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  • 201.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Pediatric reference intervals for liver markers derived from healthy community-based subjects will improve diagnostic interpretation in children and adolescents2018Inngår i: Journal of Laboratory and Precision Medicine, ISSN 2519-9005, Vol. 3, s. 2-Artikkel i tidsskrift (Fagfellevurdert)
  • 202.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Reference intervals for parathyroid hormone for 70-year-old males and females: exclusion of individuals from the reference interval based on sex, calcium, diabetes, cardiovascular diseases or reduced kidney function has limited effects on the interval2015Inngår i: Annals of Clinical Biochemistry, ISSN 0004-5632, E-ISSN 1758-1001, Vol. 52, nr 1, s. 39-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: A problem when producing reference intervals for elderly individuals is that they often suffer from a number of diseases and they are most often on medication. If all such persons are excluded, there is a risk that the residual subgroup may not be representative of the population, we therefore wanted to compare the effects different exclusion criteria has on the reference intervals.

    METHODS: We measured parathyroid hormone (PTH), calcium, albumin and cystatin C in a cohort of 70-year-old males and females (n = 1003). Reference intervals for PTH for males and females were calculated for the entire population and after exclusion of persons with calcium >2.60 mmol/L, calcium >2.51 mmol/L, diabetes, reduced glomerular filtration rate (GFR), and cardiovascular diseases.

    RESULTS: The calculated PTH reference interval 16 (CI 14-17) to 94 (CI 87-101) ng/L. Exclusion of study subjects resulted in smaller reference sample groups, but the reference limits remained within the 90% confidence intervals of the original reference limits. The selections thus had a very limited effect on the calculated reference interval for PTH.

    CONCLUSIONS: Exclusion of elderly individuals with high calcium concentrations, diabetes, reduced GFR or cardiovascular disease has little effect on the reference interval for PTH. It is better not to exclude these individuals, as it will provide a broader base for the reference interval.

  • 203. Leinonen, Ville
    et al.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Aalto, Sargo
    Suotunen, Timo
    Savolainen, Sakari
    Någren, Kjell
    Tapiola, Tero
    Pirttilä, Tuula
    Rinne, Jaakko
    Jääskeläinen, Juha E
    Soininen, Hilkka
    Rinne, Juha O
    Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B.2008Inngår i: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, nr 10, s. 1304-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens.

    DESIGN: Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens.

    SETTING: Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus.

    INTERVENTIONS: [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests.

    MAIN OUTCOME MEASURES: Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET.

    RESULTS: In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits.

    CONCLUSIONS: Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.

  • 204. Leinonen, Ville
    et al.
    Koivisto, Anne M
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Pyykkö, Okko T
    Rummukainen, Jaana
    von Und Zu Fraunberg, Mikael
    Jääskeläinen, Juha E
    Soininen, Hilkka
    Rinne, Jaakko
    Savolainen, Sakari
    Cortical Brain Biopsy in Long-Term Prognostication of 468 Patients with Possible Normal Pressure Hydrocephalus2012Inngår i: Neuro-degenerative diseases, ISSN 1660-2862, Vol. 10, nr 1-4, s. 166-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Normal pressure hydrocephalus (NPH) can be alleviated by cerebrospinal fluid shunting but the differential diagnosis and patient selection are challenging. Intraventricular intracranial pressure monitoring as part of the diagnostic workup as well as shunting enable to obtain cortical brain biopsies to detect amyloid-β (Aβ) and hyperphosphorylated tau (HPτ), the hallmark lesions of Alzheimer's disease (AD). In possible NPH, Aβ alone indicates an increased risk of AD and when present with HPτ probable AD, but the effect of those brain lesions on survival is not known. The aim of this study was to evaluate the predictive value of brain biopsy for the long-term outcome of possible NPH. Between 1991 and 2006, the Neurosurgery Department of the Kuopio University Hospital evaluated 468 patients for possible NPH by intraventricular intracranial pressure monitoring and frontal cortical brain biopsy immunostained against Aβ and HPτ. All patients were followed up until the end of 2008 (n = 201) or death (n = 267) with a median follow-up of 4.6 years (range 0-17). Logistic regression analysis with Cox models was applied. Out of the 468 cases, Aβ was detected in 197 (42%) cortical biopsies, and together with HPτ in 44 (9%). Aβ alone indicated increased risk of AD and with HPτ probable AD, but it did not affect survival. Vascular aetiology was the most frequent cause of death. Cortical biopsy findings indicate that NPH is at present a heterogeneous syndrome and has notable overlapping with AD. Brain biopsy did not predict survival but may open a novel research window to study the pathobiology of neurodegeneration.

  • 205.
    Li, M
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Li, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Marx, J
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Scaling of motility speed and its temperature sensitivity in mammals representing a 5,500-fold difference in body size2011Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 202, nr 4, s. 671-681Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: 

    The predictions of scaling of skeletal muscle shortening velocity made by A.V. Hill 60-years ago have proven to be remarkably accurate at the cellular level. The current investigation looks to extend the study of scaling of contractile speed to the level of the molecular motor protein myosin at both physiological and unphysiological low temperatures.

    Methods: 

    A single muscle cell in vitro motility assay to test myosin function, i.e. myosin extracted from short single muscle fibre segments, was used in four species representing a 5 500-fold difference in body mass (rat, man, horse and rhinoceros) at temperatures ranging from 15 to 35 °C.

    Results: 

    The in vitro motility speed increased as the temperature of the assay increased, but a more profound effect was observed on the slower isoforms, narrowing the relative differences between fast and slow myosin heavy chain (MyHC) isoforms at physiological temperature in all species. The in vitro motility speed varied according to MyHC isoform within each species: I < IIa < IIx < IIb, but the expected scaling relationship within orthologous myosin isoforms was not observed at any temperature.

    Conclusion: 

    The scaling effect of body size and limb length on shortening velocity at the muscle fibre level, i.e. the decreasing shortening velocity associated with increasing body weight and limb length, was not confirmed at the motor protein level when including mammals of very large size. Thus, other factors than myosin structure and function appear to cause this scaling effect and thin filament isoform expression or myofilament lattice spacing are forwarded as alternative underlying factors.

  • 206.
    Libard, Sylwia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Cerjan, Dijana
    Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Characteristics of the tissue section that influence the staining outcome in immunohistochemistry2019Inngår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 151, nr 1, s. 91-96Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immunohistochemistry (IHC) is influenced by several factors such as cold ischemia time, fixative, fixation time, paraffin, storage time, antibody, antigen retrieval technique and detection systems. In the setting of post-mortem tissue, not only post-mortem delay, but also agonal state is of interest. Here, we assessed an additional variable, i.e., the thickness of the section, and noted that this variable also influenced the IHC outcome. This is of significance when the extent of labelling is a parameter to be assessed, for example when assigning a stage or grade of a disease. Furthermore, when assessing brain tissue with neurons, soma measuring from 4 to 100 µm, various cellular compartments composed of different proteins are localised in sections measuring 4 or 7 µm. Thus, what is seen in a 7-µm-thick section might be lacking in a 4-µm-thick section. Lack of information regarding the molecular size of commercial antibodies is also disturbing as this parameter might influence the distribution of the molecule in the three-dimensional section. The choice of antibody to be used and the staining methodology have been acknowledged being of significance for IHC outcome; however, neither sections thickness or the molecular weight has been discussed sufficiently. IHC has been shown to be an unpredictable technique used for assessment of tissue. This emphasises the need for detailed methodological descriptions in publications, the need to acknowledge and to harmonize all eventual pitfalls related to this methodology.

  • 207.
    Libard, Sylwia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Laurell, Katarina
    Umeå Univ, Dept Pharmacol & Clin Neurosci, Östersund.
    Cesarini, Kristina G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus2018Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, nr 4, s. 1451-1461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We had an opportunity to assess the change observed in the brain regarding Alzheimer’s disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

  • 208.
    Libard, Sylwia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Popova, Svetlana N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kärjä, Vesa
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Pietiläinen, Timo
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Hämäläinen, Kirsi M
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi. Department of Neurosurgery, Uppsala University Hospital, Sweden.
    Bergqvist, Michael
    Department of radiation sciences, Umeå University, Sweden.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Zetterling, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Nilsson, Pelle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Pfeifer, Susan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    de Ståhl, Teresita Diaz
    Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 9, s. e108861-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  • 209.
    Liberta, Falk
    et al.
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Loerch, Sarah
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.
    Rennegarbege, Matthies
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Schierhorn, Angelika
    Martin Luther Univ Halle Wittenberg, Inst Biochem & Biotechnol, D-06120 Halle, Saale, Germany.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Westermark, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hazenberg, Bouke P. C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9700 RB Groningen, Netherlands.
    Grigorieff, Nikolaus
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.
    Faendrich, Marcus
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Schmidt, Matthias
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids2019Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikkel-id 1104Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 angstrom and 2.7 angstrom for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-beta sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar beta-arch conformations within the N-terminal similar to 21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.

  • 210. Liem, David A
    et al.
    Nsair, Ali
    Setty, Shaun P
    Cadeiras, Martin
    Wang, Ding
    Maclellan, Robb
    Lotz, Chris
    Lin, Amanda J
    Tabaraki, Jason
    Li, Hua
    Ge, Junbo
    Odeberg, Jacob
    Pontén, Fredrik
    Larsson, Erik
    Mulder, Jan
    Lundberg, Emma
    Weiss, James N
    Uhlen, Mathias
    Ping, Peipei
    Deng, Mario C
    Molecular- and organelle-based predictive paradigm underlying recovery by left ventricular assist device support2014Inngår i: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 7, nr 2, s. 359-366Artikkel i tidsskrift (Fagfellevurdert)
  • 211.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments.

    In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments.

    Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls.

    In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation.

    Delarbeid
    1. A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients
    Åpne denne publikasjonen i ny fane eller vindu >>A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients
    Vise andre…
    2016 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 2, artikkel-id e0149821Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 μL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-281233 (URN)10.1371/journal.pone.0149821 (DOI)000371175700030 ()26914813 (PubMedID)
    Forskningsfinansiär
    Swedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research Council, 316929EU, European Research Council, 294409
    Tilgjengelig fra: 2016-03-21 Laget: 2016-03-21 Sist oppdatert: 2017-11-30bibliografisk kontrollert
    2. Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis
    Åpne denne publikasjonen i ny fane eller vindu >>Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis
    Vise andre…
    2016 (engelsk)Inngår i: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403, Vol. 19, nr 6, s. 549-562Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    ObjectivesElectrical neuromodulation by spinal cord stimulation (SCS) is a well-established method for treatment of neuropathic pain. However, the mechanism behind the pain relieving effect in patients remains largely unknown. In this study, we target the human cerebrospinal fluid (CSF) proteome, a little investigated aspect of SCS mechanism of action. MethodsTwo different proteomic mass spectrometry protocols were used to analyze the CSF of 14 SCS responsive neuropathic pain patients. Each patient acted as his or her own control and protein content was compared when the stimulator was turned off for 48 hours, and after the stimulator had been used as normal for three weeks. ResultsEighty-six proteins were statistically significantly altered in the CSF of neuropathic pain patients using SCS, when comparing the stimulator off condition to the stimulator on condition. The top 12 of the altered proteins are involved in neuroprotection (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein), synaptic plasticity/learning/memory (gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein), nociceptive signaling (neurosecretory protein VGF), and immune regulation (dickkopf-related protein 3). ConclusionPreviously unknown effects of SCS on levels of proteins involved in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity are demonstrated. These findings, in the CSF of neuropathic pain patients, expand the picture of SCS effects on the neurochemical environment of the human spinal cord. An improved understanding of SCS mechanism may lead to new tracks of investigation and improved treatment strategies for neuropathic pain.

    Emneord
    Cerebrospinal fluid, mechanism of action, neuropathic pain, spinal cord stimulation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-304434 (URN)10.1111/ner.12473 (DOI)000382755300001 ()27513633 (PubMedID)
    Forskningsfinansiär
    VINNOVASwedish Research Council
    Tilgjengelig fra: 2016-10-05 Laget: 2016-10-05 Sist oppdatert: 2019-04-29bibliografisk kontrollert
    3. Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation
    Åpne denne publikasjonen i ny fane eller vindu >>Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation
    Vise andre…
    2016 (engelsk)Inngår i: INTERNATIONAL JOURNAL OF INFLAMMATION, ISSN 2090-8040, artikkel-id UNSP 3874964Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Earlier studies suggest that lumbar radicular pain following disc herniation may be associated with a local or systemic inflammatory process. In the present study, we investigated the serum inflammatory protein profile of such patients. All 45 patients were recruited from Oslo University Hospital, Ulleval, Norway, during the period 2007-2009. The new multiplex proximity extension assay (PEA) technology was used to analyze the levels of 92 proteins. Interestingly, the present data showed that patients with radicular pain 12 months after disc herniation may be different from other patients with regard to many measurable serum cytokines. Given a false discovery rate (FDR) of 0.10 and 0.05, we identified 41 and 13 proteins, respectively, which were significantly upregulated in the patients with severe pain one year after disc herniation. On the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 (CXCM5; 217% increase), epidermal growth factor (EGF; 142% increase), and monocyte chemotactic protein 4 (MCP-4; 70% increase). Moreover, a clear overall difference in the serum cytokine profile between the chronic and the recovered patients was demonstrated. Thus, the present results may be important for future protein serum profiling of lumbar radicular pain patients with regard to prognosis and choice of treatment. We conclude that serum proteins may be measurable molecular markers of persistent pain after disc herniation.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-317717 (URN)10.1155/2016/3874964 (DOI)000394106300001 ()27293953 (PubMedID)
    Forskningsfinansiär
    VINNOVASwedish Research Council, P29797-1
    Tilgjengelig fra: 2017-03-17 Laget: 2017-03-17 Sist oppdatert: 2018-01-13bibliografisk kontrollert
    4. Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and Fibromyalgia
    Åpne denne publikasjonen i ny fane eller vindu >>Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and Fibromyalgia
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective: Today, there are no biological tests on which to base pain diagnoses, treatment choices or to understand the biological processes underlying and accompanying chronic pain for the individual pain patient. Relevant biological markers would greatly aid in diagnosis and treatment of patients with chronic pain. Our study aimed to find proteins in CSF associated with fibromyalgia and neuropathic pain, two common and poorly understood chronic pain conditions.

    Methods: We have performed CSF protein profiling of 55 proteins using a 100-plex antibody suspension bead array. We collected, analyzed and compared CSF samples from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery and n=11 for verification), 40 patients with fibromyalgia and 135 controls without neurological disease from two different populations.

    Results: We found significant differences in CSF protein levels between patients and controls (p<0.05). Among these proteins, Apolipoprotein C1 (APOC1) was found to be increased in CSF of neuropathic pain patients compared to controls and there was a non-significant trend for increased levels also in fibromyalgia patient CSF. Ectonucleotide pyrophosphatase (ENPP2, Autotaxin) was increased in the CSF of fibromyalgia patients compared to all other groups including neuropathic pain patients.  Multivariate analysis revealed partially overlapping and partially distinct CSF profiles in neuropathic pain patients compared with fibromyalgia and controls for several other proteins including angiotensinogen (AGT), prostaglandin-H2 D-isomerase (PTGDS), neurexin-1 (NRXN1), superoxide dismutase 1 (SOD1) and superoxide dismutase 3 (SOD3).

    Conclusions: Our results, suggest that the CSF protein profiles of neuropathic pain and fibromyalgia patients may be different from each other and from those of controls. CSF levels of APOC1, ENPP2, AGT, PTGDS, NRXN1, SOD1 and SOD3 should be further investigated for their potential to serve as biomarkers of different kinds of pain pathophysiology.

    Emneord
    cerebrospinal fluid, biomarker, human, chronic pain, neuropathic pain, fibromyalgia, spinal cord stimulation, mechanism of action, radiculopathy, protein, inflammation, neuroinflammation, mass spectrometry, antibody suspension bead array, protein profiling
    HSV kategori
    Forskningsprogram
    Anestesiologi och intensivvård; Bioinformatik; Biokemi; Biologi med inriktning mot molekylärbiologi; Biomedicinsk laboratorievetenskap; Kemi med inriktning mot analytisk kemi; Klinisk kemi; Medicinsk vetenskap; Molekylär medicin
    Identifikatorer
    urn:nbn:se:uu:diva-326158 (URN)
    Prosjekter
    Berzelii Technology Centre of Neurodiagnostics
    Forskningsfinansiär
    AFA Insurance, 140341VINNOVASwedish Research Council
    Tilgjengelig fra: 2017-07-03 Laget: 2017-07-03 Sist oppdatert: 2018-01-13
    5. High Levels of Cerebrospinal Fluid Chemokines Point to the Presence of Neuroinflammation in Peripheral Neuropathic Pain: A Cross-Sectional Study of Two Cohorts of Patients Compared to Healthy Controls
    Åpne denne publikasjonen i ny fane eller vindu >>High Levels of Cerebrospinal Fluid Chemokines Point to the Presence of Neuroinflammation in Peripheral Neuropathic Pain: A Cross-Sectional Study of Two Cohorts of Patients Compared to Healthy Controls
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called “gliotransmitters”, a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile for neuropathic pain patients. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation.  

    CSF samples were collected from two cohorts of patients with neuropathic pain (n=11 and n=16, respectively) and healthy controls (n=11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek® Multiplex Inflammation I, Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares – discriminant analysis, were used for statistical analyses.

    CSF levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared to healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in fibromyalgia patients. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Since it has been suggested that prevalent co-morbidities to chronic pain (e.g., depression, anxiety, poor sleep, and tiredness) also are associated with inflammation, it will be important to determine whether inflammation is a common mediator.

    Emneord
    biomarker; cerebrospinal fluid; chemokines; cytokines; human; inflammation; neuroinflammation; neuropathic pain; protein profile; proximity extension assay (PEA), chronic pain
    HSV kategori
    Forskningsprogram
    Anestesiologi och intensivvård; Biomedicinsk laboratorievetenskap; Kemi med inriktning mot analytisk kemi; Medicinsk vetenskap; Medicinsk biokemi; Molekylär medicin
    Identifikatorer
    urn:nbn:se:uu:diva-326161 (URN)
    Prosjekter
    Uppsala Berzelii Technology Centre for NeurodiagnosticsAFA Insurance (140341)Swedish Research Council (grant no. K2015-99x-21874-05-4)the Swedish Research Council (grant no. P29797-1).Swedish Governmental Agency for Innovation Systems (Vinnova)County Council of Östergötland (LIO-35923, SC-2013-00395-36)
    Forskningsfinansiär
    AFA Insurance, 140341VINNOVA, P29797-1Swedish Research Council, P29797-1Swedish Research Council, K2015-99x-21874-05-4
    Tilgjengelig fra: 2017-07-03 Laget: 2017-07-03 Sist oppdatert: 2018-01-13
  • 212.
    Lind, Anne-Li
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Just, David
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Mikus, Maria
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Fredolini, Claudia
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Ioannou, Marina
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Gerdle, Björn
    Linköping University, Linköping, Sweden.
    Bäckryd, Emmanuel
    Linköping University, Linköping, Sweden.
    Tanum, Lars
    Akershus University Hospital, Lørenskog, Norway.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Nilsson, Peter
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Månberg, Anna
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and FibromyalgiaManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective: Today, there are no biological tests on which to base pain diagnoses, treatment choices or to understand the biological processes underlying and accompanying chronic pain for the individual pain patient. Relevant biological markers would greatly aid in diagnosis and treatment of patients with chronic pain. Our study aimed to find proteins in CSF associated with fibromyalgia and neuropathic pain, two common and poorly understood chronic pain conditions.

    Methods: We have performed CSF protein profiling of 55 proteins using a 100-plex antibody suspension bead array. We collected, analyzed and compared CSF samples from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery and n=11 for verification), 40 patients with fibromyalgia and 135 controls without neurological disease from two different populations.

    Results: We found significant differences in CSF protein levels between patients and controls (p<0.05). Among these proteins, Apolipoprotein C1 (APOC1) was found to be increased in CSF of neuropathic pain patients compared to controls and there was a non-significant trend for increased levels also in fibromyalgia patient CSF. Ectonucleotide pyrophosphatase (ENPP2, Autotaxin) was increased in the CSF of fibromyalgia patients compared to all other groups including neuropathic pain patients.  Multivariate analysis revealed partially overlapping and partially distinct CSF profiles in neuropathic pain patients compared with fibromyalgia and controls for several other proteins including angiotensinogen (AGT), prostaglandin-H2 D-isomerase (PTGDS), neurexin-1 (NRXN1), superoxide dismutase 1 (SOD1) and superoxide dismutase 3 (SOD3).

    Conclusions: Our results, suggest that the CSF protein profiles of neuropathic pain and fibromyalgia patients may be different from each other and from those of controls. CSF levels of APOC1, ENPP2, AGT, PTGDS, NRXN1, SOD1 and SOD3 should be further investigated for their potential to serve as biomarkers of different kinds of pain pathophysiology.

  • 213. Lindahl, Bengt
    et al.
    Måsbäck, Anna
    Persson, Jan
    Ranstam, Jonas
    Willlén, Roger
    Adenocarcinoma corpus uteri stage I-II: results of a treatment programme based upon cytometry2009Inngår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, nr 11, s. 4731-4735Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The results of a treatment method on adenocarcinoma corpus uteri stage I-II based upon cytometrically measured DNA ploidy are presented. All patients had a simple hysterectomy. Adjuvant treatment (postoperative vaginal brachytherapy) were given only to those patients with non-diploid tumours regardless of stage and grade. A total of 1,634 women with endometroid adenocarcinoma corpus uteri stage I-II were included where 1,396 patients were followed-up for at least 5 years or until death and the remaining 238 patients were followed-up 3.5-5 years or until death. By using cytometry only, we identified a low-risk group comprising 83% of the patients (with 5.2% dead from their disease) and a high-risk group of 17% (with 15.7% dead from their disease). By using grade only (well- and moderately differentiated vs poorly differentiated), the low-risk group comprised 87% of the patients (with 4.6% dead from their disease) and the high-risk group 13% (with 13% dead from their disease). By using stage only (stage Ia and Ib vs stage Ic and II), the low-risk group comprised 78% of the patients (with 3.6% dead from their disease) and the high risk group 22% (with 14.5% dead from their disease). By combining these prognostic parameters, we were able to identify small subgroups with increased mortality rates in need of adjuvant therapy. As ploidy still had a strong prognostic strength regardless of given adjuvant radiotherapy, we do not believe that this treatment was effective. We therefore recommend future research to be directed toward cytostatics as an alternative adjuvant treatment.

  • 214.
    Lindahl, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Astrom, Eva
    Karolinska Univ Hosp, Pediat Neurol, Astrid Lindgren Childrens Hosp, Stockholm, Sweden;Karolinska Inst, Dept Woman & Child Hlth, Stockholm, Sweden.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Symoens, Sofie
    Univ Hosp Ghent, Dept Med Genet, Ghent, Belgium.
    Coucke, Paul
    Univ Hosp Ghent, Dept Med Genet, Ghent, Belgium.
    Larsson, Sune
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Paschalis, Eleftherios
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Roschger, Paul
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Gamsjaeger, Sonja
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Klaushofer, Klaus
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Fratzl-Zelman, Nadja
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy2018Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 114, s. 268-277Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Mutations of the endoplasmic reticulum (ER) stress transducer OASIS (encoded by CREB3L1), cause severe recessive osteogenesis imperfecta (OI) not compatible with surviving the neonatal period, as has been shown in two unrelated families through a whole gene deletion vs. a qualitative alteration of OASIS Heterozygous carriers in the described families have exhibited a mild phenotype. OASIS is a transcription factor highly expressed in osteoblasts, and OASIS(-/-) mice exhibit severe osteopenia and spontaneous fractures. Here, we expand the clinical spectrum by a detailed phenotypic characterization of the first case of OASIS-associated OI surviving the neonatal period, with heterozygous family members being unaffected.

    Methods: All OI-associated genes were sequenced. Primary human osteoblast-like cell (hOB) and fibroblast (FB) cultures were obtained for qPCR, and steady-state collagen biochemistry. FB, hOB and skin biopsies were ultrastructurally analyzed. Bone was analyzed by |mu CT, histomorphometry, quantitative backscattered electron imaging (qBEI), and Raman microspectroscopy.

    Results: The proband, a boy with severe OI, had blue sclera and tooth agenesis A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%), however, collagen I levels were only reduced in hOBs (5-10%) Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to lifelong bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures.

    Conclusions: Deficiency of OASIS can cause severe OI compatible with surviving the neonatal period A marked decrease of collagen type I transcription was noted in bone tissue, but not in skin, and ultrastructure of hOBs was pathological. Results also suggested OASIS involvement in glycosaminoglycan secretion in bone.

  • 215.
    Lindblom, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning Dalarna.
    Wallménius, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Nordberg, M
    Forsberg, P
    Eliasson, I
    Påhlson, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Seroreactivity for spotted fever rickettsiae and co-infections with other tick-borne agents among habitants in central and southern Sweden2013Inngår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 32, nr 3, s. 317-323Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients seeking medical care with erythema migrans or flu-like symptoms after suspected or observed tick bite in the southeast of Sweden and previously investigated for Borrelia spp. and/or Anaplasma sp. were retrospectively examined for serological evidence of rickettsial infection (Study 1). Twenty of 206 patients had IgG and/or IgM antibodies to Rickettsia spp. equal to or higher than the cut-off titre of 1:64. Seven of these 20 patients showed seroconversion indicative of recent or current infection and 13 patients had titres compatible with past infection, of which five patients were judged as probable infection. Of 19 patients with medical records, 11 were positive for Borrelia spp. as well, and for Anaplasma sp., one was judged as positive. Five of the 19 patients had antibodies against all three pathogens. Erythema migrans or rash was observed at all combinations of seroreactivity, with symptoms including fever, muscle pain, headache and respiratory problems. The results were compared by screening an additional 159 patients (Study 2) primarily sampled for the analysis of Borrelia spp. or Mycoplasma pneumoniae. Sixteen of these patients were seroreactive for Rickettsia spp., of which five were judged as recent or current infection. Symptoms of arthritis, fever, cough and rash were predominant. In 80 blood donors without clinical symptoms, approximately 1 % were seroreactive for Rickettsia spp., interpreted as past infection. The study shows that both single and co-infections do occur, which illustrate the complexity in the clinical picture and a need for further studies to fully understand how these patients should best be treated.

  • 216. Linnankivi, T
    et al.
    Valanne, L
    Paetau, A
    Alafuzoff, Irina
    Kuopio University, Finland.
    Hakumäki, J M
    Kivelä, T
    Lönnqvist, T
    Mäkitie, O
    Pääkkönen, L
    Vainionpää, L
    Vanninen, R
    Herva, R
    Pihko, H
    Cerebroretinal microangiopathy with calcifications and cysts.2006Inngår i: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 67, nr 8, s. 1437-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation.

    METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively.

    RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen.

    CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.

  • 217.
    Llano-Diez, Monica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Renaud, Guillaume
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Andersson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Gonzales Marrero, Humberto
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Cacciani, Nicola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Engquist, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Corpeno, Rebeca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Artemenko, Konstantin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading2012Inngår i: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 16, nr 5, s. R209-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ABSTRACT: INTRODUCTION: Critical ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life of survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model have shown that the "mechanical silencing" associated with the ICU condition is the primary triggering factor. This study aims at (1) unraveling the mechanisms underlying CIM, and (2) evaluating the effects of a specific intervention aiming at reducing the mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading 10 hours per day (2.5 hours, 4 times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM, i.e., severe muscle wasting and a preferential myosin loss (P<0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of nNOS. Passive mechanical loading for 9 +/- 1 resulted in a 35% higher specific force (P<0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSIONS: Mechanical silencing is suggested to be a primary mechanism underlying CIM, i.e., triggering the myosin loss, muscle wasting and myosin PTMs. The higher nNOS expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

  • 218. Low, Nicola
    et al.
    Cassell, Jackie A
    Spencer, Brenda
    Bender, Nicole
    Martin Hilber, Adriane
    van Bergen, Jan
    Andersen, Berit
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    Dubois-Arber, Françoise
    Hamers, Françoise F
    van de Laar, Marita
    Stephenson, Judith M
    Chlamydia control activities in Europe: cross-sectional survey2012Inngår i: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 22, nr 4, s. 556-561Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Chlamydia is the most commonly reported bacterial sexually transmitted infection in Europe. The objective of the Screening for Chlamydia in Europe (SCREen) project was to describe current and planned chlamydia control activities in Europe.

    METHODS: The authors sent a questionnaire asking about different aspects of chlamydia epidemiology and control to public health and clinical experts in each country in 2007. The principles of sexually transmitted infection control were used to develop a typology comprising five categories of chlamydia control activities. Each country was assigned to a category, based on responses to the questionnaire.

    RESULTS: Experts in 29 of 33 (88%) invited countries responded. Thirteen of 29 countries (45%) had no current chlamydia control activities. Six countries in this group stated that there were plans to introduce chlamydia screening programmes. There were five countries (17%) with case management guidelines only. Three countries (10%) also recommended case finding amongst partners of diagnosed chlamydia cases or people with another sexually transmitted infection. Six countries (21%) further specified groups of asymptomatic people eligible for opportunistic chlamydia testing. Two countries (7%) reported a chlamydia screening programme. There was no consistent association between the per capita gross domestic product of a country and the intensity of chlamydia control activities (P = 0.816).

    CONCLUSION: A newly developed classification system allowed the breadth of ongoing national chlamydia control activities to be described and categorized. Chlamydia control strategies should ensure that clinical guidelines to optimize chlamydia diagnosis and case management have been implemented before considering the appropriateness of screening programmes.

  • 219.
    Lubenow, Norbert
    et al.
    Staatl. Medizinaluntersuchungsamt, Hannover Medical School, Germany.
    Diepenbrock, F
    Schickling, H
    Bock, D
    Heckler, R
    Sander, J
    Phenylketonuria screening with a fluorometric microplate assay.1994Inngår i: European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies, ISSN 0939-4974, Vol. 32, nr 7, s. 525-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A fluorometric assay in microtitre plates for the screening of phenylketonuria was evaluated and adapted to a neonatal screening programme. Using this assay, it is possible to determine quantitatively the phenylalanine concentration in dried blood spots on filter paper. The test exhibited a linear calibration curve with a good slope as well as sufficient precision and accuracy in the statistical analysis. Interference by other amino acids and antibiotics was not observed. Only elevated concentrations of leucine interfered to a small degree. The phenylalanine concentration in dried blood spots of 13 phenylketonuria patients correlated to that in serum. 7381 dried blood samples of newborn infants were tested simultaneously by both the fluorometric and the Guthrie test. The results did not show significant differences. We screened 29,182 newborns using the fluorometric assay and an online data processing programme. The internal repetition rate was 0.64%, the external recall rate 0.15%. False negative results were not observed. In December 1991 the fluorometric method replaced the Guthrie test in our routine programme for phenylketonuria screening, and was introduced as a follow up test for phenylketonuria patients.

  • 220.
    Lundström, Yasmin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lundström, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Popova, Svetlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindblom, Rickard P.F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time2019Inngår i: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 27, nr 3, s. 238-245Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study, we have systematically assessed the influence of postmortem delay (PMD) and fixation time (FT) on the immunohistochemical (IHC) staining outcome. The IHC method is frequently applied on surgical and postmortem samples in diagnostics and research. To replicate the routine situation, brain tissues from pigs were exposed to either storage in a refrigerator (+8°C), that is, PMD (1 to 168 h), or fixed in 10% buffered formalin, that is, FT (18 to 94 d). Subsequently, the tissue was routinely processed into paraffin blocks to enable construction of tissue microarrays (TMA). Sections cut from the TMA blocks were stained applying 13 different antibodies directed against neuronal and glial antigens. Immunoreactivity applying 5 antibodies was influenced by prolonged PMD and applying 2 antibodies by prolonged FT. None of the staining outcomes related to the PMD or FT were predictable. Loss of TMA cores during processing was primarily influenced by pretreatment and by tissue characteristics (gray/white matter). The test model described here confirmed that these 2 variables, PMD and FT, indeed influence the IHC outcome. The PMD and FT are particularly of importance while assessing tissue samples obtained at autopsy. The result above is also of importance while comparing the IHC outcomes seen in the postmortem setting (various PMD/FT) with surgical samples or with IHC outcome seen in experimental animal setting (controlled PMD/FT). Thus, we suggest that the test model described here is considered when assessing the reliability of the IHC outcome when analyzing tissues with various characteristics.

  • 221.
    Löf, Liza
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Arngården, Linda
    Olsson-Strömberg, Ulla
    Jansson, Mattias
    Dahlin, Joakim
    Thörn, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Christiansson, Lisa
    Hermansson, Monica
    Larsson, Anders
    Ahlstrand, Erik
    Wålinder, Göran
    Rosenquist Brandell, Richard
    Söderberg, Ola
    Landegren, Ulf
    Kamali-Moghaddam, Masood
    Flow Cytometric Measurement of BCR-ABL Fusion Protein Positive Cells in Blood from Patients with Chronic Myeloid LeukemiaManuskript (preprint) (Annet vitenskapelig)
  • 222. Löfdahl, Britta
    et al.
    Ahlin, Cecilia
    Holmqvist, Marit
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Zhou, Wenjing
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Fjällskog, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Inflammatory cells in node-negative breast cancer2012Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, nr 5, s. 680-686Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background.

    To study the impact of inflammatory cells in a clinically well-defined cohort of women with node-negative breast cancer in a nested case-control study design.

    Material and methods.

    The cohort was comprised of 190 women who died from breast cancer and 190 women still alive at the date of death for the corresponding breast cancer patients were used as controls. The inclusion criteria included; a tumour size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy. Immunohistochemical stainings for CD3, CD4, CD8, FoxP3, CD20, tryptase and CD68 were performed on TMA blocks, evaluated and correlated to each other and to age, tumour size, histological grade, ER, PgR, Ki67 and cyclin A.

    Results.

    There was no difference regarding the amount or content of inflammatory cells in the cases compared to controls. T- and B-cells were highly correlated to each other but these cell types correlated to a lesser extent to macrophages and not at all to mast cells. A weak tendency of correlations between all the subsets of inflammatory cells and histological grade, Ki67 and cyclin A was observed, although a negative correlation was seen for mast cells.

    Conclusion.

    The amount or content of inflammatory cells in invasive breast cancer did not appear to influence death in node-negative breast cancer.

  • 223. Manojlovic-Gacic, Emilija
    et al.
    Skender-Gazibara, Milica
    Popovic, Vera
    Soldatovic, Ivan
    Boricic, Novica
    Raicevic, Savo
    Pekic, Sandra
    Doknic, Mirjana
    Miljic, Dragana
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Casar-Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Oncogene-Induced Senescence in Pituitary Adenomas-an Immunohistochemical Study.2016Inngår i: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 27, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal β-galactosidase (SA-β-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-β-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.

  • 224.
    Mansouri, Larry
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Noerenberg, Daniel
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Young, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mylonas, Elena
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Abdulla, Maysaa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Frick, Mareike
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Asmar, Fazila
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Ljungström, Viktor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Schneider, Markus
    Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
    Yoshida, Kenichi
    Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    Skaftason, Aron
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pandzic, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gonzalez, Blanca
    Department of Pathology, Hospital Clinic and Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
    Tasidou, Anna
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Waldhueter, Nils
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Rivas-Delgado, Alfredo
    Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Angelopoulou, Maria
    Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Ziepert, Marita
    Institute for Medical Informatics, Statistics, and Epidemiology, University at Leipzig, Leipzig, Germany.
    Arends, Christopher-Maximilian
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Couronne, Lucile
    Service d’Hematologie Adulte, Assistance Publique–Hopitaux de Paris, Hopital Necker, Paris, France.
    Lenze, Dido
    Institute of Pathology, Charite University Medical Center, Berlin, Germany.
    Claudia, Baldus
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Bastard, Christian
    INSERM U918, Universite de Rouen, Centre Henri Becquerel, Rouen, France.
    Okosun, Jessica
    Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
    Fitzgibbon, Jude
    Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
    Dörken, Bernd
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Drexler, Hans G
    Leibniz-Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
    Roos-Weil, Damien
    University Paris-Sud, Orsay, France, INSERM, U1170, Institut Gustave Roussy, Villejuif, France and Equipe Labellisee Ligue Nationale Contre le Cancer, Paris, France.
    Schmitt, Clemens A
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Munch-Petersen, Helga D
    Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Zenz, Thorsten
    Departments of Molecular Therapy in Haematology and Oncology and Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany and German Consortium for Translational Cancer Research, Heidelberg, Germany .
    Hansmann, Martin-Leo
    Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
    Strefford, Jonathan C
    Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bernard, Olivier
    University Paris-Sud, Orsay, France, INSERM, U1170, Institut Gustave Roussy, Villejuif, France and Equipe Labellisee Ligue Nationale Contre le Cancer, Paris, France.
    Ralfkiaer, Elisabeth
    Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Erlanson, Martin
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Korkolopoulou, Penelope
    Department of Pathology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Hultdin, Magnus
    Department of Medical Biosciences, Pathology, Umeå University, Umeå Sweden.
    Papadaki, Theodora
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Grønbæk, Kirsten
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Lopez-Guillermo, Armando
    Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Ogawa, Seishi
    Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    Küppers, Ralf
    Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
    Stavroyianni, Niki
    Hematology Department and Hematopoietic Cell Transplantation Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
    Kanellis, George
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Rosenwald, Andreas
    Institute of Pathology, University of Würzburg, Würzburg, Germany and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
    Campo, Elias
    Department of Pathology, Hospital Clinic and Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ott, German
    Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
    Vasslakopoulos, Theodoros P
    Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Hummel, Michael
    Institute of Pathology, Charite University Medical Center, Berlin, Germany.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Damm, Frederik
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany and Berlin Institute of Health, Berlin, Germany.
    Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma2016Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, nr 23, s. 2666-2670Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

  • 225. Margretardottir, Olof Birna
    et al.
    Geirsson, Gudmundur
    Agnarsdóttir, Margrét
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Ulfarsson, Elfar
    [Case of the month: woman with hematuria and depressed mental status]2012Inngår i: Læknablađiđ, ISSN 0023-7213, Vol. 98, nr 7-8, s. 413-415Artikkel i tidsskrift (Fagfellevurdert)
  • 226. Marquardt, Nicole
    et al.
    Ivarsson, MA
    Sundström, E
    Åkesson, E
    Martini, E
    Eidsmo, L
    Friberg, Danielle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Mjösberg, J
    Kublickas, M
    Ek, S
    Tegerstedt, G
    Seiger, Å
    Westgren, M
    Michaëlsson, J
    Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid.2016Inngår i: Journal of immunology (Baltimore, Md. : 1950), Vol. 197, nr 8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amniotic fluid (AF) surrounds the growing fetus, and cells derived from AF are commonly used for diagnosis of genetic diseases. Intra-amniotic infections are strongly linked to preterm birth, which is the leading cause of perinatal mortality worldwide. Surprisingly little is known, however, about mature hematopoietic cells in AF, which could potentially be involved in immune responses during pregnancy. In this study, we show that the dominating population of viable CD45+ cells in AF is represented by a subset of fetal CD103+ group 3 innate lymphoid cells (ILCs) producing high levels of IL-17 and TNF. Fetal CD103+ ILC3s could also be detected at high frequency in second-trimester mucosal tissues (e.g., the intestine and lung). Taken together, our data indicate that CD103+ ILC3s accumulate with gestation in the fetal intestine and subsequently egress to the AF. The dominance of ILC3s producing IL-17 and TNF in AF suggests that they could be involved in controlling intra-amniotic infections and inflammation and as such could be important players in regulating subsequent premature birth.

  • 227.
    Marusik, C
    et al.
    Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.
    Frykholm, C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ericson, Katharina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Axelsson, Ove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Diagnosis of Placental Mesenchymal Dysplasia with a focus on magnetic resonance imaging (MRI)2017Inngår i: Ultrasound in Obstetrics and Gynecology, ISSN 0960-7692, E-ISSN 1469-0705, Vol. 49, nr 3, s. 410-412Artikkel i tidsskrift (Fagfellevurdert)
  • 228.
    Mathot, Lucy
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Kundu, Snehangshu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Svedlund, Jessica
    Moens, Lotte
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Adlerteg, Tom
    Falk-Sörqvist, Elin
    Rendo, Verónica
    Bellomo, Claudia
    Mayrhofer, Markus
    Cortina, Carme
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Isaksson, Anders
    Moustakas, Aristidis
    Batlle, Eduard
    Birgisson, Helgi
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nilsson, Mats
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer2017Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 7, nr 77, s. 1730-1740Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.

  • 229.
    Mattsson, Johanna Sofia Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bergman, Bengt
    Grinberg, Marianna
    Edlund, Karolina
    Marincevic, Millaray
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jirstrom, Karin
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hengstler, Jan G
    Rahnenfuhrer, Jorg
    Karlsson, Mats G
    Karlsson, Christina
    Helenius, Gisela
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Prognostic impact of COX-2 in non-small cell lung cancer: A comprehensive compartment-specific evaluation of tumor and stromal cell expression2015Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 356, nr 2, s. 837-845Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n=1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n=616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC.

  • 230.
    Mattsson, Johanna Sofia Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden; Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Jabs, Verena
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Edlund, Karolina
    Dortmund TU, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Jirström, Karin
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden.
    Mindus, Stephanie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Karlsson, Mats
    Univ Orebro, Fac Med & Hlth, Dept Res & Educ, Orebro, Sweden.
    Karlsson, Christina
    Univ Orebro, Sch Hlth Sci, Orebro, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Helenius, Gisela
    Univ Orebro, Fac Med & Hlth, Dept Lab Med, Orebro, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Svensson, Maria
    Univ Orebro, Fac Med & Hlth, Clin Res Ctr, Orebro, Sweden.
    Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer2016Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, artikkel-id 603Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.

    Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.

    Results: ALK rearrangements were detected in 1.7% in the complete cohort and 2.0% in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.9% and 1.5% when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>99%), while the sensitivity was between 69% (Ventana) and 62% (in house Dako protocol). Furthermore, only 67% of the ALK IHC positive cases were positive in both IHC assays. Gene expression analysis revealed that 6/194 (3%) tumors showed high ALK gene expression (≥6AU) and of them only three were positive by either FISH or IHC.

    Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

  • 231.
    Medin, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Post-exercise elevation of cardiac risk markers in young athletes and evaluation of possible screening methods to prevent sudden heart failure2014Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 232.
    Mezheyeuski, Artur
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bergsland, Christian Holst
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bruun, Jarle
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.2018Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 244, nr 4, s. 421-431Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA-sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38-0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8(+) T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy.

  • 233.
    Mezheyeuski, Artur
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus..
    Lindh, Maja Bradic
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pfeiffer, Per
    Univ Southern Denmark, Dept Oncol, Odense, Denmark..
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Ikdahl, Tone
    Akershus Univ Hosp, Lorenskog, Norway..
    Skovlund, Eva
    Univ Oslo, Sch Pharm, Oslo, Norway.;Norwegian Inst Publ Hlth, Oslo, Norway..
    Corvigno, Sara
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Strell, Carina
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Pietras, Kristian
    Lund Univ, Div Translat Canc Res, Lund, Sweden..
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mulder, Jan
    Karolinska Inst, Sci Life Lab, Dept Neurosci, Stockholm, Sweden..
    Qvortrup, Camilla
    Univ Southern Denmark, Dept Oncol, Odense, Denmark..
    Portyanko, Anna
    Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus..
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway..
    Östman, Arne
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 27, s. 41948-41958Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown. Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC). Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-beta or alpha-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-alpha and -beta and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-alpha and -beta remained independent factors for survival in multivariate analyses. Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-alpha and -beta were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.

  • 234.
    Mezheyeuski, Artur
    et al.
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, R8 03, Stockholm, Sweden;Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus.
    Strell, Carina
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, R8 03, Stockholm, Sweden.
    Hrynchyk, Ina
    City Clin Pathologoanat Bur, Minsk, Byelarus.
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Doroshenko, Tatyana
    Republ Res & Prod Ctr Transfusiol & Med Biotechno, Lab Antibodies & Cytokines Biotechnol, Minsk, Byelarus.
    Pashkova, Oksana
    Republ Res & Prod Ctr Transfusiol & Med Biotechno, Lab Antibodies & Cytokines Biotechnol, Minsk, Byelarus.
    Gorgun, Julia
    Belarusian Med Acad Postgrad Educ, Dept Gastroenterol & Nutr, Minsk, Byelarus.
    Ruksha, Kseniya
    NN Alexandrov Natl Canc Ctr Belarus, Minsk, Byelarus.
    Pfeiffer, Per
    Univ Southern Denmark, Dept Oncol, Odense, Denmark.
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Edler, David
    Karolinska Univ Hosp Solna, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.
    Martling, Anna
    Karolinska Univ Hosp Solna, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ostman, Arne
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, R8 03, Stockholm, Sweden.
    Portyanko, Anna
    Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus.
    Treatment-related survival associations of claudin-2 expression in fibroblasts of colorectal cancer2018Inngår i: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 472, nr 3, s. 395-405Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Claudin-2 is a trans-membrane protein-component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi-quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer-associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression-free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU +/- irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients.

  • 235.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Skane Univ Hosp, Dept Resp Med & Allergol, SE-22185 Lund, Sweden.
    Tran, Lena
    Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Vidarsdottir, Halla
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Helsingborg Hosp, Dept Surg, SE-25187 Helsingborg, Sweden.
    Nodin, Bjorn
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden.
    Jirstrom, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Mucin staining is of limited value in addition to basic immunohistochemical analyses in the diagnostics of non-small cell lung cancer2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 1319Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Accurate diagnosis of histological type is important for therapy selection in lung cancer. Immunohistochemical (IHC) and histochemical stains are often used to complement morphology for definite diagnosis and are incorporated in the WHO classification. Our main aim was to compare different mucin stains and assess their value in relation to common IHC analyses in lung cancer diagnostics. Using tissue microarrays from 657 surgically treated primary lung cancers, we evaluated the mucin stains periodic acid-Schiff with diastase (PASD), alcian blue-periodic acid-Schiff (ABPAS) and mucicarmine, and compared with the IHC markers p40, p63, cytokeratin 5, thyroid transcription factor 1 (TTF-1), napsin A and cytokeratin 7. Ten or more cytoplasmic mucin inclusions in a tissue microarray core were seen in 51%, 48% and 31% of the 416 adenocarcinomas and 3%, 4% and 0.5% of the 194 squamous cell carcinomas with PASD, ABPAS and mucicarmine, respectively. Diagnostic pitfalls, such as entrapped benign epithelium, apoptotic/necrotic cells and glycogen, partly differed for the mucin stains. TTF-1 and napsin A IHC stainings had similar specificity but better sensitivity for adenocarcinoma than the mucin stains, but addition of PASD or ABPAS identified more tumors as adenocarcinomas (n = 8 and n = 10, respectively) than napsin A (n = 1) in cases with solid growth that were negative for TTF-1 and p40. We conclude that PASD and ABPAS have similar diagnostic performance and that these markers are of value in poorly differentiated cases. However, morphology and TTF-1 and p40 IHC staining is sufficient for correct diagnosis in most non-small cell lung cancers.

  • 236.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kühn, S
    Buchauer, L
    Harries, J R
    Bücking, T M
    Blaum, K
    Cieluch, A
    Egl, A
    Hollain, D
    Kraemer, S
    Pfeifer, T
    Schmidt, P O
    Schüssler, R X
    Schweiger, Ch
    Stöhlker, T
    Sturm, S
    Wolf, R N
    Bernitt, S
    Crespo López-Urrutia, J R
    The Heidelberg compact electron beam ion traps.2018Inngår i: Review of Scientific Instruments, ISSN 0034-6748, E-ISSN 1089-7623, Vol. 89, nr 6, artikkel-id 063109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Electron beam ion traps (EBITs) are ideal tools for both production and study of highly charged ions (HCIs). In order to reduce their construction, maintenance, and operation costs, we have developed a novel, compact, room-temperature design, the Heidelberg Compact EBIT (HC-EBIT). Four already commissioned devices operate at the strongest fields (up to 0.86 T) reported for such EBITs using permanent magnets, run electron beam currents up to 80 mA, and energies up to 10 keV. They demonstrate HCI production, trapping, and extraction of pulsed Ar16+ bunches and continuous 100 pA ion beams of highly charged Xe up to charge state 29+, already with a 4 mA, 2 keV electron beam. Moreover, HC-EBITs offer large solid-angle ports and thus high photon count rates, e.g., in x-ray spectroscopy of dielectronic recombination in HCIs up to Fe24+, achieving an electron-energy resolving power of E/ΔE > 1500 at 5 keV. Besides traditional on-axis electron guns, we have also implemented a novel off-axis gun for laser, synchrotron, and free-electron laser applications, offering clear optical access along the trap axis. We report on its first operation at a synchrotron radiation facility demonstrating the resonant photoexcitation of highly charged oxygen.

  • 237.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Nodin, Björn
    Jirström, Karin
    Tran, Lena
    Jönsson, Per
    Planck, Maria
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Brunnström, Hans
    The Impact of the Fourth Edition of the WHO Classification of Lung Tumours on Histological Classification of Resected Pulmonary NSCCs2016Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 11, nr 6, s. 862-872Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Histopathological classification of lung cancer is of central importance in the diagnostic routine and guides therapy in the majority of patients. The 4(th) edition of the WHO classification was recently published and includes changes to the diagnostic procedure of non-small cell carcinomas (NSCC) with more emphasis on immunohistochemical (IHC) staining.

    METHODS: 656 unselective cases of resected pulmonary NSCC were diagnosed according to the 2004 WHO classification. After IHC staining with cytokeratin 5, p40, p63, thyroid transcription factor 1 (clones 8G7G3/1 and SPT24) and napsin A the diagnoses were revised in accordance with the new 4(th) edition of the WHO classification.

    RESULTS: Reclassification led to a new histological annotation in 36 (5%) of the 656 cases. Most notable was the decrease of cases previously classified as large cell carcinomas (56 vs. 12 cases). This was partially due to the exclusion of 21 neuroendocrine tumors from this group, while 20 cases were ascribed to the group of adenocarcinoma based on IHC markers. Only 7 cases of adenocarcinoma or squamous cell carcinoma were reclassified after the addition of IHC staining. There was a substantial overlap in staining properties between different markers of squamous and adenocarcinomatous differentiation, respectively, but in 17-31 cases (3-5%) the diagnosis depended on the choice of markers.

    CONCLUSIONS: The 4(th) edition of the WHO classification of lung tumours leads to changes of histological type in 5% of resected NSCC cases. The incorporation of IHC staining in NSCC diagnostics demands awareness that the choice of ancillary stains has an effect on diagnosis.

  • 238. Mignardi, Marco
    et al.
    Mezger, Anja
    Qian, Xiaoyan
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Larsson, Chatarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nilsson, Mats
    Oligonucleotide gap-fill ligation for mutation detection and sequencing in situ.2015Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, nr 22, artikkel-id e151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In clinical diagnostics a great need exists for targeted in situ multiplex nucleic acid analysis as the mutational status can offer guidance for effective treatment. One well-established method uses padlock probes for mutation detection and multiplex expression analysis directly in cells and tissues. Here, we use oligonucleotide gap-fill ligation to further increase specificity and to capture molecular substrates for in situ sequencing. Short oligonucleotides are joined at both ends of a padlock gap probe by two ligation events and are then locally amplified by target-primed rolling circle amplification (RCA) preserving spatial information. We demonstrate the specific detection of the A3243G mutation of mitochondrial DNA and we successfully characterize a single nucleotide variant in the ACTB mRNA in cells by in situ sequencing of RCA products generated by padlock gap-fill ligation. To demonstrate the clinical applicability of our assay, we show specific detection of a point mutation in the EGFR gene in fresh frozen and formalin-fixed, paraffin-embedded (FFPE) lung cancer samples and confirm the detected mutation by in situ sequencing. This approach presents several advantages over conventional padlock probes allowing simpler assay design for multiplexed mutation detection to screen for the presence of mutations in clinically relevant mutational hotspots directly in situ.

  • 239.
    Miyashita, Naoya
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan.
    Horie, Masafumi
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan;Univ Southern Calif, Hastings Ctr Pulm Res, Div Pulm Crit Care & Sleep Med, Dept Med,Keck Sch Med, Los Angeles, CA USA;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.
    Suzuki, Hiroshi I.
    MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
    Yoshihara, Masahito
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Persson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Brunnstrom, Hans
    Lund Univ, Lab Med Reg Skane, Dept Clin Sci Lund, Pathol, Lund, Sweden.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Elfving, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan;Univ Tokyo, Div Hlth Serv Promot, Tokyo, Japan.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan.
    An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas2018Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 11, s. 1676-1691Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting thatASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

  • 240. Modvig, S
    et al.
    Madsen, H O
    Siitonen, S M
    Rosthøj, S
    Tierens, A
    Juvonen, V
    Osnes, L T N
    Vålerhaugen, H
    Hultdin, M
    Thörn, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Matuzeviciene, R
    Stoskus, M
    Marincevic, Millaray
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Fogelstrand, L
    Lilleorg, A
    Toft, N
    Jónsson, O G
    Pruunsild, K
    Vaitkeviciene, G
    Vettenranta, K
    Lund, B
    Abrahamsson, J
    Schmiegelow, K
    Marquart, H V
    Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia2019Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, nr 6, s. 1324-1336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol. MRD was measured by six-color FCM and real-time quantitative PCR. Day 29 PCR-MRD (cut-off 10-3) was used for risk stratification. At diagnosis, 93% had an FCM-marker for MRD monitoring, 84% a PCR-marker, and 99.3% (272/274) had a marker when combining the two. Adjusted for age and WBC, the hazard ratio for relapse was 3.55 (95% CI 1.4-9.0, p = 0.008) for day 29 FCM-MRD ≥ 10-3 and 5.6 (95% CI 2.0-16, p = 0.001) for PCR-MRD ≥ 10-3 compared with MRD < 10-3. Patients stratified to intermediate-risk therapy on day 29 with MRD 10-4-<10-3 had a 5-year event-free survival similar to intermediate-risk patients with MRD < 10-4 or undetectable, regardless of method for monitoring. Patients with day 15 FCM-MRD < 10-4 had a cumulative incidence of relapse of 2.3% (95% CI 0-6.8, n = 59). Thus, FCM-MRD allows early identification of patients eligible for reduced intensity therapy, but this needs further studies. In conclusion, FCM-MRD provides reliable risk prediction for T-ALL and can be used for stratification when no PCR-marker is available.

  • 241. Monoranu, Camelia Maria
    et al.
    Apfelbacher, Manuela
    Grünblatt, Edna
    Puppe, Bernhard
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Ferrer, Isidro
    Al-Saraj, Safa
    Keyvani, Kathy
    Schmitt, Andrea
    Falkai, Peter
    Schittenhelm, Jens
    Halliday, Glenda
    Kril, Jillian
    Harper, Clive
    McLean, Catriona
    Riederer, Peter
    Roggendorf, Wolfgang
    pH measurement as quality control on human postmortem brain tissue: A Study of the BrainNet Europe Consortium.2009Inngår i: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 35, nr 3, s. 329-337Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Most brain diseases are complex entities. Although animal models or cell culture experiments mimic some disease aspects, human postmortem brain tissue remains essential to advance our understanding of brain diseases using biochemical and molecular techniques. Postmortem artifacts must be properly understood, standardized, and either eliminated or factored into such experiments. Here we examine the influence of several pre- and postmortem factors on pH, and discuss the role of pH as a biochemical marker for brain tissue quality. Methods: We assessed brain tissue pH in 339 samples from 116 brains provided by 8 different European and 2 Australian brain bank centres. We correlated brain pH with tissue source, postmortem delay, age, gender, freezing method, storage duration, agonal state, or and brain ischaemia. Results: Our results revealed that only prolonged agonal state and ischaemic brain damage influenced brain tissue pH next to repeated freeze/thaw cycles. Conclusions: pH measurement in brain tissue is a good indicator of premortem events in brain tissue and it signals limitations for postmortem investigations.

  • 242. Murphy, C
    et al.
    Wang, S
    Macy, S
    Makovitzky, J
    Athanasou, N
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    Weiss, D T
    Solomon, A
    Nature of os labrum-associated amyloid deposits:  2011Inngår i: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis, ISSN 1744-2818, Vol. 18, nr Suppl 1, s. 206-207Artikkel i tidsskrift (Fagfellevurdert)
  • 243. Narkilahti, Susanna
    et al.
    Jutila, Leena
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Karkola, Kari
    Paljärvi, Leo
    Immonen, Arto
    Vapalahti, Matti
    Mervaala, Esa
    Kälviäinen, Reetta
    Pitkänen, Asla
    Increased expression of caspase 2 in experimental and human temporal lobe epilepsy.2007Inngår i: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 9, nr 2, s. 129-44Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Temporal lobe epilepsy (TLE) is often caused by a neurodegenerative brain insult that triggers epileptogenesis, and eventually results in spontaneous seizures, i.e., epilepsy. Understanding the mechanisms of cell death is a key for designing new drug therapies for preventing the neurodegeneration associated with TLE. Here, we investigated the expression of caspase 2, a protein involved in programmed cell death, during the course of epilepsy. We investigated caspase 2 expression in hippocampal samples derived from patients operated on for drug refractory TLE. To understand the evolution of altered-caspase 2 expression during the epileptic process, we also examined caspase 2 expression and activity in the rat hippocampus after status epilepticus-induced acute damage, during epileptogenesis, and after the onset of epilepsy. Caspase 2 expression was enhanced in the hippocampal neurons in chronic TLE patients. In rats, status epilepticus-induced caspase 2 labeling paralleled the progression of neurodegeneration. Proteolytic activation and cleavage of caspase 2 was also detected in the rat brain undergoing epileptogenesis. Our data suggest that caspase 2-mediated programmed cell death participates in the seizure-induced degenerative process in experimental and human TLE.

  • 244. Navallas, Javier
    et al.
    Rodriguez, Javier
    Stålberg, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Scanning electromyography2012Inngår i: EMG Methods for evaluating Muscle and Nerve function / [ed] Schwartz M, InTech , 2012, s. 471-490Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    The study of the anatomy and physiology of the motor unit has important implications in the diagnosis and follow-up of neuromuscular pathologies. Muscle action potentials allow the use of electrophysiological techniques based on electromyography (EMG) to make inferences about muscle structure, state and behaviour. Scanning EMG is one such technique that can record the temporal and spatial distribution of electrical activity of a single motor unit, allowing for deep insight into the structure and function of motor units. In this chapter, we describe the scanning EMG technique in detail, both from a technical and clinical point of view. A brief review of the motor unit anatomy and physiology is provided in Section 2. The technique, the apparatus setup, the recording procedure and the signal processing required are described in Section 3. Key results of studies using scanning EMG are reviewed in Section 4, including findings related to motor unit organisation in normal muscle and how changes due to pathology are reflected using this electrophysiological technique. Finally, Section 5 provides some hints regarding the use of scanning EMG in research.

  • 245.
    Nicholson, Andrew G.
    et al.
    Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Torkko, Kathleen
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA..
    Viola, Patrizia
    Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Duhig, Edwina
    Sullivan Nicolaides Pathol, Taringa, Qld, Australia..
    Geisinger, Kim
    Univ Mississippi, Med Ctr, Jackson, MS 39216 USA..
    Borczuk, Alain C.
    Weill Cornell Med, New York, NY USA..
    Hiroshima, Kenzo
    Tokyo Womens Med Univ, Yachiyo, Japan..
    Tsao, Ming S.
    Princess Margaret Canc Ctr, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Warth, Arne
    Heidelberg Univ Hosp, Heidelberg, Germany..
    Lantuejoul, Sylvie
    Canc Inst Leon Berard, Lyon, France..
    Russell, Prudence A.
    St Vincents Pathol, Fitzroy, Vic, Australia..
    Thunnissen, Erik
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Marchevsky, Alberto
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Mino-Kenudson, Mari
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Beasley, Mary Beth
    Mt Sinai Med Ctr, New York, NY 10029 USA..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Dacic, Sanja
    Univ Pittsburgh, Pittsburgh, PA USA..
    Yatabe, Yasushi
    Aichi Canc Ctr, Nagoya, Aichi, Japan..
    Noguchi, Masayuki
    Univ Tsukuba, Tsukuba, Ibaraki, Japan..
    Travis, William D.
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Kerr, Keith
    Aberdeen Royal Infirm, Aberdeen, Scotland..
    Hirsch, Fred R.
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA..
    Chirieac, Lucian R.
    Harvard Med Sch, Boston, MA USA..
    Wistuba, Ignacio I.
    MD Anderson, Houston, TX USA..
    Moreira, Andre
    NYU, Langone Med Ctr, New York, NY USA..
    Chung, Jin-Haeng
    Seoul Natl Univ, Bundang Hosp, Seoul, South Korea..
    Chou, Teh Ying
    Taipei Vet Gen Hosp, Taipei, Taiwan..
    Bubendorf, Lukas
    Univ Hosp Basel, Basel, Switzerland..
    Chen, Gang
    Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China..
    Pelosi, Giuseppe
    Univ Milan, Dept Oncol & Hematooncol, Milan, Italy..
    Poleri, Claudia
    Detterbeck, Frank C.
    Yale Univ, Dept Thorac Surg, New Haven, CT USA..
    Franklin, Wilbur A.
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA..
    Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung2018Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 2, s. 205-217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen kappa statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (kappa score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status.

  • 246. Nicholson, George
    et al.
    Rantalainen, Mattias
    Li, Jia V
    Maher, Anthony D
    Malmodin, Daniel
    Ahmadi, Kourosh R
    Faber, Johan H
    Barrett, Amy
    Min, Josine L
    Rayner, N William
    Toft, Henrik
    Krestyaninova, Maria
    Viksna, Juris
    Neogi, Sudeshna Guha
    Dumas, Marc-Emmanuel
    Sarkans, Ugis
    Donnelly, Peter
    Illig, Thomas
    Adamski, Jerzy
    Suhre, Karsten
    Allen, Maxine
    Zondervan, Krina T
    Spector, Tim D
    Nicholson, Jeremy K
    Lindon, John C
    Baunsgaard, Dorrit
    Holmes, Elaine
    McCarthy, Mark I
    Holmes, Chris C
    A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection2011Inngår i: PLoS genetics, ISSN 1553-7404, Vol. 7, nr 9, s. e1002270-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have performed a metabolite quantitative trait locus (mQTL) study of the 1H nuclear magnetic resonance spectroscopy (1H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by 1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10−11<p<2.8×10−23). Three of these—trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound—were measured in urine. The other—dimethylamine—was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%–64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects.

  • 247.
    Niinivirta, Marjut
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala University Hospital, Department of Oncology.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala University Hospital, Department of Oncology.
    Edqvist, Per-Henrik D
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ullenhag, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala University Hospital, Department of Oncology.
    Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients2017Inngår i: Journal of Cancer, ISSN 1837-9664, E-ISSN 1837-9664, Vol. 8, nr 19, s. 3975-3983Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and aims: There is no established predictive marker for the treatment of renal cancer. Metastatic renal cell carcinoma (mRCC) patients are often treated with sunitinib, a tyrosine kinase inhibitor. Sunitinibs anti-cancer effect is at least partly mediated through interfering with angiogenesis. Our aim with the current study was to assess annexin A1 (ANXA1), which stimulates angiogenesis, as a predictive marker for sunitinib therapy in mRCC patients. Since previous studies have indicated a predictive potential for cubilin, we also investigated the predictivity of ANXA1 combined with cubilin.

    Methods: ANXA1 expression was analysed in tumor tissue from a cohort of patients with advanced RCC (n= 139) using immunohistochemistry. Ninety-nine of the patients were treated with sunitinib in the first or second-line setting. Twenty-two of these were censored because of toxicity leading to the termination of treatment and the remaining (n= 77) were selected for the present study.

    Results: Twenty-five (32%) out of seventy-seven of the tumors lacked ANXA1 in the cytoplasm. On statistical analyses using Kaplan-Meier method, aNXA1 negative tumors were significantly associated with a longer treatment benefit in terms of progression free survival (PFS). Overall survival was also significantly better for patients with ANXA1 negative tumors. The combined ANXA1 positive and cubilin negative expression could more accurately than ANXA1 alone define the group not benefitting from treatment.

    Conclusions: Our results indicate that cytoplasmic expression of ANXA1 is a negative predictive marker for sunitinib therapy in mRCC patients. A possible explanation for this finding is that sunitinibs anti-angiogenic effect cannot overcome the pro-angiogenic drive from many ANXA1 proteins.

  • 248.
    Niinivirta, Marjut
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Edqvist, Per-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ullenhag, Gustav J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib2017Inngår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 143, nr 6, s. 961-970Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose Tyrosine kinase inhibitors like sunitinib and sorafenib are commonly used to treat metastatic renal cell cancer patients. Cubilin is a membrane protein expressed in the proximal renal tubule. Cubilin and megalin function together as endocytic receptors mediating uptake of many proteins. There is no established predictive marker for metastatic renal cell cancer patients and the purpose of the present study was to assess if cubilin can predict response to treatment with tyrosine kinase inhibitors.

    Methods Cubilin protein expression was analyzsed in tumor tissue from a cohort of patients with metastatic renal cell cancer (n = 139) using immunohistochemistry. One hundred and thirty six of the patients were treated with sunitinib or sorafenib in the first- or second-line setting. Thirty of these were censored because of toxicity leading to the termination of treatment and the remaining (n = 106) were selected for the current study.

    Results Fifty-three (50%) of the tumors expressed cubilin in the membrane. The median progression-free survival was 8 months in patients with cubilin expressing tumors and 4 months in the cubilin negative group. In addition, the overall survival was better for patients with cubilin positive tumors. We also found that the fraction of cubilin negative patients was significantly higher in the non-responding group (PFS ≤3 months) compared to responding patients (PFS >3 months).

    Conclusions We show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib.

  • 249.
    Nilsen, Tom
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi. Gentian AS.
    Avian antibodies applied in particle enhanced turbidimetric immunoassay: Developement of serum/plasma calprotectin immunoassay and its clinical performance as a marker for bacterial infections2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Calprotectin is a cytosolic protein in the granulocytes, consisting of S100A8 and S100A9. On the site of inflammation, the neutrophils release the cytosol as an inflammatory response. The circulating calprotectin concentration increases and can therefore be used as marker for neutrophil activation and inflammation.

    To raise specific antibodies, it is crucial to immunize with pure calprotectin antigen. We purified calprotectin from human granulocytes by ion-exchange chromatography, dialysed it towards saline and concentrated it to required levels, suited for immunisation of the hens. The purified antigen solutions were assigned concentration values by the Biuret method and the purity was checked by SDS PAGE and size exclusion chromatography. The yield was approximately 2 mg purified antigens per unit of 450 ml blood.

    A prototype calprotectin particle enhanced turbidimetric immunoassay was developed from the purified antigen and the affinity purified antibodies. The antigen was spiked into PBS to prepare calibrators and controls. The antibodies were coated to latex particles to prepare immunoparticles. The performance of the immunoassay was technically tested on a clinical chemistry analyser. LoQ, antigen excess, linearity, precision and calibration stability met the pre-set criteria.

    In the production process of immunoparticles there are several factors affecting the performance of the assay. Investigating eight factors applying a Taguchi L12 screening, we experienced that conductivity and pH of conjugate buffer, coating grade and conductivity of dialysis buffer II affected the sensitivity and antigen excess the most.

    The assay was used to measure clinical samples. Serum samples from elderly people aged 70+ were collected. Only patients with no infections were included to establish a reference interval for this patient group. The reference interval in serum was 0.3 mg/L to 2.5 mg/L for both genders. Furthermore, the plasma calprotectin immunoassay was tested clinically on critically ill patients to assess the ability of plasma calprotectin as an early marker for detection of bacterial infections. It showed promising results. Calprotectin was a better predictive marker for sepsis than procalcitonin and white blood cell count. Because some patients with an inflammation have low numbers of granulocytes, we examined the correlation between white blood cell count and the calprotectin levels in a group of patients with an inflammation. There was a weak correlation between the number of white blood cells and calprotectin concentration.

    Delarbeid
    1. Extraction,isolation, and concentration of calprotectin antigen (S100A8/S100A9) fromgranulocytes
    Åpne denne publikasjonen i ny fane eller vindu >>Extraction,isolation, and concentration of calprotectin antigen (S100A8/S100A9) fromgranulocytes
    2018 (engelsk)Inngår i: Health Science Reports, Vol. 1, nr 5, artikkel-id e35Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background

    Calprotectin is a promising biomarker for granulocyte activation. It is mainly measured in faeces as a marker for inflammatory bowel disease. A limitation is that there is no widely accepted calibrator.

    Aim

    To establish a method for purification of calprotectin from human granulocytes that is easily reproducible, reliable, and could contribute to a better agreement between different calprotectin methods.

    Methods and results

    Calprotectin was purified from granulocyte extracts using ion‐exchange chromatography. The granulocytes were separated from blood bags. The purity was analysed by analysing pixel density of a picture of the sodium dodecyl sulfate polyacrylamide gel electrophoresis and by size exclusion chromatography. The calprotectin concentration of the pure antigen solution was determined using Biuret method. The purity was >95% for 3 preparations, and their concentrations were 1079, 1080, and 1813 mg/L.

    Conclusion

    It is possible to reproducibly prepare highly purified calprotectin antigen from human granulocytes. The preparations can be used for preparing calibrators, controls for immunological calprotectin assays, and immunisation for raising antibodies against human calprotectin in hens.

    sted, utgiver, år, opplag, sider
    Wiley-Blackwell Publishing Inc., 2018
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-355220 (URN)10.1002/hsr2.35 (DOI)
    Tilgjengelig fra: 2018-06-27 Laget: 2018-06-27 Sist oppdatert: 2018-10-15bibliografisk kontrollert
    2. A new turbidimetric immunoassay for serum calprotectin for fully automatized clinical analysers
    Åpne denne publikasjonen i ny fane eller vindu >>A new turbidimetric immunoassay for serum calprotectin for fully automatized clinical analysers
    2015 (engelsk)Inngår i: Journal of Inflammation, ISSN 1476-9255, E-ISSN 1476-9255, Vol. 12, artikkel-id 45Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Serum and plasma calprotectin concentration is shown to be elevated when neutrophils are activated, and may therefore be used as a marker for inflammatory diseases. A serum calprotectin immunoassay was developed based on calprotectin values observed in samples from the intensive care unit. The polyclonal avian antibodies were raised and affinity purified with calprotectin antigens. The performance was tested and it was observed that the assay was linear in the range 0.3-24.7 mg/L, the limit of quantitation was observed to be lower than 0.3 mg/L, no antigen excess was observed up to 54 mg/L, all CVs were lower than 1.8 % in the precision study, the calibration curve stability was longer than 6 weeks, and there was no significant interference detected for haemoglobin, intralipid or bilirubin. The serum calprotectin immunoassay presented in this paper performs well within the criteria carefully set from the limited clinical experience obtained in both serum and plasma. In addition it is commutable with Bühlmann MRP8/14 ELISA.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-259346 (URN)10.1186/s12950-015-0090-3 (DOI)000358486900002 ()26213499 (PubMedID)
    Merknad

    Economical support was given from the Norwegian Research Council.

    Tilgjengelig fra: 2015-07-31 Laget: 2015-07-31 Sist oppdatert: 2018-10-15bibliografisk kontrollert
    3. Influence of 8 parameters when coating avian calprotectin antibodies to latex particles
    Åpne denne publikasjonen i ny fane eller vindu >>Influence of 8 parameters when coating avian calprotectin antibodies to latex particles
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Aim: To find the parameters affecting sensitivity and security zone in the preparation process of immunoparticles with avian antibodies for use in particle enhanced turbidimetric immunoassays. Method: 12 combinations of 8 parameters were tested in the preparation process of the immunoparticles. The study was designed according to Taguchi L12 screening method and analysed using DOE KISS PRO XL. Results/Conclusion: The parameters affecting the sensitivity and security zone the most were conductivity of the conjugate buffer, coating grade and pH of the conjugate buffer.

    HSV kategori
    Forskningsprogram
    Klinisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-363262 (URN)
    Forskningsfinansiär
    The Research Council of Norway
    Tilgjengelig fra: 2018-10-15 Laget: 2018-10-15 Sist oppdatert: 2018-10-17
    4. Serum calprotectin levels in elderly males and females without bacterial or viral infections
    Åpne denne publikasjonen i ny fane eller vindu >>Serum calprotectin levels in elderly males and females without bacterial or viral infections
    2014 (engelsk)Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 47, nr 12, s. 1065-1068Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES: Calprotectin is released from activated leukocytes and calprotectin can thus be used as a marker for leukocyte activation. Faeces calprotectin is not only used as a marker for inflammatory bowel disease but can also be used to detect leukocyte activation in other body fluids. The aim of the present study was to study serum calprotectin levels in non-infected elderly individuals to establish reference intervals for the marker.

    METHODS: Serum calprotectin was analyzed by immunoturbidimetry in 75year old females and males without known infections. Individuals with CRP>20mg/L were excluded as this could indicate a subclinical infection. The calprotectin levels in the remaining 713 individuals were used to calculate reference values for this population. The Spearman rank correlations between calprotectin and 27 other laboratory biomarkers were also investigated.

    RESULTS: There was a strong positive Spearman rank correlation between calprotectin and CRP (p<0.000001) and alkaline phosphatase (p<0.000001). There were also significant negative correlations between calprotectin and ApoA1 and direct HDL-cholesterol.

    CONCLUSIONS: The reference interval for serum-calprotectin for all study subjects was 0.3-2.6mg/L. Leukocyte alkaline phosphatase contributes to serum alkaline phosphatase levels.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-220516 (URN)10.1016/j.clinbiochem.2014.01.003 (DOI)000340995900016 ()24440500 (PubMedID)
    Tilgjengelig fra: 2014-03-17 Laget: 2014-03-17 Sist oppdatert: 2018-10-15bibliografisk kontrollert
    5. Calprotectin as an early biomarker of bacterial infections in critically ill patients: an exploratory cohort assessment
    Åpne denne publikasjonen i ny fane eller vindu >>Calprotectin as an early biomarker of bacterial infections in critically ill patients: an exploratory cohort assessment
    Vise andre…
    2017 (engelsk)Inngår i: Criminology & Public Policy, ISSN 1441-2772, E-ISSN 1941-1006, Vol. 19, nr 3, s. 205-213Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Calprotectin is the most abundant protein in the cytosolic fraction of neutrophils, and neutrophil degranulation is a major response to bacterial infections.

    OBJECTIVES: To assess the value of plasma calprotectin as an early marker of bacterial infections in critically ill patients and compare it with the corresponding values for procalcitonin (PCT), C-reactive protein (CRP) and white blood cell count (WBC).

    METHODS: We measured daily plasma calprotectin levels in 110 intensive care unit patients using a newly developed turbidimetric assay run on clinical chemistry analysers. The likelihood of infection was determined according to the International Sepsis Forum criteria.

    RESULTS: Overall, 58 patients (52.7%) developed a suspected or confirmed bacterial infection. Plasma calprotectin predicted such infections within 24 hours with an area under the receiver operating characteristics curve (ROC area) of 0.78 (95% CI, 0.68-0.89). The ROC area for calprotectin was significantly greater than the corresponding ROC areas for WBC (P < 0.001) and PCT (P = 0.02) but only marginally better than the ROC area for CRP (0.71; 95% CI, 0.68-0.89).

    CONCLUSION: Plasma calprotectin appears to be a useful early marker of bacterial infections in critically ill patients, with better predictive characteristics than WBC and PCT.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-329205 (URN)000408400800003 ()28866970 (PubMedID)
    Tilgjengelig fra: 2017-09-14 Laget: 2017-09-14 Sist oppdatert: 2018-10-15bibliografisk kontrollert
  • 250.
    Nilsen, Tom
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi. Gentian Technology AS, Moss, Norway.
    Haugen, SH
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Extraction,isolation, and concentration of calprotectin antigen (S100A8/S100A9) fromgranulocytes2018Inngår i: Health Science Reports, Vol. 1, nr 5, artikkel-id e35Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Calprotectin is a promising biomarker for granulocyte activation. It is mainly measured in faeces as a marker for inflammatory bowel disease. A limitation is that there is no widely accepted calibrator.

    Aim

    To establish a method for purification of calprotectin from human granulocytes that is easily reproducible, reliable, and could contribute to a better agreement between different calprotectin methods.

    Methods and results

    Calprotectin was purified from granulocyte extracts using ion‐exchange chromatography. The granulocytes were separated from blood bags. The purity was analysed by analysing pixel density of a picture of the sodium dodecyl sulfate polyacrylamide gel electrophoresis and by size exclusion chromatography. The calprotectin concentration of the pure antigen solution was determined using Biuret method. The purity was >95% for 3 preparations, and their concentrations were 1079, 1080, and 1813 mg/L.

    Conclusion

    It is possible to reproducibly prepare highly purified calprotectin antigen from human granulocytes. The preparations can be used for preparing calibrators, controls for immunological calprotectin assays, and immunisation for raising antibodies against human calprotectin in hens.

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