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  • 1.
    Aasebo, Kristine
    et al.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Sundström, Magnus
    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.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Eide, Geir Egil
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Lifestyle Epidemiol Grp, Bergen, Norway;Haukeland Hosp, Clin Res Ctr, Bergen, Norway.
    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.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Glimelius, Bengt
    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.
    Sorbye, Halfdan
    Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Oncol, Bergen, Norway.
    CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup2020Inngår i: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 10, artikkel-id 8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated. Methods: Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (n = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated. Results: Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if BRAF mutated (BRAFmut) and in 9% if KRAS mutated (KRASmut). CDX2 loss was associated with microsatellite instability, BRAFmut, and poor differentiation and inversely associated with KRASmut. Patients with CDX2 loss received less first-line (53 vs. 64%, p = 0.050) and second-line (23 vs. 39%, p = 0.006) chemotherapy and secondary surgery (1 vs. 9%, p = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed (p = 0.001, p < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (p = 0.003). Median OS in patients with BRAFmut or KRASmut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in BRAFmut and KRASmut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, p = 0.027) and BRAFmut (hazard ratio: 1.62, p = 0.012) were independent poor prognostic markers for OS. Conclusion: In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of BRAFmut cases with a much better prognosis. Loss of CDX2 defines a small group of KRASmut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.

    Fulltekst (pdf)
    FULLTEXT01
  • 2.
    Aasebö, Kristine Ö.
    et al.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Eide, Geir Egil
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Lifestyle Epidemiol Grp, Bergen, Norway;Haukeland Hosp, Ctr Clin Res, Bergen, Norway.
    Pontén, Fredrik
    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.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sorbye, Halfdan
    Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients2019Inngår i: Cancer Medicine, E-ISSN 2045-7634, Vol. 8, nr 7, s. 3623-3635Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.

    Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.

    Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).

    Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).

    Fulltekst (pdf)
    FULLTEXT01
  • 3.
    Abdulla, Maysaa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Prognostic signficance of tumor cell markers in diffuse large B-cell lymphoma with special emphasis on lymphoma localization2020Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of high-grade B-cell lymphoma with different clinical, morphological, immunophenotypical, and molecular features. DLBCL is curable in 60-70% of patients when treated with standard immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).

    The main aim of this thesis is to identify prognostic factors in DLBCL by studying tumor markers (paper I and II), site of disease (paper III) and tumor microenvironment markers in primary DLBCL of the CNS (PCNSL) (paper IV) in order to better identify different risk groups of DLBCL patients.

    In papers I-III, we studied DLBCL patients treated homogeneously with R-CHOP. The negative prognostic impact of double protein expression of MYC and BCL2 so called “double-expressor lymphoma” (DEL) was a common finding in the three papers. In paper I, we detected DEL in 27% of patients, distributed with no significant difference between the germinal center derived B-cell subgroup (GCB) in 52% of cases and the non-GCB subgroup in 37% of cases. There was no significant difference in survival between GCB and non-GCB patients. The diagnosis in most of the patients with DEL was made on core needle biopsy in this paper. This finding was more thoroughly investigated in paper III with attention paid to the site of biopsy. In paper II, we evaluated the concordance of cell of origin (COO) assignment between gene expression profile (GEP) and immunohistochemistry (IHC) to identify the best predictor of survival in a DLBCL cohort including patients from Sweden and Denmark. The overall concordance between the two methods was 83%. We found that ABC/non-GCB subtype identified by both GEP and IHC is associated with the worst outcome. This finding indicates the importance of precise risk stratification in the era of precision medicine. DEL was more common in ABC patients categorized by GEP. In paper III, we identified abdominal lymph node involvement by radiological examination in 63% of DLBCL patients with an inferior survival, adverse clinical characteristics and significantly more frequent DEL. These findings may indicate a distinct biological behavior in patients with abdominal nodal disease. In paper IV, we demonstrated a significant association between IDO1 and PD-L1 in PCNSL patients. This finding indicates the crucial immunosuppressive role of these two molecules. In addition, in PCNSL low frequencies of MYC and BCL2 translocations and high frequency of BCL6 translocation was observed and DEL was detected in 49% of cases. Contrary to our results in systemic DLBCL in papers I-III, there was no significant prognostic impact of DEL in PCNSL.

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

    Background

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

    Material and methods

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

    Results

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

    Conclusion

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

    Fulltekst (pdf)
    fulltext
  • 5.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Guglielmo, Priscilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Brotzu General Hospital, Cagliari, Italy.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Åström, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Prognostic impact of abdominal lymph node involvement in diffuse large B-cell lymphoma2020Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 104, nr 3, s. 207-213Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: The prognostic value of site of nodal involvement in diffuse large B-cell lymphomas (DLBCL) is mainly unknown. We aimed to determine the prognostic significance of nodal abdominal involvement in relation to tumour cell markers and clinical characteristics of 249 DLBCL patients in a retrospective single-centre study.

    METHODS: Contrast-enhanced computed tomography (CT) of the abdomen and thorax revealed pathologically enlarged abdominal lymph nodes in 156 patients, while in 93 patients there were no pathologically enlarged lymph nodes in the abdomen. In 81 cases, the diagnosis of DLBCL was verified by histopathological biopsy obtained from abdominal lymph node.

    RESULTS: Patients with abdominal nodal disease had inferior lymphoma-specific survival (P = .04) and presented with higher age-adjusted IPI (P < .001), lactate dehydrogenase (P < .001) and more often advanced stage (P < .001), bulky disease (P < .001), B symptoms (P < .001), and double expression of MYC and BCL2 (P = .02) compared to patients without nodal abdominal involvement, but less often extranodal involvement (P < .02). The worst outcome was observed in those where the abdominal nodal involvement was verified by histopathological biopsy.

    CONCLUSION: Diffuse large B-cell lymphomas patients with abdominal nodal disease had inferior outcome and more aggressive behaviour, reflected both in clinical and biological characteristics.

    Fulltekst (pdf)
    fulltext
  • 6.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Hosp, Uppsala, Sweden..
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Univ Hosp, Uppsala, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Univ Hosp, Uppsala, Sweden..
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Hosp, Uppsala, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Saft, Leonie
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Hosp, Uppsala, Sweden..
    Outcome in PCNSL patients and its association with PD-L1+leukocytes in the tumor microenvironment2022Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 61, nr 7, s. 824-829Artikkel i tidsskrift (Fagfellevurdert)
  • 7.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pandzic, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mansouri, Larry
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Ednersson, Susanne Bram
    Sahlgrens Univ Hosp, Dept Pathol, Gothenburg, Sweden.
    Andersson, Per-Ola
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden;Sodra Alvsborg Hosp Borås, Dept Med, Borås, Sweden.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå, Sweden.
    Fors, Maja
    Umeå Univ, Dept Med Biosci, Pathol, Umeå, Sweden.
    Erlanson, Martin
    Umeå Univ, Dept Radiat Sci, Oncol, Umeå, Sweden.
    Degerman, Sofie
    Umeå Univ, Dept Med Biosci, Pathol, Umeå, Sweden.
    Petersen, Helga Munch
    Copenhagen Univ Hosp, Dept Pathol, Rigshosp, Copenhagen, Denmark.
    Asmar, Fazila
    Copenhagen Univ Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark.
    Enblad, Gunilla
    Uppsala Univ, Expt & Clin Oncol, Dept Immunol Genet & Pathol, Uppsala, Sweden.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma2020Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 95, nr 1, s. 57-67Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

    Fulltekst (pdf)
    fulltext
  • 8.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Laszlo, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Triumf, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hedström, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Berglund, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Biosci & Nutr, Novum, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients2016Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 9-10, s. 1126-1131Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

  • 9.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Laszlo, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Triumf, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Hedström, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Berglund, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research2017Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, nr 1, s. 106-109Artikkel i tidsskrift (Fagfellevurdert)
  • 10.
    Abu Hamdeh, Sami
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rollman Waara, Erik
    BioArctic Neurosci AB, Stockholm, Sweden.
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden.
    Söderberg, Linda
    BioArctic Neurosci AB, Stockholm, Sweden.
    Basun, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2018Inngår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, nr 4, s. 451-462Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 11.
    Abu Hamdeh, Sami
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Enblad: Neurokirurgi.
    Virhammar, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Enblad: Neurokirurgi.
    Sehlin, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Cesarini, Kristina G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Enblad: Neurokirurgi.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Enblad: Neurokirurgi.
    Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus2019Inngår i: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 130, nr 1, s. 121-129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aβ) reflect the propensity of cortical Aβ aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment.

    Methods Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aβ40, Aβ42, and neurotoxic Aβ oligomers/protofibrils, associated with Aβ aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aβ species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale.

    Rrsults The brain tissue levels of Aβ42 were negatively correlated with CSF Aβ42 (Spearman's r = -0.53, p < 0.05). The Aβ40, Aβ42, and Aβ oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aβ aggregates (p < 0.05). The preoperative CSF Aβ42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aβ aggregates and high brain tissue Aβ42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05).

    Conclusions Brain tissue measurements of soluble Aβ species are feasible. Since high Aβ42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aβ species may be associated with the clinical response to shunt treatment.

  • 12. Adam, A
    et al.
    Robison, J
    Lu, J
    Jose, R
    Badran, N
    Vivas-Buitrago, T
    Rigamonti, D
    Sattar, A
    Omoush, O
    Hammad, M
    Dawood, M
    Maghaslah, M
    Belcher, T
    Carson, K
    Hoffberger, J
    Jusué Torres, I
    Foley, S
    Yasar, S
    Thai, Q A
    Wemmer, J
    Klinge, P
    Al-Mutawa, L
    Al-Ghamdi, H
    Carson, K A
    Asgari, M
    de Zélicourt, D
    Kurtcuoglu, V
    Garnotel, S
    Salmon, S
    Balédent, O
    Lokossou, A
    Page, G
    Balardy, L
    Czosnyka, Z
    Payoux, P
    Schmidt, E A
    Zitoun, M
    Sevestre, M A
    Alperin, N
    Baudracco, I
    Craven, C
    Matloob, S
    Thompson, S
    Haylock Vize, P
    Thorne, L
    Watkins, L D
    Toma, A K
    Bechter, Karl
    Pong, A C
    Jugé, L
    Bilston, L E
    Cheng, S
    Bradley, W
    Hakim, F
    Ramón, J F
    Cárdenas, M F
    Davidson, J S
    García, C
    González, D
    Bermúdez, S
    Useche, N
    Mejía, J A
    Mayorga, P
    Cruz, F
    Martinez, C
    Matiz, M C
    Vallejo, M
    Ghotme, K
    Soto, H A
    Riveros, D
    Buitrago, A
    Mora, M
    Murcia, L
    Bermudez, S
    Cohen, D
    Dasgupta, D
    Curtis, C
    Domínguez, L
    Remolina, A J
    Grijalba, M A
    Whitehouse, K J
    Edwards, R J
    Eleftheriou, A
    Lundin, F
    Fountas, K N
    Kapsalaki, E Z
    Smisson, H F
    Robinson, J S
    Fritsch, M J
    Arouk, W
    Garzon, M
    Kang, M
    Sandhu, K
    Baghawatti, D
    Aquilina, K
    James, G
    Thompson, D
    Gehlen, M
    Schmid Daners, M
    Eklund, A
    Malm, J
    Gomez, D
    Guerra, M
    Jara, M
    Flores, M
    Vío, K
    Moreno, I
    Rodríguez, S
    Ortega, E
    Rodríguez, E M
    McAllister, J P
    Guerra, M M
    Morales, D M
    Sival, D
    Jimenez, A
    Limbrick, D D
    Ishikawa, M
    Yamada, S
    Yamamoto, K
    Junkkari, A
    Häyrinen, A
    Rauramaa, T
    Sintonen, H
    Nerg, O
    Koivisto, A M
    Roine, R P
    Viinamäki, H
    Soininen, H
    Luikku, A
    Jääskeläinen, J E
    Leinonen, V
    Kehler, U
    Lilja-Lund, O
    Kockum, K
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Riklund, K
    Söderström, L
    Hellström, P
    Laurell, K
    Kojoukhova, M
    Sutela, A
    Vanninen, R
    Vanha, K I
    Timonen, M
    Rummukainen, J
    Korhonen, V
    Helisalmi, S
    Solje, E
    Remes, A M
    Huovinen, J
    Paananen, J
    Hiltunen, M
    Kurki, M
    Martin, B
    Loth, F
    Luciano, M
    Luikku, A J
    Hall, A
    Herukka, S K
    Mattila, J
    Lötjönen, J
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jurjević, I
    Miyajima, M
    Nakajima, M
    Murai, H
    Shin, T
    Kawaguchi, D
    Akiba, C
    Ogino, I
    Karagiozov, K
    Arai, H
    Reis, R C
    Teixeira, M J
    Valêncio, C G
    da Vigua, D
    Almeida-Lopes, L
    Mancini, M W
    Pinto, F C G
    Maykot, R H
    Calia, G
    Tornai, J
    Silvestre, S S S
    Mendes, G
    Sousa, V
    Bezerra, B
    Dutra, P
    Modesto, P
    Oliveira, M F
    Petitto, C E
    Pulhorn, H
    Chandran, A
    McMahon, C
    Rao, A S
    Jumaly, M
    Solomon, D
    Moghekar, A
    Relkin, N
    Hamilton, M
    Katzen, H
    Williams, M
    Bach, T
    Zuspan, S
    Holubkov, R
    Rigamonti, A
    Clemens, G
    Sharkey, P
    Sanyal, A
    Sankey, E
    Rigamonti, K
    Naqvi, S
    Hung, A
    Schmidt, E
    Ory-Magne, F
    Gantet, P
    Guenego, A
    Januel, A C
    Tall, P
    Fabre, N
    Mahieu, L
    Cognard, C
    Gray, L
    Buttner-Ennever, J A
    Takagi, K
    Onouchi, K
    Thompson, S D
    Thorne, L D
    Tully, H M
    Wenger, T L
    Kukull, W A
    Doherty, D
    Dobyns, W B
    Moran, D
    Vakili, S
    Patel, M A
    Elder, B
    Goodwin, C R
    Crawford, J A
    Pletnikov, M V
    Xu, J
    Blitz, A
    Herzka, D A
    Guerrero-Cazares, H
    Quiñones-Hinojosa, A
    Mori, S
    Saavedra, P
    Treviño, H
    Maitani, K
    Ziai, W C
    Eslami, V
    Nekoovaght-Tak, S
    Dlugash, R
    Yenokyan, G
    McBee, N
    Hanley, D F
    Abstracts from Hydrocephalus 2016.2017Inngår i: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 14, nr Suppl 1, artikkel-id 15Artikkel i tidsskrift (Fagfellevurdert)
  • 13.
    Adhikari, Subash
    et al.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia..
    Nice, Edouard C.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia.;Monash Univ, Dept Biochem & Mol Biol, Fac Med Nursing & Hlth Sci, Melbourne, Vic 3800, Australia..
    Deutsch, Eric W.
    Inst Syst Biol, 401 Terry Ave North, Seattle, WA 98109 USA..
    Lane, Lydie
    Univ Geneva, SIB Swiss Inst Bioinformat, Fac Med, CMU, Michel Servet 1, CH-1211 Geneva, Switzerland.;Univ Geneva, Dept Microbiol & Mol Med, Fac Med, CMU, Michel Servet 1, CH-1211 Geneva, Switzerland..
    Omenn, Gilbert S.
    Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Pennington, Stephen R.
    Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, Sch Med, Dublin, Ireland..
    Paik, Young-Ki
    Yonsei Proteome Res Ctr, Sudaemoon Ku, 50 Yonsei ro, Seoul 120749, South Korea..
    Overall, Christopher M.
    Univ British Columbia, Fac Dent, Vancouver, BC, Canada..
    Corrales, Fernando J.
    Ctr Nacl Biotecnol CSIC, Funct Prote Lab, Proteored ISCIII, Madrid 28049, Spain..
    Cristea, Ileana M.
    Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA..
    Van Eyk, Jennifer E.
    Smidt Heart Inst, Cedars Sinai Med Ctr, Adv Clin Biosyst Res Inst, Los Angeles, CA 90048 USA..
    Uhlen, Mathias
    KTH Royal Inst Technol, Sch Engn Sci Chem, Sci Life Lab Biotechnol & Hlth, S-17121 Solna, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Chan, Daniel W.
    Johns Hopkins Univ, Dept Pathol & Oncol, Sch Med, Baltimore, MD 21224 USA..
    Bairoch, Amos
    Arizona State Univ, Biodesign Inst, Tempe, AZ USA..
    Waddington, James C.
    Justice, Joshua L.
    Arizona State Univ, Biodesign Inst, Tempe, AZ USA..
    LaBaer, Joshua
    Rodriguez, Henry
    NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA..
    He, Fuchu
    Beijing Inst Life, Beijing Proteome Res Ctr, Natl Ctr Prot Sci Beijing, State Key Lab Prote, Beijing 102206, Peoples R China..
    Kostrzewa, Markus
    Bruker Daltonik GmbH, Microbiol & Diagnost, Fahrenheitstr, D-428359 Bremen, Germany..
    Ping, Peipei
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Cardiac Prote & Signaling Lab, Los Angeles, CA USA..
    Gundry, Rebekah L.
    Univ Nebraska Med Ctr, Div Cardiovasc Med, Cardiom Program, Ctr Heart & Vasc Res, Omaha, NE 68198 USA.;Univ Nebraska Med Ctr, Dept Cellular & Integrat Physiol, Cardiom Program, Ctr Heart & Vasc Res, Omaha, NE 68198 USA..
    Stewart, Peter
    Royal Prince Alfred Hosp, Dept Chem Pathol, Camperdown, NSW, Australia..
    Srivastava, Sanjeeva
    Indian Inst Technol, Powai 400076, Maharashtra, India..
    Srivastava, Sudhir
    Natl Canc Inst, Natl Inst Hlth, Canc Biomarkers Res Branch, Med Ctr Dr, Suite 5E136, Rockville, MD 20852 USA.;Fed Univ Rio Janeiro, Inst Chem, Lab Prote, Athos da Silveria Ramos,149, BR-21941909 Rio De Janeiro, RJ, Brazil..
    Nogueira, Fabio C. S.
    Fed Univ Rio Janeiro, Inst Chem, Prote Unit, Athos da Silveria Ramos,149, BR-21941909 Rio De Janeiro, RJ, Brazil.;Univ Grenoble Alpes, INSERM, CEA, IRIG BGE,U1038, F-38000 Grenoble, France..
    Domont, Gilberto B.
    Univ Grenoble Alpes, INSERM, CEA, IRIG BGE,U1038, F-38000 Grenoble, France..
    Vandenbrouck, Yves
    Univ Colorado, Dept Med Cardiol, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Biochem, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Mol Genet, Anschutz Med Campus, Aurora, CO USA..
    Lam, Maggie P. Y.
    Univ Colorado, Dept Med, Div Cardiol, Anschutz Med Campus, Aurora, CO USA.;European Bioinformat Inst, Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England..
    Wennersten, Sara
    Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia..
    Vizcaino, Juan Antonio
    Univ Calif San Diego, Dept Comp Sci & Engn, 9500 Gilman Dr,Mail Code 0404, San Diego, CA 92093 USA..
    Wilkins, Marc
    Lund Univ, Dept Biomed Engn, Lund, Sweden..
    Schwenk, Jochen M.
    Lundberg, Emma
    Bandeira, Nuno
    Univ Texas Hlth Sci Ctr San Antonio, UT Hlth, Dept Biochem & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA..
    Marko-Varga, Gyorgy
    Univ Rennes, INSERM, EHESP, IREST,UMR S 1085, F-35042 Rennes, France..
    Weintraub, Susan T.
    Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands..
    Pineau, Charles
    Stanford Sch Med, Dept Genet, Stanford, CA 94305 USA..
    Kusebauch, Ulrike
    Moritz, Robert L.
    Ahn, Seong Beom
    Palmblad, Magnus
    Univ Rennes, INSERM, EHESP, IREST,UMR S 1085, F-35042 Rennes, France..
    Snyder, Michael P.
    Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands..
    Aebersold, Ruedi
    Stanford Sch Med, Dept Genet, Stanford, CA 94305 USA..
    Baker, Mark S.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia.;Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands.;Univ Zurich, Fac Sci, Zurich, Switzerland..
    A high-stringency blueprint of the human proteome2020Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1, artikkel-id 5301Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
    FULLTEXT01
  • 14.
    Agnarsdóttir, Margrét
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Clinical Pathology, Akademiska University Hospital.
    Popova, Svetlana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Clinical Pathology, Akademiska University Hospital.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Clinical Pathology, Akademiska University Hospital.
    Expression of CMV protein pp65 in cutaneous malignant melanoma2019Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 14, nr 10, artikkel-id e0223854Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human cytomegalovirus (CVM) has been detected by immunohistochemistry (IHC) in brain tumours; however, whether CMV antigen is seen in melanomas has not yet been elucidated. Applying IHC, melanoma tissue was assessed for the expression of pp65, a tegument protein of CMV. Two cohorts were available, cohort-I and II, the latter included also related metastasis. In addition to IHC, in situ hybridisation (ISH) was carried out to assess whether CMV related genetic sequences were detectable in a subset of cases. Seventy per cent of the 142 cases in cohort-I and 50% of the 37 cases in cohort-II displayed immunoreactivity (IR). In both cohorts, the IHC outcome correlated with T-stage (Cohort I: Spearman 0.22, p = 0.01, Cohort II: Fisher exact text 0.04). In 30 of cohort-II cases, when IHC staining was carried out on both the primary tumour and the corresponding metastasis, no change in IR was noted in 53%; in 20%, the IR was lower and in 27% higher in the metastasis when compared with the primary tumour. These results were significant (Fisher exact test 0.03). Applying ISH technique on four tumour cases with detectable pp65 protein, CMV related genetic sequence was not detected. Here, we demonstrate, congruent with observations published for brain tumours, that the protein pp65 is indeed observed in substantial number of melanoma cases with IHC; however, no signal was detected with ISH technique. These findings are in line with previously reported studies, demonstrating that the role of CMV in tumours is still debatable.

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  • 15.
    Agnarsdóttir, Margrét
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Päären, Helen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Vassilaki, Ismini
    The impact of standardized care pathway on reporting time for invasive melanoma: results from one pathology department in Sweden2019Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, nr 4, s. 260-264Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Standardized care pathway (SCP) was introduced by the Swedish health authorities to eliminate unwanted delay in the diagnostics of cancer patients; for melanoma, SCP started in 2016. The aim of this study was to investigate the impact of SCP on reporting time for invasive melanomas.

    Materials and methods: Information on reporting time was collected on all samples handled according to the SCP and on all invasive melanomas diagnosed in 2016–2018 at the Department of Clinical Pathology, Akademiska University Hospital, Uppsala, Sweden.

    Results: During the study period, 205 samples were handled according to the SCP, resulting in 53 cases (26%) diagnosed with invasive melanomas. A total of 301 invasive melanomas from 286 patients were diagnosed during the study period; 67 (22%) were submitted as SCP, 36 (12%) as a general priority case, and 198 (66%) as non-priority. The reporting time for the SCP cases was 8 days, for general priority cases 6 days, and for non-priority cases it was 24 days. The reporting time increased from 18 to 31 days for the non-priority cases and from 15 to 25 days for all cases with invasive melanomas during the study period.

    Conclusion: This study demonstrates prolonged reporting times for invasive melanomas since the implementation of SCP. This is probably caused by the crowd-out effect of the SCP samples, limited personnel resources, and inaccuracy of the clinical diagnosis. SCP might therefore be a suboptimal method to shorten reporting times for invasive melanomas.

    Fulltekst (pdf)
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  • 16.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Minimal neuropathologic diagnosis for brain banking in the normal middle-aged and aged brain and in neurodegenerative disorders.2018Inngår i: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 150, s. 131-141, artikkel-id B978-0-444-63639-3.00010-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 17.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Techniques in neuropathology.2017Inngår i: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, s. 3-7, artikkel-id B978-0-12-802395-2.00001-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 18.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hartikainen, Päivi
    Alpha-synucleinopathies.2017Inngår i: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, s. 339-353, artikkel-id B978-0-12-802395-2.00024-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 19.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kovacs, Gabor G
    Comorbidities.2017Inngår i: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, s. 573-577, artikkel-id B978-0-12-802395-2.00036-5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 20.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mixed Brain Pathology Is the Most Common Cause of Cognitive Impairment in the Elderly2020Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 78, nr 1, s. 453-465Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer's disease neuropathologic change (ADNC).

    Objective: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney.

    Methods: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry.

    Results: Hyperphosphorylated tau (HP tau) was seen in 99%, amyloid-beta (A beta) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and alpha-synuclein (alpha S) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPt increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology.

    Conclusion: In most (66%) subjects with CI, the cause of impairment was "mixed pathology", i.e., ADNC combined with TDP43, alpha S, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DMand CaVD, are risk factors for CI but not related to ADNC.

  • 21.
    Alafuzoff, Irina
    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.
    Wanders, Alkwin
    Department of Clinical Pathology and Cytology, Umea University Hospital, Umea, Sweden.
    Veress, Bela
    Department of Clinical Pathology and Cytology, Skane University Hospital, Malmo, Sweden.
    Neuronal Protein Alteration in Enteric Dysmotility Syndrome2016Inngår i: Journal of Alzheimer’s Disease & Parkinsonism, ISSN 2161-0460, Vol. 6, nr 1, artikkel-id 1000212Artikkel i tidsskrift (Annet vitenskapelig)
    Fulltekst (pdf)
    fulltext
  • 22.
    Albertsson-Lindblad, Alexandra
    et al.
    Skane Univ Hosp, Dept Oncol, SE-22185 Lund, Sweden..
    Kolstad, Arne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Laurell, Anna
    Univ Uppsala Hosp, Dept Oncol, Uppsala, Sweden..
    Raty, Riikka
    Helsinki Univ Hosp, Dept Hematol, Helsinki, Finland..
    Gronbaek, Kirsten
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Sundberg, Jan
    Skane Univ Hosp, Dept Oncol, SE-22185 Lund, Sweden..
    Pedersen, Lone Bredo
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Ralfkiaer, Elisabeth
    Rigshosp, Dept Pathol, Copenhagen, Denmark..
    Karjalainen-Lindsberg, Marja-Liisa
    Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland..
    Sundström, Christer
    Uppsala 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; and..
    Ehinger, Mats
    Univ Lund Hosp, Dept Pathol Cytol, Lund, Sweden..
    Geisler, Christian
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Jerkeman, Mats
    Skane Univ Hosp, Dept Oncol, SE-22185 Lund, Sweden..
    Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma2016Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, nr 14, s. 1814-1820Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 23.
    Ali, Abir Salwa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Langer, Seppo W.
    Federspiel, Birgitte
    Hjortland, Geir Olav
    Grønbæk, Henning
    Ladekarl, Morten
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Weber Vestermark, Lene
    Arola, Johanna
    Osterlund, Pia
    Knigge, Ulrich
    Sørbye, Halfdan
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    PD-L1 expression in gastroenteropancreatic neuroendocrine neoplasms grade 32020Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 15, nr 12, artikkel-id e0243900Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.

    Fulltekst (pdf)
    fulltext
  • 24.
    Ali, Abir Salwa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Perren, Aurel
    Univ Bern, Dept Pathol, Bern, Switzerland..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Grönberg, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Candidate protein biomarkers in pancreatic neuroendocrine neoplasms grade 32020Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikkel-id 10639Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
    FULLTEXT01
  • 25.
    Ambroise, Gorbatchev
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Yu, Ting-ting
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden.;Nanjing Med Univ, Sch Basic Med Sci, Dept Med Genet, Nanjing 211166, Jiangsu, Peoples R China..
    Zhang, Boxi
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Kacal, Merve
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Hao, Yuqing
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Queiroz, Andre L.
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Ouchida, Amanda T.
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Norberg, Erik
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Vakifahmetoglu-Norberg, Helin
    Karolinska Inst, Dept Physiol & Pharmacol, Biomed, Solnavagen 9, S-17165 Stockholm, Sweden..
    Systematic analysis reveals a functional role for STAMBPL1 in the epithelial-mesenchymal transition process across multiple carcinomas2020Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 123, nr 7, s. 1164-1177Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 26.
    Amini, Rose-Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Laszlo, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Eriksson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Gustafsson, Kristin Ayoola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Loskog, Angelica S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Lokon Pharma, AB,Uppsala, Sweden.
    Thörn, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients2019Inngår i: BMC Cancer, E-ISSN 1471-2407, Vol. 19, artikkel-id 316Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome. Methods: Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome. Results: The percentage of CD3-positive T-cells was lower (p=0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p=0.2) nor the T-cell/monocyte ratio (p=0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7(+)/CD3(-)/CD56(bright)/CD16(dim/-)) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p=0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p=0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p=0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p=0.04). Conclusions: An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.

    Fulltekst (pdf)
    FULLTEXT01
  • 27.
    Amini, Rose-Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    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. Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
    Abdulla, Maysaa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Cavelier, Lucia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
    Djureinovic, 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. Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Baliakas, Panagiotis
    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. Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
    Clonal hematopoiesis in patients with high-grade B-cell lymphoma is associated with inferior outcome2020Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 95, nr 10, s. E287-E289Artikkel i tidsskrift (Fagfellevurdert)
    Fulltekst (pdf)
    fulltext
  • 28.
    Amini, Rose-Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Akademiska sjukhuset, Uppsala.
    Nålbiopsi är inte bästa metod för att diagnostisera lymfom: [Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research]2017Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, artikkel-id EMDHArtikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

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

  • 29.
    Anan, Intissar
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Bång, Joakim
    Umea Univ, Dept Surg & Perioperat Sci Orthopaed, Umea, Sweden.
    Lundgren, Hans-Erik
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wixner, Jonas
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    A case report of osteoarthritis associated with hereditary transthyretin amyloidosis ATTRV30M2019Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, nr Suppl. 1, s. 29-30Artikkel i tidsskrift (Fagfellevurdert)
  • 30.
    Anan, Intissar
    et al.
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.;Umeå Univ, Wallenberg Ctr Mol Med, Umeå, Sweden..
    Suhr, Ole B.
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Liszewska, Katarzyna
    Pitea Hosp, Dept Med, Pitea, Sweden..
    Baranda, Jorge Mejia
    Pitea Hosp, Dept Med, Pitea, Sweden..
    Pilebro, Bjorn
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Wixner, Jonas
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amyloid fibril composition type is consistent over time in patients with Val30Met (p.Val50Met) transthyretin amyloidosis2022Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 17, nr 3, artikkel-id e0266092Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.

    Material and method:s Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.

    Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.

    Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

    Fulltekst (pdf)
    FULLTEXT01
  • 31.
    Andersson, Sandra
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Danielsson, Angelika
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Uhlen, Mathias
    Asplund, Anna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues2014Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 12, s. e115911-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
    fulltext
  • 32.
    Antonodimitrakis, Pantelis Clewemar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wassberg, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Neuroendocrine tumors with syndromic vasoactive intestinal polypeptide hypersecretion: a retrospective study2017Inngår i: International Journal of Endocrine Oncology, Vol. 4, nr 1, s. 9-22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Vasoactive intestinal polypeptide producing neuroendocrine tumors are rare and cause severe hormonal symptoms. Patients/methods: Eighteen patients with vasoactive intestinal polypeptide producing neuroendocrine tumors were analyzed with reviews of medical records, radiology and tumor tissue specimens. Results: Twelve patients (67%) had liver metastases at diagnosis. Chemotherapy, somatostatin analogs and interferon were given as medical therapies. Streptozocin/5-fluorouracil produced an objective response in 40% of the evaluable patients. Somatostatin analogs gave a clinical/biochemical response in eight out of nine patients. Transarterial embolization of the liver and peptide receptor radionuclide therapy was given to refractory cases. Sixteen patients died during the observation period. The median overall survival from diagnosis was 102 months. Conclusion: Systemic chemotherapy and somatostatin analogs should be given in cases of advanced disease or for hormonal symptoms.

  • 33.
    Aresdahl, Alexander
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Käkkirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Plastikkirurgi.
    Lindell, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Käkkirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Plastikkirurgi.
    Dukic, Milena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Thor, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Käkkirurgi.
    Congenital granular cell epulis: a case report2015Inngår i: Oral and Maxillofacial Surgery Cases, ISSN 2214-5419, Vol. 1, nr 1, s. 8-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Congenital granular cell epulis (CGCE) is an uncommon benign lesion found in newborns. It has predominance for females with an 8:1 ratio in relation to males and is exclusively encountered in the oral cavity. The most affected oral site is located around the canine/incisor region of the maxillary alveolar ridge, where the lesion arises from the soft tissue as a solitary pedunculated mass. CGCE's histogenesis remains obscure and controversial. We present a rare case of 2 separate CGCE lesions adjacent to each other measuring 23 × 18 × 10 and 15 × 10 mm, positioned facially on the right maxillary alveolar process. The patient, a 2-day-old female newborn, did not experience any serious difficulty regarding breathing or deglutition. Complete surgical excision was the treatment of choice in this case, and the procedure was performed under both general and local anesthesia. Histologic and immunohistochemical analysis confirmed the diagnosis of CGCE. The patient showed satisfactory postoperative healing and excellent health at both the 10-day recall appointment and the 6-month follow-up.

  • 34. Asa, Sylvia L
    et al.
    Asioli, Sofia
    Bozkurt, Suheyla
    Casar-Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Chinezu, Laura
    Comunoglu, Nil
    Cossu, Giulia
    Cusimano, Michael
    Delgrange, Etienne
    Earls, Peter
    Ezzat, Shereen
    Gazioglu, Nurperi
    Grossman, Ashley
    Guaraldi, Federica
    Hickman, Richard A.
    Ikeda, Hidetoshi
    Jaffrain-Rea, Marie-Lise
    Karavitaki, Niki
    Kraljević, Ivana
    La Rosa, Stefano
    Manojlović-Gačić, Emilija
    Maartens, Niki
    McCutcheon, Ian E
    Messerer, Mahmoud
    Mete, Ozgur
    Nishioka, Hiroshi
    Oz, Buge
    Pakbaz, Sara
    Pekmezci, Melike
    Perry, Arie
    Reiniger, Lilla
    Roncaroli, Federico
    Saeger, Wolfgang
    Söylemezoğlu, Figen
    Tachibana, Osamu
    Trouillas, Jacqueline
    Turchini, John
    Uccella, Silvia
    Villa, Chiara
    Yamada, Shozo
    Yarman, Sema
    Pituitary neuroendocrine tumors (PitNETs): nomenclature evolution, not clinical revolution2020Inngår i: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 23, nr 3, s. 322-325Artikkel i tidsskrift (Annet vitenskapelig)
  • 35.
    Asa, Sylvia L.
    et al.
    Case Western Reserve Univ, Univ Hosp Cleveland, Med Ctr, Dept Pathol, Cleveland, OH 44106 USA..
    Mete, Ozgur
    Univ Toronto, Univ Hlth Network, Dept Pathol, Toronto, ON, Canada..
    Cusimano, Michael D.
    Univ Toronto, Dept Neurosurg, St Michaels Hosp, Toronto, ON, Canada..
    McCutcheon, Ian E.
    Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA..
    Perry, Arie
    Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA..
    Yamada, Shozo
    Moriyama Neurol Ctr Hosp, Hypothalam & Pituitary Ctr, Tokyo, Japan..
    Nishioka, Hiroshi
    Toranomon Gen Hosp, Dept Hypothalam & Pituitary Surg, Tokyo, Japan..
    Casar Borota, Olivera
    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.
    Uccella, Silvia
    Univ Insubria, Dept Pathol, Varese, Italy..
    La Rosa, Stefano
    Univ Hosp, Inst Pathol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Grossman, Ashley B.
    Univ Oxford, Dept Endocrinol, London, England.;Royal Free London, London, England.;Barts & London Queen Marys Sch Med & Dent, London, England.;London Clin Ctr Endocrinol, London, England..
    Ezzat, Shereen
    Univ Toronto, Univ Hlth Network, Dept Med, Toronto, ON, Canada..
    Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification2021Inngår i: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 34, nr 9, s. 1634-1650Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

  • 36.
    Avenel, Christophe
    et al.
    CADESS Med AB, Uppsala, Sweden.
    Tolf, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Dragomir, Anca
    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..
    Carlbom, Ingrid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion. CADESS Med AB, Uppsala, Sweden.
    Glandular Segmentation of Prostate Cancer: An Illustration of How the Choice of Histopathological Stain Is One Key to Success for Computational Pathology2019Inngår i: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 7, artikkel-id 125Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Digital pathology offers the potential for computer-aided diagnosis, significantly reducing the pathologists' workload and paving the way for accurate prognostication with reduced inter-and intra-observer variations. But successful computer-based analysis requires careful tissue preparation and image acquisition to keep color and intensity variations to a minimum. While the human eye may recognize prostate glands with significant color and intensity variations, a computer algorithm may fail under such conditions. Since malignancy grading of prostate tissue according to Gleason or to the International Society of Urological Pathology (ISUP) grading system is based on architectural growth patterns of prostatic carcinoma, automatic methods must rely on accurate identification of the prostate glands. But due to poor color differentiation between stroma and epithelium from the common stain hematoxylin-eosin, no method is yet able to segment all types of glands, making automatic prognostication hard to attain. We address the effect of tissue preparation on glandular segmentation with an alternative stain, Picrosirius red-hematoxylin, which clearly delineates the stromal boundaries, and couple this stain with a color decomposition that removes intensity variation. In this paper we propose a segmentation algorithm that uses image analysis techniques based on mathematical morphology and that can successfully determine the glandular boundaries. Accurate determination of the stromal and glandular morphology enables the identification of the architectural pattern that determine the malignancy grade and classify each gland into its appropriate Gleason grade or ISUP Grade Group. Segmentation of prostate tissue with the new stain and decomposition method has been successfully tested on more than 11000 objects including well-formed glands (Gleason grade 3), cribriform and fine caliber glands (grade 4), and single cells (grade 5) glands.

    Fulltekst (pdf)
    FULLTEXT01
  • 37.
    Backman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kurppa, Pinja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Elfving, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Division of Pathology, Lund University Skåne University Hospital Lund Sweden.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindberg, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pontén, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Eltahir, Mohamed
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mangsbo, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Isaksson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Respiratory Medicine Gävle Hospital Gävle Sweden.
    Jirström, Karin
    Division of Oncology and Therapeutic Pathology Department of Clinical Sciences Lund, Lund, Sweden.
    Kärre, Klas
    Department of Microbiology, Cell and Tumor Biology Karolinska Institutet, Stockholm, Sweden.
    Leandersson, Karin
    Cancer Immunology, Department of Translational Medicine, Lund University Skånes University Hospital, Malmö, Sweden.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer2021Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 255, nr 3, s. 243-256Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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  • 38.
    Baliakas, Panagiotis
    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. Uppsala Univ Hosp, Dept Clin Genet, Uppsala, Sweden.
    Kättström, Magdalena
    Orebro Univ Hosp, Dept Med, Sect Hematol, Orebro, Sweden.
    Rossing, Maria
    Copenhagen Univ Hosp, Ctr Genom Med, Copenhagen, Denmark.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Refractory chronic "ITP": When platelet size matters2018Inngår i: Clinical Case Reports, E-ISSN 2050-0904, Vol. 6, nr 9, s. 1779-1780Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
    FULLTEXT01
  • 39.
    Bauer, Wolfgang
    et al.
    Charite Univ Med Berlin, Dept Emergency Med, Freie Univ Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany..
    Weber, Marcus
    Zuse Inst Berlin ZIB, Takustr 7, D-14195 Berlin, Germany..
    Diehl-Wiesenecker, Eva
    Charite Univ Med Berlin, Dept Emergency Med, Freie Univ Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany..
    Galtung, Noa
    Charite Univ Med Berlin, Dept Emergency Med, Freie Univ Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany..
    Prpic, Monika
    Free Univ Berlin, Charite Univ Med Berlin, Inst Lab Med Clin Chem & Pathobiochem, Augustenburger Pl 1, D-13353 Berlin, Germany..
    Somasundaram, Rajan
    Charite Univ Med Berlin, Dept Emergency Med, Freie Univ Berlin, Hindenburgdamm 30, D-12203 Berlin, Germany..
    Tauber, Rudolf
    Free Univ Berlin, Charite Univ Med Berlin, Inst Lab Med Clin Chem & Pathobiochem, Augustenburger Pl 1, D-13353 Berlin, Germany.;Labor Berlin Charite Vivantes GmbH, D-13353 Berlin, Germany..
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kappert, Kai
    Free Univ Berlin, Charite Univ Med Berlin, Inst Lab Med Clin Chem & Pathobiochem, Augustenburger Pl 1, D-13353 Berlin, Germany.;Labor Berlin Charite Vivantes GmbH, D-13353 Berlin, Germany..
    Plasma Proteome Fingerprints Reveal Distinctiveness and Clinical Outcome of SARS-CoV-2 Infection2021Inngår i: Viruses, E-ISSN 1999-4915, Vol. 13, nr 12, artikkel-id 2456Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We evaluated how plasma proteomic signatures in patients with suspected COVID-19 can unravel the pathophysiology, and determine kinetics and clinical outcome of the infection.

    Methods: Plasma samples from patients presenting to the emergency department (ED) with symptoms of COVID-19 were stratified into: (1) patients with suspected COVID-19 that was not confirmed (n = 44); (2) non-hospitalized patients with confirmed COVID-19 (n = 44); (3) hospitalized patients with confirmed COVID-19 (n = 53) with variable outcome; and (4) patients presenting to the ED with minor diseases unrelated to SARS-CoV-2 infection (n = 20). Besides standard of care diagnostics, 177 circulating proteins related to inflammation and cardiovascular disease were analyzed using proximity extension assay (PEA, Olink) technology.

    Results: Comparative proteome analysis revealed 14 distinct proteins as highly associated with SARS-CoV-2 infection and 12 proteins with subsequent hospitalization (p < 0.001). ADM, IL-6, MCP-3, TRAIL-R2, and PD-L1 were each predictive for death (AUROC curve 0.80-0.87). The consistent increase of these markers, from hospital admission to intensive care and fatality, supported the concept that these proteins are of major clinical relevance.

    Conclusions: We identified distinct plasma proteins linked to the presence and course of COVID-19. These plasma proteomic findings may translate to a protein fingerprint, helping to assist clinical management decisions.

    Fulltekst (pdf)
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  • 40.
    Bekkhus, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Martikainen, Teemu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Olofsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Franzén Boger, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Vasiliu Bacovia, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wärnberg, Fredrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Surg, S-41345 Gothenburg, Sweden..
    Ulvmar, Maria H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells2021Inngår i: Cancers, ISSN 2072-6694, Vol. 13, nr 2, artikkel-id 211Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers.

    Simple Summary

    Tumor draining lymph nodes (TDLNs) are the most common metastatic sites in human cancer but are also essential sites for induction of tumor immunity. How different types of primary tumors affect the anti-tumor immune response in the LNs is not fully understood. By analyzing biobank tissue from breast cancer patients, we demonstrate that invasive breast cancer induce dramatic pre-metastatic LN changes affecting the structure and function of the specialized LN vasculature and associated stromal cells, required for recruitment of T-lymphocytes into the LNs. These changes could not be seen in patients with non-invasive breast cancer and provide new insights of how invasive tumors can disrupt essential functions within the immune system. The data also shows promise of LN stromal and vascular changes as possible future biomarkers for prediction of disease progression in human cancer.

    Fulltekst (pdf)
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  • 41.
    Bellotti, Vittorio
    et al.
    UCL, Div Med, Ctr Amyloidosis & Acute Phase Prot, Wolfson Drug Discovery Unit, London, England;Univ Pavia, Inst Biochem, Dept Mol Med, Pavia, Italy.
    Merlini, Giampaolo
    Univ Pavia, Fdn IRCCS Policlin San Matteo, Amyloidosis Res & Treatment Ctr, Biotechnol Res Labs,Dept Mol Med, Pavia, Italy.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Robert Kisilevsky, MD, PhD, 1937–20192019Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, nr 4, s. 179-179Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
  • 42.
    Benson, Merrill D.
    et al.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA..
    Berk, John L.
    Boston Univ, Sch Med, Amyloidosis Ctr, Boston, MA 02118 USA..
    Dispenzieri, Angela
    Mayo Clin, Div Hematol, Rochester, MN USA..
    Damy, Thibaud
    Henri Mondor Teaching Hosp, AP HP, Mondor Amyloidosis Network, Creteil, France.;Henri Mondor Teaching Hosp, AP HP, GRC Amyloid Res Inst, Creteil, France.;Henri Mondor Teaching Hosp, AP HP, Dept Cardiol, Creteil, France.;UPEC, Creteil, France..
    Gillmore, Julian D.
    UCL, Div Med, Natl Amyloidosis Ctr, Royal Free Campus, London, England..
    Hazenberg, Bouke P.
    Univ Groningen, Univ Med Ctr Groningen, Amyloidosis Ctr Expertise, Groningen, Netherlands..
    Lavatelli, Francesca
    IRCCS Policlin San Matteo, Amyloidosis Res & Treatment Ctr, Pavia, Italy.;Univ Pavia, Pavia, Italy..
    Picken, Maria M.
    Loyola Univ Med Ctr, Dept Pathol, Chicago, IL USA..
    Röcken, Christoph
    Univ Kiel, Univ Hosp Schleswig Holstein, Dept Pathol, Kiel, Germany..
    Schönland, Stefan
    Univ Hosp Heidelberg, Amyloidosis Ctr, Med Dept 5, Heidelberg, Germany..
    Ueda, Mitsuharu
    Kumamoto Univ, Dept Neurol, Amyloidosis Ctr, Kumamoto, Japan..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Tissue biopsy for the diagnosis of amyloidosis: experience from some centres2022Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 29, nr 1, s. 8-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A reliable diagnosis of amyloidosis is usually based on a tissue biopsy. With increasing options for specific treatments of the different amyloid diseases, an exact and valid diagnosis including determination of the biochemical fibril nature is imperative. Biopsy sites as well as amyloid typing principles vary and this paper describes methods employed at some laboratories specialised in amyloidosis in Europe, Japan and USA.

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  • 43.
    Benson, Merrill D.
    et al.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA.
    Buxbaum, Joel N.
    Scripps Res Inst, Dept Mol Med, La Jolla, CA USA.
    Eisenberg, David S.
    Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA USA.
    Merlini, Giampaolo
    Univ Pavia, Amyloid Res & Treatment Ctr, Pavia, Italy; IRCCS Policlin San Matteo, Pavia, Italy.
    Saraiva, Maria J. M.
    Univ Porto, Inst Mol & Cellular Biol, Amyloid Unit, Porto, Portugal.
    Sekijima, Yoshiki
    Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano, Japan.
    Sipe, Jean D.
    Boston Univ, Sch Med, Dept Biochem, Boston, MA USA.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee2018Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, nr 4, s. 215-219Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

    Fulltekst (pdf)
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  • 44.
    Benson, Merrill D.
    et al.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA..
    Buxbaum, Joel N.
    Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA..
    Eisenberg, David S.
    Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA..
    Merlini, Giampaolo
    Fdn IRCCS Policlin San Matteo, Amyloid Res & Treatment Ctr, Pavia, Italy.;Univ Pavia, Pavia, Italy..
    Saraiva, Maria J. M.
    Univ Porto, Mol Neurobiol, Inst Mol & Cellular Biol, Porto, Portugal..
    Sekijima, Yoshiki
    Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano, Japan..
    Sipe, Jean D.
    Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee2020Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 27, nr 4, s. 217-222Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques. Recommendations for their use are given. Definitions of amyloid and amyloidosis are confirmed. Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation, and these are included in a new Table.

    Fulltekst (pdf)
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  • 45.
    Berglund, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Kinch, Amelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Edman, Elin
    Halmstad Hospital.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Pauksens, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes2015Inngår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, nr 5, s. 1036-1042Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

  • 46.
    Bergman, Julia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Hallström, Björn M.
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Djureinovic, Dijana
    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.
    Uhlén, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Ponten, 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.
    The human adrenal gland proteome defined by transcriptomics and antibody-based profiling2017Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 158, nr 2, s. 239-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 47.
    Bergman-Larsson, Julia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Gustafsson, Sofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Méar, Loren
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Huvila, Jutta
    Univ Turku, Turku Univ Hosp, Dept Pathol & Forens Med, Turku, Finland..
    Tolf, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Reproduktionsbiologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Dag Hammarskjolds Vag 20, SE-75185 Uppsala, Sweden..
    Combined expression of HOXA11 and CD10 identifies endometriosis versus normal tissue and tumors2022Inngår i: Annals of Diagnostic Pathology, ISSN 1092-9134, E-ISSN 1532-8198, Vol. 56, artikkel-id 151870Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The gold standard for diagnosing endometriosis is by laparoscopic visual demonstration of ectopic endometrial lesions outside the uterus, preferably verified by biopsy and microscopical examination. Molecular markers to facilitate the microscopical diagnosis of endometriosis and for distinguishing endometriosis from other benign and malignant lesions are lacking. Our aim was to test and validate an immunohistochemical antibody panel for improved diagnostic accuracy of endometriosis. Both CD10 and HOXA11 have been implicated in regulation of endometrial homeostasis. Here we have analyzed the expression pattern of these two proteins using immunohistochemistry on human tissues in a tissue microarray format. CD10 and HOXA11 expression in endometriosis lesions were compared to expression patterns in a range of normal tissues and in primary- and metastatic lesions of endometrial-, cervical- and ovarian cancer. HOXA11 and CD10 were expressed in 98% and 91% of endometriosis lesions and the combined double-positive expression profile of both HOXA11 and CD10 was highly sensitive for ectopic endometrial tissue (90%). The specificity and sensitivity for this double-positive signature in endometriosis was significantly different from all investigated tissues, cancers and metastases except normal, eutopic endometrial- and cervical mucosa. The combination of HOXA11 and CD10 expression profiles provides a useful tool to identify ectopic endometrial tissue and for distinguishing endometriosis from various types of gynecological malignancies and metastases.

    Fulltekst (pdf)
    fulltext
  • 48.
    Bieder, Andrea
    et al.
    Karolinska Inst, Dept Biosci & Nutr, Halsovagen 7, S-14183 Huddinge, Sweden..
    Einarsdottir, Elisabet
    Karolinska Inst, Dept Biosci & Nutr, Halsovagen 7, S-14183 Huddinge, Sweden.;Univ Helsinki, Stem Cells & Metab Res Program STEMM, Helsinki, Finland.;Folkhalsan Inst Genet, Helsinki, Finland.;KTH Royal Inst Technol, Dept Gene Technol, Sci Life Lab, Solna, Sweden..
    Matsson, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Karolinska Inst, Dept Womens & Childrens Hlth, Solna, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Nilsson, Harriet E.
    Karolinska Inst, Dept Biosci & Nutr, Halsovagen 7, S-14183 Huddinge, Sweden.;KTH Royal Inst Technol, Sch Engn Sci Chem, Dept Biomed Engn & Hlth Syst, Biotechnol & Hlth, Huddinge, Sweden..
    Eisfeldt, Jesper
    Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Sci Pk, Solna, Sweden..
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala Univ Hosp, Dept Pathol, Uppsala, Sweden..
    Paucar, Martin
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Granberg, Tobias
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Radiol, Stockholm, Sweden..
    Li, Tie-Qiang
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Lindstrand, Anna
    Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Kere, Juha
    Karolinska Inst, Dept Biosci & Nutr, Halsovagen 7, S-14183 Huddinge, Sweden.;Univ Helsinki, Stem Cells & Metab Res Program STEMM, Helsinki, Finland.;Guys Hosp, Kings Coll London, Sch Basic & Med Biosci, London, England..
    Tapia-Paez, Isabel
    Karolinska Inst, Dept Med, Solnavagen 30, S-17176 Solna, Sweden..
    Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia: a case report2020Inngår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 21, nr 1, artikkel-id 87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies.

    Case presentation: Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified.

    Conclusions: We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.

    Fulltekst (pdf)
    FULLTEXT01
  • 49.
    Biswas, Dhruva
    et al.
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;UCL, Inst Canc, Bill Lyons Informat Ctr, Paul OGorman Bldg, London, England;Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Birkbak, Nicolai J.
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England;Aarhus Univ, Dept Mol Med, Aarhus, Denmark;Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark.
    Rosenthal, Rachel
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;UCL, Inst Canc, Bill Lyons Informat Ctr, Paul OGorman Bldg, London, England;Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Hiley, Crispin T.
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Lim, Emilia L.
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Papp, Krisztian
    Eotvos Lorand Univ, Dept Phys Complex Syst, Budapest, Hungary.
    Boeing, Stefan
    Francis Crick Inst, Bioinformat & Biostat, London, England.
    Krzystanek, Marcin
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Greco, Maria
    Francis Crick Inst, Genom Equipment Pk, London, England.
    Doeme, Balazs
    Semmelweis Univ, Natl Koranyi Inst Pulmonol, Dept Tumor Biol, Budapest, Hungary;Med Univ Vienna, Ctr Comprehens Canc, Div Thorac Surg, Vienna, Austria;Semmelweis Univ, Natl Inst Oncol, Dept Thorac Surg, Budapest, Hungary.
    Fillinger, Janos
    Semmelweis Univ, Natl Koranyi Inst Pulmonol, Dept Pathol, Budapest, Hungary;Natl Inst Oncol, Dept Pathol, Budapest, Hungary.
    Brunnstrom, Hans
    Lund Univ, Lab Med Reg Skane, Dept Clin Sci Lund, Pathol, Lund, Sweden.
    Wu, Yin
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England.
    Moore, David A.
    UCL Canc Inst, Dept Pathol, London, England.
    Skrzypski, Marcin
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;Med Univ Gdansk, Dept Oncol & Radiotherapy, Gdansk, Poland.
    Abbosh, Christopher
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England.
    Litchfield, Kevin
    Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Al Bakir, Maise
    Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Watkins, Thomas B. K.
    Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Veeriah, Selvaraju
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England.
    Wilson, Gareth A.
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    Jamal-Hanjani, Mariam
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England.
    Moldvay, Judit
    Semmelweis Univ, Natl Koranyi Inst Pulmonol, Dept Tumor Biol, Budapest, Hungary;Semmelweis Univ, Dept Pathol 2, SE NAP Brain Metastasis Res Grp, Budapest, Hungary.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Chinnaiyan, Arul M.
    Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA;Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA;Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA;Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA;Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hackshaw, Allan
    UCL, Canc Res UK, London, England;UCL, Univ Coll London Canc Trials Ctr, London, England.
    Bartek, Jiri
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark;Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Csabai, Istvan
    Eotvos Lorand Univ, Dept Phys Complex Syst, Budapest, Hungary.
    Szallasi, Zoltan
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark;Semmelweis Univ, Dept Pathol 2, SE NAP Brain Metastasis Res Grp, Budapest, Hungary;Harvard Med Sch, Boston Childrens Hosp, Computat Hlth Informat Program, Boston, MA 02115 USA.
    Herrero, Javier
    UCL, Inst Canc, Bill Lyons Informat Ctr, Paul OGorman Bldg, London, England.
    McGranahan, Nicholas
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;UCL, Univ Coll London Canc Inst, Canc Genome Evolut Res Grp, London, England.
    Swanton, Charles
    UCL, Inst Canc, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg, London, England;Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England.
    A clonal expression biomarker associates with lung cancer mortality2019Inngår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 25, nr 10, s. 1540-1548Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage(1). Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types(2-6). Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.

  • 50.
    Bogatyrova, Olga
    et al.
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Mattsson, Johanna S M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ross, Edith M.
    Merck KGaA, Translat Med, Darmstadt, Germany.
    Sanderson, Michael P.
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Backman, Max
    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.
    Brunnström, Hans
    Lund Univ, Skåne Univ Hosp, Div Pathol, Lund, Sweden.
    Kurppa, Pinja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wilm, Claudia
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Zimmermann, Astrid
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Esdar, Christina
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response2021Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 151, s. 136-149Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response.

    In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123.

    A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123.

    The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents.

    Fulltekst (pdf)
    FULLTEXT01
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