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  • 1.
    Chilkova, Olga
    et al.
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Stenlund, Peter
    Isoz, Isabelle
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Stith, Carrie M
    Grabowski, Pawel
    Lundström, Else-Britt
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Burgers, Peter M
    Johansson, Erik
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    The eukaryotic leading and lagging strand DNA polymerases are loaded onto primer-ends via separate mechanisms but have comparable processivity in the presence of PCNA.2007In: Nucleic Acids Research, ISSN 1362-4962, Vol. 35, no 19, p. 6588-6597Article in journal (Refereed)
    Abstract [en]

    Saccharomyces cerevisiae DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon) are replicative DNA polymerases at the replication fork. Both enzymes are stimulated by PCNA, although to different levels. To understand why and to explore the interaction with PCNA, we compared Pol delta and Pol epsilon in physical interactions with PCNA and nucleic acids (with or without RPA), and in functional assays measuring activity and processivity. Using surface plasmon resonance technique, we show that Pol epsilon has a high affinity for DNA, but a low affinity for PCNA. In contrast, Pol delta has a low affinity for DNA and a high affinity for PCNA. The true processivity of Pol delta and Pol epsilon was measured for the first time in the presence of RPA, PCNA and RFC on single-stranded DNA. Remarkably, in the presence of PCNA, the processivity of Pol delta and Pol epsilon on RPA-coated DNA is comparable. Finally, more PCNA molecules were found on the template after it was replicated by Pol epsilon when compared to Pol delta. We conclude that Pol epsilon and Pol delta exhibit comparable processivity, but are loaded on the primer-end via different mechanisms.

  • 2.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length as prognostic parameter in chronic lymphocytic leukemia2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia among the adult population in western countries and accounts for 30-40% of all leukemias. With survival time ranging from months to decades, the clinical course of individual CLL patients is highly variable. This heterogeneity and in the end the need for means to identify the patients with less favorable disease has encouraged the search for biomarkers that can predict the prognosis.

    Telomeres are repetitive structures protecting the chromosomal endings and shorten at each cell division. Telomere length (TL) has been indicated as a prognostic factor both in hematological malignancies and solid tumors. In B-CLL, TL is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and with clinical course. In the present thesis the main aim was to evaluate TL as a biomarker in B-CLL using a quantitative PCR-based method for TL determination.

    In paper I, TL was shown to be a prognostic factor for stage A and stage B/C patients, whereas IGHV mutation status predicted outcome only in stage A patients. Moreover, IGHV mutated CLL cases were subdivided by TL into two groups with different prognosis, a subdivision not seen for unmutated cases. Interestingly, the IGHV-mutated group with short telomeres had en overall survival close to that of the unmutated cases. Thus, a combination of IGHV mutation status and telomere length gave an improved subclassification of CLL identifying previously unrecognized patient groups with different outcomes.

    TL correlates with cellular origin of B-cell malignancies in relation to the germinal center (GC). In paper II different B-cell lymphoma/leukemia subtypes were analyzed. Shortest telomeres were found in IGHV unmutated CLLs, differing significantly from IGHV mutated cases. Contrary to this, mantle cell lymphomas (MCL) demonstrated similar TL regardless of IGHV mutation status. TL differed significantly between GC-like and non-GC-like diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas (FL) had shorter telomeres than GC-like DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. In conclusion, TL seemed not to simply correlate with GC origin.

    Paper III presents a B-CLL cohort assessed for TL, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression. An inverse correlation existed between TL and IGHV homology, CD38 and ZAP-70 expression. The presence of genomic aberrations was similar among patients regardless of TL. In contrast, 13q deletion, a favorable biomarker, was more frequent in patients with long telomeres, while 11q and 17p deletions (markers of less favorable outcome) were more frequent in the subgroup with short telomeres.

    In paper IV a large group of mainly indolent CLL cases from a population based cohort was studied again showing an association between TL and prognosis, especially in “good” prognosis cases as defined by other biomarkers. Multivariate analysis indicated a strong connection between IGHV mutation status, lipoprotein lipase (LPL) expression and TL. A comparison of TL in diagnostic and follow up samples demonstrated a significant correlation, and also in the follow samples TL constituted a significant biomarker for survival.

  • 3.
    Grabowski, Pawel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karlsson, Karin
    Tobin, Gerard
    Aleskog, Anna
    Thunberg, Ulf
    Laurell, Anna
    Sundström, Christer
    Rosenquist, Richard
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 12, p. 4807-4812Article in journal (Refereed)
    Abstract [en]

    B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.

  • 4.
    Grabowski, Radoslaw
    et al.
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies, Environmental Archaeology Lab.
    Olsen, Bjørnar
    Tromsø Universitet.
    Petursdottir, Þora
    Witmore, Christopher
    Teillager 6 Sværholt: The Archaeology of a World War II Prisoner of War Camp in Finnmark, Arctic Norway2014In: Fennoscandia Archaeologica, ISSN 0781-7126, Vol. 31, p. 3-24Article in journal (Refereed)
    Abstract [en]

    This article presents the results of fieldwork undertaken over the last four summers at a World War II prisoner of war camp at Sværholt in northernmost Norway. The labour camp for Soviet prisoners was established in 1942 as part of the construction of the German coastal battery at Sværholt, a fortification within the Atlantic Wall. In late fall 1944 the camp, the coastal fort, and the local Norwegian hamlet were abandoned and destroyed in step with the massive and abrupt German retreat from this northern region. This paper describes the remains of the camp and the coastal fort, as still manifest in the barren landscape, and presents in detail the findings of excavations and associated investigations conducted in the camp area. Analysing these findings, particular emphasis is placed on the question of what an archaeological approach can divulge concerning the camp, its construction and conditions, and the ‘trivial’ details of everyday life often passed over by historical accounts. Ultimately, we suggest that the things found challenge our common assumptions about the relationship between prisoners, guards, and locals, and further discuss to what extent the forced encounter at Sværholt also may have included some measures of sympathy within the yet hostile context of war and occupation.

  • 5.
    Mansouri, Larry
    et al.
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gunnarsson, Rebeqa
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Cahill, Nicola
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Ekström Smedby, Karin
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Geisler, Christian
    Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden.
    Rosenquist, Richard
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length is a robust prognostic marker in early chronic lymphocytic leukemiaManuscript (preprint) (Other academic)
  • 6. Mansouri, Larry
    et al.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gunnarsson, Rebeqa
    Cahill, Nicola
    Smedby, Karin Ekstrom
    Geisler, Christian
    Juliusson, Gunnar
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rosenquist, Richard
    Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 8, p. 647-651Article in journal (Refereed)
  • 7.
    Roos, Göran
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kröber, Alexander
    Universität Ulm, Innere Medizin III, Ulm, Germany.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kienle, Dirk
    Universität Ulm, Innere Medizin III, Ulm, Germany.
    Bühler, Andreas
    Universität Ulm, Innere Medizin III, Ulm, Germany.
    Döhner, Hartmut
    Universität Ulm, Innere Medizin III, Ulm, Germany.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden .
    Stilgenbauer, Stephan
    Universität Ulm, Innere Medizin III, Ulm, Germany.
    Short telomeres are associated with genetic complexity, high risk genomic aberrations, and short survival in chronic lymphocytic leukemia2008In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, no 4, p. 2246-2252Article in journal (Refereed)
    Abstract [en]

    Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P = .01). Patients with telomere lengths below median (ie, "short telomeres") and above median (ie, "long telomeres") had similar incidences of genomic aberrations (74% vs 68%), 13q– (57% vs 49%), and +12q (5% vs 12%). In contrast, 13q– as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P = .006), whereas 11q– (27% vs 9%; P = .014), 17p– (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres. Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P = .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. These observations have biological and prognostic implications in B-CLL.

  • 8.
    Sitaram, Raviprakash T
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cairney, Claire J
    Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Glasgow, Scotland.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Keith, W Nicol
    Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Glasgow, Scotland.
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The PTEN regulator DJ-1 is associated with hTERT expression in clear cell renal cell carcinoma2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 125, no 4, p. 783-790Article in journal (Refereed)
    Abstract [en]

    DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p = 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p = 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p = 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC.

  • 9.
    Walsh, Sarah H
    et al.
    Department of Genetics and Pathology, Uppsala University, Uppsala.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Berglund, Mattias
    Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala.
    Thunberg, Ulf
    Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala.
    Thorsélius, Mia
    Department of Genetics and Pathology, Uppsala University, Uppsala.
    Tobin, Gerard
    Department of Genetics and Pathology, Uppsala University, Uppsala.
    Aleskog, Anna
    Department of Medical Sciences, Uppsala University, Uppsala.
    Karlsson, Karin
    Department of Hematology, Linköping University Hospital, Linköping, Sweden.
    Sundström, Christer
    Department of Genetics and Pathology, Uppsala University, Uppsala.
    Laurell, Anna
    Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala.
    Enblad, Gunilla
    Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, Uppsala.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas2007In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 78, no 4, p. 283-289Article in journal (Refereed)
    Abstract [en]

    Telomere length was recently reported to correlate with cellular origin of B-cell malignancies in relation to the germinal center (GC). In this report, we measured telomere length by quantitative-PCR in 223 B-cell lymphomas/leukemias and correlated results with immunoglobulin (Ig) mutation status and immunostainings for GC/non-GC subtypes of diffuse large B-cell lymphoma (DLBCL). Shortest telomeres were found in Ig-unmutated chronic lymphocytic leukemia (CLL) [median telomere to single copy gene value (T/S) 0.33], differing significantly to Ig-mutated CLL (0.63). Contrary to this, mantle cell lymphomas (MCLs) exhibited similar telomere lengths regardless of Ig mutation status (0.47). Telomere length differed significantly between GC-like (0.73) and non-GC-like DLBCLs (0.43), and follicular lymphomas (FLs) had shorter telomeres (0.53) than GC-DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres (0.62) than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. We conclude that although DLBCL and CLL subsets can be clearly distinguished, telomere length reflects many parameters and may not simply correlate with GC-related origin.

  • 10.
    Wänman, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Nyström, Helena
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gustafsson, Patrik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Metastatic spinal cord compression as the first sign of malignancy: Outcome after surgery in 69 patients2017In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 88, no 4, p. 457-462Article in journal (Refereed)
    Abstract [en]

    Background and purpose - Metastatic spinal cord compression (MSCC) as the initial manifestation of malignancy (IMM) limits the time for diagnostic workup; most often, treatment is required before the final primary tumor diagnosis. We evaluated neurological outcome, complications, survival, and the manner of diagnosing the primary tumor in patients who were operated for MSCC as the IMM.

    Patients and methods - Records of 69 consecutive patients (51 men) who underwent surgery for MSCC as the IMM were reviewed. The patients had no history of cancer when they presented with pain (n = 2) and/or neurological symptoms (n = 67).

    Results - The primary tumor was identified in 59 patients. In 10 patients, no specific diagnosis could be established, and they were therefore defined as having cancer of unknown primary tumor (CUP). At the end of the study, 16 patients were still alive (median follow-up 2.5 years). The overall survival time was 20 months. Patients with CUP had the shortest survival (3.5 months) whereas patients with prostate cancer (6 years) and myeloma (5 years) had the longest survival. 20 of the 39 patients who were non-ambulatory preoperatively regained walking ability, and 29 of the 30 ambulatory patients preoperatively retained their walking ability 1 month postoperatively. 15 of the 69 patients suffered from a total of 20 complications within 1 month postoperatively.

    Interpretation - Postoperative survival with MSCC as the IMM depends on the type of primary tumor. Surgery in these patients maintains and improves ambulatory function.

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