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  • 301.
    Batool, Tahira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate dependent cell signaling and associated pathophysiology: Implications in tumorigenesis and embryogenesis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heparan sulfate proteoglycans (HSPGs) consist of a protein core to which several linear, negatively charged heparan sulfate (HS) chains are covalently attached. HSPGs are expressed on the cell surface and in the extra-cellular matrix (ECM) where they have diverse biological functions, for example co-receptor functions. The diverse functions of HS are linked to structural variability of the polysaccharide. In this thesis, I investigated HS structure-function relationship by using different cell and animal models of one HS-biosynthetic enzyme, glucuronyl C5-epimerase (Hsepi) and one enzyme responsible for post synthetic modification, heparanase.

    Deletion of Hsepi in mice resulted in neonatal lethality, with multiple organ defects, indicating the importance of HS in embryogenesis. Up-regulated expression of heparanase is found in most human tumor tissues, correlating with increased metastatic potential and decreased survival of cancer patients.

    In the first project, I focused on the effects of HS on cancer associated cell signaling and found that heparanase overexpression attenuated TGF-β1 stimulated Smad phosphorylation in tumor cells because of increased sulfation degree and turnover rate of HS.

    Heparanase role in cancer progression has led to clinical trials where inhibition of heparanase activity is currently being evaluated as a potential cancer treatment. Heparin, a HS-related polysaccharide, is being used to inhibit heparanase activity. In my second project, we studied the effect of low molecular weight heparin (LMWH) on cisplatin resistance of ovarian cancer cells (A2780cis). LMWH treatment of A2780cis cells reduced Wnt-activity in these cells and consequently reduce the drug resistance.

    In paper III, we continued exploring the HS/heparanase role in cancer by using heparanase overexpressing mice (Hpa-tg). We found Lewis Lung Carcinoma (LLC2) cells showed faster growth, bigger tumors and more metastasis in the Hpa-tg mice as compared to wild-type (WT) mice, because of suppressed antitumor immunity in the Hpa-tg mice.

    In paper IV and V, we studied the structure-function relationship of HS by using Hsepi-/- mice model. Hsepi-/- results in HS-chains lacking IdoA, which makes the chain rigid and consequently affects its co-receptor function. Skeletal malformation in Hsepi-/- mice, led us in paper IV to investigate bone morphogenic protein (BMP), an important signal molecule during embryogenesis and known to interact with HS. We found upregulation of a number of BMPs and expression of P-smad1/5/8, but reduced expression of inhibitory Smads and Gremlin1 in the Hsepi-/- MEF cells. The study indicated that the developmental defects in Hsepi mice could be contributed by a higher BMP signaling. In paper V we investigated the lung of the Hsepi-/- mice. The distal lung of 17.5 days old embryos remained populated by epithelial tubules, because of impaired differentiation of type I cells of the lungs. Potential mechanisms behind the failure of type I cell formation was identified to be reduced vascularization and a sustained signaling of Smad pathways.

  • 302.
    Batool, Tahira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fang, Jianping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. GlycoNovo Technol Co Ltd, Shanghai, Peoples R China..
    Barash, Uri
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vlodavsky, Israel
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells2017In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 3, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) mediates the activity of various growth factors including TGF-beta. Heparanase is an endo-glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF-beta 1-dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF-beta 1-stimulated Smad phosphorylation and led to a slower cell proliferation. TGF-beta 1-stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF-beta 1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF-beta 1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF-beta 1 function in tumorigenesis.

  • 303.
    Baudin, Eric
    et al.
    Inst Gustave Roussy, Oncol Endocrinienne & Med Nucl, Villejuif, France.
    Hayes, Aimee R.
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Scoazec, Jean-Yves
    Univ Lyon, Dept Pathol, Lyon, France.
    Filosso, Pier Luigi
    Univ Torino, Dept Thorac Surg, Turin, Italy.
    Lim, Eric
    Royal Brompton Hosp, Dept Thorac Surg, London, England.
    Kaltsas, Gregory
    Natl Univ Athens, Div Endocrinol, Dept Pathophysiol, Athens, Greece.
    Frilling, Andrea
    Imperial Coll London, Dept Surg & Canc, London, England.
    Chen, Jie
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China.
    Kos-Kudła, Beata
    Slaska Akad Med, Klin Endokrynol, Zabrze, Poland.
    Gorbunova, Vera
    Russian Acad Med Sci, FSBI NN Blokhin Russian Canc Res Ctr, Moscow, Russia.
    Wiedenmann, Bertram
    Charite Univ Med Berlin, Campus Charite Mitte, Dept Gastroenterol & Hepatol, Berlin, Germany; Charite Univ Med Berlin, Campus Virchow Klinikum, Berlin, Germany.
    Nieveen van Dijkum, Els
    Acad Med Ctr, Dept Surg, Amsterdam, Netherlands.
    Ćwikła, Jaroslaw B
    Univ Warmia & Mazury, Fac Med Sci, Dept Radiol, Olsztyn, Poland.
    Falkerby, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Valle, Juan W.
    Univ Manchester, Inst Canc Sci, Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England.
    Kulke, Matthew H
    Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA.
    Caplin, Martyn E
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Sundin, Anders (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tiensuu Janson, Eva (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Welin, Staffan (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms2019In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, no 1, p. 7-17Article in journal (Refereed)
    Abstract [en]

    Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.

  • 304. Bauerschmidt, Christina
    et al.
    Woodcock, Michael
    Stevens, David L.
    Hill, Mark A.
    Rothkamm, Kai
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cells2011In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 317, no 3, p. 330-337Article in journal (Refereed)
    Abstract [en]

    Cohesin, a hetero-tetrameric complex of SMC1, SMC3, Rad21 and Scc3, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. Following DNA damage, cohesin accumulates at and promotes the repair of DNA double-strand breaks. In addition, phosphorylation of the SMC1/3 subunits contributes to DNA damage-induced cell cycle checkpoint regulation. The aim of this study was to determine the regulation and consequences of SMC1/3 phosphorylation as part of the cohesin complex. We show here that the ATM-dependent phosphorylation of SMC1 and SMC3 is mediated by H2AX, 53BP1 and MDC1. Depletion of RAD21 abolishes these phosphorylations, indicating that only the fully assembled complex is phosphorylated. Comparison of wild type SMC1 and SMC1S966A in fluorescence recovery after photo-bleaching experiments shows that phosphorylation of SMC1 is required for an increased mobility after DNA damage in G2-phase cells, suggesting that ATM-dependent phosphorylation facilitates mobilization of the cohesin complex after DNA damage.

  • 305. Baumann, Pia
    et al.
    Nyman, Jan
    Hoyer, Morten
    Wennberg, Berit
    Gagliardi, Giovanna
    Lax, Ingmar
    Drugge, Ninni
    Ekberg, Lars
    Friesland, Signe
    Johansson, Karl-Axel
    Lund, Jo-Asmund
    Morhed, Elisabeth
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Levin, Nina
    Paludan, Merete
    Sederholm, Christer
    Traberg, Anders
    Wittgren, Lena
    Lewensohn, Rolf
    Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.2009In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 27, no 20, p. 3290-6Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study.

    PATIENTS AND METHODS: Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume.

    RESULTS: Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027).

    CONCLUSION: With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.

  • 306. Baust, H.
    et al.
    Schiessl, I.
    Mueller, B.
    Roedel, F.
    Distel, L.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Thomas, S.
    Rolf, S.
    Implications for the role of PKD2 in the radiotherapy of tumours2006In: Strahlentherapie und Onkologie (Print), ISSN 0179-7158, E-ISSN 1439-099X, Vol. 182, p. 81-81Article in journal (Refereed)
  • 307.
    Baust, H.
    et al.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Schoke, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Brey, A.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Gern, U.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, D-48149 Muenster, Germany.
    Schmid, R. M.
    2nd Department of Internal Medicine, University of Munich, D-81675 Munich, Germany.
    Röttinger, E. M.
    Department of Radiation Oncology, University of Ulm, D-89081 Ulm, Germany.
    Seufferlein, T.
    Department of Internal Medicine, University of Ulm, D-89081 Ulm, Germany.
    Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappa B independent mechanisms2003In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 54, p. 8786-8796Article in journal (Refereed)
    Abstract [en]

    Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radio-sensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.

  • 308. Beckmann, Kerri
    et al.
    Russell, Beth
    Josephs, Debra
    Garmo, Hans
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Holmberg, Lars
    Stattin, Pär
    Van Hemelrijck, Mieke
    Adolfsson, Jan
    Chronic inflammatory diseases, anti-inflammatory medications and risk of prostate cancer: a population-based case-control study2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 612Article in journal (Refereed)
    Abstract [en]

    Background: Whether chronic inflammation increases prostate cancer risk remains unclear. This study investigated whether chronic inflammatory diseases (CID) or anti-inflammatory medication use (AIM) were associated with prostate cancer risk.

    Methods: Fifty-five thousand nine hundred thirty-seven cases (all prostate cancer, 2007–2012) and 279,618 age-matched controls were selected from the Prostate Cancer Database Sweden. CIDs and AIMs was determined from national patient and drug registers. Associations were investigated using conditional logistic regression, including for disease/drug subtypes and exposure length/dose.

    Results: Men with a history of any CID had slightly increased risk of any prostate cancer diagnosis (OR: 1.08; 95%CI: 1.04–1.12) but not ‘unfavourable’ (high-risk or advanced) prostate cancer. Generally, risk of prostate cancer was highest for shorter exposure times. However, a positive association was observed for asthma > 5 years before prostate cancer diagnosis (OR: 1.21; 95%CI: 1.05–1.40). Risk of prostate cancer was increased with prior use of any AIMs (OR: 1.26; 95%CI: 1.24–1.29). A positive trend with increasing cumulative dose was only observed for inhaled glucocorticoids (p < 0.011).

    Conclusion: Detection bias most likely explains the elevated risk of prostate cancer with prior history of CIDs or use of AIMs, given the higher risk immediately after first CID event and lack of dose response. However, findings for length of time with asthma and dose of inhaled glucocorticoids suggest that asthma may increase risk of prostate cancer through other pathways.

  • 309.
    Beckmann, Kerri
    et al.
    Univ South Australia, UniSA Canc Res Inst, Adelaide, SA, Australia;Kings Coll London, Sch Canc & Pharmaceut Studies Translat Oncol, Sch Canc & Pharmaceut Studies, TOUR, London, England.
    Russell, Beth
    Kings Coll London, Sch Canc & Pharmaceut Studies Translat Oncol, Sch Canc & Pharmaceut Studies, TOUR, London, England.
    Josephs, Debra
    Kings Coll London, Sch Canc & Pharmaceut Studies Translat Oncol, Sch Canc & Pharmaceut Studies, TOUR, London, England.
    Garmo, Hans
    Kings Coll London, Sch Canc & Pharmaceut Studies Translat Oncol, Sch Canc & Pharmaceut Studies, TOUR, London, England;Uppsala Univ Hosp, Reg Canc Ctr Uppsala, Uppsala, Sweden.
    Häggström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umea Univ, Dept Biobank Res, Umea, Sweden.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Sch Canc & Pharmaceut Studies Translat Oncol, Sch Canc & Pharmaceut Studies, TOUR, London, England.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Van Hemelrijck, Mieke
    Kings Coll London, Sch Canc & Pharmaceut Studies Translat Oncol, Sch Canc & Pharmaceut Studies, TOUR, London, England;Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden.
    Adolfsson, Jan
    Karolinska Inst, CLINTEC Dept, Stockholm, Sweden.
    Chronic inflammatory diseases, anti-inflammatory medications and risk of prostate cancer: a population-based case-control study2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 612Article in journal (Refereed)
    Abstract [en]

    Background: Whether chronic inflammation increases prostate cancer risk remains unclear. This study investigated whether chronic inflammatory diseases (CID) or anti-inflammatory medication use (AIM) were associated with prostate cancer risk.

    Methods: Fifty-five thousand nine hundred thirty-seven cases (all prostate cancer, 2007-2012) and 279,618 age-matched controls were selected from the Prostate Cancer Database Sweden. CIDs and AIMs was determined from national patient and drug registers. Associations were investigated using conditional logistic regression, including for disease/drug subtypes and exposure length/dose.

    Results: Men with a history of any CID had slightly increased risk of any prostate cancer diagnosis (OR: 1.08; 95%CI: 1.04-1.12) but not unfavourable' (high-risk or advanced) prostate cancer. Generally, risk of prostate cancer was highest for shorter exposure times. However, a positive association was observed for asthma >5years before prostate cancer diagnosis (OR: 1.21; 95%CI: 1.05-1.40). Risk of prostate cancer was increased with prior use of any AIMs (OR: 1.26; 95%CI: 1.24-1.29). A positive trend with increasing cumulative dose was only observed for inhaled glucocorticoids (p<0.011).

    Conclusion: Detection bias most likely explains the elevated risk of prostate cancer with prior history of CIDs or use of AIMs, given the higher risk immediately after first CID event and lack of dose response. However, findings for length of time with asthma and dose of inhaled glucocorticoids suggest that asthma may increase risk of prostate cancer through other pathways.

  • 310. Beckmann, L
    et al.
    Hüsing, A
    Setiawan, VW
    Amiano, P
    Clavel-Chapelon, F
    Chanock, SJ
    Cox, DG
    Diver, R
    Dossus, L
    Feigelson, HS
    Haiman, C
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hayes, RB
    Henderson, BE
    Hoover, RN
    Hunter, DJ
    Khaw, K
    Kolonel, LN
    Kraft, P
    Lund, E
    Le Marchand, L
    Peeters, PHM
    Riboli, E
    Stram, D
    Thomas, G
    Thun, MJ
    Tumino, R
    Trichopoulos, D
    Vogel, U
    Willett, WC
    Yeager, M
    Ziegler, R
    Hankinson, SE
    Kaaks, R
    Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium (BPC3)2011In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 2, p. E360-E367Article in journal (Refereed)
    Abstract [en]

    We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.

  • 311. Beer, Tomasz M
    et al.
    Armstrong, Andrew J
    Rathkopf, Dana E
    Loriot, Yohann
    Sternberg, Cora N
    Higano, Celestia S
    Iversen, Peter
    Bhattacharya, Suman
    Carles, Joan
    Chowdhury, Simon
    Davis, Ian D
    de Bono, Johann S
    Evans, Christopher P
    Fizazi, Karim
    Joshua, Anthony M
    Kim, Choung-Soo
    Kimura, Go
    Mainwaring, Paul
    Mansbach, Harry
    Miller, Kurt
    Noonberg, Sarah B
    Perabo, Frank
    Phung, De
    Saad, Fred
    Scher, Howard I
    Taplin, Mary-Ellen
    Venner, Peter M
    Tombal, Bertrand
    Enzalutamide in metastatic prostate cancer before chemotherapy.2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.

    METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.

    RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.

    CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

  • 312. Beghini, Alessandro
    et al.
    Corlazzoli, Francesca
    Del Giacco, Luca
    Re, Matteo
    Lazzaroni, Francesca
    Brioschi, Matteo
    Valentini, Giorgio
    Ferrazzi, Fulvia
    Ghilardi, Anna
    Righi, Marco
    Turrini, Mauro
    Mignardi, Marco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cesana, Clara
    Bronte, Vincenzo
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Morra, Enrica
    Cairoli, Roberto
    Regeneration-associated WNT Signaling Is Activated in Long-term Reconstituting AC133(bright) Acute Myeloid Leukemia Cells2012In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 14, no 12, p. 1236-+Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/beta-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT 10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated beta-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)gamma c(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration. Neoplasia (2012) 14, 1236-1248

  • 313.
    Behnam Motlagh, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brännstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Co-expression of Globotriasosylceramide (Gb3) With MDR1 in Cisplatin-resistant Pleural Mesothelioma and Non-small Cell Lung Cancer Cell May Lead to a New Tumour Resistance Treatment Approach2011Conference paper (Refereed)
  • 314.
    Behnam-Motlagh, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Verotoxin-1 Treatment or Manipulation of its Receptor Globotriaosylceramide (Gb3) for Reversal of Multidrug Resistance to Cancer Chemotherapy2010In: Toxins, ISSN 2072-6651, Vol. 2, no 10, p. 2467-2477Article, review/survey (Refereed)
    Abstract [en]

    A major problem with anti-cancer drug treatment is the development of acquired multidrug resistance (MDR) of the tumor cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the globotriaosylceramide membrane receptor (Gb3), a glycolipid associated with multidrug resistance. Gb3 is overexpressed in many human tumors and tumor cell lines with inherent or acquired MDR. Gb3 is co-expressed and interplays with the membrane efflux transporter P-gp encoded by the MDR1 gene. P-gp could act as a lipid flippase and stimulate Gb3 induction when tumor cells are exposed to cancer chemotherapy. Recent work has shown that apoptosis and inherent or acquired multidrug resistance in Gb3-expressing tumors could be affected by VT-1 holotoxin, a sub-toxic concentration of the holotoxin concomitant with chemotherapy or its Gb3-binding B-subunit coupled to cytotoxic or immunomodulatory drug, as well as chemical manipulation of Gb3 expression. The interplay between Gb3 and P-gp thus gives a possible physiological approach to augment the chemotherapeutic effect in multidrug resistant tumors.

  • 315.
    Behrens, Thomas
    et al.
    Bremen Institute of Prevention Research & Social Medicine, Bremen, Germany; Institute of Prevention & Occupational Medicine of German Social Accidents Insurance, Bochum, Germany.
    Lynge, Elsebeth
    Inst Publ Hlth, Univ Copenhagen, Copenhagen, Denmark..
    Cree, Ian
    Inst Ophthalmol, University College London (UCL), London, England.
    Lutz, Jean-Michel
    National Institute for Cancer Epidemiology and Registration (NICER), Univ Zurich, Zurich, Switzerland.
    Eriksson, Mikael
    Dept of Oncology, Lund University Hospital, Lund, Sweden..
    Guenel, Pascal
    Centre de recherche en épidémiologie et santé des populations (CESP), French National Institute of Health and Medical Research (INSERM), Villejuif, France; Univ Paris Sud, Villejuif, France.
    Merletti, Franco
    Cancer Epidemiology Unit, Univ Turin, Piemonte, Italy; ll Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica (CPO), Piemonte, Italy.
    Morales-Suarez-Varela, Maria
    Dept of Prevention Medicine, Unit Public Health & Environmental Care, University Valencia, Valencia, Spain; CIBER Act Epidemiology & Public Health, Res Grp CIBER CB06, Valencia, Spain; Center Public Health Research CSISP, Valencia, Spain.
    Afonso, Noemia
    Med Oncol Serv, Inst Portugues Oncol Francisco Gentil, Oporto, Portugal.
    Stengrevics, Aivars
    Latvia Canc Registry, Riga, Latvia.
    Fevotte, Joelle
    Umrestte UCB Lyon 1 InVS Inrets, Lyon, France.
    Sabroe, Svend
    Dept Epidemiol, Univ Aarhus, Aarhus, Denmark..
    Llopis-Gonzalez, Agustin
    Dept Prevent Med, Unit Publ Hlth & Environm Care, Univ Valencia, Valencia, Spain; CIBER Act Epidemiol & Publ Hlth, Res Grp CIBER CB06, Valencia, Spain.
    Gorini, Giuseppe
    Environm & Occupat Epidemiol Unit, ISPO Canc Prevent & Res Inst, Florence, Italy.
    Hardell, Lennart
    Department of Oncology, Örebro University Hospital, Region Örebro län, Örebro, Sweden.
    Stang, Andreas
    Inst Clin Epidemiol, Univ Halle Wittenberg, Halle, Germany; Inst Med Informat Biometry & Epidemiol, Univ Duisburg Essen, Essen, Germany..
    Ahrens, Wolfgang
    Bremen Inst Prevent Res & Social Med, Bremen, Germany; Inst Med Informat Biometry & Epidemiol, Univ Duisburg Essen, Essen, Germany.
    Pesticide exposure in farming and forestry and the risk of uveal melanoma2012In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 23, no 1, p. 141-151Article in journal (Refereed)
    Abstract [en]

    Since pesticides are disputed risk factors for uveal melanoma, we studied the association between occupational pesticide exposure and uveal melanoma risk in a case-control study from nine European countries.

    Incident cases of uveal melanoma and population as well as hospital controls were included and frequency-matched by country, 5-year age groups and sex. Self-reported exposure was quantified with respect to duration of exposure and pesticide application method. We calculated the exposure intensity level based on application method and use of personal protective equipment. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression analyses and adjusted for several potential confounders.

    293 case and 3,198 control subjects were interviewed. We did not identify positive associations with activities in farming or forestry, pesticide application or pesticide mixing. No consistent positive associations were seen with exposure intensity level scores either. The only statistically significantly raised association in this study was for exposure to chemical fertilizers in forestry (OR = 8.93; 95% CI 1.73-42.13), but this observation was based on only six exposed subjects. Results did not change when we restricted analyses to morphologically verified cases and excluded proxy interviews as well as cancer controls. We did not observe effect modification by sex or eye color.

    Risk estimates for pesticide exposures and occupational activities in agriculture and forestry were not increased and did not indicate a hormonal mechanism due to these exposures.

  • 316.
    Beiranvand, Samira
    et al.
    Ahvaz Jundishapur Univ Med Sci, IRN.
    Zarea, Kourosh
    Ahvaz Jundishapur Univ Med Sci, IRN.
    Ghanbari, Saeed
    Shiraz Univ Med Sci, IRN.
    Tuvesson, Hanna
    Blekinge Institute of Technology, Faculty of Engineering, Department of Health.
    Keikhaei, Bijan
    Ahvaz Jundishapur Univ Med Sci, IRN.
    Ten years incidence of cancer in Iran: a systematic review and meta-analysis2018In: CLINICAL EPIDEMIOLOGY AND GLOBAL HEALTH, ISSN 2452-0918, Vol. 6, no 2, p. 94-102Article, review/survey (Refereed)
    Abstract [en]

    Background: Designing and implementation of screening programs depend on greatly epidemiologic basic data in every country. Also Variation in the incidence of various cancers in our country has been a favorite topic. Objectives: This systematic review was conducted to provide an overall perspective about incidence, geographical and age distribution of cancers in Iran. Methods: A comprehensive search were done according to MOOSE guideline criteria in national and international databases for selecting eligible articles from 2005 to 2015. After screening titles and abstracts, duplicated and irrelevant studies were excluded. Selected papers are written in Persian or English. The standard error of the cancer incidence was calculated based on the binomial distribution. Because of the significant heterogeneity observed among the results, we used a random-effects model combine the results of the primary studies. Moreover, a sensitivity analysis was undertaken to explore the effects of the risk of bias and other sources of heterogeneity. Results: Overall 16 articles met eligibility criteria for inclusion. The total incidence of cancer was 19.4 and 17.2 per hundred thousand of people in males and females respectively. The five most common cancers in male were: Lymphoma, leukemia, esophagus, stomach, colorectal and in the female are: breast, colorectal, stomach, thyroid and esophagus. The highest incidence rate was seen in Golestan Province and in the age group over 65 years. Conclusion: According to increasing incidence rate of cancers in Iran, Development, holding and accomplish of universal public cancer control program should be the first precedence for health policy. (c) 2017 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of INDIACLEN.

  • 317.
    Beiranvand, Samira
    et al.
    Ahvaz Jundishapur University of Medical Sciences, Iran.
    Zarea, Kourosh
    Ahvaz Jundishapur University of Medical Sciences, Iran.
    Ghanbari, Saeed
    Shiraz University of Medical Sciences, Iran.
    Tuvesson, Hanna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Health and Caring Sciences. Blekinge Institute of Technology.
    Keikhaei, Bijan
    Ahvaz Jundishapur University of Medical Sciences, Iran.
    Ten years incidence of cancer in Iran: a systematic review and meta-analysis2018In: Clinical Epidemiology and Global Health, ISSN 2452-0918, Vol. 6, no 2, p. 94-102Article in journal (Refereed)
    Abstract [en]

    Background

    Designing and implementation of screening programs depend on greatly epidemiologic basic data in every country. Also Variation in the incidence of various cancers in our country has been a favorite topic.

    Objectives

    This systematic review was conducted to provide an overall perspective about incidence, geographical and age distribution of cancers in Iran.

    Methods

    A comprehensive search were done according to MOOSE guideline criteria in national and international databases for selecting eligible articles from 2005 to 2015. After screening titles and abstracts, duplicated and irrelevant studies were excluded. Selected papers are written in Persian or English. The standard error of the cancer incidence was calculated based on the binomial distribution. Because of the significant heterogeneity observed among the results, we used a random-effects model combine the results of the primary studies. Moreover, a sensitivity analysis was undertaken to explore the effects of the risk of bias and other sources of heterogeneity.

    Results

    Overall 16 articles met eligibility criteria for inclusion. The total incidence of cancer was 19.4 and 17.2 per hundred thousand of people in males and females respectively. The five most common cancers in male were: Lymphoma, leukemia, esophagus, stomach, colorectal and in the female are: breast, colorectal, stomach, thyroid and esophagus. The highest incidence rate was seen in Golestan Province and in the age group over 65 years.

    Conclusion

    According to increasing incidence rate of cancers in Iran, Development, holding and accomplish of universal public cancer control program should be the first precedence for health policy.

  • 318. Belitskaya-Lévy, Ilana
    et al.
    Zeleniuch-Jacquotte, Anne
    Russo, Jose
    Russo, Irma H
    Bordás, Pal
    Ahman, Janet
    Afanasyeva, Yelena
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Li, Xiaochun
    de Cicco, Ricardo López
    Peri, Suraj
    Ross, Eric
    Russo, Patricia A
    Santucci-Pereira, Julia
    Sheriff, Fathima S
    Slifker, Michael
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Toniolo, Paolo
    Arslan, Alan A
    Characterization of a genomic signature of pregnancy identified in the breast2011In: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 4, no 9, p. 1457-1464Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer.

  • 319.
    Belka, C.
    et al.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Marini, P.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Lepple-Wienhues, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Budach, W.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    Jekle, A.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Los, Marek Jan
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Lang, F.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Schulze-Osthoff, K.
    Department of Internal Medicine I, University of Tuebingen (Germany), Otfried Müller Str. 10, 72076 Tuebingen, Germany.
    Gulbins, E.
    Department of Physiology, University of Tuebingen (Germany), Gmelinstrasse 5, 72076 Tuebingen, Germany.
    Bamberg, M.
    Department of Radiation Oncology, University of Tuebingen (Germany), Hoppe Seyler Str. 3, 72076 Tuebingen, Germany.
    The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation1999In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 18, no 35, p. 4983-4992Article in journal (Refereed)
    Abstract [en]

    Induction of apoptosis is a hallmark of cytostatic drug and radiation-induced cell death in human lymphocytes and lymphoma cells. However, the mechanisms leading to apoptosis are not well understood. We provide evidence that ionizing radiation induces a rapid activation of caspase-8 (FLICE) followed by apoptosis independently of CD95 ligand/receptor interaction. The radiation induced cleavage pattern of procaspase-8 into mature caspase-8 resembled that following CD95 crosslinking and resulted in cleavage of the proapoptotic substrate BID. Overexpression of dominant-negative caspase-8 interfered with radiation-induced apoptosis, Caspase-8 activation by ionizing radiation was not observed in cells genetically defective for the Src-like tyrosine kinase Lck, Cells lacking Lck also displayed a marked resistance towards apoptosis induction upon ionizing radiation. After retransfection of Lck, caspase-8 activation and the capability to undergo apoptosis in response to ionizing radiation was restored. We conclude that radiation activates caspase-8 via an Lck-controlled pathway independently of CD95 ligand expression, This is a novel signaling event required for radiation induced apoptosis in T lymphoma cells.

  • 320.
    Bellomo, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transforming growth factor beta as regulator of cancer stemness and metastasis2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 7, p. 761-769Article, review/survey (Refereed)
    Abstract [en]

    Key elements of cancer progression towards metastasis are the biological actions of cancer stem cells and stromal cells in the tumour microenvironment. Cross-communication between tumour and stromal cells is mediated by secreted cytokines, one of which, the transforming growth factor beta (TGF beta), regulates essentially every cell within the malignant tissue. In this article, we focus on the actions of TGF beta on cancer stem cells, cancer-associated fibroblasts and immune cells that assist the overall process of metastatic dissemination. We aim at illustrating intricate connections made by various cells in the tumour tissue and which depend on the action of TGF beta.

  • 321.
    Beltran-Pardo, Eliana
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonsson, K. Ingemar
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Kristianstad University, Sweden.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tolerance to Gamma Radiation in the Tardigrade Hypsibius dujardini from Embryo to Adult Correlate Inversely with Cellular Proliferation2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133658Article in journal (Refereed)
    Abstract [en]

    Tardigrades are highly tolerant to desiccation and ionizing radiation but the mechanisms of this tolerance are not well understood. In this paper, we report studies on dose responses of adults and eggs of the tardigrade Hypsibius dujardini exposed to gamma radiation. In adults the LD50/48h for survival was estimated at similar to 4200 Gy, and doses higher than 100 Gy reduced both fertility and hatchability of laid eggs drastically. We also evaluated the effect of radiation (doses 50 Gy, 200 Gy, 500 Gy) on eggs in the early and late embryonic stage of development, and observed a reduced hatchability in the early stage, while no effect was found in the late stage of development. Survival of juveniles from irradiated eggs was highly affected by a 500 Gy dose, both in the early and the late stage. Juveniles hatched from eggs irradiated at 50 Gy and 200 Gy developed into adults and produced offspring, but their fertility was reduced compared to the controls. Finally we measured the effect of low temperature during irradiation at 4000 Gy and 4500 Gy on survival in adult tardigrades, and observed a slight delay in the expressed mortality when tardigrades were irradiated on ice. Since H. dujardini is a freshwater tardigrade with lower tolerance to desiccation compared to limno-terrestrial tardigrades, the high radiation tolerance in adults, similar to limno-terrestrial tardigrades, is unexpected and seems to challenge the idea that desiccation and radiation tolerance rely on the same molecular mechanisms. We suggest that the higher radiation tolerance in adults and late stage embryos of H. dujardini (and in other studied tardigrades) compared to early stage embryos may partly be due to limited mitotic activity, since tardigrades have a low degree of somatic cell division (eutely), and dividing cells are known to be more sensitive to radiation.

  • 322.
    Benda, Birgitta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Islet xenotransplantation: An immunological study in the pig-to-mouse model1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Successful clinical xenotransplantation, i.e., transplantation between species, would eliminate the shortage of donor organs. In order to study the acute cellular rejection reaction following discordant xenogeneic transplantation, an experimental pig-to- mouse islet xenotransplantation model was established. Further, immunological processes were evaluated using genetically deficient (knock-out) recipient mice and pharmacological agents exerting cytokine-modulatory actions.

    Xenogeneic islet transplantation persists in mice deficient in antibodies, interleukin-6, perforin or granzyme B, suggesting that neither xenoreactive antibodies or interleukin-6 nor granule-mediated lysis are of critical importance to the rejection process. Instead, the immune response following pig-to-mouse islet xenotransplantation bears a close morphological resemblance to a T helper (Th) 1-dependent delayed-type hypersensitivity-reaction with a massive infiltration of macrophages and comparatively small amounts of peripherally accumulated T cells. It may be speculated that islet xenograft destruction is a macrophage-mediated process regulated by T cells. Indeed, Th1-associated cytokines with macrophage-activating properties (interferon-γ and tumor necrosis factor-α) and interleukin-2 seem to be important to islet xenograft rejection, even though other cytokines eventually substitute for the lack of those in a majority of animals.

    Key words: xenotransplantation, porcine, islet, in vivo, knock-out mouse,immunohistochemistry, CsA, MDL 201,449A, Ig, FcR, IL-6, perforin, granzyme B,macrophage, eosinophilic granulocyte, T cell, TCR, IFN- g, TNF- a, IL-2.

  • 323.
    Bender, Brendan C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schindler, Emilie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetic pharmacodynamic modelling in oncology: a tool for predicting clinical response2015In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 79, no 1, p. 56-71Article, review/survey (Refereed)
    Abstract [en]

    In oncology trials, overall survival (OS) is considered the most reliable and preferred endpoint to evaluate the benefit of drug treatment. Other relevant variables are also collected from patients for a given drug and its indication, and it is important to characterize the dynamic effects and links between these variables in order to improve the speed and efficiency of clinical oncology drug development. However, the drug-induced effects and causal relationships are often difficult to interpret because of temporal differences. To address this, population pharmacokinetic-pharmacodynamic (PKPD) modelling and parametric time-to-event (TTE) models are becoming more frequently applied. Population PKPD and TTE models allow for exploration towards describing the data, understanding the disease and drug action over time, investigating relevance of biomarkers, quantifying patient variability and in designing successful trials. In addition, development of models characterizing both desired and adverse effects in a modelling framework support exploration of risk-benefit of different dosing schedules. In this review, we have summarized population PKPD modelling analyses describing tumour, tumour marker and biomarker responses, as well as adverse effects, from anticancer drug treatment data. Various model-based metrics used to drive PD response and predict OS for oncology drugs and their indications are also discussed.

  • 324.
    Benfeitas, Rui
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, A.
    New challenges to study heterogeneity in cancer redox metabolism2017In: Frontiers in Cell and Developmental Biology, ISSN 2296-634X, Vol. 5, no JUL, article id 65Article in journal (Refereed)
    Abstract [en]

    Reactive oxygen species (ROS) are important pathophysiological molecules involved in vital cellular processes. They are extremely harmful at high concentrations because they promote the generation of radicals and the oxidation of lipids, proteins, and nucleic acids, which can result in apoptosis. An imbalance of ROS and a disturbance of redox homeostasis are now recognized as a hallmark of complex diseases. Considering that ROS levels are significantly increased in cancer cells due to mitochondrial dysfunction, ROS metabolism has been targeted for the development of efficient treatment strategies, and antioxidants are used as potential chemotherapeutic drugs. However, initial ROS-focused clinical trials in which antioxidants were supplemented to patients provided inconsistent results, i.e., improved treatment or increased malignancy. These different outcomes may result from the highly heterogeneous redox responses of tumors in different patients. Hence, population-based treatment strategies are unsuitable and patient-tailored therapeutic approaches are required for the effective treatment of patients. Moreover, due to the crosstalk between ROS, reducing equivalents [e.g., NAD(P)H] and central metabolism, which is heterogeneous in cancer, finding the best therapeutic target requires the consideration of system-wide approaches that are capable of capturing the complex alterations observed in all of the associated pathways. Systems biology and engineering approaches may be employed to overcome these challenges, together with tools developed in personalized medicine. However, ROS- and redox-based therapies have yet to be addressed by these methodologies in the context of disease treatment. Here, we review the role of ROS and their coupled redox partners in tumorigenesis. Specifically, we highlight some of the challenges in understanding the role of hydrogen peroxide (H2O2), one of the most important ROS in pathophysiology in the progression of cancer. We also discuss its interplay with antioxidant defenses, such as the coupled peroxiredoxin/thioredoxin and glutathione/glutathione peroxidase systems, and its reducing equivalent metabolism. Finally, we highlight the need for system-level and patient-tailored approaches to clarify the roles of these systems and identify therapeutic targets through the use of the tools developed in personalized medicine. © 2017 Benfeitas, Uhlen, Nielsen and Mardinoglu.

  • 325.
    Bengtsson, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Joost, Patrick
    Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Off Medical Serv, Sweden; Lund University, Sweden.
    Backman, Ann-Sofie
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Melin, Beatrice
    Umeå University, Sweden.
    von Salome, Jenny
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Zagoras, Theofanis
    Sahlgrens University Hospital, Sweden.
    Gebre-Medhin, Samuel
    Lund University, Sweden; Karolinska University Hospital, Sweden.
    Burman, Pia
    Lund University, Sweden.
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 3928-3932Article in journal (Refereed)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 326.
    Bengtsson, Daniel
    et al.
    Linkoping Univ, Dept Clin & Expt Med, S-58183 Linkoping, Sweden.;Kalmar Cty Hosp, Dept Internal Med, S-39185 Kalmar, Sweden..
    Joost, Patrick
    Lund Univ, Inst Clin Sci, Dept Oncol & Pathol, S-22184 Lund, Sweden..
    Aravidis, Christos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Stenmark, Marie Askmalm
    Linkoping Univ, Div Clin Genet, Dept Clin & Expt Med, S-58185 Linkoping, Sweden.;Off Med Serv, Dept Clin Genet, S-22184 Lund, Sweden.;Lund Univ, Div Clin Genet, Dept Lab Med, S-22184 Lund, Sweden..
    Backman, Ann-Sofie
    Karolinska Univ Hosp, Ctr Digest Dis, S-17176 Stockholm, Sweden.;Karolinska Inst, Inst Med, S-17176 Stockholm, Sweden..
    Melin, Beatrice
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    von Salome, Jenny
    Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, S-17176 Stockholm, Sweden..
    Zagoras, Theofanis
    Sahlgrens Univ Hosp, Dept Clin Pathol & Genet, S-41345 Gothenburg, Sweden..
    Gebre-Medhin, Samuel
    Lund Univ, Div Clin Genet, Dept Lab Med, S-22184 Lund, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, S-17176 Stockholm, Sweden..
    Burman, Pia
    Lund Univ, Dept Endocrinol, Skane Univ Hosp, SE-20502 Malmo, Sweden..
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 3928-3932Article in journal (Refereed)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patient's germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 327. Bengtsson, Daniel
    et al.
    Joost, Patrick
    Aravidis, Christos
    Stenmark, Marie Askmalm
    Backman, Ann-Sofie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    von Salome, Jenny
    Zagoras, Theofanis
    Gebre-Medhin, Samuel
    Burman, Pia
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 3928-3932Article in journal (Refereed)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported.

    Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patient’s germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS.

    Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected).

    Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 328.
    Bengtsson, Jenny
    et al.
    Mid Sweden University, Faculty of Human Sciences, Department of Health Sciences.
    Mohlin, Madelene
    Mid Sweden University, Faculty of Human Sciences, Department of Health Sciences.
    Akut lymfatisk leukemi hos barn: Föräldrars upplevelser2010Independent thesis Basic level (degree of Bachelor), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: När ett barn får diagnosen akut lymfatisk leukemi drabbas föräldrarna ofta av psykisk ohälsa. Sjukdomen och behandlingen orsakar förändringar i hela familjens tillvaro. Syfte: Syftet med denna litteraturstudie var att belysa föräldrars upplevelser av att ha ett barn som drabbats av akut lymfatisk leukemi. Metod: En litteratursökning gjordes på databaserna PubMed och Cinahl samt genom manuell sökning. Totalt ingår 14 artiklar i litteraturstudien. Resultat: Resultatet redovisades i fyra olika kategorier: känslomässig berg- och dalbana, sjukdomens inverkan på det normala livet, behov av stöd och information samt föräldrars upplevda roller. Diskussion: Föräldrarna upplevde många olika känslor i samband med barnets ALL. Sjuksköterskans kunskap och den information hon ger föräldrarna är viktigt för att minska rädsla och oro. Slutsats: Denna litteraturstudie kan vara till hjälp för sjuksköterskor vid omhändertagandet av föräldrar med ett barn som drabbats av ALL.

  • 329.
    Bengtsson Ågren, Elsa
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rehabilitation needs before, during and after adjuvant chemotherapy2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 330.
    Bennati, Paolo
    et al.
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Dasu, Alexandru
    The Skandion Clinic, Uppsala, Sweden.
    Colarieti-Tosti, Massimiliano
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Lönn, Gustaf
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Larsson, David
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Fabbri, Andrea
    INFN, National Institute for Nuclear Physics, Rome, Italy.
    Galasso, Matteo
    INFN, National Institute for Nuclear Physics, Rome, Italy.
    Cinti, Maria Nerina
    Sapienza University, Rome, Italy.
    Pellegrini, Rosanna
    Sapienza University, Rome, Italy.
    Pani, Roberto
    Sapienza University, Rome, Italy.
    Preliminary study of a new gamma imager for on-line proton range monitoring during proton radiotherapy2017In: Journal of Instrumentation, ISSN 1748-0221, E-ISSN 1748-0221, Vol. 12, no 5, article id C05009Article in journal (Refereed)
    Abstract [en]

    We designed and tested new concept imaging devices, based on a thin scintillating crystal, aimed at the online monitoring of the range of protons in tissue during proton radiotherapy. The proposed crystal can guarantee better spatial resolution and lower sensitivity with respect to a thicker one, at the cost of a coarser energy resolution. Two different samples of thin crystals were coupled to a position sensitive photo multiplier tube read out by 64 independent channels electronics. The detector was equipped with a knife-edge Lead collimator that defined a reasonable field of view of about 10 cm in the target. Geant4 Monte Carlo simulations were used to optimize the design of the experimental setup and assess the accuracy of the results. Experimental measurements were carried out at the Skandion Clinic, the recently opened proton beam facility in Uppsala, Sweden. PMMA and water phantoms studies were performed with a first prototype based on a round 6.0 mm thick Cry019 crystal and with a second detector based on a thinner 5 × 5 cm2, 2.0 mm thick LFS crystal. Phantoms were irradiated with mono-energetic proton beams whose energy was in the range between 110 and 160 MeV. According with the simulations and the experimental data, the detector based on LFS crystal seems able to identify the peak of prompt-gamma radiation and its results are in fair agreement with the expected shift of the proton range as a function of energy. The count rate remains one of the most critical limitations of our system, which was able to cope with only about 20% of the clinical dose rate. Nevertheless, we are confident that our study might provide the basis for developing a new full-functional system.

  • 331.
    Bens, Annet
    et al.
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Papadopoulos, Fotios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Pukkala, Eero
    Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, Helsinki, Finland.;Univ Tampere, Fac Social Sci, Tampere, Finland..
    Ekbom, Anders
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Gissler, Mika
    THL Natl Inst Hlth & Welf, Informat Serv Dept, Helsinki, Finland.;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Mellemkjaer, Lene
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Worse survival after breast cancer in women with anorexia nervosa2018In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 2, p. 495-500Article in journal (Refereed)
    Abstract [en]

    A history of anorexia nervosa has been associated with a reduced risk of developing breast cancer. We investigated survival after breast cancer among women with a prior anorexia nervosa diagnosis compared with women in a population comparison group. This register-based study included combined data from Sweden, Denmark and Finland. A total of 76 and 1462 breast cancer cases identified among 22,654 women with anorexia nervosa and 224,619 women in a population comparison group, respectively, were included in the study. Hazard ratios (HR) for overall and breast cancer-specific mortality after breast cancer diagnosis were estimated using Cox regression. Cause of death was available only for Swedish and Danish women; therefore, the analysis on breast cancer-specific mortality was restricted to these women. We observed 23 deaths after breast cancer among anorexia nervosa patients and 247 among population comparisons. The overall mortality after the breast cancer diagnosis was increased in women with a history of anorexia nervosa compared with population comparisons (HR 2.5, 95% CI 1.6-3.9) after adjustment for age, period and extent of disease. Results were similar for overall (HR 2.3, 95% CI 1.4-3.6) and breast cancer-specific mortality (HR 2.1, 95% CI 1.3-3.6) among Swedish and Danish women. We found that female breast cancer patients with a prior diagnosis of anorexia nervosa have a worse survival compared with other breast cancer patients.

  • 332. Benyi, Emelie
    et al.
    Linder, Marie
    Adami, Johanna
    Sophiahemmet University.
    Kieler, Helle
    Palme, Mårten
    Sävendahl, Lars
    Adult height is associated with risk of cancer and mortality in 5.5 million Swedish women and men2019In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, article id jech-2018-211040Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies have indicated that taller individuals are at greater risk of developing cancer. Death from cancer and other specific causes have also been linked to height, but the results have been inconclusive. We aimed to shed further light on the associations between height, cancer incidence and mortality.

    METHODS: We conducted a nationwide, population-based prospective cohort study, including 5.5 million Swedish women and men (aged 20-74). They were followed over a period of up to 54 years. Heights were retrieved from national registers (mainly the Passport Register where heights are most often self-reported). The risks of overall and specific cancers, as well as overall and cause-specific mortality, were presented as HR with 95% CIs per 10 cm increase in height.

    RESULTS: A total of 278 299 cases of cancer and 139 393 cases of death were identified. For overall cancer, HR was 1.19 (1.18-1.20) in women and 1.11 (1.10-1.12) in men for every 10 cm increase in height. All 15 specific cancer types were positively associated with height-most strongly for malignant melanoma in both genders, with HRs of 1.39 (1.35-1.43) in women and 1.34 (1.30-1.38) in men. For overall mortality, HR was 0.98 (0.97-0.99) in women and 0.91 (0.90-0.92) in men for every 10 cm increase in height. Cancer mortality was increased in taller individuals, with HR 1.15 (1.13-1.17) in women and 1.05 (1.03-1.07) in men for every 10 cm increase in height, whereas shorter individuals had increased overall mortality due to a number of other causes, such as cardiovascular disease.

    CONCLUSION: Overall and specific cancer risks, particularly malignant melanoma, were positively associated with height. Cancer mortality also increased with height. In contrast, overall mortality was decreased with height, particularly in men due to inverse associations with height for other causes of death.

  • 333. Benyi, Emelie
    et al.
    Linder, Marie
    Adami, Johanna
    Kieler, Helle
    Palme, Mårten
    Stockholm University, Faculty of Social Sciences, Department of Economics.
    Sävendahl, Lars
    Adult height is associated with risk of cancer and mortality in 5.5 million Swedish women and men2019In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, Vol. 73, no 8, p. 730-736Article in journal (Refereed)
    Abstract [en]

    Background Previous studies have indicated that taller individuals are at greater risk of developing cancer. Death from cancer and other specific causes have also been linked to height, but the results have been inconclusive. We aimed to shed further light on the associations between height, cancer incidence and mortality.

    Methods We conducted a nationwide, population-based prospective cohort study, including 5.5 million Swedish women and men (aged 20-74). They were followed over a period of up to 54 years. Heights were retrieved from national registers (mainly the Passport Register where heights are most often self-reported). The risks of overall and specific cancers, as well as overall and cause-specific mortality, were presented as HR with 95% CIs per 10 cm increase in height.

    Results A total of 278 299 cases of cancer and 139 393 cases of death were identified. For overall cancer, HR was 1.19 (1.18-1.20) in women and 1.11 (1.10-1.12) in men for every 10 cm increase in height. All 15 specific cancer types were positively associated with height-most strongly for malignant melanoma in both genders, with HRs of 1.39 (1.35-1.43) in women and 1.34 (1.30-1.38) in men. For overall mortality, HR was 0.98 (0.97-0.99) in women and 0.91 (0.90-0.92) in men for every 10 cm increase in height. Cancer mortality was increased in taller individuals, with HR 1.15 (1.13-1.17) in women and 1.05 (1.03-1.07) in men for every 10 cm increase in height, whereas shorter individuals had increased overall mortality due to a number of other causes, such as cardiovascular disease.

    Conclusion Overall and specific cancer risks, particularly malignant melanoma, were positively associated with height. Cancer mortality also increased with height. In contrast, overall mortality was decreased with height, particularly in men due to inverse associations with height for other causes of death.

  • 334. Berenjian, Saideh
    et al.
    Hu, Kefei
    Abedi-Valugerdi, Manuchehr
    Hassan, Moustapha
    Hassan, Sadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Morein, Bror
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    The nanoparticulate Quillaja saponin KGI exerts anti-proliferative eff ects by down-regulation of cell cycle molecules in U937 and HL-60 human leukemia cells2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 7, p. 1618-1624Article in journal (Refereed)
    Abstract [en]

    Cancer cells are characterized by uncontrolled replication involving loss of control of cyclin dependent kinases (CDKs) and cyclins, and by abolished differentiation. In this study we introduce KGI, which is a nanoparticle with a Quillaja saponin as an active molecule. By the use of RNA array analysis and confirmation at the protein level, we show that KGI affects myeloid leukemia cells (in particular, the U937 monoblast cancer cell) by the following mechanisms: (A) ceasing cell replication via proteasome degradation, (B) down-regulation of key molecules at check points between G1/S and G2/M phases, (C) reduction of thymidine kinase activity, followed by (D) exit to differentiation and production of interleukin-8 (IL-8), eventually leading to apoptosis. Leukemia cell lines (U937 and HL-60 cells) were exposed to KGI for 8 h, after which the drug was removed. The cancer cells did not revert to replication over the following 10 days. Thus our findings suggest that the nanoparticle KGI inhibits proliferation and promotes differentiation in leukemic cells by interfering with the cell cycle process.

  • 335.
    Berg, L.
    et al.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Sundström, Y.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Aftab, Obaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bergqvist, F.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Sundström, M.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Ossipova, E.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Lengqvist, J.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Jakobsson, P-J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Characterizing the effects of epigenetic regulation in assays using peripheral blood mononuclear cells from patients with inflammatory diseases2016In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 45, p. 44-45Article in journal (Other academic)
  • 336. Bergandi, Loredana
    et al.
    Skorokhod, Oleksii A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Torino, Italy.
    Franzone, Federica
    La Grotta, Rosalba
    Schwarzer, Evelin
    Nuzzi, Raffaele
    Induction of oxidative stress in human aqueous and vitreous humors by Nd: YAG laser posterior capsulotomy2018In: International journal of ophthalmology, ISSN 2222-3959, Vol. 11, no 7, p. 1145-1151Article in journal (Refereed)
    Abstract [en]

    AIM: To evaluate whether the Q-switched Nd:YAG laser treatment applied in routine capsulotomy elicits oxidative stress in aqueous and vitreous humors. METHODS: Thirty-six patients who had to undergo a 25 gauge pars plana vitrectomy due to vitreoretinal disorders were enrolled, 15 of them underwent a Q-switched Nd:YAG laser capsulotomy 7d before vitrectomy due to posterior capsule opacification (PCO) (Nd:YAG laser group) while the remaining 21 patients were not laser treated before vitrectomy (no Nd:YAG laser group). Samples of the aqueous and vitreous humors were collected during vitrectomy from all patients for the assessment of oxidative parameters which were compared between the Nd:YAG laser group and no Nd:YAG laser group. Thiobarbituric acid reactive substances (TBARS), a product of membrane lipid peroxidation, nitrite levels, the antioxidative activities of SOD and catalase, the 4-HNE-protein conjugate formation, indicating structural modifications in proteins due to lipoperoxidation, were assessed in aqueous and vitreous samples. RESULTS: In the human vitreous humor TBARS levels are significantly higher in the Nd:YAG laser group compared to the no Nd:YAG laser group and importantly, there is a significant correlation between the TBARS levels and the total energy of Nd:YAG laser used during capsulotomy. Moreover the anti-oxidative activities of SOD and catalase were significantly decreased by Nd:YAG laser treatment, both in aqueous and vitreous humors. In accordance with the TBARS data and anti-oxidative enzyme activities, significantly higher levels of proteins were conjugated with the lipoperoxidation product 4-HNE in the aqueous and vitreous humors in the Nd:YAG laser-treated group in comparison to no Nd:YAG laser group. CONCLUSION: These data, clearly suggest that any change that Q-switched Nd:YAG photo disruption may cause in the aqueous and vitreous compartments, resulting in a higher level of oxidative damage might be of considerable clinical significance particularly by accelerating the aging of the anterior and posterior segments of the eye and by worsening the intraocular pressure, the uveal, the retinal (especially macular) pathologies.

  • 337.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Department of Women’s Health, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women2018In: International Journal of Gynecology & Obstetrics, ISSN 0020-7292, E-ISSN 1879-3479, Vol. 142, no 3, p. 359-364Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether self-sampling is as reliable as professional sampling for HPV testing and genotype detection among postmenopausal women.

    METHODS: In the present prospective cross-sectional study, women in Örebro County, Sweden, who had high-risk HPV (hrHPV) and normal cytology results in exit screening tests conducted in between January 1, 2012, and December 31, 2014, were invited to follow-up screenings between February 24, 2015 and May 15, 2015, that included professional sampling and self-sampling. HPV genotypes were identified by a DNA-based assay that could detect 35 HPV genotypes. Findings between the different sampling methods were compared.

    RESULTS: Of 143 women who participated, 119 returned a self-sample. Completely concordant results were observed in 67 of these samples when both hrHPV and low-risk HPV genotypes were analyzed. Overall, 99 (83.2%) women had the same clinically relevant finding from both sampling methods. Twenty women had discordant hrHPV results (hrHPV detected in 10 self-samples vs 10 professionally collected samples; Cohen κ 0.66, 95% confidence interval 0.53-0.80). There was no significant difference between the two sampling methods for clinically significant infections (P>0.99) or extended genotyping (P=0.827).

    CONCLUSION: Postmenopausal women could be offered self-sampling devices to increase screening-program coverage while maintaining test quality.

  • 338.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Dept. of Women's Health.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Dept. of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Dept. of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Dept. of Laboratory Medicine.
    HPV-based screening for cervical cancer among women 55-59 years of age2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217108Article in journal (Refereed)
    Abstract [en]

    AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied.

    METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone.

    RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+.

    CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.

  • 339. Berger, Eloise
    et al.
    Delpierre, Cyrille
    Hosnijeh, Fatemeh Saberi
    Kelly-Irving, Michelle
    Portengen, Lutzen
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ann Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Kyrtopoulos, Soterios A.
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Vermeulen, Roel
    Castagné, Raphaële
    Association between low-grade inflammation and Breast cancer and B-cell Myeloma and Non-Hodgkin Lymphoma: findings from two prospective cohorts2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10805Article in journal (Refereed)
    Abstract [en]

    Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and.-cell Non-Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (β = -1.28, p = 0.012), and, to lesser, extent with BC (β= -0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers.

  • 340. Bergerot, Cristiane Decat
    et al.
    Battle, Dena
    Bergerot, Paulo Gustavo
    Dizman, Nazli
    Jonasch, Eric
    Hammers, Hans J.
    George, Daniel J.
    Bex, Axel
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Pal, Sumanta Kumar
    Staehler, Michael D.
    Sources of Frustration Among Patients Diagnosed With Renal Cell Carcinoma2019In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 11Article in journal (Refereed)
    Abstract [en]

    Despite numerous therapeutic advances in renal cell carcinoma (RCC), little is known about patients' perspectives on cancer care. An international survey was conducted to identify points of frustration associated with cancer care reported by patients with RCC. Data were obtained from an online survey, conducted from April 1 to June 15, 2017, through social media and patient networking platforms. This survey obtained baseline demographic, clinicopathologic, and treatment-related information. Open-ended questions accessed sources of frustration in cancer-related care and patients' suggestions for amelioration. Responses were categorized and reviewed by independent reviewers. A qualitative analysis was performed and the Kruskal-Wallis test was used to define associations between baseline characteristics and sources of frustration. Among 450 patients surveyed, 71.5% reported sources of frustration, classified as either emotional (48.4%) or practical (23.1%). The most common were fear of recurrence/progression (15.8%), distrust of their cancer care system (12.9%), and lack of appropriate information (9.8%). Female gender and non-clear cell histology were associated with both types of frustration, and older age was linked to practical sources of frustration. Patients suggested solutions included greater compassion among health care practitioners (20.7%), better access to information (15.1%) and research to improve their chances of being cured (14.7%). Sources of frustration related to emotional and practical causes were identified amongst patients with RCC. Certain demographic and clinical characteristics were associated with more sources of frustration. This study provides the first characterization of specific ways to improve the patient experience by addressing common frustrations.

  • 341. Bergerot, Cristiane Decat
    et al.
    Battle, Dena
    Bergerot, Paulo Gustavo
    George, Daniel J.
    Hammers, Hans J.
    Jonasch, Eric
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bex, Axel
    Dizman, Nazli
    Staehler, Michael D.
    Pal, Sumanta K.
    Frustration and distress during treatment for advanced renal cell carcinoma2018In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 34, article id 47Article in journal (Other academic)
  • 342.
    Bergfelt, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kozlowski, Piotr
    Ahlberg, Lucia
    Hulegardh, Erik
    Hagglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Karlsson, Karin
    Markuszewska-Kuczymska, Alicja
    Tomaszewska-Toporska, Beata
    Smedmyr, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Astrom, Maria
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hallböök, Hélene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study2015In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, article id 135Article in journal (Refereed)
    Abstract [en]

    The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >= 2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

  • 343.
    Bergfelt, Emma
    et al.
    Department of Medical Sciences, Haematology, Uppsala University, Uppsala, Sweden.
    Kozlowski, Piotr
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ahlberg, Lucia
    Department of Haematology, University Hospital of Linköping, Linköping, Sweden.
    Hulegårdh, Erik
    Department of Haematology and Coagulation, Sahlgrenska University Hospital, Göteborg, Sweden.
    Hägglund, Hans
    Division of Haematology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Karlsson, Karin
    Department of Haematology, Skåne University Hospital, Lund, Sweden.
    Markuszewska-Kuczymska, Alicja
    Department of Haematology, Cancer Center, University Hospital of Umeå, Umeå , Sweden.
    Tomaszewska-Toporska, Beata
    Department of Haematology, Skåne University Hospital, Lund, Sweden.
    Smedmyr, Bengt
    Department of Medical Sciences, Haematology, Uppsala University, Uppsala, Sweden.
    Åström, Maria
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Amini, Rose-Marie
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hallböök, Helene
    Department of Medical Sciences, Haematology, Uppsala University, Uppsala, Sweden.
    Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study2015In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, article id 135Article in journal (Refereed)
    Abstract [en]

    The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >= 2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

  • 344. Berggrund, Malin
    et al.
    Enroth, Stefan
    Lundberg, Martin
    Assarsson, Erika
    Stålberg, Karin
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Olovsson, Matts
    Gyllensten, Ulf
    Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay2019In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 4, p. 735-743, article id RA118.001208Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared to controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared to population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

  • 345.
    Berggrund, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lundberg, Martin
    OLINK Prote, Uppsala Sci Pk, SE-75183 Uppsala, Sweden.
    Assarsson, Erika
    OLINK Prote, Uppsala Sci Pk, SE-75183 Uppsala, Sweden.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Lindquist, David
    Umeå Univ, Dept Radiat Sci, SE-90187 Umeå, Sweden.
    Hallmans, Göran
    Umeå Univ, Dept Publ Hlth & Clin Med, Nutr Res, SE-90187 Umeå, Sweden.
    Grankvist, Kjell
    Umeå Univ, Dept Med Biosci, Clin Chem, SE-90187 Umeå, Sweden.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay2019In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 4, p. 735-743Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared with controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared with population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

  • 346.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Characterization and functional role of the stroma compartment in prostate tumors.2009In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 5, no 8, p. 1231-1235Article in journal (Refereed)
    Abstract [en]

    Prostate tumors are composed of many cell types, yet the biological significances of the different nonepithelial cells have been largely overlooked. According to recent studies, however, the stroma, which constitutes a substantial part of the tumor volume, plays an important role during the initiation, progression, metastasis and metastatic growth of prostate cancers. To explore this further, Dakhova and co-workers compared gene expression in laser microdissected normal peripheral zone stroma with stroma in peripheral zone cancers (only those with reactive stroma grade 3). A total of 544 genes were upregulated and 606 genes downregulated in tumor stroma. The cancer stroma showed signs of formation of nerves, increased number of stem cells, and responses to DNA damage. Further studies are needed to explore the functional consequences of this, particularly the role of nerves. If these stroma changes can be used as prognostic markers, as targets for therapy, and if similar changes occur in metastases also need to be explored.

  • 347.
    Bergh Drott, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    The role of microorganisms in prostate cancer development2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostate cancer is the most common cancer among Swedish men, but the aetiology of this disease is largely unknown. There is evidence for a linkage between chronic inflammation and prostate cancer. The mechanisms causing prostate inflammation and how this could promote tumour development and progression are however largely unknown. Chronic inflammatory infiltrates are common findings in prostate tissue samples and infection is proposed to be one possible cause for this inflammation. Inflammatory cells release free radicals, cytokines, and growth factors that facilitate increased cell proliferation, DNA damage, mutations, and angiogenesis. However, the present literature on the presence of microbes in prostate tissue and their possible linkage to inflammation and cancer development is limited. Therefore, the aim of this thesis was to investigate if microorganisms are present in prostate tissue and to evaluate their role in inducing prostatitis and prostate epithelial neoplasia.

    The presence of microorganisms (virus, bacteria and fungi) was studied in clinical prostate tissue samples to evaluate whether or not the occurrences of microorganisms were different in patients that later developed cancer compared with matched controls that did not. Viruses, bacteria and fungi were found in prostate tissues. Out of eight different viruses investigated, EBV and JC virus were detected, but there were no differences in occurrence in the case group compared to the control group. The fungus Candida albicans was present in a very small proportion of the prostate tissue samples. The predominant bacterium was Propionibacterium acnes and the second most prevalent was Escherichia coli. The presence of Propionibacterium acnes was associated with inflammation and subsequent prostate cancer development. Propionibacterium acnes was further evaluated for its capacity to induce an inflammatory response both in vitro and in vivo. Live Propionibacterium acnes induced a strong immune reaction in prostate epithelial cells in vitro with up-regulation of inflammatory genes and secretion of pro-inflammatory cytokines. Infection with Propionibacterium acnes in rat prostate resulted in a lobe specific inflammation with the most intense inflammation in the dorso-lateral prostate, lasting up to 3 months post-inoculation. Propionibacterium acnes inflammation was also associated with altered epithelial cell morphology, signs of DNA damage and increased cell proliferation.

    Taken together, this thesis shows that different viruses and bacteria can be found in prostate tissue. Propionibacterium acnes, the most abundant among the bacteria detected and more prevalent in the cancer than in the control group, exhibits strong prostatitis promoting properties both in vitro and in vivo. In addition, Propionibacterium acnes can induce some of the epithelial changes known to occur during prostate neoplasia formation. This thesis therefore suggests that Propionibacterium acnes induced chronic prostatitis could promote prostate cancer development. Further studies are needed to elucidate the molecular interplay linking Propionibacterium acnes induced inflammation and the formation of a pre-neoplastic state that could evolve into prostate cancer.

  • 348.
    Bergh Drott, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Alexeyev, Oleg
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergström, Patrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells2010In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 10, p. 126-Article in journal (Refereed)
    Abstract [en]

    Background: The immune stimulating bacterium Propionibacterium acnes is a frequent colonizer of benign and malignant prostate tissue. To understand the pathogenesis of the earliest phase of this infection, we examined the P. acnes triggered immune response in cultivated prostate epithelial cells.

    Results: Prostate epithelial cells are triggered to secrete IL-6, IL-8 and GM-CSF when infected with P. acnes. The secretion of cytokines is accompanied by NFκB related upregulation of the secreted cytokines as well as several components of the TLR2-NFκB signaling pathway.

    Conclusions: P. acnes has potential to trigger a strong immune reaction in the prostate glandular epithelium. Upon infection of prostate via the retrograde urethral route, the induced inflammatory reaction might facilitate bacterial colonization deeper in the prostate tissue where persistent inflammation may impact the development of prostate diseases as hyperplasia and/or malignancy.

  • 349.
    Bergh Drott, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Propionibacterium acnes induces chronic inflammation and precancerous epithelial lesions in the dorso-lateral prostate in ratsManuscript (preprint) (Other academic)
  • 350.
    Bergh, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Marklund, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Gustavsson, C
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Alexeyev, Olog
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    No link between viral findings in the prostate and subsequent cancer development2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 1, p. 137-139Article in journal (Refereed)
    Abstract [en]

    In an investigation of 201 prostate tissue samples from patients with benign prostate hyperplasia that later progressed to prostate cancer and 201 matched controls that did not, there were no differences in the prevalence of adenovirus, herpesvirus, papilloma virus, polyoma virus and Candida albicans DNA.

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