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  • 1.
    Abdsaleh, Shahin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Azavedo, E
    Lindgren, P G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Comparison of core needle biopsy and surgical specimens in malignant breast lesions regarding histological features and hormone receptor expression2008In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 52, no 6, p. 773-775Article in journal (Refereed)
  • 2.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Biosci & Nutr, Novum, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 9-10, p. 1126-1131Article in journal (Refereed)
    Abstract [en]

    Aim: To determine the prognostic significance of co-expression of MYC, BCL-2 and BCL-6 proteins in combination with other biomarkers and clinical characteristics within a population-based cohort of diffuse large B-cell lymphoma (DLBCL) patients uniformly treated with R-CHOP.

    Patients and methods: The immunohistochemical (IHC) expression of CD10, BCL-2, BCL-6, MUM1, MYC, CD5, CD30, Ki-67 and p53 was evaluated in a retrospective, population-based study comprising 188 DLBCL patients treated with R-CHOP and diagnosed in Sweden between 2002 and 2012.

    Results: Patients had a median age at diagnosis of 64 years (26-85 years) with a male:female ratio of 1.4:1. Approximately half (52%) of the patients presented with an International Prognostic Index (IPI) age adjusted (IPIaa)2. Median follow-up time was 51 months (range 0.4-158) and the five-year lymphoma-specific survival (LSS) was 76%, five-year overall survival (OS) was 65% and five-year progression-free survival (PFS) was 61%. A high Ki-67 value was found in 59% of patients, while p53 overexpression was detected in 12% of patients and MYC, BCL-2 and BCL-6 expression were detected in 42%, 55% and 74% of patients, respectively. IPIaa2 (p=0.002), Ki-6770% (p=0.04) and p53 overexpression50% (p=0.02) were associated with inferior LSS and OS. Co-expression of both MYC (>40%) and BCL-2 (>70%) proteins was detected in 27% of patients and correlated with a significantly inferior LSS (p=0.0002), OS (p=0.009) and PFS (p=0.03). In addition, triple expression of MYC, BCL-2 and BCL-6, also correlated with a significantly inferior LSS (p=0.02).

    Conclusion: Concurrent expression of MYC and BCL-2 proteins, as detected by IHC, was strongly associated with an inferior survival in DLBCL patients treated with R-CHOP. Other markers affecting survival were triple expression of MYC, BCL-2 and BCL-6, IPIaa, high Ki-67 and p53 overexpression.

  • 3.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, p. 106-109Article in journal (Refereed)
  • 4.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Cesarini, Kristina G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus2018In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, p. 1-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aβ) reflect the propensity of cortical Aβ aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment. METHODS Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aβ40, Aβ42, and neurotoxic Aβ oligomers/protofibrils, associated with Aβ aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aβ species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale. RESULTS The brain tissue levels of Aβ42 were negatively correlated with CSF Aβ42 (Spearman's r = -0.53, p < 0.05). The Aβ40, Aβ42, and Aβ oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aβ aggregates (p < 0.05). The preoperative CSF Aβ42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aβ aggregates and high brain tissue Aβ42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05). CONCLUSIONS Brain tissue measurements of soluble Aβ species are feasible. Since high Aβ42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aβ species may be associated with the clinical response to shunt treatment.

  • 5. Adam, A
    et al.
    Robison, J
    Lu, J
    Jose, R
    Badran, N
    Vivas-Buitrago, T
    Rigamonti, D
    Sattar, A
    Omoush, O
    Hammad, M
    Dawood, M
    Maghaslah, M
    Belcher, T
    Carson, K
    Hoffberger, J
    Jusué Torres, I
    Foley, S
    Yasar, S
    Thai, Q A
    Wemmer, J
    Klinge, P
    Al-Mutawa, L
    Al-Ghamdi, H
    Carson, K A
    Asgari, M
    de Zélicourt, D
    Kurtcuoglu, V
    Garnotel, S
    Salmon, S
    Balédent, O
    Lokossou, A
    Page, G
    Balardy, L
    Czosnyka, Z
    Payoux, P
    Schmidt, E A
    Zitoun, M
    Sevestre, M A
    Alperin, N
    Baudracco, I
    Craven, C
    Matloob, S
    Thompson, S
    Haylock Vize, P
    Thorne, L
    Watkins, L D
    Toma, A K
    Bechter, Karl
    Pong, A C
    Jugé, L
    Bilston, L E
    Cheng, S
    Bradley, W
    Hakim, F
    Ramón, J F
    Cárdenas, M F
    Davidson, J S
    García, C
    González, D
    Bermúdez, S
    Useche, N
    Mejía, J A
    Mayorga, P
    Cruz, F
    Martinez, C
    Matiz, M C
    Vallejo, M
    Ghotme, K
    Soto, H A
    Riveros, D
    Buitrago, A
    Mora, M
    Murcia, L
    Bermudez, S
    Cohen, D
    Dasgupta, D
    Curtis, C
    Domínguez, L
    Remolina, A J
    Grijalba, M A
    Whitehouse, K J
    Edwards, R J
    Eleftheriou, A
    Lundin, F
    Fountas, K N
    Kapsalaki, E Z
    Smisson, H F
    Robinson, J S
    Fritsch, M J
    Arouk, W
    Garzon, M
    Kang, M
    Sandhu, K
    Baghawatti, D
    Aquilina, K
    James, G
    Thompson, D
    Gehlen, M
    Schmid Daners, M
    Eklund, A
    Malm, J
    Gomez, D
    Guerra, M
    Jara, M
    Flores, M
    Vío, K
    Moreno, I
    Rodríguez, S
    Ortega, E
    Rodríguez, E M
    McAllister, J P
    Guerra, M M
    Morales, D M
    Sival, D
    Jimenez, A
    Limbrick, D D
    Ishikawa, M
    Yamada, S
    Yamamoto, K
    Junkkari, A
    Häyrinen, A
    Rauramaa, T
    Sintonen, H
    Nerg, O
    Koivisto, A M
    Roine, R P
    Viinamäki, H
    Soininen, H
    Luikku, A
    Jääskeläinen, J E
    Leinonen, V
    Kehler, U
    Lilja-Lund, O
    Kockum, K
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Riklund, K
    Söderström, L
    Hellström, P
    Laurell, K
    Kojoukhova, M
    Sutela, A
    Vanninen, R
    Vanha, K I
    Timonen, M
    Rummukainen, J
    Korhonen, V
    Helisalmi, S
    Solje, E
    Remes, A M
    Huovinen, J
    Paananen, J
    Hiltunen, M
    Kurki, M
    Martin, B
    Loth, F
    Luciano, M
    Luikku, A J
    Hall, A
    Herukka, S K
    Mattila, J
    Lötjönen, J
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Jurjević, I
    Miyajima, M
    Nakajima, M
    Murai, H
    Shin, T
    Kawaguchi, D
    Akiba, C
    Ogino, I
    Karagiozov, K
    Arai, H
    Reis, R C
    Teixeira, M J
    Valêncio, C G
    da Vigua, D
    Almeida-Lopes, L
    Mancini, M W
    Pinto, F C G
    Maykot, R H
    Calia, G
    Tornai, J
    Silvestre, S S S
    Mendes, G
    Sousa, V
    Bezerra, B
    Dutra, P
    Modesto, P
    Oliveira, M F
    Petitto, C E
    Pulhorn, H
    Chandran, A
    McMahon, C
    Rao, A S
    Jumaly, M
    Solomon, D
    Moghekar, A
    Relkin, N
    Hamilton, M
    Katzen, H
    Williams, M
    Bach, T
    Zuspan, S
    Holubkov, R
    Rigamonti, A
    Clemens, G
    Sharkey, P
    Sanyal, A
    Sankey, E
    Rigamonti, K
    Naqvi, S
    Hung, A
    Schmidt, E
    Ory-Magne, F
    Gantet, P
    Guenego, A
    Januel, A C
    Tall, P
    Fabre, N
    Mahieu, L
    Cognard, C
    Gray, L
    Buttner-Ennever, J A
    Takagi, K
    Onouchi, K
    Thompson, S D
    Thorne, L D
    Tully, H M
    Wenger, T L
    Kukull, W A
    Doherty, D
    Dobyns, W B
    Moran, D
    Vakili, S
    Patel, M A
    Elder, B
    Goodwin, C R
    Crawford, J A
    Pletnikov, M V
    Xu, J
    Blitz, A
    Herzka, D A
    Guerrero-Cazares, H
    Quiñones-Hinojosa, A
    Mori, S
    Saavedra, P
    Treviño, H
    Maitani, K
    Ziai, W C
    Eslami, V
    Nekoovaght-Tak, S
    Dlugash, R
    Yenokyan, G
    McBee, N
    Hanley, D F
    Abstracts from Hydrocephalus 2016.2017In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, no Suppl 1, article id 15Article in journal (Refereed)
  • 6. Aho, Leena
    et al.
    Jolkkonen, Jukka
    Alafuzoff, Irina
    Kuopio University, Finland.
    Beta-amyloid aggregation in human brains with cerebrovascular lesions.2006In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 37, no 12, p. 2940-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: The present study assessed beta-amyloid (Abeta) protein aggregates in postmortem human brains in subjects who had experienced stroke to examine the proposed association between ischemic stress and the accumulation of Abeta reported in rodents.

    METHODS: A sample of 484 postmortem brains from nondemented subjects, lacking isocortical neurodegenerative pathology with verified cerebrovascular lesions, and 57 age-matched controls were assessed with respect to Abeta, Abeta40, and Abeta42 aggregates in the cortex and thalamus by immunohistochemical techniques.

    RESULTS: The load of Abeta aggregates did not display a significant association with cerebrovascular lesions. The load of Abeta, Abeta40, and Abeta42 aggregates increased with age, and there was a tendency toward higher odds ratios for Abeta aggregates, though not statistically significant, in subjects with acute cerebrovascular lesions. In the oldest subjects with cerebrovascular lesions and with both thalamic and cortical Abeta aggregates, the load of thalamic Abeta42 was significantly higher than the load of Abeta40.

    CONCLUSIONS: Our findings indicate that cerebrovascular disease does not influence the load of Abeta, whereas a shift of aggregation from the Abeta40 to the Abeta42 residue is noted in the thalamus but only in aged subjects. It is impossible, however, to state whether this result is attributable to increased Abeta production, its insufficient elimination, or other susceptibility factors.

  • 7. Aho, Leena
    et al.
    Parkkinen, Laura
    Pirttila, Tuula
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Systematic appraisal using immunohistochemistry of brain pathology in aged and demented subjects.2008In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 25, no 5, p. 423-32Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIMS: Abnormal processing of hyperphosphorylated tau (HPtau), amyloid-beta (Abeta) and alpha-synuclein (alphaS) proteins is considered as causative with regard to the clinical symptoms in age-related neurodegenerative diseases.

    METHODS: In this retrospective, postmortem study applying immunohistochemical methodology, we assessed Alzheimer's-disease (AD)-related HPtau and Abeta pathology in 178 subjects with alphaS pathology.

    RESULTS: These pathologies were frequently seen concomitantly, i.e. HPtau in 83% and Abeta in 62% of the alphaS-positive cases. Furthermore, the striatum was frequently involved, particularly in subjects with cognitive impairment (65%). The predictive value of widespread HPtau pathology, i.e. stages V-VI, with respect to cognitive impairment was high, since all 18 subjects presenting with this stage were demented. In contrast, the predictive value of widespread alphaS pathology, i.e. stages 5-6 according to Braak's Parkinson disease staging, was debatable. Fifty-three percent of the subjects with widespread alphaS pathology and no or mild AD-related HPtau pathology were cognitively unimpaired. It is noteworthy that striatal Abeta pathology was more often seen in demented subjects independently of HPtau and/or alphaS status.

    CONCLUSION: The causative pathology in subjects with clinically diagnosed dementia with Lewy bodies needs to be clarified in future studies.

  • 8. Aho, Leena
    et al.
    Pikkarainen, Maria
    Hiltunen, Mikko
    Leinonen, Ville
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Immunohistochemical Visualization of Amyloid-β Protein Precursor and Amyloid-β in Extra- and Intracellular Compartments in the Human Brain2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 4, p. 1015-1028Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta (Abeta) peptide, a cleavage product of the amyloid-beta protein precursor (AbetaPP), has been reported to be detected in the intracellular compartment. Most studies reporting the presence of intracellular Abeta are based on the use of immunohistochemistry. In this study, the presence of AbetaPP and Abeta was assessed by applying immunohistochemistry in postmortem human brain tissue samples obtained from 10 neurologically intact subjects, the youngest being 2 years of age, one aged with mild cognitive impairment, 14 neurologically diseased, and in one brain biopsy sample obtained from a subject with normal pressure hydrocephalus. Intracellular immunoreactivity was detected in all ages independent of the disease state or existence of extracellular Abeta aggregates with all antibodies directed to AbetaPP, with three Abeta antibodies (4G8, 6E10, and 82E1), clones that are unable to distinguish Abeta from AbetaPP. These results suggest that it is AbetaPP rather than Abeta that is detected intracellularly when using the antibodies listed above. Furthermore, the staining results varied when different pretreatment strategies were applied. Interestingly intracellular Abeta was detected with antibodies directed to the C-terminus of Abeta (neoepitope) in subjects with Alzheimer's disease. The lack of intracellular immunoreactivity in unimpaired subjects, when using antibodies against neoepitopes, may be due to a lack or a low level of the protein that is thus undetectable at light microscopic level by immunohistochemistry method. The staining results and conclusions depended strongly on the chosen antibody and the pretreatment strategy and thus multiple antibodies must be used when assessing the intracellular accumulation of Abeta.

  • 9.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alzheimerin tauti: (Alzheimer’s sjukdom)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1029-1031Chapter in book (Other academic)
  • 10.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alzheimer's disease-related lesions2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, no Suppl 1, p. S173-S179Article, review/survey (Refereed)
    Abstract [en]

    The invitation to contribute to "Alzheimer's Disease: Advances for a New Century" gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that the degenerative process is initiated much earlier than we ever suspected.

  • 11.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Cerebral amyloid angiopathy, hemorrhages and superficial siderosis.2008In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 39, no 10, p. 2699-700Article in journal (Refereed)
  • 12.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Frontotemporaaliset lobaariset degeneraatiot: (Frontoremporal degeneration)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1032-1033Chapter in book (Other academic)
  • 13.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Minimal neuropathologic diagnosis for brain banking in the normal middle-aged and aged brain and in neurodegenerative disorders.2018In: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 150, p. 131-141, article id B978-0-444-63639-3.00010-4Article in journal (Refereed)
    Abstract [en]

    Research on human brain diseases is currently often conducted on cell cultures and animals. Several questions however can only be addressed by studying human postmortem brain tissue. However, brain tissue obtained postmortem almost always displays pathology that is often related to the aging phenomenon. Thus, in order to be certain that the answers obtained are reliable, a systematic and thorough assessment of the brain tissue to be studied should be carried out. We are currently aware of several protein alterations that are found in middle-aged and aged brains that are obtained from neurologically unimpaired subjects. The most common alteration is hyperphosphorylation of τ, observed in both neurons and glial cells, in certain brain regions, followed by β-amyloid aggregation in the neuropil and vessel walls. Less common protein alterations are those noted for α-synuclein and Tar DNA-binding protein 43. It is noteworthy that these alterations, when found in excess, are diagnostic for various neurodegenerative diseases, such as Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Parkinson disease, Lewy body dementia, and frontotemporal lobar degeneration. Since 1990, the neuropathology community has been aware that these protein alterations tend to progress in an orderly neuroanatomically defined manner and have thus designed a method to define a stage or a phase of the protein alteration. The neuropathology community has defined an initiation site, or neuroanatomic area that they presume the alteration originates from, and defined a presumed pattern of progression from the initiation site to other brain areas. Thus a reliable and reproducible description of each case regarding these alterations can be achieved. In addition to the above alterations, the brain tissue is also prone to various vascular alterations that should be registered as seen or not seen even if the significance of these alterations is still unclear.

  • 14.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Neuropatologinen tutkimus: Neuropatologisk undersökning2010In: Muistisairaudet: (Minnestörningar) / [ed] Erkinjuntti T, Rinne J, Soininen H, Helsingfors: Duodecim , 2010, 1, p. 438-446Chapter in book (Other academic)
  • 15.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Neuropatologinen tutkimus: Neuropatologisk undersökning2015In: Muistisairaudet: (Minnestörningar) / [ed] Erkinjuntti T, Rinne J, Soininen H, Helsingfors: Duodecim , 2015, 2, p. 426-434Chapter in book (Other academic)
  • 16.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Parkinsonin tauti ja lewynkappaledementia: (Parkinsons sjukdom)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1031-1032Chapter in book (Other academic)
  • 17.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Rapeuttavat aivosairaudet: (Degenerativa hjärnsjukdomar)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1023-1028Chapter in book (Other academic)
  • 18.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Techniques in neuropathology.2017In: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, p. 3-7, article id B978-0-12-802395-2.00001-8Article in journal (Refereed)
    Abstract [en]

    The primary objective for a neuropathologist is the characterization of the tissue that is being assessed and thus all available techniques ranging from naked-eye examination to assessment of genetic/epigenetic characteristics are currently applied. What is observed in the tissue obtained from a diseased subject is compared with what is observed in a healthy individual and, based on the outcome, neuropathologic definitions of diseases are constructed. Thus, with the naked eye a neuropathologist can confirm that a hemorrhage is observed in the brain, by histologic examination that the hemorrhage is caused by alterations in the brain vessels and, since 1954, applying Congo red dye neuropathologists have been able to state that congophilic angiopathy is detected. Since 1984, applying immunohistochemical methods neuropathologists have been able to verify that the protein seen in the vessel walls is β-amyloid and by genetic/epigenetic analysis eventual mutation or modifications of genome might be detected. The development of new techniques is staggering and throughout this book the authors have listed techniques currently applied while assessing various disease-related hallmark lesions. In the following a general summary of techniques applied is given.

  • 19.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Arzberger, Thomas
    Al-Sarraj, Safa
    Bodi, Istvan
    Bogdanovic, Nenad
    Braak, Heiko
    Bugiani, Orso
    Del-Tredici, Kelly
    Ferrer, Isidro
    Gelpi, Ellen
    Giaccone, Giorgio
    Graeber, Manuel B
    Ince, Paul
    Kamphorst, Wouter
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G
    Larionov, Sergey
    Meyronet, David
    Monoranu, Camelia
    Parchi, Piero
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Seilhean, Danielle
    Tagliavini, Fabrizio
    Stadelmann, Christine
    Streichenberger, Nathalie
    Thal, Dietmar R
    Wharton, Stephen B
    Kretzschmar, Hans
    Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe Consortium.2008In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 18, no 4, p. 484-96Article in journal (Refereed)
    Abstract [en]

    It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and beta-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-microm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V-VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I-II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.

  • 20.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hartikainen, Päivi
    Alpha-synucleinopathies.2017In: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, p. 339-353, article id B978-0-12-802395-2.00024-9Article in journal (Refereed)
    Abstract [en]

    A neurodegenerative disorder displaying an altered α-synuclein (αS) in the brain tissue is called α-synucleinopathy (αS-pathy) and incorporates clinical entities such as Parkinson disease (PD), PD with dementia, dementia with Lewy bodies, and multiple-system atrophy. Neuroradiologic techniques visualizing αS pathology in the brain or assays of αS in the cerebrospinal fluid or blood are probably available and will be implemented in the near future but currently the definite diagnosis of αS-pathy relies on a postmortem examination of the brain. Since the 1980s immunohistochemical technique based on the use of antibodies directed to proteins of interest has become a method of choice for neuropathologic diagnosis. Furthermore, since the 1990s it has been acknowledged that progressions of most neurodegenerative pathologies follow a certain predictable time-related neuroanatomic distribution. Currently, for Lewy body disease, two staging techniques are commonly used: McKeith and Braak staging. Thus, the neuropathologic diagnosis of a αS-pathy is based on detection of altered αS in the tissue and registration of the neuroanatomic distribution of this alteration in the brain. The clinicopathologic correlation is not absolute due to the quite frequent observation of incidental and concomitant αS pathology.

  • 21.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Kovacs, Gabor G
    Comorbidities.2017In: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, p. 573-577, article id B978-0-12-802395-2.00036-5Article in journal (Refereed)
    Abstract [en]

    The term comorbidities or mixed pathologies is used when brain tissue, a surgical sample, or postmortem brain displays a mixture of protein alterations or other pathologies. Most of the alterations when seen in sufficient extent are considered causative, are related to a certain clinical phenotype, i.e., when hyperphosphorylated τ (HPτ) is observed in occipital cortex concomitant with β-amyloid (Aβ), the diagnosis is Alzheimer disease (AD). When HPτ is observed in hippocampal structures in a subject with extensive and widespread α-synuclein pathology, a Lewy body disease (LBD), the HPτ pathology is considered as a concomitant alteration. There are numerous reports indicating that when "concomitant" pathologies are seen in a subject with certain neurodegenerative diseases, the clinical phenotype might be altered. In addition there are those cases where many alterations are seen in a sparse extent, but jointly they lead to a clinical syndrome. Thus today it is not sufficient to confirm a certain pathology to be seen, i.e., AD- or LBD-related; in addition the concomitant aging-related alterations have to be looked for.

  • 22.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Parkkinen, Laura
    Staged pathology in Parkinson's disease2014In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 20, no Suppl. 1, p. S57-S61Article in journal (Refereed)
    Abstract [en]

    There has been a tremendous development since a regional progression of pathology in subjects with Lewy bodies (LB) was initially proposed 30 years ago. The entity of dementia with Lewy bodies has been acknowledged, the main protein constituent of LBs--aggregated α-synuclein (αS)--has been identified and a stepwise progression of the pathology has been reported. Implementation of the staging strategies published provides a common ground for handling a case with a suspected α-synucleinopathy. It is always important to state the staging strategy implemented while assessing a case, as the strategy applied might influence both the reported stage of LB pathology and, ultimately, the final diagnosis of the patient.

  • 23.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Parkkinen, Laura
    Al-Sarraj, Safa
    Arzberger, Thomas
    Bell, Jeanne
    Bodi, Istvan
    Bogdanovic, Nenad
    Budka, Herbert
    Ferrer, Isidro
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Kamphorst, Wouter
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G
    Larionov, Sergey
    Meyronet, David
    Monoranu, Camelia
    Morris, Jodie
    Parchi, Piero
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Seilhean, Danielle
    Streichenberger, Nathalie
    Thal, Dietmar R
    Kretzschmar, Hans
    Assessment of alpha-synuclein pathology: a study of the BrainNet Europe Consortium.2008In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 67, no 2, p. 125-43Article in journal (Refereed)
    Abstract [en]

    To determine the reliability of assessment of alpha-synuclein-immunoreactive (alphaS-IR) structures by neuropathologists, 28 evaluators from 17 centers of BrainNet Europe examined current methods and reproducibility of alphaS-IR evaluation using a tissue microarray (TMA) technique. Tissue microarray blocks were constructed of samples from the participating centers that contained alphaS-IR structures. Slides from these blocks were stained in each center and assessed for neuronal perikaryal inclusions, neurites, and glial cytoplasmic inclusions. The study was performed in 2 phases. First, the TMA slides were stained with the antibody of the center's choice. In this phase, 59% of the sections were of good or acceptable quality, and 4 of 9 antibodies used performed consistently. Differences in interpretation and categorization of alphaS-IR structures, however, led to differing results between the laboratories. Prior to the second phase, the neuropathologists participated in a training session on the evaluation of alphaS-IR structures. Based on the results of the first phase, selected antibodies using designated antigen retrieval methods were then applied to TMA slides in the second phase. When the designated methods of both staining and evaluation were applied, all 26 subsequently stained TMA sections evaluated were of good/acceptable quality, and a high level of concordance in the assessment of the presence or absence of specific alphaS-IR structures was achieved. A semiquantitative assessment of alphaS-IR neuronal perikaryal inclusions yielded agreements ranging from 49% to 82%, with best concordance in cortical core samples. These results suggest that rigorous methodology and dichotomized assessment (i.e. determining the presence or absence of alphaS-IR) should be applied, and that semiquantitative assessment can be recommended only for the cortical samples. Moreover, the study demonstrates that there are limitations in the scoring of alphaS-IR structures.

  • 24.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pikkarainen, M
    Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
    Parkkinen, L
    Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
    Synucleinopathies2015In: Neuropathology of neurodegenerative diseases: A practical guide / [ed] Gabor G Kovacs, Cambridge University Press, 2015, p. 149-175Chapter in book (Refereed)
    Abstract [en]

    Definition, structure and biochemical background Similar to other “proteinopathies,” the process that links α-synuclein (αS) protein to disease pathogenesis originated from the discovery that a single point mutation in the αS gene (i.e. SNCA) can cause autosomal-dominant Parkinson’s disease (PD) [1]. This was followed by the breakthrough finding that the actual transcribed protein was a major fibrillar component of pathological hallmarks known as Lewy bodies (LBs), Lewy neurites (LNs) and glial cytoplasmic inclusions characterizing a heterogeneous group of diseases, now collectively referred to as “synucleinopathies,” i.e. PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) [2, 3]. Currently, there are five missense mutations (pA53T, p.A30P, p.E46K, p.H50Q and p.G51D) [1, 4–8] and multiplication mutations (SNCA duplication and triplication) [9–11] that are genetically linked to clinical parkinsonism (Table 9.1). This genetic and pathological linkage establishes αS as an important player in the development of these disorders.

  • 25.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Pikkarainen, Maria
    Arzberger, Thomas
    Thal, Dietmar R
    Al-Sarraj, Safa
    Bell, Jeanne
    Bodi, Istvan
    Budka, Herbert
    Capetillo-Zarate, Estibaliz
    Ferrer, Isidro
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Kavantzas, Nikolaos
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G
    Meyronet, David
    Monoranu, Camelia
    Parchi, Piero
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Stadelmann, Christine
    Streichenberger, Nathalie
    Tagliavini, Fabricio
    Kretzschmar, Hans
    Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein: a study of the BrainNet Europe consortium.2008In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 115, no 5, p. 533-46Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta-protein (Abeta) is generally assessed by neuropathologists in diagnostics. This BrainNet Europe ( http://www.brainnet-europe.org/ ) (15 centres and 26 participants) study was carried out to investigate the reliability of such an assessment. In the first part of this trial, tissue microarray sections were stained with the antibody of each centre's choice. Reflecting the reality, seven antibodies and a plethora of pretreatment strategies were used. Ninety-two percent of the stainings were of good/acceptable quality and the estimation of presence of Abeta aggregates yielded good results. However, a poor agreement was reached particularly regarding quantitative (density) and qualitative (diffuse/cored plaques) results. During a joint meeting, the clone 4G8 was determined to label best the fleecy/diffuse plaques, and thus, this clone and the formic acid pretreatment technique were selected for the second part of this study. Subsequently, all stained sections were of good/acceptable quality and again a high level of concordance of the dichotomized (presence/absence) assessment of plaques and CAA was achieved. However, even when only one antibody was used, the type of Abeta-aggregates (diffuse/cored), type of vessel and Vonsattel grade, were not reliably assigned. Furthermore, the quantification of lesions was far from reliable. In line with the first trial, the agreement while assessing density (some, moderate and many) was unimpressive. In conclusion, we can confirm the utility of immunohistochemical detection of Abeta-protein in diagnostics and research. It is noteworthy that to reach reproducible results a dichotomized assessment of Abeta-immunoreactivity rather than quantification and assignment of various types of lesions should be applied, particularly when comparing results obtained by different neuropathologists.

  • 26.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Popova, Svetlana N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wanders, Alkwin
    Department of Clinical Pathology and Cytology, Umea University Hospital, Umea, Sweden.
    Veress, Bela
    Department of Clinical Pathology and Cytology, Skane University Hospital, Malmo, Sweden.
    Neuronal Protein Alteration in Enteric Dysmotility Syndrome2016In: Journal of Alzheimer’s Disease & Parkinsonism, ISSN 2161-0460, Vol. 6, no 1, article id 1000212Article in journal (Other academic)
  • 27. Alamdari, Nima
    et al.
    Toraldo, Gianluca
    Aversa, Zaira
    Smith, Ira J
    Castillero, Estibaliz
    Renaud, Guillaume
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Qaisar, Rizwan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Jasuja, Ravi
    Hasselgren, Per-Olof
    Loss of muscle strength during sepsis is in part regulated by glucocorticoids and is associated with reduced muscle fiber stiffness2012In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 303, no 10, p. R1090-R1099Article in journal (Refereed)
    Abstract [en]

    Sepsis is associated with impaired muscle function but the role of glucocorticoids in sepsis-induced muscle weakness is not known. We tested the role of glucocorticoids in sepsis-induced muscle weakness by treating septic rats with the glucocorticoid receptor antagonist RU38486. In addition, normal rats were treated with dexamethasone to further examine the role of glucocorticoids in the regulation of muscle strength. Sepsis was induced in rats by cecal ligation and puncture and muscle force generation (peak twitch and tetanic tension) was determined in lower extremity muscles. In other experiments, absolute and specific force as well as stiffness (reflecting the function of actomyosin cross-bridges) were determined in isolated skinned muscle fibers from control and septic rats. Sepsis and treatment with dexamethasone resulted in reduced maximal twitch and tetanic force in intact isolated extensor digitorum longus muscles. The absolute and specific maximal force in isolated muscle fibers was reduced during sepsis together with decreased fiber stiffness. These effects of sepsis were blunted (but not abolished) by RU38486. The results suggest that muscle weakness during sepsis is at least in part regulated by glucocorticoids and reflects loss of contractility at the cellular (individual muscle fiber) level. In addition, the results suggest that reduced function of the cross-bridges between actin and myosin (documented as reduced muscle fiber stiffness) may be involved in sepsis-induced muscle weakness. An increased understanding of mechanisms involved in loss of muscle strength will be important for the development of new treatment strategies in patients with this debilitating consequence of sepsis.

  • 28.
    Albertsson-Lindblad, Alexandra
    et al.
    Skane Univ Hosp, Dept Oncol, SE-22185 Lund, Sweden..
    Kolstad, Arne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Laurell, Anna
    Univ Uppsala Hosp, Dept Oncol, Uppsala, Sweden..
    Raty, Riikka
    Helsinki Univ Hosp, Dept Hematol, Helsinki, Finland..
    Gronbaek, Kirsten
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Sundberg, Jan
    Skane Univ Hosp, Dept Oncol, SE-22185 Lund, Sweden..
    Pedersen, Lone Bredo
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Ralfkiaer, Elisabeth
    Rigshosp, Dept Pathol, Copenhagen, Denmark..
    Karjalainen-Lindsberg, Marja-Liisa
    Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland..
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden; and..
    Ehinger, Mats
    Univ Lund Hosp, Dept Pathol Cytol, Lund, Sweden..
    Geisler, Christian
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Jerkeman, Mats
    Skane Univ Hosp, Dept Oncol, SE-22185 Lund, Sweden..
    Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 14, p. 1814-1820Article in journal (Refereed)
    Abstract [en]

    For elderly patients with mantle cell lymphoma (MCL), there is no defined standard therapy. In this multicenter, open-label phase 1/2 trial, we evaluated the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment for elderly patients with MCL. Patients >65 years with untreated MCL, stages II-IV were eligible for inclusion. Primary end points were maximally tolerable dose (MTD) of LEN and progression-free survival (PFS). Patients received 6 cycles every four weeks of L-B-R (L D1-14, B 90 mg/m(2) IV, days 1-2 and R 375 mg/m(2) IV, day 1) followed by single LEN (days 1-21, every four weeks, cycles 7-13). Fifty-one patients (median age 71 years) were enrolled from 2009 to 2013. In phase 1, the MTD of LEN was defined as 10 mg in cycles 2 through 6, and omitted in cycle 1. After 6 cycles, the complete remission rate (CRR) was 64%, and 36% were MRD negative. At a median follow-up time of 31 months, median PFS was 42 months and 3-year overall survival was 73%. Infection was the most common nonhematologic grade 3 to 5 event and occurred in 21 (42%) patients. Opportunistic infections occurred in 3 patients: 2 Pneumocystis carinii pneumonia and 1 cytomegalovirus retinitis. Second primary malignancies (SPM) were observed in 8 patients (16%). LEN could safely be combined with R-B when added from the second cycle in patients with MCL, and was associated with a high rate of CR and molecular remission. However, we observed a high degree of severe infections and an unexpected high number of SPMs, which may limit its use. This trial is registered at www.Clinicaltrials.gov as #NCT00963534.

  • 29. Alfstad, K Å
    et al.
    Lossius, M I
    Røste, G K
    Mowinckel, P
    Scheie, D
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Dept. of Laboratory medicine/Pathology, Umeå University, Umeå Sweden.
    Larsson, P G
    Nakken, K O
    Acute postoperative seizures after epilepsy surgery: a long-term outcome predictor?2011In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, no 1, p. 48-53Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The prognostic value of acute postoperative seizures (APS) after epilepsy surgery is much debated. This study evaluated APS, defined as seizures in the first week post-surgery, as a predictor of long-term seizure outcome, and investigated the utility of other potential outcome predictors.

    MATERIALS AND METHODS: Medical records of 48 patients with temporal and extra-temporal epilepsy surgery were studied. Forty patients had lesional surgery. All had at least 2 year postoperative follow-up.

    RESULTS: At 2 year follow-up, 25 patients (53%) were seizure free. Univariate analysis showed that APS (P = 0.048), using ≥ six AEDs prior to surgery (P = 0.03), pathological postoperative EEG (P = 0.043) and female gender (P = 0.012) were associated with seizure recurrence.

    CONCLUSIONS: Univariate analysis indicate that APS, a high number of AEDs used prior to surgery, and pathological postoperative EEG are possible predictors of seizure recurrence after epilepsy surgery. Only gender retained significance in the multivariate analysis.

  • 30. Allander, Susanne Vilhelmsdotter
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Marké, Lars-Åke
    Svensson, Maria K
    Björn, Wihlén
    Elinder, Carl-Gustaf
    Kreatinin fortfarande den vanligaste njurfunktionsanalysen: Undersökning av praxis i Sverige2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 19, p. 960-962Article in journal (Refereed)
    Abstract [en]

    Markers of renal function (glomerular filtration rate; GFR) are frequently used. In most cases GFR is estimated based on plasma creatinine, but cystatin C, creatinine clearance (with urine collection), iohexol clearance and 51Cr-EDTA clearance are also used. A questionnaire was sent to representatives for clinical chemistry laboratories in Sweden to collect information regarding the use of these markers during the years 2006 2009. The aim was to compare the use in different parts of Sweden and how it has changed over time. The overall use of markers of renal function, including creatinine, continues to increase on a national level, with the exception for endogenous creatinine clearance and 51Cr-EDTA clearance. Creatinine, the most frequently used marker, continues to grow in numbers. 5,6 million creatinine analyses and about two hundred thousand cystatin C analyses were performed during year 2009. There were considerable variations between counties in the use of the studied markers.

  • 31.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    [Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research].2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, article id EMDHArticle in journal (Refereed)
    Abstract [sv]

    Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research Core needle biopsies (CNBs) are widely used in clinical diagnostic labs to aid in the diagnosis of malignant lymphomas and in latter years their use is increasing. CNBs provide a rapid method for obtaining tumour material and may be beneficial when the affected lymph nodes are located deep in the abdominal cavity or mediastinum and surgical excisional biopsies may be difficult to perform. However, according to the Swedish Haematopathology Quality and Standardization Committee, CNBs are insufficient for lymphoma diagnostic purposes and the guidelines state that material from surgical excisional biopsies are mandatory in order to obtain a robust histopathological evaluation of the lymph node architecture, cellular composition and growth pattern. Surgical excision biopsies also ensure that adequate material is available if additional molecular analyses should be required and also to facilitate future research.

  • 32. Amirian, E Susan
    et al.
    Armstrong, Georgina N
    Zhou, Renke
    Lau, Ching C
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill S
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Lachance, Daniel
    Olson, Sara H
    Bernstein, Jonine L
    Merrell, Ryan T
    Wrensch, Margaret R
    Davis, Faith G
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I
    Scheurer, Michael E
    Aldape, Kenneth
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Brännström, Thomas
    Broholm, Helle
    Collins, Peter
    Giannini, Caterina
    Rosenblum, Marc
    Tihan, Tarik
    Melin, Beatrice S
    Bondy, Melissa L
    The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium2016In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 183, no 2, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

  • 33.
    Andersson, Sandra
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Danielsson, Angelika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhlen, Mathias
    Asplund, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e115911-Article in journal (Refereed)
    Abstract [en]

    Background: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue-specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas-strategy that combines high throughput transcriptomics with affinity-based proteomics. Results: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59. Conclusions: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images.

  • 34. Asa, S L
    et al.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Chanson, P
    Delgrange, E
    Earls, P
    Ezzat, S
    Grossman, A
    Ikeda, H
    Inoshita, N
    Karavitaki, N
    Korbonits, M
    Laws, E R
    Lopes, M B
    Maartens, N
    McCutcheon, I E
    Mete, O
    Nishioka, H
    Raverot, G
    Roncaroli, F
    Saeger, W
    Syro, L V
    Vasiljevic, A
    Villa, C
    Wierinckx, A
    Trouillas, J
    From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal2017In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 4, p. C5-C8Article in journal (Refereed)
    Abstract [en]

    The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

  • 35.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asawa, Kenta
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Yuuki, Inoue
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Ishihara, Kazuhiko
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Lindell, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Holmgren, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ryden, Anneli
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden.
    Jensen-Waern, Marianne
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
    Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models2019In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed)
    Abstract [en]

    Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

  • 36.
    Axelson, Hans W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Microdialysis and electromyography of experimental muscle fatigue in healthy volunteers and patients with mitochondrial myopathy2002In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 26, no 4, p. 520-526Article in journal (Refereed)
    Abstract [en]

    Consecutive 60-min microdialysis samples were taken from the tibial anterior muscle in 11 healthy subjects and 4 patients with mitochondrial myopathy before (2-3 samples) and after (3-4 samples, 2 controls and 1 patient excluded) sustained isometric foot dorsiflexions. Before exercise, mean concentrations of lactate, pyruvate, hypoxanthine, urate, aspartate, and glutamate did not significantly differ between controls and patients. After exercise, the controls showed significantly increased concentrations of lactate, pyruvate, and urate, decreased hypoxanthine, and no change in aspartate and glutamate. Similar findings were observed in the patients. Plasma lactate was unchanged. Exercise-induced increase in integrated electromyogram amplitude and rated subjective fatigue were correlated to increased post-exercise lactate concentrations, with no obvious difference between the groups. Microdialysis of skeletal muscle allows the detection and monitoring of biochemical changes in the interstitial space. With the exercise protocol used, however, it was not possible to demonstrate any biochemical difference between healthy controls and patients with mitochondrial myopathy.

  • 37.
    Axelson, Hans W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Öberg, Gunnar
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Successful repeated treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP2009In: BMJ case reports, ISSN 1757-790XArticle in journal (Refereed)
    Abstract [en]

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterised by the occurrence of symmetrical weakness and sensory impairment in arms and legs. The course is relapsing or chronic and progressing. CIDP is considered to be an autoimmune disease, which is supported by the beneficial response to immunomodulating therapies in most patients. We report on a patient with CIDP who has been in remission for more than 3 years after treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP on two occasions.

  • 38.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala Univ Hosp, Dept Clin Genet, Uppsala, Sweden.
    Kättström, Magdalena
    Orebro Univ Hosp, Dept Med, Sect Hematol, Orebro, Sweden.
    Rossing, Maria
    Copenhagen Univ Hosp, Ctr Genom Med, Copenhagen, Denmark.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Refractory chronic "ITP": When platelet size matters2018In: Clinical Case Reports, E-ISSN 2050-0904, Vol. 6, no 9, p. 1779-1780Article in journal (Refereed)
    Abstract [en]

    Key Clinical Message Inherited conditions associated with thrombocytopenia should be included in the differential diagnosis of young patients with refractory immune thrombocytopenia (ITP), even in the absence of a positive family history. Early identification of such conditions is of vital importance in order to reach the right diagnosis and avoid unnecessary or even harmful medication.

  • 39. Bell, Jeanne E
    et al.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Al-Sarraj, Safa
    Arzberger, Thomas
    Bogdanovic, Nenad
    Budka, Herbert
    Dexter, David T
    Falkai, Peter
    Ferrer, Isidro
    Gelpi, Elena
    Gentleman, Steven M
    Giaccone, Giorgio
    Huitinga, Inge
    Ironside, James W
    Klioueva, Natasja
    Kovacs, Gabor G
    Meyronet, David
    Palkovits, Miklos
    Parchi, Piero
    Patsouris, Efstatios
    Reynolds, Richard
    Riederer, Peter
    Roggendorf, Wolfgang
    Seilhean, Danielle
    Schmitt, Andrea
    Schmitz, Peer
    Streichenberger, Nathalie
    Schwalber, Ameli
    Kretzschmar, Hans
    Management of a twenty-first century brain bank: experience in the BrainNet Europe consortium.2008In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 115, no 5, p. 497-507Article in journal (Refereed)
    Abstract [en]

    Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.

  • 40. Bender, Nicole
    et al.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Andersen, Berit
    Hocking, Jane S
    van Bergen, Jan
    Morgan, Jane
    van den Broek, Ingrid Vf
    Zwahlen, Marcel
    Low, Nicola
    Chlamydia infection, pelvic inflammatory disease, ectopic pregnancy and infertility: cross-national study2011In: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, Vol. 87, no 7, p. 601-608Article in journal (Refereed)
    Abstract [en]

    Objectives To describe, using routine data in selected countries, chlamydia control activities and rates of chlamydia infection, pelvic inflammatory disease (PID), ectopic pregnancy and infertility and to compare trends in chlamydia positivity with rates of PID and ectopic pregnancy. Methods Cross-national comparison including national data from Australia, Denmark, the Netherlands, New Zealand, Sweden and Switzerland. Routine data sources about chlamydia diagnosis and testing and International Classification of Disease-10 coded diagnoses of PID, ectopic pregnancy and infertility in women aged 15-39 years from 1999 to 2008 were described. Trends over time and relevant associations were examined using Poisson regression. Results Opportunistic chlamydia testing was recommended in all countries except Switzerland, but target groups differed. Rates of chlamydia testing were highest in New Zealand. Chlamydia positivity was similar in all countries with available data (Denmark, New Zealand and Sweden) and increased over time. Increasing chlamydia positivity rates were associated with decreasing PID rates in Denmark and Sweden and with decreasing ectopic pregnancy rates in Denmark, New Zealand and Sweden. Ectopic pregnancy rates appeared to increase over time in 15-19-year-olds in several countries. Trends in infertility diagnoses were very variable. Conclusions The intensity of recommendations about chlamydia control varied between countries but was not consistently related to levels of chlamydia diagnosis or testing. Relationships between levels of chlamydia infection and complication rates between or within countries over time were not straightforward. Development and validation of indicators of chlamydia-related morbidity that can be compared across countries and over time should be pursued.

  • 41.
    Benson, Merrill D.
    et al.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA.
    Buxbaum, Joel N.
    Scripps Res Inst, Dept Mol Med, La Jolla, CA USA.
    Eisenberg, David S.
    Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA USA.
    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, Porto, Portugal.
    Sekijima, Yoshiki
    Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano, Japan.
    Sipe, Jean D.
    Boston Univ, Sch Med, Dept Biochem, Boston, MA USA.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee2018In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 4, p. 215-219Article in journal (Refereed)
    Abstract [en]

    The nomenclature committee of the International Society of Amyloidosis (ISA) meets every second year to discuss and formulate recommendations. The conclusions from the discussion at the XVI International Symposium on Amyloidosis in Kumamoto, Japan, 25–29 March 2018 and afterwards are summarized in this Nomenclature Article. From having recommended the use of the designation “amyloid fibril” for in vivo material only, ISA’s nomenclature committee now accepts its use more broadly following the international scientific literature. However, it is important always to stress the origin of the β-fibrils in order to avoid misunderstanding. Given the more broad use of the word “amyloid” several classes of amyloid fibrils may be distinguished. For the medical in vivo situation, and to be included in the amyloid nomenclature list, “amyloid” still means mainly extracellular tissue deposits of protein fibrils, recognized by specific properties, such as green-yellow birefringence after staining with Congo red. It should also be underlined that in vivo amyloid fibrils, in addition to the main protein contain associated compounds, particularly serum amyloid P-component (SAP) and proteoglycans, mainly heparan sulfate proteoglycan. With this definition there are presently 36 human amyloid proteins of which 14 appear only associated with systemic amyloidosis and 19 as localized forms. Three proteins can occur both as localized and systemic amyloidosis. Strictly intracellular aggregates are not included in this list.

  • 42. Benyamin, Beben
    et al.
    Maihofer, Adam X
    Schork, Andrew J
    Hamilton, Bruce A
    Rao, Fangwen
    Schmid-Schönbein, Geert W
    Zhang, Kuixing
    Mahata, Manjula
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology. Univ Calif San Diego, La Jolla, CA 92093 USA..
    Schork, Nicholas J
    Biswas, Nilima
    Hook, Vivian Y
    Wei, Zhiyun
    Montgomery, Grant W
    Martin, Nicholas G
    Nievergelt, Caroline M
    Whitfield, John B
    O'Connor, Daniel T
    Identification of novel loci affecting circulating chromogranins and related peptides2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 1, p. 233-242Article in journal (Refereed)
    Abstract [en]

    Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10(-30) for rs4253311 and 1.85 × 10(-19) for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.

  • 43.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Kinch, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Edman, Elin
    Halmstad Hospital.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 5, p. 1036-1042Article in journal (Refereed)
    Abstract [en]

    Background. The infiltration of regulatory T cells (Tregs) in lymphomas is associated with better prognosis for some types of lymphomas, but knowledge of their role in posttransplant lymphoproliferative disorders (PTLDs) is limited. We therefore investigated the association between the expression of the Treg marker forkhead box protein 3 (FoxP3) in biopsies of PTLDs and survival, PTLD subtype, and clinical characteristics.

    Methods. Seventy-four cases of PTLD after solid organ transplantation with sufficient material for further analysis were included from a population-based study of PTLDs in Sweden. The PTLD biopsies were reevaluated and stained with the 236A/E7 antibody to detect FoxP3 in lymphoma tissue. Detailed clinical data were collected retrospectively from medical records.

    Results. Based on a cutoff level of 29 FoxP3+ cells per mm2, most (80%) of the PTLDs were FoxP3-. Forty-seven of 74 PTLDs displayed no FoxP3+ cells at all. The frequency of FoxP3+ cells did not influence median overall survival. The FoxP3- PTLDs were more frequently of T-cell phenotype (P=0.04), located at the graft (P=0.03), occurred earlier after transplantation (P=0.04), were more likely to develop in lung recipients (P=0.04), and in patients that had received anti T-cell globulin as induction therapy (P=0.02). The FoxP3+ PTLDs were associated with hepatitis C seropositivity (P=0.03). In multivariate analysis, B-cell PTLD and hepatitis C infection were independent predictors of FoxP3 positivity.

    Conclusion. Our findings suggest that intratumoral FoxP3+ Tregs do not influence survival in patients with PTLD. FoxP3+ Tregs are rare in PTLD, possibly because of heavy immunosuppression.

  • 44.
    Bergman, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Hallström, Björn M.
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The human adrenal gland proteome defined by transcriptomics and antibody-based profiling2017In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 158, no 2, p. 239-251Article in journal (Refereed)
    Abstract [en]

    The adrenal gland is a composite endocrine organ with vital functions that include the synthesis and release of glucocorticoids and catecholamines. To define the molecular landscape that underlies the specific functions of the adrenal gland, we combined a genome-wide transcriptomics approach based on mRNA sequencing of human tissues with immunohistochemistry-based protein profiling on tissue microarrays. Approximately two-thirds of all putative protein coding genes were expressed in the adrenal gland and the analysis identified 253 genes with an elevated pattern of expression in the adrenal gland, with only 37 genes showing a markedly higher expression level (>5-fold) in the adrenal gland compared to 31 other normal human tissue types analyzed. The analyses allowed for an assessment of the relative expression levels for well-known proteins involved in adrenal gland function, but also identified previously poorly characterized proteins in the adrenal cortex, such as FERM domain containing 5 (FRMD5) and protein NOV homolog (NOV). In summary, we provide a global analysis of the adrenal gland transcriptome and proteome, with a comprehensive list of genes with elevated expression in the adrenal gland and spatial information with examples of protein expression patterns for corresponding proteins. These genes and proteins constitute important starting points for an improved understanding of the normal function and pathophysiology of the adrenal glands.

  • 45.
    Björk, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Peterson, C G B
    Pharmacia & Upjohn Diagnostics, Uppsala, Sweden .
    Measurements of ECP in serum and the impact of plasma coagulation2000In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 55, no 5, p. 442-448Article in journal (Refereed)
    Abstract [en]

    Serum measurement of ECP (eosinophil cationic protein) is used as an indication of eosinophil activation in diseases such as asthma. The levels are dependent on sample handling, since a certain amount of ECP is released during storage. The mechanisms that induce this in vitro release are not known, but are supposed to be related to the coagulation process. The aim of this study was to investigate this further. ECP was measured in EDTA plasma and serum at 22 and 37°C from healthy individuals and patients with asthma and allergy. The serum levels of ECP increased with temperature. Recalcification of citrated plasma in the presence of granulocytes with increasing concentrations of Ca2+ showed a dissociation between the levels of ECP and the occurrence of coagulation. Further experiments indicated that plasma coagulation is not of any importance for the degranulation of eosinophils, nor did the addition of platelets or mononuclear cells affect the ECP levels. Incubations of granulocytes with fresh or frozen plasma and Ca2+suggested the existence of a freezing labile factor in plasma, necessary for the degranulation of healthy eosinophils, but not for allergic/asthmatic eosinophils. Further experiments with pure eosinophils indicated the existence of factors in serum and plasma which facilitate ECP secretion of an active, temperature-dependent nature. We conclude that the raised ECP levels in serum, as compared to EDTA plasma, are unrelated to the coagulation process, but are due to the continuous secretion ex vivo of ECP from active eosinophils. This process is time and temperature dependent and may be facilitated by eosinophil-activating components in the extracellular environment.

  • 46.
    Björkesten, Johan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shen, Qiujin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wik, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hougaard, David
    Statens Serum Inst, Danish Ctr Neonatal Screening, Copenhagen, Denmark.
    Cohen, Arieh
    Statens Serum Inst, Danish Ctr Neonatal Screening, Copenhagen, Denmark.
    Sörensen, Lene
    Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stability of Proteins in Dried Blood Spot Biobanks.2017In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, no 7, p. 1286-1296Article in journal (Refereed)
    Abstract [en]

    An important motivation for the construction of biobanks is to discover biomarkers that identify diseases at early, potentially curable stages. This will require biobanks from large numbers of individuals, preferably sampled repeatedly, where the samples are collected and stored under conditions that preserve potential biomarkers. Dried blood samples are attractive for biobanking because of the ease and low cost of collection and storage. Here we have investigated their suitability for protein measurements. 92 proteins with relevance for oncology were analyzed using multiplex proximity extension assays (PEA) in dried blood spots collected on paper and stored for up to 30 years at either +4&deg;C or -24&deg;C.</p> <p>Our main findings were that 1) the act of drying only slightly influenced detection of blood proteins (average correlation of 0.970), and in a reproducible manner (correlation of 0.999), 2) detection of some proteins was not significantly affected by storage over the full range of three decades (34% and 76% of the analyzed proteins at +4&deg;C and -24&deg;C, respectively), while levels of others decreased slowly during storage with half-lives in the range of 10 to 50 years, and 3) detectability of proteins was less affected in dried samples stored at -24&deg;C compared to at +4&deg;C, as the median protein abundance had decreased to 80% and 93% of starting levels after 10 years of storage at +4&deg;C or -24&deg;C, respectively. The results of our study are encouraging as they suggest an inexpensive means to collect large numbers of blood samples, even by the donors themselves, and to transport, and store biobanked samples as spots of whole blood dried on paper. Combined with emerging means to measure hundreds or thousands of protein, such biobanks could prove of great medical value by greatly enhancing discovery as well as routine analysis of blood biomarkers.

  • 47.
    Bohjort, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Method verification for homocysteine and a sustainability study on glucose, homocysteine and lactate in different sampling tubes2016Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The pre-analytical phase is known for being the most important step in the laboratory process to reach reliable test results. If handling, transport or preparation of the sample is performed incorrectly the results can deviate from the true value. Today, sampling tubes contains various additives to stabilize concentration levels. The aim of this study was to test a new sampling tube containing fluoride/citrate for glucose, lactate and homocysteine. It was also of interest to evaluate the stability of those three analytes in lithium-heparin, sodium-fluoride/potassium oxalate and fluoride/citrate tubes. To perform the sustainability study, a method verification was done for homocysteine in plasma. The study was performed in a hospital laboratory on the routine instrument Roche Cobas 6000 analyzer. Blood was drawn from 20 patients and was analyzed at the hospital laboratory in Gävle. The blood samples were transported frozen to the laboratory in Hudiksvall and were used in the method verification. For the sustainability study, blood was drawn from 10 healthy volunteers in lithium-heparin, sodium-fluoride/potassium oxalate and fluoride/citrate tubes. The method verification was approved. The results showed that glucose was stable for up to 72 hours in Vacuette Glycaemia tube with fluoride/citrate and this tube also gave more accurate results. Lactate and homocysteine were also stable in fluoride/citrate, but needs further studies. All three analytes were more stable if the sample tubes were centrifuged as soon as possible after blood collection. Fluoride/citrate tubes were stable without centrifugation directly.

  • 48.
    Bondeson, Marie-Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ericson, Katharina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, Dept Pathol & Cytol, Uppsala, Sweden.
    Gudmundsson, Sanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wesström, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Frykholm, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.2017In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 92, no 5, p. 510-516Article in journal (Refereed)
    Abstract [en]

    Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.

  • 49.
    Botling, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lohr, Miriam
    Hellwig, Birte
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Berglund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    König, André
    Fernandes, Oswaldo
    Karlsson, Mats
    Helenius, Gisela
    Karlsson, Christina
    Rahnenführer, Jörg
    Hengstler, Jan G
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis and tissue microarray validation2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 1, p. 194-204Article in journal (Refereed)
    Abstract [en]

    Background:

    Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multi-gene signatures in clinical practice is unclear and the biological importance of individual genes is difficult to assess as the published signatures virtually do not overlap

    Methods:

    Here we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data was used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level p<0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n=860).

    RESULTS:

    The meta-analysis revealed 14 genes that were significantly associated with survival (p<0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from two independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    CONCLUSIONS:

    Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.

  • 50.
    Botling, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Immune Biomarkers on the Radar-Comprehensive "Immunograms" for Multimodal Treatment Prediction2017In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, no 5, p. 770-772Article in journal (Other academic)
1234567 1 - 50 of 377
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