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  • 1. Aleksandrova, Krasimira
    et al.
    Jenab, Mazda
    Boeing, Heiner
    Jansen, Eugene
    Bueno-de-Mesquita, H Bas
    Rinaldi, Sabina
    Riboli, Elio
    Overvad, Kim
    Dahm, Christina C
    Olsen, Anja
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Kaaks, Rudolf
    Rohrmann, Sabine
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    van Duijnhoven, Fränzel JB
    Leufkens, Anke M
    Peeters, Petra H
    Rodríguez, Laudina
    Bonet, Catalina
    Sánchez, María-José
    Dorronsoro, Miren
    Navarro, Carmen
    Barricarte, Aurelio
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E
    Spencer, Elizabeth
    Romaguera, Dora
    Norat, Teresa
    Pischon, Tobias
    Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition2010In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 172, no 4, p. 407-418Article in journal (Refereed)
    Abstract [en]

    The authors investigated associations between serum C-reactive protein (CRP) concentrations and colon and rectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (1992-2003) among 1,096 incident cases and 1,096 controls selected using risk-set sampling and matched on study center, age, sex, time of blood collection, fasting status, menopausal status, menstrual cycle phase, and hormone replacement therapy. In conditional logistic regression with adjustment for education, smoking, nutritional factors, body mass index, and waist circumference, CRP showed a significant nonlinear association with colon cancer risk but not rectal cancer risk. Multivariable-adjusted relative risks for CRP concentrations of > or = 3.0 mg/L versus <1.0 mg/L were 1.36 (95% confidence interval (CI): 1.00, 1.85; P-trend = 0.01) for colon cancer and 1.02 (95% CI: 0.67, 1.57; P-trend = 0.65) for rectal cancer. Colon cancer risk was significantly increased in men (relative risk = 1.74, 95% CI: 1.11, 2.73; P-trend = 0.01) but not in women (relative risk = 1.06, 95% CI: 0.67, 1.68; P-trend = 0.13). Additional adjustment for C-peptide, glycated hemoglobin, and high density lipoprotein cholesterol did not attenuate these results. These data provide evidence that elevated CRP concentrations are related to a higher risk of colon cancer but not rectal cancer, predominantly among men and independently of obesity, insulin resistance, and dyslipidemia.

  • 2. Benetou, Vassiliki
    et al.
    Orfanos, Philippos
    Benetos, Ioannis S
    Pala, Valeria
    Evangelista, Alberto
    Frasca, Graziella
    Giurdanella, Maria Concetta
    Peeters, Petra HM
    van der Schouw, Yvonne T
    Rohrmann, Sabine
    Linseisen, Jakob
    Boeing, Heiner
    Weikert, Cornelia
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bueno-de-Mesquita, H Bas
    Altzibar, Jone
    Boffetta, Paolo
    Trichopoulou, Antonia
    Anthropometry, physical activity and hip fractures in the elderly2011In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 42, no 2, p. 188-193Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Hip fractures constitute a major and growing public health problem amongst the elderly worldwide. We examined the association of anthropometry and physical activity with hip fracture incidence in a cohort of elderly Europeans, participants in the European Prospective Investigation into Cancer and nutrition (EPIC) study.

    MATERIALS AND METHODS: The study population consisted of 27982 volunteers (10553 men and 17429 women) aged 60 years and above from five European countries. Information on anthropometry, physical activity, medical history and other characteristics was collected at baseline. During a median follow-up of 8 years, 261 incident hip fractures (203 women and 58 men) were recorded. Data were analysed through Cox proportional hazard regression with adjustment for potential confounders.

    RESULTS: A higher body mass index (BMI) was associated with lower hip fracture risk (hazard ratio (HR) per increasing sex-specific-quintile: 0.85, 95% confidence interval (95% CI): 0.77-0.94). Body height was associated with increased hip fracture risk (HR per 5cm: 1.13, 95% CI: 1.01-1.25). Waist-to-hip ratio was not related to hip fracture risk. Increasing levels of leisure-time physical activity were related to lower risk (HR per increasing tertile: 0.84, 95% CI: 0.70-0.99, p for trend: 0.039).

    CONCLUSIONS: In a prospective cohort study of elderly Europeans, we found evidence that high body stature increased and high BMI decreased the incidence of hip fractures. After adjustment for BMI, waist-to-hip ratio was not associated with hip fracture risk. Leisure-time physical activity appears to play a beneficial role in the prevention of hip fractures.

  • 3.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jacobsson, Maria
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status2010In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 6, p. 1845-1855Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.

    EXPERIMENTAL DESIGN: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry.

    RESULTS: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMP-negative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected.

    CONCLUSIONS: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research.

  • 4.
    Ebrahimi, Majid
    Umeå University, Faculty of Medicine, Department of Odontology.
    Studies of p63 and p63 related proteins in patients diagnosed with oral lichen planus2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa and also one of the more common mucosal conditions mostly affecting middle aged individuals. Even though OLP is well investigated the etiology of this disease is still unknown, even if autoimmunity as a possible etiologic factor has been suggested. WHO classifies OLP as a pre malignant condition but malignant transformation of OLP is a matter of great controversy. The p53 protein is a tumour suppressor with the potential to induce apoptosis or cell cycle arrest of DNA damaged cells. Another member of the p53 family, p63, comprises six different isoforms, and plays a crucial role in the formation of oral mucosa, salivary glands, teeth and skin. p63 has also been suggested to be involved in development of squamous cell carcinoma of the head and neck (SCCHN). β-catenin, E-cadherin and epidermal growth factor receptor (EGFR) are p63 related proteins and abnormalities in their expression are suggested to be involved in development of SCCHN.

    Methods. Using immunohistochemistry and antibodies directed against p53 and those distinguishing between the p63 isoforms we analysed biopsies of OLP, SCCHN and normal oral tissue. We also mapped levels of p63 and p53 isoforms using RT-PCR technique. Furthermore expression of the p63 related proteins β-catenin, E-cadherin and EGFR was studied using immunoblot analysis. In an attempt to investigate autoimmunity as a causative factor of OLP we analysed sera from patients diagnosed with OLP and matched control individuals in order to see if there were autoantibodies directed against the p53 family.

    Results. When mapping p53 and p63 protein status decreased expression of p63 and increased expression of p53 was seen in OLP compared to normal tissue. In accordance with these results, levels of p63 RNA were also lower in OLP lesions compared with normal tissue. Concerning p53 isoforms, the “original” p53 isoform was expressed in all OLP lesions and normal control tissue. Of the other isoforms, p53β and Δ133p53 were expressed in the majority of samples. Our results regarding p63 related proteins showed a generally lower expression of these proteins in OLP lesions compared to normal control tissue. When studying sera from patients with OLP we found circulating autoantibodies against all six p63 and four p73 isoforms in two patients.

    Conclusions. The potential for malignant transformation of OLP is still a subject of discussion and rather controversial. While some of our results regarding status of p53 and p63 both at protein and RNA levels support this theory, other results concerning for example p63 related proteins point in the opposite direction. Based on our studies it is thus not possible to either support nor contradict the statement that OLP is a clear-cut premalignant condition. In our effort to understand the etiology of OLP we were the first to demonstrate autoantibodies against p63 and p73 in what could be a subgroup of OLP patients. OLP could thus be suggested to be not one distinct disease, but based on our data a disease comprising different subgroups.

  • 5. Enlund, Fredrik
    et al.
    Helenius, Gisela
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edsjö, Anders
    Sundström, Magnus
    [Mutational analysis of KRAS prior to targeted therapy in colorectal cancer. Quality control of molecular pathological methods in Sweden].2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 5, p. 255-259Article in journal (Refereed)
  • 6. Eussen, Simone JPM
    et al.
    Vollset, Stein Emil
    Hustad, Steinar
    Midttun, Øivind
    Meyer, Klaus
    Fredriksen, Ase
    Ueland, Per Magne
    Jenab, Mazda
    Slimani, Nadia
    Boffetta, Paolo
    Overvad, Kim
    Thorlacius-Ussing, Ole
    Tjønneland, Anne
    Olsen, Anja
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Weikert, Cornelia
    Pischon, Tobias
    Linseisen, Jakob
    Kaaks, Rudolf
    Trichopoulou, Antonia
    Zilis, Demosthenes
    Katsoulis, Michael
    Palli, Domenico
    Pala, Valeria
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Peeters, Petra HM
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel JB
    Skeie, Guri
    Muñoz, Xavier
    Martínez, Carmen
    Dorronsoro, Miren
    Ardanaz, Eva
    Navarro, Carmen
    Rodríguez, Laudina
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Manjer, Jonas
    Ericson, Ulrika
    Bingham, Sheila
    Khaw, Kay-Tee
    Norat, Teresa
    Riboli, Elio
    Plasma vitamins B2, B6, and B12, and related genetic variants as predictors of colorectal cancer risk2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 10, p. 2549-2561Article in journal (Refereed)
    Abstract [en]

    This European population-based study is the first to indicate that vitamin B2 is inversely associated with colorectal cancer, and is in agreement with previously suggested inverse associations of vitamin B6 with colorectal cancer.

  • 7. Eussen, Simone JPM
    et al.
    Vollset, Stein Emil
    Igland, Jannicke
    Meyer, Klaus
    Fredriksen, Ase
    Ueland, Per Magne
    Jenab, Mazda
    Slimani, Nadia
    Boffetta, Paolo
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Weikert, Cornelia
    Pischon, Tobias
    Linseisen, Jakob
    Kaaks, Rudolf
    Trichopoulou, Antonia
    Zilis, Demosthenes
    Katsoulis, Michael
    Palli, Domenico
    Berrino, Franco
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Peeters, Petra HM
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel JB
    Gram, Inger Torhild
    Skeie, Guri
    Lund, Eiliv
    González, Carlos A
    Martínez, Carmen
    Dorronsoro, Miren
    Ardanaz, Eva
    Navarro, Carmen
    Rodríguez, Laudina
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Manjer, Jonas
    Ericson, Ulrika
    Bingham, Sheila
    Khaw, Kay-Tee
    Norat, Teresa
    Riboli, Elio
    Plasma folate, related genetic variants, and colorectal cancer risk in EPIC2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 5, p. 1328-1340Article in journal (Refereed)
    Abstract [en]

    Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions.

  • 8. Fitchev, Philip P
    et al.
    Wcislak, Susan M
    Lee, Chung
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brendler, Charles B
    Stellmach, Veronica M
    Crawford, Susan E
    Mavroudis, Constantine D
    Cornwell, Mona L
    Doll, Jennifer A
    Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-beta activation2010In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 90, no 7, p. 1078-1090Article in journal (Refereed)
    Abstract [en]

    Castration experiments in rodents show that the stromal vasculature is critical to the androgen-mediated prostate growth regulation. However, the role of angiogenesis inhibitors, such as thrombospondin-1 (TSP-1), in this process is unclear. TSP-1 is a multifunctional glycoprotein that can function as a potent angiogenesis inhibitor and an in vivo activator of latent transforming growth factor-beta (TGF-beta) in some tissues. On the basis of these observations, we hypothesized that TSP-1 regulated androgen withdrawal-induced prostate regression and that this process was mediated not only through antiangiogenic activity but also through TGF-beta activation. To test this, we evaluated angiogenic activity in human prostate epithelial and stromal cells treated with androgens and hypoxia in vitro. TSP-1 knockout mice were characterized to investigate the in vivo functions of TSP-1. In vitro, we found that androgens and hypoxia differentially regulated TSP-1 and angiogenic activity. Androgens stimulated normal epithelial cell, but inhibited normal stromal cell, angiogenic activity. Conversely, hypoxia stimulated stromal while inhibiting epithelial activity. Thus, in vivo, net angiogenic activity must reflect cellular interactions. And, we found that media conditioned by epithelial cells grown under normoxic conditions stimulated stromal cell angiogenic activity, and if epithelial cells were grown under hypoxic conditions, stromal activity was further increased. TSP-1 levels, however, were unchanged. In vivo, TSP-1 loss in a mouse model led to prostate epithelial hyperplasia by 3 months of age with only a modest stromal effect. Androgens suppressed TSP-1 as expression increased after castration both in normal mouse prostate and in human prostate cancer tissues. In addition, TSP-1 expression corresponded to increased TGF-beta activation in mouse tissues, specifically in the stromal compartment. These data show a critical role for TSP-1 in prostate epithelial and stromal growth regulation through angiogenic inhibition and activation of latent TGF-beta. Therefore, loss of TSP-1 during tumorigenesis would eliminate two barriers to cancer progression.

  • 9.
    Guo, Yongzhi
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Plasmin: a potent pro-inflammatory factor2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plasmin, the central molecule of the plasminogen activator system, is a broad-spectrum serine protease. Plasmin is important for the degradation of fibrin and other components of the extracellular matrix (ECM) during a number of physiological and pathological processes. The aim of this thesis was to elucidate the functional roles of plasmin during pathological inflammation and infection in autoimmune and non-autoimmune diseases. For this purpose, mouse models of rheumatoid arthritis (RA), bacterial arthritis, infection, and sepsis have been used.

    Previous studies from our laboratory have shown that plasminogen-deficient mice are resistant to the development of collagen type II-induced arthritis (CIA). In contrast, others have shown that plasmin plays a protective role in antigen-induced arthritis (AIA). To investigate the contrasting roles of plasminogen deficiency in models of CIA and AIA, a new animal model of arthritis called local injection-induced arthritis (LIA) was developed. In this model, we replaced methylated bovine serum albumin, which is normally used as an immunogen in the AIA model, with collagen type II (CII) to induce arthritis. When wild-type and plasminogen-deficient mice were injected intra-articularly with CII or 0.9% NaCl following CIA induction, plasminogen-deficient mice developed typical CIA, but the disease was less severe than in wild-type mice and was restricted to the injected joints. When the AIA model was used, plasminogen-deficient mice developed a much more severe arthritis than the wild-type mice. These results indicate that both the antigen and joint trauma caused by the local injection are critical to explaining the contrasting roles of plasminogen deficiency in CIA and AIA. This indicates that CIA and AIA have distinct pathogenic mechanisms and plasmin plays contrasting roles in different types of arthritis models.

    To study the functional roles of plasmin in the host inflammatory response during infectious arthritis, a Staphylococcus aureus-induced bacterial arthritis model was established. When wild-type mice were injected intra-articularly with 1 × 106 colony-forming units (CFU) of S. aureus per joint, all the bacteria were completely eliminated from the injected joints in 28 days. However, in the plasminogen-deficient mice, the S. aureus counts were 27-fold higher at day 28 than at day 0. When human plasminogen was given to the plasminogen-deficient mice daily for 7 days, the bacterial clearance was greatly improved and the necrotic tissue in the joint cavity was also completely eliminated. Supplementation of plasminogen-deficient mice with plasminogen also restored the expression level of interleukin-6 (IL-6) in the arthritic joints. In summary, plasmin has protective roles during S. aureus-induced arthritis by enhancing cytokine expression, removing necrotic tissue, and mediating bacterial killing and inflammatory cell activation.

    The functional roles of plasmin during infection and sepsis were also studied in mice. Infection was induced by injecting 1 × 107 CFU of S. aureus intravenously and the sepsis model was induced by injecting 1.6 × 108 CFU of S. aureus. In the infection model, the wild-type mice had a 25-day survival rate of 86.7%, as compared to 50% in the plasminogen-deficient group. However, when sepsis was induced, the average survival for plasminogen-deficient mice was 3 days longer than for wild-type mice. Twenty-four hours after the induction of sepsis, the serum levels of IL-6 and IL-10 as well as the bacterial counts in all organs investigated were significantly higher in wild-type mice than in plasminogen-deficient mice. In wild-type mice, blockade of IL-6 by intravenous injection of anti-IL-6 antibodies significantly prolonged the onset of mortality and improved the survival rate during sepsis. These data indicate that plasmin plays different roles during infection and sepsis. Furthermore, plasmin appears to be involved in the regulation of inflammatory cytokine expression during sepsis.

    Taken together, our data indicate that plasmin plays multifunctional pro-inflammatory roles in different autoimmune and non-autoimmune diseases. The pro-inflammatory roles of plasmin include activation of inflammatory cells, regulation of cytokine expression, and enhancement of the bacterial killing ability of the host.

  • 10.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Androgen controlled regulatory systems in prostate cancer: potential new therapeutic targets and prognostic markers2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    BACKGROUND: Prostate cancer is by far the most common cancer among Swedish men. Some patients have an aggressive lethal disease, but the majority of affected men have long expected survival. Unfortunately, the diagnostic tools available are insufficient in predicting disease aggressiveness. Novel prognostic markers are therefore urgently needed. Furthermore, metastatic prostate cancer is generally treated with castration, but the long-term effects are insufficient. Additional studies are therefore needed to explore how the effects of this therapy can be enhanced. Prostate growth and regression is beside testosterone controlled by locally produced regulators. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are two of the major regulators in the normal prostate and in prostate tumours.

    MATERIALS AND METHODS: VEGF and EGFR were explored in the prostate, by treating rats with either anti-VEGF or anti-EGFR treatment during castration and testosterone-stimulated prostate growth. Rats with implanted androgen-independent prostate tumours were treated with an inhibitor of both VEGF receptor-2 (VEGFR-2) and EGFR. Stereological techniques, immunohistochemistry, western blotting and quantitative real-time PCR were used to evaluate these experiments. Furthermore, prostate tissue from untreated prostate cancer patients was used to retrospectively explore the expression of phosphorylated-EGFR (pEGFR) in relation to outcome.

    RESULTS: Anti-VEGF treatment during testosterone-stimulated prostate growth, inhibited vascular and prostate growth. Anti-EGFR treatment during castration and testosterone-stimulated prostate growth resulted in enhanced castration effects and inhibited prostate growth. Anti-vascular treatment of androgen-independent prostate cancer with an inhibitor of VEGFR-2 and EGFR, that targets the normal and tumour vasculature, enhanced the effects of castration. Low immunoreactivity for pEGFR in prostate epithelial cells, both in the tumour and also in the surrounding non-malignant tissue, was associated with good prognosis.

    CONCLUSIONS: Anti-vascular treatment, with an inhibitor of VEGFR-2 and EGFR, in combination with castration could be an effective way to treat androgen-insensitive prostate tumours. VEGF and EGFR signalling are necessary components in testosterone-stimulated prostate growth. Phosphorylation of EGFR could be a useful prognostic marker for prostate cancer patients. Tumours may affect the surrounding non-malignant tissue and pEGFR immunoreactivity in the morphologically normal prostate tissue can be used to retrieve prognostic information.

  • 11.
    Hägglöf, Christina
    et al.
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Paulsson, Janna
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Östman, Arne
    Stromal PDGFRbeta expression in prostate tumors and non-malignant prostate tissue predicts prostate cancer survival2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 5, p. e10747-Article in journal (Refereed)
    Abstract [en]

    The study revealed a number of novel associations between stromal PDGFRbeta expression in prostate tumors and several important clinical characteristics, including survival.

  • 12. Jenab, Mazda
    et al.
    Bueno-de-Mesquita, H Bas
    Ferrari, Pietro
    van Duijnhoven, Franzel J B
    Norat, Teresa
    Pischon, Tobias
    Jansen, Eugène H J M
    Slimani, Nadia
    Byrnes, Graham
    Rinaldi, Sabina
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Kaaks, Rudolf
    Linseisen, Jakob
    Boeing, Heiner
    Bergmann, Manuela M
    Trichopoulou, Antonia
    Misirli, Gesthimani
    Trichopoulos, Dimitrios
    Berrino, Franco
    Vineis, Paolo
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Ros, Martine M
    van Gils, Carla H
    Peeters, Petra H
    Brustad, Magritt
    Lund, Eiliv
    Tormo, María-José
    Ardanaz, Eva
    Rodríguez, Laudina
    Sánchez, Maria-José
    Dorronsoro, Miren
    Gonzalez, Carlos A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roddam, Andrew
    Key, Timothy J
    Khaw, Kay-Tee
    Autier, Philippe
    Hainaut, Pierre
    Riboli, Elio
    Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study2010In: BMJ. British Medical Journal (International Ed.), ISSN 0959-8146, E-ISSN 0959-535X, Vol. 340, p. b5500-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations. DESIGN: Nested case-control study. Setting The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries. PARTICIPANTS: 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls MAIN OUTCOME MEASURES: Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders. RESULTS: 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); >or=100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation. CONCLUSIONS: The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.

  • 13.
    Johansson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pietras, Kristian
    Jones, Jonathan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Granfors, Torvald
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy2010In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 177, no 2, p. 1031-1041Article in journal (Refereed)
    Abstract [en]

    Mast cells affect growth in various human tumors, but their role in prostate cancer (PC) is unclear. Here, we identify mast cells as independent prognostic markers in PC using a large cohort of untreated PC patients with a long follow-up. By analyzing mast cells in different tissue compartments, our data indicate that intratumoral and peritumoral mast cells have anti- opposed to protumor properties. Intratumoral mast cells negatively regulate angiogenesis and tumor growth, whereas peritumoral mast cells stimulate the expansion of human prostate tumors. We also observed mast cell recruitment particularly to the peritumoral compartment in men during the formation of castrate-resistant prostate tumors. In our ortothopic rat model, mast cells accumulated in the peritumoral tissue where they enhanced angiogenesis and tumor growth. In line with this, prostate mast cells expressed high levels of the angiogenic factor FGF-2. Similar to the situation in men, mast cells infiltrated rat prostate tumors that relapsed after initially effective castration treatment, concurrent with a second wave of angiogenesis and an up-regulation of FGF-2. We conclude that mast cells are novel independent prognostic markers in PC and affect tumor progression in animals and patients. In addition, peritumoral mast cells provide FGF-2 to the tumor micro environment, which may contribute to their stimulating effect on angiogenesis.

  • 14. Källberg, Eva
    et al.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ivars, Fredrik
    Leanderson, Tomas
    Indoleamine 2,3-dioxygenase (IDO) activity influence tumor growth in the TRAMP prostate cancer model2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 13, p. 1461-1470Article in journal (Refereed)
    Abstract [en]

    Our results argue for a role for IDO mediated immune suppression in the early stages of prostate cancer progression. However, since the intra-tumor IDO expression in J(-/-) mice was indistinguishable from that of C57BL/6 animals the IDO expression in the tumor tissue appears to be irrelevant for TRAMP tumor incidence.

  • 15. Leufkens, Anke M
    et al.
    Van Duijnhoven, Fränzel J B
    Siersema, Peter D
    Boshuizen, Hendriek C
    Vrieling, Alina
    Agudo, Antonio
    Gram, Inger T
    Weiderpass, Elisabete
    Dahm, Christina
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Sacerdote, Charlotta
    Mattiello, Amalia
    Herman, Silke
    Kaaks, Rudolf
    Steffen, Annika
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H
    van Gils, Carla H
    van Kranen, Henk
    Lund, Eliv
    Dumeaux, Vanessa
    Engeset, Dagrun
    Rodríguez, Laudina
    Sánchez, Maria-José
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Manjer, Jonas
    Almquist, Martin
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nick
    Tsilidis, Konstantinos K
    Straif, Kurt
    Leon-Roux, Maria
    Vineis, Paul
    Norat, Teresa
    Riboli, Elio
    Bueno-de-Mesquita, H Bas
    Cigarette smoking and colorectal cancer risk in the European prospective investigation into cancer and nutrition study2011In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 9, no 2, p. 137-144Article in journal (Refereed)
    Abstract [en]

    Ever smokers have an increased risk of colon cancer, which appeared to be more pronounced in the proximal than the distal colon location.

  • 16.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Increased epidermal growth factor receptor expression at the invasive margin is a negative prognostic factor in colorectal cancer2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 9, p. 2031-2037Article in journal (Refereed)
    Abstract [en]

    The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is often expressed in solid malignant tumours, and the expression has been correlated to disease progression. Multiple new agents targeted against the EGFR have been developed during the last decade, but treatment selecting criteria are still not clear. This immunohistochemical study includes 386 colorectal cancer patients and focuses on EGFR expression variations within the tumour, comparing central parts to the invasive margin. Positive immunostaining for EGFR was evident in the central part in 176/386 (46%) of analyzed primary tumours. The invasive margin was positive in 222/386 (58%). A similar expression in both the central part and the invasive front was evident in 286/386 (74%). An increased score at the invasive margin compared to central parts (EGFR(i)) was evident in 97/386 (25%) of the tumours. Moreover, the results show a significant survival disadvantage for the EGFR(i) group, both in potentially curatively resected colon cancer patients (n = 170, p = 0.01) and in potentially curatively resected colon and rectal cancer patients combined (n = 273, p = 0.013). Multivariate survival analysis adjusted for age, gender, bowel localisation, grade, stage and tumour type showed an increased risk of cancer death for EGFR(i) tumours (HR, 1.53; 95% CI, 1.04-2.23; p = 0.029). A significant correlation between EGFR expression at the invasive margin and the presence of budding was seen (p = 0.0001). This investigation of a large patient material implies that EGFR immunohistochemical analysis still has a role in risk evaluation of colorectal cancer patients.

  • 17.
    Löfgren, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Meyerson, Bengt
    Department of Neuroscience, Division of Pharmacology, Box 593, BMC, SE-751 24 Uppsala, Sweden..
    Bäcktröm, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chronic subordination stress augments combined progesterone and estradiol withdrawal behaviorManuscript (Other academic)
    Abstract [en]

    Exposure to stress is a risk factor for developing pre-menstrual syndrome (PMS) and pre-menstrual dysphoric disorder (PMDD), and stress enhances the anxiogenic effect of female sex steroids in animals. This study examines the interaction between chronic subordination stress and withdrawal from progesterone (P4) and estradiol (E2) (PEWD) in producing behaviors analogous to anxiety and irritability in rats. At the start of the experiment, male Wistar rats were housed in triads consisting of one younger rat (~35 days) and two older rats (~50 days). The housing condition was aimed at producing chronic subordination stress in the younger animals. Chronic subordination stress was assessed by the elevated plus maze (EPM) and by corticosterone (CORT) analysis. A triad of three 35-day-old rats was used as age control. Social rank within the triads was determined using a food competition test (FCT) and the tube test (TT). The younger rats (subordinate) and the dominant rats were assigned to 10 days of treatment with 5 mg/kg progesterone combined with 10 µg/kg 17β estradiol. Twenty-four hours after the last injection, the subordinate and dominant animals were tested in the open-field test (OFT) and in the intruder test (IT). The IT consists of a 10-minute exposure to 3 unfamiliar rats. Chronic subordination stress reduced EPM open-arm time and altered the CORT response. It also made the subordinate animals more vulnerable to PEWD. The effects were increased locomotion in the OFT, increased defensive burying, and increased social anxiety in the intruder test (IT). Dominant animals did not react to PEWD. Thus, chronic subordination stress augments PEWD.

  • 18. Perez-Cornago, Aurora
    et al.
    Appleby, Paul N.
    Pischon, Tobias
    Tsilidis, Konstantinos K.
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Steffen, Annika
    Trichopoulou, Antonia
    Lagiou, Pagona
    Kritikou, Maria
    Krogh, Vittorio
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Bueno-de-Mesquita, H. Bas
    Agudo, Antonio
    Larranaga, Nerea
    Molina-Portillo, Elena
    Barricarte, Aurelio
    Chirlaque, Maria-Dolores
    Ramon Quiros, J.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University.
    Wareham, Nick
    Khaw, Kay-Tee
    Schmidt, Julie A.
    Gunter, Marc
    Freisling, Heinz
    Aune, Dagfinn
    Ward, Heather
    Riboli, Elio
    Key, Timothy J.
    Travis, Ruth C.
    Tall height and obesity are associated with an increased risk of aggressive prostate cancer: results from the EPIC cohort study2017In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 15, article id 115Article in journal (Refereed)
    Abstract [en]

    Background: The relationship between body size and prostate cancer risk, and in particular risk by tumour characteristics, is not clear because most studies have not differentiated between high-grade or advanced stage tumours, but rather have assessed risk with a combined category of aggressive disease. We investigated the association of height and adiposity with incidence of and death from prostate cancer in 141,896 men in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Multivariable-adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average of 13.9 years of follow-up, there were 7024 incident prostate cancers and 934 prostate cancer deaths. Results: Height was not associated with total prostate cancer risk. Subgroup analyses showed heterogeneity in the association with height by tumour grade (P-heterogeneity = 0.002), with a positive association with risk for high-grade but not low-intermediate-grade disease (HR for high-grade disease tallest versus shortest fifth of height, 1.54; 95% CI, 1.18-2.03). Greater height was also associated with a higher risk for prostate cancer death (HR = 1.43, 1.14-1.80). Body mass index (BMI) was significantly inversely associated with total prostate cancer, but there was evidence of heterogeneity by tumour grade (P-heterogeneity = 0.01; HR = 0.89, 0.79-0.99 for low-intermediate grade and HR = 1.32, 1.01-1.72 for high-grade prostate cancer) and stage (P-heterogeneity = 0.01; HR = 0.86, 0.75-0.99 for localised stage and HR = 1.11, 0.92-1.33 for advanced stage). BMI was positively associated with prostate cancer death (HR = 1.35, 1.09-1.68). The results for waist circumference were generally similar to those for BMI, but the associations were slightly stronger for high-grade (HR = 1.43, 1.07-1.92) and fatal prostate cancer (HR = 1.55, 1.23-1.96). Conclusions: The findings from this large prospective study show that men who are taller and who have greater adiposity have an elevated risk of high-grade prostate cancer and prostate cancer death.

  • 19.
    Thors, Lina
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Granfors, Torvald
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fatty acid amide hydrolase in prostate cancer: association with disease severity and outcome, CB1 receptor expression and regulation by IL-42010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 8, p. e12275-Article in journal (Refereed)
    Abstract [en]

    Background

    Recent data have indicated that there may be a dysregulation of endocannabinoid metabolism in cancer. Here we have investigated the expression of the endocannabinoid metabolising enzyme fatty acid amide hydrolase (FAAH) in a well characterised tissue microarray from patients diagnosed with prostate cancer at transurethral resection for voiding problems.

    Methodology/Principal Findings

    FAAH immunoreactivity (FAAH-IR) was assessed in formalin-fixed paraffin-embedded non-malignant and tumour cores from 412 patients with prostate cancer. CB1 receptor immunoreactivity (CB1IR) scores were available for this dataset. FAAH-IR was seen in epithelial cells and blood vessel walls but not in the stroma. Tumour epithelial FAAH-IR was positively correlated with the disease severity at diagnosis (Gleason score, tumour stage, % of the specimen that contained tumour) for cases with mid-range CB1IR scores, but not for those with high CB1IR scores. For the 281 cases who only received palliative therapy at the end stages of the disease, a high tumour epithelial FAAH-IR was associated with a poor disease-specific survival. Multivariate Cox proportional-hazards regression analyses indicated that FAAH-IR gave additional prognostic information to that provided by CB1IR when a midrange, but not a high CB1IR cutoff value was used. Interleukin-4 (IL-4) receptor IR was found on tumour epithelial cells and incubation of prostate cancer PC-3 and R3327 AT1 cells with IL-4 increased their FAAH activity.

    Conclusions/Significance

    Tumour epithelial FAAH-IR is associated with prostate cancer severity and outcome at mid-range, but not high, CB1IR scores. The correlation with CB1IR in the tumour tissue may be related to a common local dysregulation by a component of the tumour microenvironment.

  • 20. Welsh, Michelle
    et al.
    Sharpe, Richard M
    Moffat, Lindsey
    Atanassova, Nina
    Saunders, Philippa TK
    Kilter, Sigrid
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Smith, Lee B
    Androgen action via testicular arteriole smooth muscle cells is important for Leydig cell function, vasomotion and testicular fluid dynamics2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 10, p. e13632-Article in journal (Refereed)
    Abstract [en]

    Regulation of blood flow through the testicular microvasculature by vasomotion is thought to be important for normal testis function as it regulates interstitial fluid (IF) dynamics which is an important intra-testicular transport medium. Androgens control vasomotion, but how they exert these effects remains unclear. One possibility is by signalling via androgen receptors (AR) expressed in testicular arteriole smooth muscle cells. To investigate this and determine the overall importance of this mechanism in testis function, we generated a blood vessel smooth muscle cell-specific AR knockout mouse (SMARKO). Gross reproductive development was normal in SMARKO mice but testis weight was reduced in adulthood compared to control littermates; this reduction was not due to any changes in germ cell volume or to deficits in testosterone, LH or FSH concentrations and did not cause infertility. However, seminiferous tubule lumen volume was reduced in adult SMARKO males while interstitial volume was increased, perhaps indicating altered fluid dynamics; this was associated with compensated Leydig cell failure. Vasomotion was impaired in adult SMARKO males, though overall testis blood flow was normal and there was an increase in the overall blood vessel volume per testis in adult SMARKOs. In conclusion, these results indicate that ablating arteriole smooth muscle AR does not grossly alter spermatogenesis or affect male fertility but does subtly impair Leydig cell function and testicular fluid exchange, possibly by locally regulating microvascular blood flow within the testis.

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