bigras, G.
    Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada.
    Hida, T.
    Aichi Canc Ctr, Dept Thorac Oncol, Nagoya, Aichi, Japan.
    Piperdi, B.
    Merck & Co Inc, Kenilworth, NJ USA.
    Burke, T.
    Merck & Co Inc, Kenilworth, NJ USA.
    Khambata-Ford, S.
    Merck & Co Inc, Kenilworth, NJ USA.
    Deitz, A.
    Merck & Co Inc, Kenilworth, NJ USA.
    Real-World Prevalence of PD-L1 Expression in Advanced NoneSmall-Cell Lung Cancer: The Global, Multicenter EXPRESS Study2018Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 9, s. S155-S156Artikkel i tidsskrift (Annet vitenskapelig)
  • 216.
    Salomonsson, A.
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    Patthey, A.
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Reutersward, C.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    Jonsson, M.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnstrom, H.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    Hussein, A.
    Sahlgrens Univ Hosp, Dept Clin Pathol & Genet, Gothenburg, Sweden.
    Monsef, N.
    Linkoping Univ, Dept Clin & Expt Med, Pathol, Linkoping, Sweden.
    Ortiz-Villalon, C.
    Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden.
    Bergman, B.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden.
    De Petris, L.
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.
    Lamberg, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Viltstrom, A.
    Linkoping Univ Hosp, Dept Resp Med, Linkoping, Sweden.
    Wagenius, G.
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden.
    Behndig, A.
    Umea Univ, Div Med, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Johansson, M.
    Umea Univ, Dept Radiat Sci, Umea, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Staaf, J.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    Planck, M.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer2018Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 10, s. S431-S432Artikkel i tidsskrift (Annet vitenskapelig)
  • 217.
    Sandberg, Dan T
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wennborg, Anders
    Affibody AB, Solna, Sweden.
    Feldwisch, Joachim
    Affibody AB, Solna, Sweden.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, nr 8, s. 1337-1346Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: In phase I/II-studies radiolabelled ABY-025 Affibody molecules identified human epidermal growth factor receptor 2 (HER2) expression in breast cancer metastases using PET and SPECT imaging. Here, we wanted to investigate the utility of a simple intra-image normalization using tumour-to-reference tissue-ratio (T/R) as a HER2 status discrimination strategy to overcome potential issues related to cross-calibration of scanning devices.

    METHODS: Twenty-three women with pre-diagnosed HER2-positive/negative metastasized breast cancer were scanned with [(111)In]-ABY-025 SPECT/CT (n = 7) or [(68)Ga]-ABY-025 PET/CT (n = 16). Uptake was measured in all metastases and in normal spleen, lung, liver, muscle, and blood pool. Normal tissue uptake variation and T/R-ratios were established for various time points and for two different doses of injected peptide from a total of 94 whole-body image acquisitions. Immunohistochemistry (IHC) was used to verify HER2 expression in 28 biopsied metastases. T/R-ratios were compared to IHC findings to establish the best reference tissue for each modality and each imaging time-point. The impact of shed HER2 in serum was investigated.

    RESULTS: Spleen was the best reference tissue across modalities, followed by blood pool and lung. Spleen-T/R was highly correlated to PET SUV in metastases after 2 h (r = 0.96, P < 0.001) and reached an accuracy of 100% for discriminating IHC HER2-positive and negative metastases at 4 h (PET) and 24 h (SPECT) after injection. In a single case, shed HER2 resulted in intense tracer retention in blood. In the remaining patients shed HER2 was elevated, but without significant impact on ABY-025 biodistribution.

    CONCLUSION: T/R-ratios using spleen as reference tissue accurately quantify HER2 expression with radiolabelled ABY-025 imaging in breast cancer metastases with SPECT and PET. Tracer binding to shed HER2 in serum might affect quantification in the extreme case.

  • 218. Schlipf, N A
    et al.
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Teigen, N
    Virtanen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Fismen, S
    Barenboim, M
    Manke, T
    Rösler, B
    Zimmer, A
    Fischer, J
    Whole-exome sequencing identifies novel autosomal recessive DSG1 mutations associated with mild SAM syndrome2016Inngår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 174, nr 2, s. 444-448Artikkel i tidsskrift (Fagfellevurdert)
  • 219.
    Schmidt, Matthias
    et al.
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Wiese, Sebastian
    Ulm Univ, Core Unit Mass Spectrometry & Prote, D-89081 Ulm, Germany.
    Adak, Volkan
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Engler, Jonas
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Agarwal, Shubhangi
    Univ Hohenheim, Inst Microbiol, D-70599 Stuttgart, Germany.
    Fritz, Günter
    Univ Hohenheim, Inst Microbiol, D-70599 Stuttgart, Germany;Univ Freiburg, Fac Med, Inst Neuropathol, D-79106 Freiburg, Germany.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Zacharias, Martin
    Tech Univ Munich, Dept Phys, D-85748 Garching, Germany.
    Fändrich, Marcus
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis2019Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikkel-id 5008Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 angstrom cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils.

  • 220. Schneider, Markus
    et al.
    Schneider, Stefanie
    Zuehlke-Jenisch, Reina
    Klapper, Wolfram
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hartmann, Sylvia
    Hansmann, Martin-Leo
    Siebert, Reiner
    Kueppers, Ralf
    Giefing, Maciej
    Alterations of the CD58 gene in classical Hodgkin lymphoma2015Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, nr 10, s. 638-645Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immune evasion plays a central role in the pathophysiology of classical Hodgkin lymphoma (cHL). As mutations of the CD58 gene contribute to immune evasion of diffuse large B cell lymphoma tumor cells, we studied whether alterations of the CD58 gene also occur in Hodgkin and Reed/Sternberg (HRS) cells of cHL. Single nucleotide polymorphism chip analysis revealed homozygous deletions within the CD58 gene in two cHL cell lines (SUP-HD1 and U-HO1). Sequencing of the CD58 gene in seven cHL cell lines disclosed in addition a homozygous splice site mutation in cell line KM-H2. None of the three mutated lines expressed CD58 protein on their surface. Thus, three of seven cHL cell lines analyzed harbor destructive CD58 mutations. Molecular analysis of isolated HRS cells from 10 primary cases of cHL; however, did not reveal any case with a CD58 mutation. A FICTION study indicated heterozygous deletions of CD58 in 3 of 13 cHL analyzed. Overall, we report frequent inactivating mutations of CD58 in cHL cell lines, but their rare occurrence in primary HRS cells. As the three cHL cell lines with CD58 mutations were all established from HRS cells located in pleural effusions, i.e., outside the normal lymph node microenvironment, in end-stages of the disease, CD58 inactivation in cHL might be predominantly prevalent to such situations.

  • 221.
    Schuster, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fatima, Ambrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sobol, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Noraddin, Feria Hikmet
    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.
    Laan, Loora
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Generation of three human induced pluripotent stem cell (iPSC) lines from three patients with Dravet syndrome carrying distinct SCN1A gene mutations2019Inngår i: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 39, artikkel-id 101523Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dravet syndrome (DS) is a childhood epilepsy syndrome caused by heterozygous mutations in the SCN1A gene encoding voltage-gated sodium channel Nav1.1. We generated iPSCs from fibroblasts of three DS patients carrying distinct SCN1A mutations (c.5502-5509dupGCTTGAAC, c.2965G>C and c.651C>G). The iPSC lines were genetically stable and each line retained the SCN1A gene mutation of the donor fibroblasts. Characterization of the iPSC lines confirmed expression of pluripotency markers, absence of exogenous vector expression and trilineage differentiation potential. These iPSC lines offer a useful resource to investigate the molecular mechanisms underlying Nav1.1 haploinsufficiency and for drug development to improve treatment of DS patients.

  • 222.
    Schuster, Jens
    et al.
    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.
    Laan, Loora
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    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.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Birnir: Molekylär fysiologi och neurovetenskap.
    Huss, Mikael
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Wallenberg Long Term Bioinformat Support, Stockholm, Sweden.
    Korol, Sergiy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Birnir: Molekylär fysiologi och neurovetenskap.
    Noraddin, Feria Hikmet
    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.
    Sobol, Maria
    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.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Birnir: Molekylär fysiologi och neurovetenskap.
    Dahl, Niklas
    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.
    Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment2019Inngår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 132, artikkel-id 104583Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the a-subunit of the neuronal sodium channel Na(v)1.1. The syndrome is characterized by age related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Na(v)1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor cells (iPSC NPC) and GABAergic interneuronal (iPSC GABA) cells. The DS-patient iPSC GABA cells showed a shift in sodium current activation and a perturbed response to induced oxidative stress. Transcriptome analysis revealed specific dysregulations of genes for chromatin structure, mitotic progression, neural plasticity and excitability in DS-patient iPSC NPCs and DS-patient iPSC GABA cells versus controls. The transcription factors FOXM1 and E2F1, positive regulators of the disrupted pathways for histone modification and cell cycle regulation, were markedly up-regulated in DS-iPSC GABA lines. Our study highlights transcriptional changes and disrupted pathways of chromatin remodeling in Na(v)1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.

  • 223.
    Schwartz, Friederike H.
    et al.
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany.;Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany..
    Cai, Qian
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany..
    Fellmann, Eva
    Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany..
    Hartmann, Sylvia
    Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany..
    Mäyränpää, Mikko I.
    Univ Helsinki, Dept Pathol, Helsinki, Finland.;Univ Helsinki, Div Pathol, Meilahti Labs Pathol, HUSLAB,Cent Hosp, Helsinki, Finland..
    Karjalainen-Lindsberg, Marja-Liisa
    Univ Helsinki, Dept Pathol, Helsinki, Finland.;Univ Helsinki, Div Pathol, Meilahti Labs Pathol, HUSLAB,Cent Hosp, Helsinki, Finland..
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Scholtysik, René
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany..
    Hansmann, Martin-Leo
    Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany.;German Canc Consortium DKTK, Heidelberg, Germany..
    Küppers, Ralf
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany.;German Canc Consortium DKTK, Heidelberg, Germany..
    TET2 mutations in B cells of patients affected by angioimmunoblastic T-cell lymphoma2017Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 242, nr 2, s. 129-133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angioimmunoblastic T-cell lymphomas (AITLs) frequently carry mutations in the TET2 and IDH2 genes. TET2 mutations represent early genetic lesions as they had already been detected in haematopoietic precursor cells of AITL patients. We show by analysis of whole-tissue sections and microdissected PD1(+) cells that the frequency of TET2-mutated AITL is presumably even higher than reported (12/13 cases in our collection; 92%). In two-thirds of informative AITLs (6/9), a fraction of B cells was also TET2-mutated. Investigation of four AITLs by TET2 and IGHV gene sequencing of single microdissected B cells showed that between 10% and 60% of polyclonal B cells in AITL lymph nodes harboured the identical TET2 mutations of the respective T-cell lymphoma clone. Thus, TET2-mutated haematopoietic precursor cells in AITL patients not only give rise to the T-cell lymphoma but also generate a large population of mutated mature B cells. Future studies will show whether this is a reason why AITL patients frequently also develop B-cell lymphomas. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 224.
    Segerman, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Univ Uppsala Hosp, Clin Chem & Pharmacol, S-75185 Uppsala, Sweden..
    Niklasson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Bergström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Xie, Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Westermark, Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sönmez, Demet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Pfizer, Vetenskapsvagen 10, S-19190 Sollentuna, Sweden..
    Hermansson, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kastemar, Marianne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Naimaie-Ali, Zeinab
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nyberg, Frida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Berglund, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Sundström, Magnus
    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.
    Hesselager, Göran
    Univ Uppsala Hosp, Dept Neurosurg, S-75185 Uppsala, Sweden..
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gustafsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Segerman, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Natl Vet Inst, S-75007 Uppsala, Sweden..
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition2016Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, nr 11, s. 2994-3009Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

  • 225.
    Siesing, Christina
    et al.
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Sorbye, Halfdan
    Univ Bergen, Haukeland Univ Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala Univ, Uppsala Univ Hosp, Sect Pathol, Uppsala, Sweden.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Qvortrup, Camilla
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala Univ, Uppsala Univ Hosp, Sect Pathol, Uppsala, Sweden.
    Jirström, Karin
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Eberhard, Jakob
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 8, artikkel-id e0182512Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy.

    Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS).

    Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively).

    Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

  • 226.
    Sipe, Jean D.
    et al.
    Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA..
    Benson, Merrill D.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA..
    Buxbaum, Joel N.
    Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Ikeda, Shu-ichi
    Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano, Japan..
    Merlini, Giampaolo
    Univ Pavia, Amyloid Res & Treatment Ctr, Pavia, Italy.;IRCCS Policlin San Matteo, Pavia, Italy..
    Saraiva, Maria J. M.
    Univ Porto, Inst Mol & Cellular Biol, Amyloid Unit, Oporto, Portugal..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines2016Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 23, nr 4, s. 209-213Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XVth Symposium of the Society, 3 July-7 July 2016, Uppsala, Sweden, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. An amyloid fibril must exhibit affinity for Congo red and with green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. While congophilia and birefringence remain the gold standard for demonstration of amyloid deposits, new staining and imaging techniques are proving useful. To be included in the nomenclature list, in addition to congophilia and birefringence, the chemical identity of the protein must be unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant changes in the amyloid fibril protein. Each distinct form of amyloidosis is uniquely characterized by the chemical identity of the amyloid fibril protein that deposits in the extracellular spaces of tissues and organs and gives rise to the disease syndrome. The fibril proteins are designated as protein A followed by a suffix that is an abbreviation of the parent or precursor protein name. To date, there are 36 known extracellular fibril proteins in humans, 2 of which are iatrogenic in nature and 9 of which have also been identified in animals. Two newly recognized fibril proteins, AApoCII derived from apolipoprotein CII and AApoCIII derived from apolipoprotein CIII, have been added. AApoCII amyloidosis and AApoCIII amyloidosis are hereditary systemic amyloidoses. Intracellular protein inclusions displaying some of the properties of amyloid, intracellular amyloid have been reported. Two proteins which were previously characterized as intracellular inclusions, tau and -synuclein, are now recognized to form extracellular deposits upon cell death and thus have been included in Table 1 as ATau and ASyn.

  • 227.
    Sjöstedt, Evelina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Bollerslev, Jens
    Oslo Univ Hosp, Rikshosp, Dept Specialized Endocrinol, Oslo, Norway.; Univ Oslo, Fac Med, Oslo, Norway.
    Mulder, Jan
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Lindskog, Cecilia
    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.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Oslo Univ Hosp, Dept Pathol, Oslo, Norway.
    A specific antibody to detect transcription factor T-Pit: a reliable marker of corticotroph cell differentiation and a tool to improve the classification of pituitary neuroendocrine tumours2017Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 134, nr 4, s. 675-677Artikkel i tidsskrift (Annet vitenskapelig)
  • 228.
    Sjöstedt, Evelina
    et al.
    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. KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Sivertsson, Åsa
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Noraddin, Feria Hikmet
    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.
    Katona, Borbala
    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.
    Näsström, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Vuu, Jimmy
    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.
    Kesti, Dennis
    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.
    Oksvold, Per
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Edqvist, Per-Henrik D
    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.
    Olsson, Ingmarie
    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.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 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.
    Integration of Transcriptomics and Antibody-Based Proteomics for Exploration of Proteins Expressed in Specialized Tissues2018Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, nr 12, s. 4127-4137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A large portion of human proteins are referred to as missing proteins, defined as protein-coding genes that lack experimental data on the protein level due to factors such as temporal expression, expression in tissues that are difficult to sample, or they actually do not encode functional proteins. In the present investigation, an integrated omics approach was used for identification and exploration of missing proteins. Transcriptomics data from three different sources-the Human Protein Atlas (HPA), the GTEx consortium, and the FANTOM5 consortium-were used as a starting point to identify genes selectively expressed in specialized tissues. Complementing the analysis with profiling on more specific tissues based on immunohistochemistry allowed for further exploration of cell-type-specific expression patterns. More detailed tissue profiling was performed for >300 genes on complementing tissues. The analysis identified tissue-specific expression of nine proteins previously listed as missing proteins (POU4F1, FRMD1, ARHGEF33, GABRG1, KRTAP2-1, BHLHE22, SPRR4, AVPR1B, and DCLK3), as well as numerous proteins with evidence of existence on the protein level that previously lacked information on spatial resolution and cell-type-specific expression pattern. We here present a comprehensive strategy for identification of missing proteins by combining transcriptomics with antibody-based proteomics. The analyzed proteins provide interesting targets for organ-specific research in health and disease.

  • 229.
    Skinner, Martha
    et al.
    Boston Univ, Sch Med, Amyloidosis Ctr, Boston, MA 02118 USA.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alan S. Cohen 1926-2018 Obituary2018Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, nr 2, s. 73-74Artikkel i tidsskrift (Annet vitenskapelig)
  • 230. Sorbye, Halfdan
    et al.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Pfeiffer, Per
    Thunberg, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bergfors, Monica
    Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Aasebo, Kristine
    Eide, Geir Egil
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Qvortrup, Camilla
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 6, artikkel-id e0131046Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated; 12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should be recognized more clearly when conclusions are made from translational mCRC studies.

  • 231.
    Sottile, Rosa
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Tannazi, Milad
    Univ Utrecht, Fac Sci, Dept Pharmaceut Sci, Utrecht, Netherlands.
    Johansson, Maria H.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Cristiani, Costanza Maria
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Calabro, Luana
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Ventura, Valeria
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Cutaia, Ornella
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Chiarucci, Carla
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Covre, Alessia
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Garofalo, Cinzia
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Ponten, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Tallerico, Rossana
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Frumento, Paolo
    Karolinska Inst, Inst Environm Med, Unit Biostat, Stockholm, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Maio, Michele
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Karre, Klas
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Carbone, Ennio
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden;Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    NK- and T-cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti-CTLA-4 therapy2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 8, s. 2238-2248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti-CTLA-4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL-15 stimulation improved NK cell-mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56(bright) and CD56(dim) NK subsets and increased serum concentrations of the cytokines IL-10, IL-8 and TNF-alpha. After tremelimumab treatment, the ratio between the CD56(bright) and CD56(dim) subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM-3(+)CD8(+) T-cell frequency, high DNAM-1(+)CD56(dim) NK-cell frequency and high expression levels of NKp46 on the CD56(dim) NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab.

  • 232.
    Sreedharan, Smitha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. CSIR, Inst Genom & Integrat Biol, South Campus,Mathura Rd, New Delhi 110025, India.
    Maturi, Naga Prathyusha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundström, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Libard, Sylwia
    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.
    Alafuzoff, Irina
    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.
    Weishaupt, Holger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Swartling, Fredrik J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype2017Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, nr 3, s. 802-812Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease.

  • 233.
    Sridhar, Sriram
    et al.
    Nanyang Technol Univ, Sch Elect & Elect Engn, 50 Nanyang Ave, Singapore 639798, Singapore.
    Mishra, Sachin
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Padmanabhan, Parasuraman
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    Gulyas, Balazs
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    An Overview of Multimodal Neuroimaging Using Nanoprobes2017Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, nr 2, artikkel-id 311Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Nanomaterials have gained tremendous significance as contrast agents for both anatomical and functional preclinical bio-imaging. Contrary to conventional medical practices, molecular imaging plays an important role in exploring the affected cells, thus providing precision medical solutions. It has been observed that incorporating nanoprobes improves the overall efficacy of the diagnosis and treatment processes. These nano-agents and tracers are therefore often incorporated into preclinical therapeutic and diagnostic applications. Multimodal imaging approaches are well equipped with nanoprobes to explore neurological disorders, as they can display more than one type of characteristic in molecular imaging. Multimodal imaging systems are explored by researchers as they can provide both anatomical and functional details of tumors and affected tissues. In this review, we present the state-of-the-art research concerning multimodal imaging systems and nanoprobes for neuroimaging applications.

  • 234.
    Strakova, Katerina
    et al.
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic;Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Kowalski-Jahn, Maria
    Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Gybel, Tomas
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Valnohova, Jana
    Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Dhople, Vishnu M.
    Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Friedrich Ludwig Jahn Str 15, D-17487 Greifswald, Germany.
    Harnos, Jakub
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Bernatik, Ondrej
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Ganji, Ranjani Sri
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic;Masaryk Univ, Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Zdrahal, Zbynek
    Masaryk Univ, Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Sci Life Lab, Tomtebodavagen 16, 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.
    Bryja, Vitezslav
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Schulte, Gunnar
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic;Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization2018Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, nr 48, s. 18477-18493Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int-1(WNT) family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be regulated by phosphorylation, leading to specific downstream signaling or receptor desensitization. The role and underlying mechanisms of FZD phosphorylation remain largely unexplored. Here, we investigated the phosphorylation of human FZD(6). Using MS analysis and a phospho-state- and -site-specific antibody, we found that Ser-648, located in the FZD(6) C terminus, is efficiently phosphorylated by casein kinase 1 is an element of (CK1 is an element of) and that this phosphorylation requires the scaffolding protein Dishevelled (DVL). In an overexpression system, DVL1, -2, and -3 promoted CK1-mediated FZD(6) phosphorylation on Ser-648. This DVL activity required an intact DEP domain and FZD-mediated recruitment of this domain to the cell membrane. Substitution of the CK1 is an element of-targeted phosphomo-tif reduced FZD(6) surface expression, suggesting that Ser-648 phosphorylation controls membrane trafficking of FZD(6). Phos-pho-Ser-648 FZD(6) immunoreactivity in human fallopian tube epithelium was predominantly apical, associated with cilia in a subset of epithelial cells, compared with the total FZD(6) protein expression, suggesting that FZD(6) phosphorylation contributes to asymmetric localization of receptor function within the cell and to epithelial polarity. Given the key role of FZD(6) in planar cell polarity, our results raise the possibility that asymmetric phosphorylation of FZD(6) rather than asymmetric protein distribution accounts for polarized receptor signaling.

  • 235.
    Strang-Karlsson, Sonja
    et al.
    Univ Helsinki, Folkhaelsan Inst Genet, Folkhaelsan Dept Med Genet, Helsinki, Finland; Univ Helsinki, Dept Med & Clin Genet, Helsinki, Finland; Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland; Univ Helsinki, Helsinki, Finland.
    Johnson, Katherine
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Töpf, Ana
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Xu, Liwen
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Lek, Monkol
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    MacArthur, Daniel G.
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Williams, Maria
    Aland Cent Hosp, Mariehamn, Aland, Finland.
    Straub, Volker
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Wallgren-Pettersson, Carina
    Univ Helsinki, Folkhaelsan Inst Genet, Folkhaelsan Dept Med Genet, Helsinki, Finland; Univ Helsinki, Dept Med & Clin Genet, Helsinki, Finland.
    A novel compound heterozygous mutation in the POMK gene causing limb-girdle muscular dystrophy-dystroglycanopathy in a sib pair2018Inngår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 28, nr 7, s. 614-618Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe two Finnish siblings in whom an incidentally detected elevated creatine kinase activity eventually led to a diagnosis of limb-girdle muscular dystrophy-dystroglycanopathy (Type C12; MDDGC12). When diagnosed at age 10 and 13 years, they were mildly affected with a slow or non-progressive disease course. The main symptoms comprised infrequent hip cramps triggered by flexion, neck cramps triggered by yawning, transient growing pains, calf hypertrophy and mild proximal muscle weakness. Their cognitive and motor developments were unremarkable and they were physically active. Whole-exome sequencing revealed compound heterozygous mutations, both of which were novel, in the protein O-mannosyl kinase (POMK) gene in both siblings; a missense mutation, p.Pro322Leu (c.965C > T), and a nonsense mutation, p.Arg46Ter (c.136C > T). The results were confirmed by Sanger sequencing, showing that the parents were heterozygous carriers of one mutation each. This report adds to the literature by providing phenotype and genotype data on this ultra-rare POMK-related dystroglycanopathy.

  • 236.
    Suhr, O. B.
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Lundgren, E.
    Umea Univ, Dept Mol Biol, Umea, Sweden..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition2017Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, nr 4, s. 337-347Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Although hereditary transthyretin (h-ATTR) amyloidosis is a monogenetic disease, a large variation in its phenotype has been observed. The common hypothesis of amyloid fibril formation involves dissociation of the transthyretin (TTR) tetramer into monomers that after misfolding reassemble into amyloid fibrils. This notion is partly challenged by the finding of two distinct types of amyloid fibrils. One of these, type A, consists of C-terminal ATTR fragments and full-length TTR, whereas the other, type B, consists only of full-length TTR. All organs of an individual patient contain ATTR deposits of either type A or type B fibrils, and the composition in each individual remains unchanged over time. The finding of two distinct types of ATTR fibrils suggests that there are at least two different pathways in operation for ATTR fibril formation. For the most common European mutation, TTR Val30Met, ATTR fibril composition is related to the outcome of liver transplantation, which is the first successful treatment for the disease, and the penetrance of the trait. In addition, the presence of C-terminal ATTR fragments has an impact on the affinity for various tracers used for noninvasive imaging of amyloid depositions such as 99 m-technetium-diphosphono-propanodicarboxylic acid scintigraphy and positron emission tomography utilizing Pittsburgh component B, and even for the gold standard diagnostic procedure, tissue biopsy stained by Congo red and examined under polarized light. The importance of amyloid fibril composition needs to be taken into consideration when designing clinical trials of treatment modalities, and also in the evaluation of diagnostic methods such as imaging techniques.

  • 237.
    Suhr, Ole Bernt
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wixner, Jonas
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Anan, Intissar
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Lundgren, Hans-Erik
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wijayatunga, Priyantha
    Umea Univ, Dept Stat, Umea, Sweden.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amyloid fibril composition within hereditary Val30Met (p. Val50Met) transthyretin amyloidosis families2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 2, artikkel-id e0211983Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The amyloid fibril in hereditary transthyretin (TTR) Val30Met (pVal50Met) amyloid (ATTR Val30Met) amyloidosis is composed of either a mixture of full-length and TTR fragments (Type A) or of only full-length TTR (Type B). The type of amyloid fibril exerts an impact on the phenotype of the disease, and on the outcome of diagnostic procedures and therapy. The aim of the present study was to investigate if the type of amyloid fibril remains the same within ATTR Val30Met amyloidosis families.

    METHODS: Fifteen families were identified in whom at least two first-degree relatives had their amyloid fibril composition determined. The type of ATTR was determined by Western blot in all but two patients. For these two patients a positive 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy indicated ATTR Type A.

    RESULTS: In 14 of the 15 families, the same amyloid fibril composition was noted irrespective of differences in age at onset. In the one family, different ATTR fibril types was found in two brothers with similar ages at onset.

    CONCLUSIONS: Family predisposition appears to have an impact on amyloid fibril composition in members of the family irrespective of their age at onset of disease, but if genetically determined, the gene/genes are likely to be situated at another location than the TTR gene in the genome.

  • 238.
    Sundblom, Jimmy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nowinski, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Plastikkirurgi.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Removal of giant intraosseous meningioma followed by cranioplasty using a custom-made bioceramic implant: case report2019Inngår i: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 131, nr 3, s. 735-739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intraosseous meningioma of the chordoid type is a rare clinical entity. Radical surgical removal and subsequent cranioplasty is the treatment of choice. Here, the authors report a severe case involving more than 70% of the calvarial surface area, which was removed and repaired using a prefabricated custom-made, titanium-reinforced, bioceramic implant and bone-cutting guides. Tumor removal and good esthetic outcome were achieved, along with a 17.1% increase of intracranial volume. Bioceramic implants have shown promising initial results and may represent an important new tool in the surgeon's armamentarium.

  • 239.
    Suveer, Amit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Sladoje, Natasa
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Lindblad, Joakim
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sintorn, Ida-Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Cilia ultrastructural visibility enhancement by multiple instance registration and super-resolution reconstruction2017Inngår i: Swedish Symposium on Image Analysis, Swedish Society for Automated Image Analysis , 2017Konferansepaper (Annet vitenskapelig)
  • 240.
    Suveer, Amit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Sladoje, Nataša
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Lindblad, Joakim
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sintorn, Ida-Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Enhancement of cilia sub-structures by multiple instance registration and super-resolution reconstruction2017Inngår i: Image Analysis: Part II, Springer, 2017, s. 362-374Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Ultrastructural analysis of cilia cross-sectional images using transmission electron microscopy (TEM) assists the pathologists to diagnose Primary Ciliary Dyskinesia, a genetic disease. The current diagnostic procedure is manual and difficult because of poor signal-to-noise ratio in TEM images. In this paper, we propose an automated multi-step registration approach to register many cilia cross-sectional instances. The novelty of the work is in the utilization of customized weight masks at each registration step to achieve good alignment of the specific cilium regions. Registration is followed by super-resolution reconstruction to enhance the substructural information. Landmarks matching based evaluation of registration results in pixel alignment error of 2.35&#x00B1;1.82" role="presentation">2.35±1.82 pixels, and the subjective analysis of super-resolution reconstructed cilium shows a clear improvement in the visibility of the substructures such as dynein arms, radial spokes, and central pair.

  • 241.
    Svensson, Maria C.
    et al.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Warfvinge, Carl Fredrik
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Fristedt, Richard
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Hedner, Charlotta
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Borg, David
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Eberhard, Jakob
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nodin, Bjoern
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Leandersson, Karin
    Lund Univ, Dept Translat Med, Canc Immunol, Malmo, Sweden..
    Jirstroem, Karin
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 42, s. 72108-72126Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Several studies have demonstrated a prognostic impact of tumor-infiltrating T lymphocytes and natural killer (NK) cells in esophageal and gastric adenocarcinoma, but whether these associations differ by the density of tumor-infiltrating immune cells of the B cell lineage remains largely unknown. Results: High infiltration of any T and NK lymphocytes investigated was in general associated with a favorable prognosis, but the strongest beneficial prognostic impact was seen in combination with high B lymphocyte infiltration. These findings were most evident in gastric cancer, where significant interactions in relation to OS were observed for CD3(+), CD8(+) and FoxP3(+) with CD20(+) cells (p(interaction) = 0.012, 0.009 and 0.007, respectively) and for FoxP3(+) with IGKC(+) cells (p(interaction) = 0.034). In esophageal tumors, there was only a significant interaction for CD3(+) and CD20 (+) cells (p(interaction) = 0.028). Methods: Immunohistochemistry and automated image analysis was applied to assess the density of T lymphocytes (CD3(+), CD8(+), FoxP3(+)) and NK cells (NKp46(+)) in chemoradiotherapy-naive tumors from a consecutive cohort of 174 patients with resected esophageal or gastric adenocarcinoma. The density of B lymphocytes (CD20(+)) and plasma cells (IGKC(+)) had been assessed previously. Kaplan-Meier analysis and Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on time to recurrence (TTR) and overall survival (OS). Conclusions: These data support that the antitumoral effects of tumor-infiltrating T lymphocytes in esophageal and gastric adenocarcinoma may be largely dependent on a functional interplay between T and B lymphocytes or plasma cells.

  • 242.
    Sörensen, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Sandberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Wennborg, Anders
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [(68)Ga]ABY-025 Affibody PET/CT2016Inngår i: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 6, nr 2, s. 262-271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with (68)Ga-gallium ([(68)Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology.

    EXPERIMENTAL DESIGN: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [(68)Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [(68)Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [(68)Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization.

    RESULTS: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [(68)Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients.

    CONCLUSION: [(68)Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer.

  • 243.
    Tammela, T L
    et al.
    Tampere Univ Hosp, Dept Urol, Tampere, Finland.; Univ Tampere, Tampere, Finland.
    Häggman, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Ladjevardi, Sam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Taari, K
    Helsinki Univ Hosp, Helsinki, Finland.
    Isotalo, T
    Paijiat Hame Cent Hosp, Lahti, Finland.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Weis, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    von Below, Catrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wassberg, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lennernäs, B
    Univ Orebro, Dept Oncol, Orebro, Sweden.
    Tolf, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Axén, N
    LIDDS AB, Uppsala, Sweden.
    Gölander, C-G
    LIDDS AB, Uppsala, Sweden.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer2017Inngår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 198, nr 6, s. 1333-1339Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To investigate tolerability, safety and antitumor effects of a novel intra-prostatic depot formulation of antiandrogen 2-hydroxyflutamide (2-HOF in NanoZolid(®)) in men with localized prostate cancer (PCa).

    MATERIALS AND METHODS: Two clinical trials, LPC-002 and LPC-003, were conducted on a total of 47 men. The formulation was injected transrectally into the prostate with ultrasound guidance. In LPC-002 the effects on prostate specific antigen (PSA) and prostate volume (PV) were measured over 6 months on 24 patients. In LPC-003, antitumor effects were evaluated with histopathology, magnetic resonance imaging (MRI) including spectroscopy (MRS) during 6 or 8 weeks on 23 patients. In both studies, testosterone and 2-HOF in plasma were measured, as well as quality-of-life parameters.

    RESULTS: In LPC-002 (mean dose 690 mg) a reduction in PSA and PV was observed. The nadir values for PSA and PV were on average 24.9 % and 14.0 % below baseline, respectively. When increasing the dose in LPC-003 (920 mg and 1740 mg), the average PSA dropped 16 % and 23 %, respectively, after 6 and 8 weeks. MRI/MRS showed morphological changes and a global drop in metabolite concentrations following treatment indicating an antitumor response. The injections did not result in hormone related side effects. In total, three serious adverse events were reported, all resolved by oral antibiotic treatment.

    CONCLUSIONS: The intraprostatic injections of 2-HOF depot formulations indicated anti-tumor effects and proved safe and tolerable. However, for better anti-cancer effects higher doses and better dose distribution are suggested.

  • 244.
    Tegler, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Ericson, Katharina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Björck, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Wanhainen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    4D-PET/CT with [11C]-PK11195 and [11C]-D-deprenyl does not identify the chronic inflammation in asymptomatic abdominal aortic aneurysms2013Inngår i: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 45, nr 4, s. 351-356Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives

    The aim of this study was to investigate the relevance of inflammation in the pathogenesis of abdominal aortic aneurysm (AAA) in vivo with two novel positron emission tomography (PET) tracers: [11C]-PK11195 which targets the translocator protein (18 kDa) expressed on macrophages and [11C]-d-deprenyl with a yet unknown target receptor expressed in chronic inflammation.

    Design

    Prospective clinical study.

    Materials/methods

    Five patients were examined with [11C]-PK11195-positron emission tomography/computed tomography (PET/CT) and 10 with [11C]-d-deprenyl-PET/CT. Nine large AAAs (54–66 mm) scheduled for repair and six small AAA (35–44 mm). All 15 patients were male and the AAAs were all asymptomatic. Regional activity was measured as standardised uptake values (SUVs) and retention index was calculated. Biopsies were taken from the aneurysm wall for histological examinations, in the nine patients operated on.

    Results

    No aortic uptake was recorded on the visual inspection, neither with [11C]-PK11195 nor with [11C]-d-deprenyl. For [11C]-PK11195 the median SUV of the AAA wall was 0.9 (range 0.8–1.0) and for [11C]-d-deprenyl, 0.7 (range 0.4–1.2). No increased uptake was seen in the aneurysmal infrarenal aorta compared with the non-aneurysmal suprarenal aorta. Histological examination of the aneurysm wall showed high inflammatory cell infiltration with lymphocytes and macrophages.

    Conclusions

    The chronic inflammation observed in the vessel wall was not detectable with [11C]-PK11195 and [11C]-d-deprenyl. In order to study the relevance of the inflammation in the pathogenesis of AAA in vivo other PET tracers need to be investigated.

  • 245.
    ten Berge, Josianne C.
    et al.
    Erasmus Univ, Med Ctr, Dept Ophthalmol, Rotterdam, Netherlands..
    van Rosmalen, Joost
    Erasmus Univ, Med Ctr, Dept Biostat, Rotterdam, Netherlands..
    Vermeer, Jacolien
    Erasmus Univ, Med Ctr, Dept Immunol, Rotterdam, Netherlands..
    Hellström, Cecilia
    KTH Royal Inst Technol, Sch Biotechnol, SciLifeLab, Affin Prote, Stockholm, Sweden..
    Lindskog, Cecilia
    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.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, SciLifeLab, Affin Prote, Stockholm, Sweden..
    Qundos, Ulrika
    KTH Royal Inst Technol, Sch Biotechnol, SciLifeLab, Affin Prote, Stockholm, Sweden..
    Rothova, Aniki
    Erasmus Univ, Med Ctr, Dept Ophthalmol, Rotterdam, Netherlands..
    Schreurs, Marco W. J.
    Erasmus Univ, Med Ctr, Dept Immunol, Rotterdam, Netherlands..
    Serum Autoantibody Profiling of Patients with Paraneoplastic and Non-Paraneoplastic Autoimmune Retinopathy2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 12, artikkel-id e0167909Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Although multiple serum antiretinal autoantibodies (ARAs) have been reported in patients with paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR), not all retinal antigens involved in (n)pAIR are specified. This study aims to serologically identify patients with presumed (n)pAIR through determination of both known and unknown ARAs by autoantibody profiling.

    Methods: An antigen suspension bead array using 188 different antigens representing 97 ocular proteins was performed to detect ARAs in serum samples of patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Logistic regressions were used to estimate the associations between ocular antigens and diagnosis. Validation of interphotoreceptor matrix proteoglycan 2 (IMPG2) and recoverin antigens was performed by immunohistochemistry and immunoblot, respectively.

    Results: Samples of patients with presumed (n)pAIR exhibited a broad spectrum of ARAs. We identified retinal antigens that have already been described previously (e.g. recoverin), but also identified novel ARA targets. Most ARAs were not specific for (n)pAIR since their presence was also observed in patients with cataract or uveitis. High titers of autoantibodies directed against photoreceptor-specific nuclear receptor and retinol-binding protein 3 were more common in patients with presumed (n)pAIR compared to uveitis (p = 0.015 and p = 0.018, respectively). The presence of all other ARAs did not significantly differ between groups. In patients with presumed (n)pAIR, anti-recoverin autoantibodies were the most prevalent ARAs. Validation of bead array results by immunohistochemistry (anti-IMPG2) and immunoblot (anti-recoverin) showed concordant results in (n)pAIR patients.

    Conclusions: Patients with (n)pAIR are characterized by the presence of a broad spectrum of ARAs. The diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs, as these are also commonly present in uveitis as well as in age-related cataract patients.

  • 246.
    Thunnissen, Erik
    et al.
    Vrije Univ Amsterdam Med Ctr, Dept Pathol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands..
    Borczuk, Alain C.
    Weill Cornell Med, Dept Pathol, New York, NY USA..
    Flieder, Douglas B.
    Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA..
    Witte, Birgit
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands..
    Beasley, Mary Beth
    Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA..
    Chung, Jin-Haeng
    Seoul Natl Univ, Bundang Hosp, Coll Med, Dept Pathol, Seoul 151, South Korea..
    Dacic, Sanja
    Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA..
    Lantuejoul, Sylvie
    Ctr Leon Berard UNICANCER, Dept Biopathol, Lyon, France..
    Russell, Prudence A.
    St Vincent Pathol, Melbourne, Vic, Australia.;Univ Melbourne, Melbourne, Vic, Australia..
    den Bakker, Michael
    Maasstad Ziekenhuis, Dept Pathol, Rotterdam, Netherlands..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brambilla, Elisabeth
    CHU Albert Michallon, Inst Biol, Dept Anat & Cytol Pathol, Grenoble, France..
    de Cuba, Erienne
    Vrije Univ Amsterdam Med Ctr, Dept Pathol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands..
    Geisinger, Kim R.
    Univ Mississippi, Med Ctr, Dept Pathol, Jackson, MS 39216 USA..
    Hiroshima, Kenzo
    Tokyo Womens Med Univ, Yachiyo Med Ctr, Dept Pathol, Yachiyo, Japan..
    Marchevsky, Alberto M.
    Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA..
    Minami, Yuko
    Univ Tsukuba, Inst Basic Med Sci, Dept Pathol, Tsukuba, Ibaraki, Japan..
    Moreira, Andre
    NYU, Ctr Biospecimen Res & Dev, Pulm Pathol, New York, NY USA..
    Nicholson, Andrew G.
    Royal Brompton & Harefield Hosp Natl Hlth Serv Fd, Dept Histopathol, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Yoshida, Akihiko
    Natl Canc Ctr, Dept Pathol & Clin Labs, Tokyo, Japan..
    Tsao, Ming-Sound
    Princess Margaret Hosp, Univ Hlth Network, Dept Pathol, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Warth, Arne
    Heidelberg Univ, Inst Pathol, Heidelberg, Germany..
    Duhig, Edwina
    John Flynn Hosp, Sullivan Nicolaides Pathol, Tugun, Qld, Australia..
    Chen, Gang
    Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China..
    Matsuno, Yoshihiro
    Hokkaido Univ Hosp, Dept Surg Pathol, Sapporo, Hokkaido, Japan..
    Travis, William D.
    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA..
    Butnor, Kelly
    Univ Vermont, Dept Pathol, Burlington, VT 05405 USA..
    Cooper, Wendy
    Royal Prince Alfred Hosp, Tissue Pathol & Diagnost Oncol, Sydney, NSW, Australia..
    Mino-Kenudson, Mari
    Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA..
    Motoi, Noriko
    Natl Canc Ctr, Dept Pathol & Clin Labs, Tokyo, Japan..
    Poleri, Claudia
    Lab Patol Torac, Buenos Aires, DF, Argentina..
    Pelosi, Giuseppe
    Univ Milan, Dept Oncol & Hematol Oncol, Milan, Italy..
    Kerr, Keith
    Aberdeen Royal Infirm, Dept Pathol, Aberdeen, Scotland..
    Aisner, Seena C.
    Rutgers State Univ, Rutgers New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ USA..
    Ishikawa, Yuichi
    Japan Fdn Canc Res, Inst Canc, Div Pathol, Tokyo, Japan..
    Buettner, Reinhard H.
    Cologne Inst Pathol, Cologne, Germany..
    Keino, Naoto
    Univ Tsukuba, Tsukuba Clin Res & Dev Org, Tsukuba, Ibaraki, Japan..
    Yatabe, Yasushi
    Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan..
    Noguchi, Masayuki
    Univ Tsukuba, Inst Basic Med Sci, Dept Pathol, Tsukuba, Ibaraki, Japan..
    The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases2017Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, nr 2, s. 334-346Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise K scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC.

    Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3).

    Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, K scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64.

    Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided. (C) 2017 International Association for the Study of Lung Cancer.

  • 247.
    Thunnissen, Erik
    et al.
    Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands.
    Borczuk, Alain
    Weill Cornell Med, New York, NY USA.
    Flieder, Douglas
    Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA.
    Witte, Birgit
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
    Beasley, Mary
    Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA.
    Chung, Jin-Haeng
    Seoul Natl Univ, Coll Med, Bundang Hosp, Seoul, South Korea.
    Dacic, Sanja
    Univ Pittsburgh, Pathol, Pittsburgh, PA USA.
    Lantuejoul, Sylvie
    Canc Inst Leon Berard, Biopathol, Lyon, France.
    Russell, Prudence
    St Vincents Pathol, Fitzroy, Vic, Australia.
    Den Bakker, Michael
    Maasstad Ziekenhuis, Rotterdam, Netherlands.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brambilla, Elisabeth
    Chu Grenoble, Pathol, Grenoble, France;INSERM, Grenoble, France.
    De Cuba, Erienne
    Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands.
    Geisinger, Kim
    Piedmont Pathol Associates Inc, Hickory, NC USA.
    Hiroshima, Kenzo
    Tokyo Womens Med Univ, Pathol, Yachiyo, Japan.
    Marchevsky, Alberto
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA.
    Minami, Yuko
    Ibarakihigashi Natl Hosp, Natl Hosp Org, Pathol, Tokai, Ibaraki, Japan.
    Moreira, Andre
    Mem Sloan Kettering Canc Ctr, Pathol, 1275 York Ave, New York, NY 10021 USA.
    Nicholson, Andrew
    Royal Brompton & Harefield NHS Fdn Trust, Pathol, London, England;Natl Heart & Lung Inst, London, England.
    Yoshida, Akihiko
    Natl Canc Ctr, Dept Pathol, Tokyo, Japan.
    Tsao, Ming
    Princess Margaret Canc Ctr, Dept Pathol, Toronto, ON, Canada;Univ Toronto, Toronto, ON, Canada.
    Warth, Arne
    Heidelberg Univ Hosp, Heidelberg, Germany.
    Duhig, Edwina
    Sullivan Nicolaides Pathol, Taringa, Qld, Australia.
    Chen, Gang
    Fudang Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China.
    Matsuno, Yoshihiro
    Hokkaido Univ Hosp, Dept Surg Pathol, Sapporo, Hokkaido, Japan.
    Travis, William
    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA.
    Butnor, Kelly
    Univ Vermont, Dept Pathol, Med Ctr, Burlington, VT 05405 USA.
    Cooper, Wendy
    Royal Prince Alfred Hosp, Tissue Pathol & Diagnost Oncol, Sydney, NSW, Australia.
    Mino-Kenudson, Mari
    Massachusetts Gen Hosp, Pathol, Boston, MA 02114 USA.
    Motoi, Noriko
    Natl Canc Ctr, Dept Pathol, Tokyo, Japan.
    Polari, Claudia
    Lab Patol Torac, Buenos Aires, DF, Argentina.
    Pelosi, Giuseppe
    Univ Milan, Dept Oncol & Hematooncol, Milan, Italy.
    Kerr, Keith
    Aberdeen Royal Infirm, Pathol, Aberdeen, Scotland.
    Ishikawa, Yuichi
    Jfcr, Canc Inst, Tokyo, Japan.
    Buettner, Reinhard
    Cologne Inst Pathol, Cologne, Germany.
    Keino, Naoto
    Inst Basic Med Sci, Dept Biostat, Tsukuba, Ibaraki, Japan.
    Yatabe, Yasushi
    Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan.
    Noguchi, Masayuki
    Univ Tsukuba, Fac Med, Dept Pathol, Tsukuba, Ibaraki, Japan.
    The Use of Immunohistochemistry Improves the Diagnosis of SCLC. An International Reproducibility Study in a Demanding Set of Cases2017Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, nr 1, s. S1454-S1455Artikkel i tidsskrift (Annet vitenskapelig)
  • 248.
    Thurner, L.
    et al.
    Univ Saarland, Klin Innere Med 1, Jose Carreras Ctr Immun & Gentherapie, Homburg, Germany..
    Hartmann, S.
    Goethe Univ Hosp Frankfurt, Dr Senckenberg Inst Pathol, Frankfurt, Germany..
    Kemele, M.
    Univ Saarland, Klin Innere Med 1, Jose Carreras Ctr Immun & Gentherapie, Homburg, Germany..
    Fadle, N.
    Univ Saarland, Klin Innere Med 1, Jose Carreras Ctr Immun & Gentherapie, Homburg, Germany..
    Regitz, E.
    Univ Saarland, Klin Innere Med 1, Jose Carreras Ctr Immun & Gentherapie, Homburg, Germany..
    Kim, Y. -J
    Bohle, R. M.
    Saarland Univ, Sch Med, Inst Pathol, Homburg, Germany..
    Nimmesgern, A.
    Univ Saarland, Inst Med Microbiol & Hyg, Homburg, Germany..
    von Mueller, L.
    Univ Saarland, Inst Med Microbiol & Hyg, Homburg, Germany..
    Schneider, N.
    Goethe Univ, Div Rheumatol, Univ Hosp Frankfurt, Frankfurt, Germany..
    Vornanen, M.
    Tampere Univ Hosp, Dept Pathol, Tampere, Finland.;Univ Tampere, Tampere, Finland..
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    de Leval, L.
    CHU Vaudois, Inst Pathol, Lausanne, Switzerland..
    Fuchs, M.
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany..
    Engert, A.
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany..
    Kempf, V. A. J.
    Hosp Johann Wolfgang Goethe Univ, Inst Med Microbiol & Infect Control, Frankfurt, Germany..
    Kueppers, R.
    Univ Duisburg Essen, Inst Cell Biol Canc Res, Sch Med, Essen, Germany..
    Preuss, K. D.
    Univ Saarland, Klin Innere Med 1, Jose Carreras Ctr Immun & Gentherapie, Homburg, Germany..
    Hansmann, M. -L
    Pfreundschuh, M.
    Univ Saarland, Klin Innere Med 1, Jose Carreras Ctr Immun & Gentherapie, Homburg, Germany..
    The role of Moraxella in the pathogenesis of IgD(+) nodular lymphocyte predominant Hodgkin lymphoma2017Inngår i: ONCOLOGY RESEARCH AND TREATMENT, ISSN 2296-5270, Vol. 40, s. 143-143Artikkel i tidsskrift (Annet vitenskapelig)
  • 249.
    Tjernberg, L. O.
    et al.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Huddinge, Sweden..
    Rising, A.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Huddinge, Sweden.;Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Johansson, J.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Huddinge, Sweden.;Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Jaudzems, K.
    Latvian Inst Organ Synth, Riga, Latvia..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Transmissible amyloid2016Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, nr 2, s. 153-163Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.

  • 250. Tjörnstrand, Axel
    et al.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Heurling, Kerstin
    Schöll, Michael
    Gjertsson, Peter
    Himmelman, Jakob
    Itsenko, Oleksiy
    Ragnarsson, Oskar
    Filipsson Nyström, Helena
    Lower 68 Ga-DOTATOC Uptake in Non-Functioning Pituitary Neuroendocrine Tumors Compared to Normal Pituitary Gland - a Proof-of-Concept Study.2019Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: 68 Ga-DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR-expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68 Ga-DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68 Ga-DOTATOC PET in the most common PitNET, i.e. non-functioning (NF)-PitNET.

    DESIGN/METHODS: NF-PitNET patients (n = 9) and controls (n = 13) were examined preoperatively with 68 Ga-DOTATOC PET for 45 min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co-registered using PMOD software. The maximum standard uptake value (SUVmax ) was analyzed in manually outlined regions of interest (ROC) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression.

    RESULTS: Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4-8.5] vs 14.1 [12.5-15.9]; P < .01]. In ROC analysis, the area under the curve was 0.87 (P < .01) for SUVmax , with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF-PitNETs were of gonadotroph (n = 7) and corticotroph (n = 2) origin. SSTR expression was high for SSTR3, low-to-moderate for SSTR2, and low for SSTR1 and SSTR5.

    CONCLUSIONS: This proof-of-concept study shows that 68 Ga-DOTATOC PET can be used to differentiate between normal pituitary tissue and NF-PitNET.

23456 201 - 250 of 282
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