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  • 1.
    Andrén, Ove
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Widmark, A.
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Fält, A.
    Ulvskog, E.
    Örebro University, School of Medical Sciences. Department of Oncology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Karlsson, C. Thellenberg
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Hjälm-Eriksson, M.
    Department of Oncology, Karolinska Institute, Stockholm, Sweden.
    Cabazitaxel followed by androgen deprivation therapy (ADT) significantly improves time to progression in patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC): A randomized, open label, phase III, multicenter trial2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no Suppl. 5, article id 811PArticle in journal (Other academic)
  • 2.
    Carlsson, Jessica
    et al.
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Prostate cancer and inflammation: The role of miRNAs2013In: European Medical Journal Oncology, ISSN 2054-619X, p. 56-60Article, review/survey (Refereed)
    Abstract [en]

    Approximately 15-20% of all human cancers are assumed to be a result of infection and chronic inflammation due to a constant supply of cytokines and reactive oxygen species, giving rise to genomic instability and a subsequent tumour development. In recent years, chronic inflammation has also been hypothesised to influence prostate carcinogenesis, since both acute and chronic inflammation is commonly seen in prostatic tissues. The signalling pathways involved in the immune response and tumour development are overlapping with each other, and it has been proposed that miRNAs are a possible link between the two processes. In this review, we are describing some of the miRNAs which could constitute a conceivable link between inflammation and prostate cancer.

  • 3.
    Carlsson, Jessica
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, University Hospital, Örebro, Sweden.
    Fridfeldt, Jonna
    Department of Urology, Faculty of Medicine and Health, University Hospital Örebro, Örebro, Sweden; Örebro University, Örebro, Sweden.
    Giunchi, Francesca
    Department of Pathology, F. Addari Institute of Oncology S. Orsola Hospital, Bologna, Italy.
    Fiano, Valentina
    Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy.
    Grasso, Chiara
    Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy.
    Zelic, Renata
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Richiardi, Lorenzo
    Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, University Hospital Örebro, Örebro, Sweden.
    Pettersson, Andreas
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Fiorentino, Michelangelo
    Department of Pathology, F. Addari Institute of Oncology S. Orsola Hospital, Bologna, Italy.
    Akre, Olof
    Department of Medicine Solna, Karolinska Institute, and Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
    Quantity and quality of nucleic acids extracted from archival formalin fixed paraffin embedded prostate biopsies2018In: BMC Medical Research Methodology, ISSN 1471-2288, E-ISSN 1471-2288, Vol. 18, no 1, article id 161Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In Sweden, human tissue samples obtained from diagnostic and surgical procedures have for decades been routinely stored in a formalin-fixed, paraffin-embedded, form. Through linkage with nationwide registers, these samples are available for molecular studies to identify biomarkers predicting mortality even in slow-progressing prostate cancer. However, tissue fixation causes modifications of nucleic acids, making it challenging to extract high-quality nucleic acids from formalin fixated tissues.

    METHODS: In this study, the efficiency of five commercial nucleic acid extraction kits was compared on 30 prostate biopsies with normal histology, and the quantity and quality of the products were compared using spectrophotometry and Agilent's BioAnalyzer. Student's t-test's and Bland-Altman analyses were performed in order to investigate differences in nucleic acid quantity and quality between the five kits. The best performing extraction kits were subsequently tested on an additional 84 prostate tumor tissues. A Spearman's correlation test and linear regression analyses were performed in order to investigate the impact of tissue age and amount of tissue on nucleic acid quantity and quality.

    RESULTS: Nucleic acids extracted with RNeasy® FFPE and QIAamp® DNA FFPE Tissue kit had the highest quantity and quality, and was used for extraction from 84 tumor tissues. Nucleic acids were successfully extracted from all biopsies, and the amount of tumor (in millimeter) was found to have the strongest association with quantity and quality of nucleic acids.

    CONCLUSIONS: To conclude, this study shows that the choice of nucleic acid extraction kit affects the quantity and quality of extracted products. Furthermore, we show that extraction of nucleic acids from archival formalin-fixed prostate biopsies is possible, allowing molecular studies to be performed on this valuable sample collection.

  • 4.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences.
    Davidsson, Sabina
    Örebro University, School of Health and Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Lubovac, Zelmina
    University of Skövde, Skövde, Sweden.
    Andrén, Ove
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Olsson, Björn
    University of Skövde, Skövde, Sweden.
    Klinga-Levan, Karin
    University of Skövde, Skövde, Sweden.
    A miRNA expression signature that separates between normal and malignant prostate tissues2011In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, no 11, p. 14-Article in journal (Refereed)
    Abstract [en]

    Background

    MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that post-transcriptionally regulate genes involved in several key biological processes and thus are involved in various diseases, including cancer. In this study we aimed to identify a miRNA expression signature that could be used to separate between normal and malignant prostate tissues.

    Results

    Nine miRNAs were found to be differentially expressed (p <0.00001). With the exception of two samples, this expression signature could be used to separate between the normal and malignant tissues. A cross-validation procedure confirmed the generality of this expression signature. We also identified 16 miRNAs that possibly could be used as a complement to current methods for grading of prostate tumor tissues.

    Conclusions

    We found an expression signature based on nine differentially expressed miRNAs that with high accuracy (85%) could classify the normal and malignant prostate tissues in patients from the Swedish Watchful Waiting cohort. The results show that there are significant differences in miRNA expression between normal and malignant prostate tissue, indicating that these small RNA molecules might be important in the biogenesis of prostate cancer and potentially useful for clinical diagnosis of the disease.

  • 5.
    Davidsson, Sabina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Infection induced chronic inflammation and it's association with prostate cancer initiation and progression2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    An association between cancer development and inflammation has long been suggested. Approximately 20% of all human cancers in adults are assumed to result from chronic inflammation. The aim of this thesis was to investigate if infection-induced chronic inflammation plays a role in prostate carcinogenesis.

    Our results revealed a greater infiltration of the bacterium Propionibacterium acnes in the prostate tissue obtained from men with prostate cancer compared to men without any histological evidence of the disease. These findings indicate that prostate cancer could potentially be included in the list of cancers with an infectious etiology.

    Further, we investigated whether chronic inflammation has a role in disease progression. Our results demonstrated that men with lethal prostate cancer had pronounced infiltration of immune cells with suppressive function of the anti-tumor immune response compared to men with a more indolent prostate cancer.

    Confirmation of our results may open up avenues for targeted prostate cancer treatment by offering men with chronic inflammation alternative therapies such as anti-inflammatory drugs. If the involvement of P. acnes in prostate cancer development is replicated in other studies, vaccination therapies may be feasible. To further individualize prostate cancer therapy, bolstering the anti-tumor immune response in order to reduce tumor progression may be determined to be advantageous for some patients.

    List of papers
    1. Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer
    Open this publication in new window or tab >>Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer
    Show others...
    2011 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 10, p. 2280-2287Article in journal (Refereed) Published
    Abstract [en]

    Background: A challenge in prostate cancer (PCa) management is identifying potentially lethal disease at diagnosis. Inflammation, focal prostatic atrophy, and prostatic intraepithelial neoplasia (PIN) are common in prostate tumor specimens, but it is not clear whether these lesions have prognostic significance. Methods: We conducted a case-control study nested in a cohort of men diagnosed with stage T1a-b PCa through transurethral resection of the prostate in Sweden. Cases are men who died of PCa (n = 228). Controls are men who survived more than 10 years after PCa diagnosis without metastases (n = 387). Slides were assessed for Gleason grade, inflammation, PIN, and four subtypes of focal prostatic atrophy: simple atrophy (SA), postatrophic hyperplasia (PAH), simple atrophy with cyst formation, and partial atrophy. We estimated OR and 95% CI for odds of lethal PCa with multivariable logistic regression. Results: Chronic inflammation and PIN were more frequently observed in tumors with PAH, but not SA. No specific type of atrophy or inflammation was significantly associated with lethal PCa overall, but there was a suggestion of a positive association for chronic inflammation. Independent of age, Gleason score, year of diagnosis, inflammation, and atrophy type, men with PIN were 89% more likely to die of PCa (95% CI: 1.04-3.42). Conclusion: Our data show that PIN, and perhaps presence of moderate or severe chronic inflammation, may have prognostic significance for PCa. Impact: Lesions in tumor adjacent tissue, and not just the tumor itself, may aid in identification of clinically relevant disease. Cancer Epidemiol Biomarkers Prev; 20(10); 2280-7. (C) 2011 AACR.

    National Category
    Urology and Nephrology
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-30105 (URN)10.1158/1055-9965.EPI-11-0373 (DOI)000295717900034 ()
    Available from: 2013-08-02 Created: 2013-08-02 Last updated: 2018-05-05Bibliographically approved
    2. Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin
    Open this publication in new window or tab >>Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin
    Show others...
    2012 (English)In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 18, no 4, p. 392-399Article in journal (Refereed) Published
    Abstract [en]

    Propionibacterium acnes is a gram-positive bacillus predominantly found on the skin. Although it is considered an opportunistic pathogen it is also been associated with severe infections. Some specific P. acnes subtypes are hypothesized to be more prone to cause infection than others. Thus, the aim of the present study was to investigate the ability to discriminate between P. acnes isolates of a refined multilocus sequence typing (MLST) method and a genotyping method, DiversiLab, based on repetitive-sequence-PCR technology.

    The MLST and DiversiLab analysis were performed on 29 P. acnes isolates of diverse origins; orthopedic implant infections, deep infections following cardiothoracic surgery, skin, and isolates from perioperative tissue samples from prostate cancer. Subtyping was based on recA, tly, and Tc12S sequences.

    The MLST analysis identified 23 sequence types and displayed a superior ability to discriminate P. acnes isolates compared to DiversiLab and the subtyping. The highest discriminatory index was found when using seven genes. DiversiLab was better able to differentiate the isolates compared to the MLST clonal complexes of sequence types.

    Our results suggest that DiversiLab can be useful as a rapid typing tool for initial discrimination of P. acnes isolates. When better discrimination is required, such as for investigations of the heterogeneity of P. acnes isolates and its involvement in different pathogenic processes, the present MLST protocol is valuable.

    Place, publisher, year, edition, pages
    Elsevier, 2012
    Keywords
    Propionibacterium acnes; Multilocus sequence typing (MLST); DiversiLab; Discrimination index; Molecular epidemiology
    National Category
    Microbiology in the medical area
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:oru:diva-25346 (URN)10.1016/j.anaerobe.2012.04.015 (DOI)000307688500003 ()22609518 (PubMedID)2-s2.0-84864371234 (Scopus ID)
    Note

    Funding Agencies:

    Örebro County Council Research Committee

    Foundation for Medical Research at Orebro University Hospital, Sweden 

    Available from: 2012-08-27 Created: 2012-08-27 Last updated: 2018-04-16Bibliographically approved
    3. Prevalence and typing of Propionibacterium acnes in prostate tissue obtained from men with prostate cancer and from health controls
    Open this publication in new window or tab >>Prevalence and typing of Propionibacterium acnes in prostate tissue obtained from men with prostate cancer and from health controls
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Urology and Nephrology
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-30106 (URN)
    Available from: 2013-08-02 Created: 2013-08-02 Last updated: 2017-10-17Bibliographically approved
    4. CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer
    Open this publication in new window or tab >>CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer
    Show others...
    2013 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, no 3, p. 448-455Article in journal (Refereed) Published
    Abstract [en]

    Prostate cancer represents a major contributor to cancer mortality, but the majority of men with prostate cancer will die of other causes. Thus, a challenge is identifying potentially lethal disease at diagnosis. Conflicting results have been reported when investigating the relationship between infiltration of lymphocytes and survival in prostate cancer. One of the mechanisms suggested is the recruitment of regulatory T cells (T(regs)), a subpopulation of T cells that have a role in promoting tumor growth. T(regs) counteract tumor rejection through suppressive functions on the anti-immune response but their prognostic significance is still unknown. We report here the results of a conducted case-control study nested in a cohort of men treated with transurethral resection of the prostate and diagnosed incidentally with prostate cancer. Cases are men who died of prostate cancer (n=261) and controls are men who survived >10 years after their diagnosis (n=474). Infiltration of both T(helper) and T(cytotoxic) cells was frequently observed and the majority of the T(regs) were CD4(+). T(helper) or T(cytotoxic) cells were not associated with lethal prostate cancer. However, we found a nearly twofold increased risk of lethal prostate cancer when comparing the highest with the lowest quartile of CD4(+) T(reg) cells (95% confidence interval: 1.3-2.9). Our conclusion is that men with greater numbers of CD4(+) T(regs) in their prostate tumor environment have an increased risk of dying of prostate cancer. Identification of CD4(+) T(regs) in tumor tissue may predict clinically relevant disease at time of diagnosis independently of other clinical factors.Modern Pathology advance online publication, 5 October 2012; doi:10.1038/modpathol.2012.164.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2013
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-27801 (URN)10.1038/modpathol.2012.164 (DOI)000315664100015 ()23041830 (PubMedID)2-s2.0-84875209263 (Scopus ID)
    Available from: 2013-03-01 Created: 2013-03-01 Last updated: 2018-08-27Bibliographically approved
  • 6.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences.
    PD-L1 Expression is Associated with Poor Prognosis in Renal Cell Carcinoma2018Conference paper (Refereed)
    Abstract [en]

    Programmed death ligand 1 (PD-L1) is an immunosuppressive membrane protein which, when interacting with its receptor programmed death 1 (PD-1), acts as a negative regulator of the anti-tumor T cell-mediated immune response. Overexpression of PD-L1 in different malignancies such as melanoma and gastric cancer is associated with poor clinical outcomes. The prognostic value of PD-L1 expression in renal cell carcinoma (RCC) has been controversial to some extent. In this study, the prognostic value of PD-L1 expression in RCC was evaluated by analyzing PD-L1 immunoreactivity in tumor cells and tumor infiltrating immune cells (TIICs) in 358 RCC patients with long term follow-up. Since the discrepancy between previous studies may be due to the lack of standardized methodology for evaluating PD-L1 expression by immunohistochemistry, the agreement between two anti-PD-L1 antibody clones, 28.8 and SP142, was also compared. PD-L1 positivity in tumor cells was associated with higher Fuhrman nuclear grade (p<0.001), recurrence (p=0.006), and death due to RCC (p=0.05). PD-L1 positivity in TIICs was associated with higher Fuhrman grade (p<0.001), higher AJCC-stage (p=0.019), and death due to RCC (p=0.001). A multivariate regression analysis revealed a significant positive association of time to cancer-specific death with both PD-L1 positive tumor cells and TIICs (p= 0.014 and p= 0.004, respectively). To conclude, RCC patients with PD-L1 positive tumor cells and TIICs are at significant risk for cancer progression, and the expression of PD-L1 on those cell types may be used as a complementary prognostic factor in the management of RCC patients.

  • 7.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Ohlson, Anna-Lena
    Department of Laboratory Medicine, Pathology, University Hospital Örebro, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giunchi, Francesca
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Rider, Jennifer R.
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Fiorentino, Michelangelo
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer2018In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 1, p. 40-47Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer.

    METHODS: Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area.

    RESULTS: In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart.

    CONCLUSIONS: Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established.

  • 8.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Gashi, Natyra
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Brzuszkiewicz, Elzbieta
    Department of Genomic and Applied Microbiology, Institute of Microbiology and Genetics, University of Göttingen, Göttingen, Germany.
    Poehlein, Anja
    Department of Genomic and Applied Microbiology, Institute of Microbiology and Genetics, University of Göttingen, Göttingen, Germany.
    Al-Zeer, Munir A.
    Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Brinkmann, Volker
    Microscopy Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
    Scavenius, Carsten
    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
    Nazipi, Seven
    Department of Biomedicine, Aarhus University, Aarhus, Denmark.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Clinical Microbiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Brüggemann, Holger
    Department of Biomedicine, Aarhus University, Aarhus, Denmark.
    Prevalence of Flp Pili-Encoding Plasmids in Cutibacterium acnes Isolates Obtained from Prostatic Tissue2017In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 8, article id 2241Article in journal (Refereed)
    Abstract [en]

    Inflammation is one of the hallmarks of prostate cancer. The origin of inflammation is unknown, but microbial infections are suspected to play a role. In previous studies, the Gram-positive, low virulent bacterium Cutibacterium (formerly Propionibacterium) acnes was frequently isolated from prostatic tissue. It is unclear if the presence of the bacterium represents a true infection or a contamination. Here we investigated Cutibacterium acnes type II, also called subspecies defendens, which is the most prevalent type among prostatic C. acnes isolates. Genome sequencing of type II isolates identified large plasmids in several genomes. The plasmids are highly similar to previously identified linear plasmids of type I C. acnes strains associated with acne vulgaris. A PCR-based analysis revealed that 28.4% (21 out of 74) of all type II strains isolated from cancerous prostates carry a plasmid. The plasmid shows signatures for conjugative transfer. In addition, it contains a gene locus for tight adherence (tad) that is predicted to encode adhesive Flp (fimbrial low-molecular weight protein) pili. In subsequent experiments a tad locus-encoded putative pilin subunit was identified in the surface-exposed protein fraction of plasmid-positive C. acnes type II strains by mass spectrometry, indicating that the tad locus is functional. Additional plasmid-encoded proteins were detected in the secreted protein fraction, including two signal peptide-harboring proteins; the corresponding genes are specific for type II C. acnes, thus lacking from plasmid-positive type I C. acnes strains. Further support for the presence of Flp pili in C. acnes type II was provided by electron microscopy, revealing cell appendages in tad locus-positive strains. Our study provides new insight in the most prevalent prostatic subspecies of C. acnes, subsp. defendens, and indicates the existence of Flp pili in plasmid-positive strains. Such pili may support colonization and persistent infection of human prostates by C. acnes.

  • 9.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fiorentino, Michelangelo
    Mol Pathol Lab, Addarii Inst Oncol, Dept Hematol Oncol, Univ Bologna, Bologna, Italy; Sch Med, Dana Farber Canc Inst, Dept Pathol, Brigham & Womens Hosp & Adult Oncol, Harvard Univ, Boston MA, USA.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fang, Fang
    Sch Med, Channing Lab, Dept Med, Brigham & Womens Hosp, Harvard Univ, Boston MA, USA; Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden.
    Mucci, Lorelei A.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston MA, USA; Sch Med, Channing Lab, Dept Med, Brigham & Womens Hosp, Harvard Univ, Boston MA, USA.
    Varenhorst, Eberhard
    Dept Urol, Linköping Univ Hosp, Linköping, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rider, Jennifer R.
    Dept Urol, Örebro Univ Hosp, Örebro, Sweden; Sch Med, Dana Farber Canc Inst, Dept Pathol, Brigham & Womens Hosp & Adult Oncol, Harvard Univ, Boston MA, USA.
    Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 10, p. 2280-2287Article in journal (Refereed)
    Abstract [en]

    Background: A challenge in prostate cancer (PCa) management is identifying potentially lethal disease at diagnosis. Inflammation, focal prostatic atrophy, and prostatic intraepithelial neoplasia (PIN) are common in prostate tumor specimens, but it is not clear whether these lesions have prognostic significance. Methods: We conducted a case-control study nested in a cohort of men diagnosed with stage T1a-b PCa through transurethral resection of the prostate in Sweden. Cases are men who died of PCa (n = 228). Controls are men who survived more than 10 years after PCa diagnosis without metastases (n = 387). Slides were assessed for Gleason grade, inflammation, PIN, and four subtypes of focal prostatic atrophy: simple atrophy (SA), postatrophic hyperplasia (PAH), simple atrophy with cyst formation, and partial atrophy. We estimated OR and 95% CI for odds of lethal PCa with multivariable logistic regression. Results: Chronic inflammation and PIN were more frequently observed in tumors with PAH, but not SA. No specific type of atrophy or inflammation was significantly associated with lethal PCa overall, but there was a suggestion of a positive association for chronic inflammation. Independent of age, Gleason score, year of diagnosis, inflammation, and atrophy type, men with PIN were 89% more likely to die of PCa (95% CI: 1.04-3.42). Conclusion: Our data show that PIN, and perhaps presence of moderate or severe chronic inflammation, may have prognostic significance for PCa. Impact: Lesions in tumor adjacent tissue, and not just the tumor itself, may aid in identification of clinically relevant disease. Cancer Epidemiol Biomarkers Prev; 20(10); 2280-7. (C) 2011 AACR.

  • 10.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Fiorentino, Michelangelo
    Molecular Pathology Laboratory, Addarii Institute of Oncology, Department of Hematology-Oncology, University of University of Bologna, Bologna, Italy.
    Giunchi, Francesca
    Molecular Pathology Laboratory, Addarii Institute of Oncology, Department of Hematology-Oncology, University of Bologna, Bologna, Italy .
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    The presence of PD-L1 in men with localized prostate cancer2017In: Medical research archives, ISSN 2375-1916, Vol. 4, no 8Article in journal (Refereed)
    Abstract [en]

    Background: Recent therapeutic strategies for different cancer types have focused on targeting immune check-points, such as programmed death-1 (PD-1) and its ligand PD-L1. However, it was recently reported that men with castration-resistant prostate cancer did not respond to PD-1 blockade as monotherapy. The unresponsiveness could potentially be explained by low expression of PD-L1 on prostate tumor cells. This study investigated the expression of PD-L1 on tumor cells and tumor infiltrating lymphocytes (TILs) in men with primary prostate cancer.

    Material and Methods: Immunohistochemical analysis of PD-L1 expression was performed in a cohort of men undergoing transurethral resection of the prostate and diagnosed with prostate cancer. The expression was evaluated in tissue microarrays from 522 patients with at least 25 years of follow-up.

    Results: Only four of the 522 evaluated cases were positive for PD-L1, positivity on tumor cells were found in three of the cases, of which one case also had positivity on TILs, while a fourth case only had positivity on TILs.

    Conclusion: Our data suggest that treatments targeting the PD-1/PD-L1 interaction may not be successful as monotherapy in patients diagnosed with localized prostate cancer due to low expression of PD-L1.

  • 11.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden .
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Unemo, Magnus
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Erratum to: Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, article id 36Article in journal (Refereed)
  • 12.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.
    Unemo, Magnus
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden; Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden .
    Andersson, Swen-Olof
    Örebro University, School of Health Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, article id 26Article in journal (Refereed)
    Abstract [en]

    Background: Prostate cancer is the most common cancer among men in Western countries but the exact pathogenic mechanism of the disease is still largely unknown. An infectious etiology and infection-induced inflammation has been suggested to play a role in prostate carcinogenesis and Propionibacterium acnes has been reported as the most prevalent microorganism in prostatic tissue. We investigated the frequency and types of P. acnes isolated from prostate tissue samples from men with prostate cancer and from control patients without the disease.

    Methods: We included 100 cases and 50 controls in this study. Cases were men diagnosed with prostate cancer undergoing radical prostatectomy and controls were men undergoing surgery for bladder cancer without any histological findings of prostate cancer. Six biopsies taken from each patient's prostate gland at the time of surgery were used for cultivation and further characterization of P. acnes.

    Results: The results revealed that P. acnes was more common in men with prostate carcinoma than in controls, with the bacteria cultured in 60 % of the cases vs. 26 % of the controls (p = 0.001). In multivariable analyses, men with P. acnes had a 4-fold increase in odds of a prostate cancer diagnosis after adjustment for age, calendar year of surgery and smoking status (OR: 4.46; 95 % CI: 1.93-11.26). To further support the biologic plausibility for a P. acnes infection as a contributing factor in prostate cancer development, we subsequently conducted cell-based experiments. P. acnes- isolates were co-cultured with the prostate cell line PNT1A. An increased cell proliferation and cytokine/chemokine secretion in infected cells was observed.

    Conclusion: The present study provides further evidence for a role of P. acnes in prostate cancer development.

  • 13.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Mölling, Paula
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rider, Jennifer R.
    Karlsson, Mats G.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Elgh, Fredrik
    Andrén, Ove
    Örebro University, School of Medicine, Örebro University, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden.
    Prevalence and typing of Propionibacterium acnes in prostate tissue obtained from men with prostate cancer and from health controlsManuscript (preprint) (Other academic)
  • 14.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Ohlson, Anna-Lena
    Dept Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Meisner, Allison
    School of Public Health, Dept Epidemiology, Harvard University, Boston MA, USA.
    Fiorentino, Michelangelo
    School of Public Health, Dept Epidemiology, Harvard University, Boston MA, USA; Molecular Pathology Lab, Dept Hematological Oncology, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Rider, Jennifer R
    School of Public Health, Dept Epidemiology and School of Medicine, Harvard Univ, Boston MA, USA; Dept Med, Channing Lab, Brigham & Womens Hosp, Boston MA, USA.
    CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer2013In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, no 3, p. 448-455Article in journal (Refereed)
    Abstract [en]

    Prostate cancer represents a major contributor to cancer mortality, but the majority of men with prostate cancer will die of other causes. Thus, a challenge is identifying potentially lethal disease at diagnosis. Conflicting results have been reported when investigating the relationship between infiltration of lymphocytes and survival in prostate cancer. One of the mechanisms suggested is the recruitment of regulatory T cells (T(regs)), a subpopulation of T cells that have a role in promoting tumor growth. T(regs) counteract tumor rejection through suppressive functions on the anti-immune response but their prognostic significance is still unknown. We report here the results of a conducted case-control study nested in a cohort of men treated with transurethral resection of the prostate and diagnosed incidentally with prostate cancer. Cases are men who died of prostate cancer (n=261) and controls are men who survived >10 years after their diagnosis (n=474). Infiltration of both T(helper) and T(cytotoxic) cells was frequently observed and the majority of the T(regs) were CD4(+). T(helper) or T(cytotoxic) cells were not associated with lethal prostate cancer. However, we found a nearly twofold increased risk of lethal prostate cancer when comparing the highest with the lowest quartile of CD4(+) T(reg) cells (95% confidence interval: 1.3-2.9). Our conclusion is that men with greater numbers of CD4(+) T(regs) in their prostate tumor environment have an increased risk of dying of prostate cancer. Identification of CD4(+) T(regs) in tumor tissue may predict clinically relevant disease at time of diagnosis independently of other clinical factors.Modern Pathology advance online publication, 5 October 2012; doi:10.1038/modpathol.2012.164.

  • 15.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Örebro University, School of Health and Medical Sciences. Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Olsson, Jan
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin2012In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 18, no 4, p. 392-399Article in journal (Refereed)
    Abstract [en]

    Propionibacterium acnes is a gram-positive bacillus predominantly found on the skin. Although it is considered an opportunistic pathogen it is also been associated with severe infections. Some specific P. acnes subtypes are hypothesized to be more prone to cause infection than others. Thus, the aim of the present study was to investigate the ability to discriminate between P. acnes isolates of a refined multilocus sequence typing (MLST) method and a genotyping method, DiversiLab, based on repetitive-sequence-PCR technology.

    The MLST and DiversiLab analysis were performed on 29 P. acnes isolates of diverse origins; orthopedic implant infections, deep infections following cardiothoracic surgery, skin, and isolates from perioperative tissue samples from prostate cancer. Subtyping was based on recA, tly, and Tc12S sequences.

    The MLST analysis identified 23 sequence types and displayed a superior ability to discriminate P. acnes isolates compared to DiversiLab and the subtyping. The highest discriminatory index was found when using seven genes. DiversiLab was better able to differentiate the isolates compared to the MLST clonal complexes of sequence types.

    Our results suggest that DiversiLab can be useful as a rapid typing tool for initial discrimination of P. acnes isolates. When better discrimination is required, such as for investigations of the heterogeneity of P. acnes isolates and its involvement in different pathogenic processes, the present MLST protocol is valuable.

  • 16.
    Erlandsson, Ann
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden; Department of Environmental and Life Sciences/Biology, Karlstad University, Karlstad, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Sven-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Vyas, Chraig
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Wikström, Pernilla
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    High inducible nitric oxide synthase in prostate tumor epithelium is associated with lethal prostate cancer2018In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 2, p. 129-133Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) in lethal prostate cancer (PCa) by studying the iNOS immunoreactivity in tumor tissue from men diagnosed with localized PCa.

    MATERIALS AND METHODS: This study is nested within a cohort of men diagnosed with incidental PCa undergoing transurethral resection of the prostate (the Swedish Watchful Waiting Cohort). To investigate molecular determinants of lethal PCa, men who died from PCa (n = 132) were selected as cases; controls (n = 168) comprised men with PCa who survived for at least 10 years without dying from PCa during follow-up. The immunoreactivity of iNOS in prostate tumor epithelial cells and in cells of the surrounding stroma was scored as low/negative, moderate or high. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for lethal PCa according to iNOS category.

    RESULTS: There was no association between iNOS immunoreactivity in stroma and lethal disease. However, when comparing high versus low/negative iNOS immunoreactivity in epithelial cells, the OR for lethal PCa was 3.80 (95% CI 1.45-9.97).

    CONCLUSION: Patients with localized PCa have variable outcomes, especially those with moderately differentiated tumors. Identifying factors associated with long-term PCa outcomes can elucidate PCa tumor biology and identify new candidate prognostic markers. These findings support the hypothesis that high iNOS in tumor epithelium of the prostate is associated with lethal disease.

  • 17.
    Erlandsson, Ann
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology.
    Lundholm, Marie
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Fält, Anna
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Andersson, Sven-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    M2 macrophages and regulatory T cells in lethal prostate cancer2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 4, p. 363-369Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs) can contribute to cancer progression by suppressing the anti‐tumor immune response. This study investigated the number of CD163‐positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs.

    METHODS: were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.

    RESULTS: showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis.

    CONCLUSIONS: Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs , promote an immunosuppressive environment.

  • 18.
    Khassebaf, Jasmine
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hellmark, Bengt
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Davidsson, Sabina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Nilsdotter-Augustinsson, Åsa
    Division of Infectious Diseases, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Infectious Diseases, County Council of Östergötland, Linköping, Sweden.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Antibiotic susceptibility of Propionibacterium acnes isolated from orthopaedic implant-associated infections2015In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 32, p. 57-62Article in journal (Refereed)
    Abstract [en]

    Introduction: Prosthetic joint infections (PJIs) caused by Propionibacterium acnes account for a larger proportion of the total number of PJIs than previously assumed and thus knowledge of the antimicrobial susceptibility patterns of P. acnes is of great value in everyday clinical practice.

    Materials and methods: Using Etest, the present study investigated the susceptibility of 55 clinical isolates of P. acnes, obtained from orthopaedic implant-associated infections of the knee joint (n = 5), hip joint (n = 17), and shoulder joint (n = 33), to eight antimicrobial agents: benzylpenicillin, clindamycin, metronidazole, fusidic acid, doxycycline, moxifloxacin, linezolid and rifampicin. Synergy testing was also conducted, in which rifampicin was combined with each of the remaining seven antibiotics.

    Results: All isolates (n = 55) were susceptible to most of the antibiotics tested, with the exception of 100% resistance to metronidazole, five (9.1%) isolates displaying decreased susceptibility to clindamycin, and one (1.8%) to moxifloxacin. None of the antimicrobial agents investigated were synergistic with each other when combined and nine isolates were antagonistic for various antimicrobial combinations. The majority of the antimicrobial combinations had an indifferent effect on the isolates of P. acnes. However, the combination of rifampicin and benzylpenicillin showed an additive effect on nearly half of the isolates.

    Conclusion: Almost all P. acnes, isolated from orthopaedic implant-associated infections, predominantly PJIs, were susceptible to the antibiotics tested, with the exception of complete resistance to metronidazole. Synergy test could not demonstrate any synergistic effect but additive effects were found when combining various antibiotics. Antagonistic effects were rare.

  • 19.
    Lu, Donghao
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Penney, Kathryn L.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, USA.
    Davidsson, Sabina
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, USA.
    Valdimarsdóttir, Unnur
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Faculty of Medicine, Center of Public Health Sciences, School of Health Sciences, University of Iceland, Reykjavík, Iceland.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Fang, Fang
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Expression and Genetic Variation in Neuroendocrine Signaling Pathways in Lethal and Nonlethal Prostate Cancer among Men Diagnosed with Localized Disease2017In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 26, no 12, p. 1781-1787Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent data suggest that neuroendocrine signaling pathways may play a role in the progression of prostate cancer, particularly for early-stage disease. We aimed to explore whether expression of selected genes in the adrenergic, serotoninergic, glucocorticoid, and dopaminergic pathways differs in prostate tumor tissue from men with lethal disease compared to men with nonlethal disease.

    METHODS: Based on the Swedish Watchful Waiting Cohort, we included 511 men diagnosed with incidental prostate cancer through TURP during 1977-1998 with follow-up up to 30 years. For those with tumor tissue (N=262), we measured mRNA expression of 223 selected genes included in neuroendocrine pathways. Using DNA from normal prostate tissue (N=396), we genotyped 36 SNPs from 14 receptor genes. Lethal prostate cancer was the primary outcome in analyses with pathway gene expression and genetic variants.

    RESULTS: Differential expression of genes in the serotoninergic pathway was associated with risk of lethal prostate cancer (P=0.007); similar but weaker associations were noted for the adrenergic (P=0.014) and glucocorticoid (P=0.020) pathways. Variants of the HTR2A (rs2296972; P=0.002) and NR3CI (rs33388; P=0.035) genes (within the serotoninergic and glucocorticoid pathways) were associated with lethal cancer in over-dominant models. These genetic variants were correlated with expression of several genes in corresponding pathways (P<0.05).

    CONCLUSIONS: Our findings lend support to hypothesis that the neuroendocrine pathways, particularly serotoninergic pathway, are associated with lethal outcome in the natural course of localized prostate cancer.

    IMPACT: The current study provides evidence of the role of neuroendocrine pathways in prostate cancer progression which may have clinical utility.

  • 20.
    Mushtaq, Muhammad
    et al.
    Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
    Jensen, Lasse
    Linköping University, Linköping, Sweden.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Grygoruk, Oleksandr V.
    Clinic Boris, Kyiv, Ukraine.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Kashuba, Vladimir
    Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
    Kashuba, Elena
    Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden; R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine (NASU), Kyiv, Ukraine.
    The MRPS18-2 protein levels correlate with prostate tumor progression and it induces CXCR4-dependent migration of cancer cells2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 2268Article in journal (Refereed)
    Abstract [en]

    We have earlier found abnormal expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2, S18-2) in endometrial cancer, compared to the expression in hyperplasia and in normal endometrium. Here we report that expression of S18-2 was increased with disease progression in clinical specimens of prostate cancer (PCa). The level of induction of epithelial to mesenchymal cell transition (EMT) correlated with the expression level of S18-2 in PCa cell lines. Moreover, cells acquired increased ability of migration upon S18-2 overexpression, as was evaluated in zebrafish embryo model and in trans-well assay. We found that this is due to increased CXCR4 cell surface expression. Neutralizing CXCR4 protein or abrogating S18-2 expression in cells significantly reduced their migratory ability directed toward CXCL12. The mRNA expression of TWIST2, encoding one of transcription factors that induce EMT upon CXCR4 increase, positively correlated with the S18-2 protein level. Together, these data suggest that the S18-2 protein induces EMT through the TWIST2/E-cadherin signalling and, consequently, CXCR4-mediated migration of PCa cells.

  • 21.
    Rider, Jennifer R.
    et al.
    Boston University School of Public Health, Boston, MA, USA.
    Erlandsson, Ann
    Örebro University Hospital, Örebro, Sweden.
    Vyas, Chirag
    Boston University School of Public Health, Boston, MA, USA.
    Davidsson, Sabina
    Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University Hospital, Örebro, Sweden.
    Andren, Ove
    Örebro University Hospital, Örebro, Sweden.
    iNOS expression and lethal prostate cancer in patients with localized disease2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 22S, article id B26Article in journal (Refereed)
    Abstract [en]

    Inducible nitric oxide synthase (iNOS) has demonstrated both tumor-promoting and tumor-inhibiting effects in prostate cancer. However, the relationship between iNOS protein expression and long-term prostate cancer outcomes is unclear. We evaluated iNOS expression in tumor epithelia and stroma in 300 men with localized tumors diagnosed incidentally by transurethral resection of the prostate (TURP) in Sweden. In this extreme case-control design, cases (N=132) died of prostate cancer and controls (N=168) survived at least 8 years following diagnosis without death from prostate cancer or a competing cause. Immunohistochemistry was undertaken with a polyclonal rabbit anti-human NOS2 antibody (Abcam) and the Ventana (Roche) semi-automated staining system. Two observers individually scored the staining according to intensity and number of positive cells from 0-3. The median value across cores in each patient were then categorized as <1, >1-<2, and >2, separately for epithelial and stromal compartments. Odds ratios for lethal prostate cancer were estimated with logistic regression controlling for the matching factors (age, calendar year of diagnosis), as well as tumor stage, Gleason score, and percent tumor. iNOS was expressed by stromal-associated M1 macrophages and fibroblasts, as well as tumor cells. Gleason score was positively associated with both stromal and epithelial iNOS staining. In the stroma, there was no statistically significant association between iNOS expression and lethal prostate cancer after adjustment for clinical covariates. However, the odds of lethal prostate cancer increased with tumor expression of iNOS in the fully adjusted model. Compared to patients with the lowest category of iNOS expression, the odds ratios for lethal prostate cancer were 2.96 (95% CI: 1.26-6.96) for patients in the second category and 3.80 (95% CI: 1.45-9.97) for patients in the top category. These results suggest that iNOS may help to identify patients with aggressive prostate cancer at the time of diagnosis, or may be a therapeutic target. Given previously reported in vitro data suggesting that iNOS promotes proliferation of androgen-independent prostate tumors, future analyses will investigate association between iNOS expression and time to castration-resistant prostate cancer in this patient population.

  • 22.
    Ugge, Henrik
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    The influence of prostatic Cutibacterium acnes infection on serum levels of IL6 and CXCL8 in prostate cancer patients2018In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 13, article id 34Article in journal (Refereed)
    Abstract [en]

    Background: Chronic prostatic inflammation, caused by Cutibacterium acnes (C. acnes), has been proposed to influence the risk of prostate cancer development. In vitro studies have demonstrated the capacity of C. acnes to induce secretion of Interleukin 6 (IL6) and C-X-C motif chemokine ligand 8 (CXCL8) by prostate epithelial cells. Both these inflammatory mediators have been implicated in prostate cancer pathophysiology. In this cohort study, we aimed to investigate the influence of prostatic C. acnes on serum levels of IL6 and CXCL8.

    Methods: We recruited 99 prostate cancer patients who underwent radical prostatectomy at orebro University Hospital. The cultivation of pre-operatively obtained prostate biopsies identified C. acnes in 60 of the 99 patients. Levels of IL6 and CXCL8 in pre-operative serum samples were analyzed using ELISA, and concentrations were compared between prostate cancer patients with and without prostatic C. acnes infection using standard statistical methods.

    Results: No statistical differences were observed in serum levels of IL6 and CXCL8 between subjects with and without prostatic C. acnes infection.

    Conclusions: Our results indicate that prostatic C. acnes infection may give rise to low-grade inflammation with little effect on systemic levels of IL6 and CXCL8.

  • 23.
    Ugge, Henrik
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Acne in late adolescence and risk of prostate cancer2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, p. 1580-1585Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence suggest that Propionibacterium acnes may play a role in prostate carcinogenesis, but data are so far limited and inconclusive. The aim of this population-based cohort study was therefore to test whether presence of acne vulgaris during late adolescence is associated with an increased risk of prostate cancer later in life. We identified a large cohort of young men born in Sweden between 1952 and 1956, who underwent mandatory assessment for military conscription around the age of 18 (n= 243,187). Test information along with health data including medical diagnoses at time of conscription was available through the Swedish Military Conscription Register and the National Patient Register. The cohort was followed through linkages to the Swedish Cancer Register to identify the occurrence of prostate cancer until December 31st 2009. We used Cox regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between acne in adolescence and prostate cancer risk. A total of 1,633 men were diagnosed with prostate cancer during a median follow-up of 36.7 years. A diagnosis of acne was associated with a statistically significant increased risk for prostate cancer (adjusted HR: 1.43 95%; CI: 1.06-1.92), particularly for advanced stage disease (HR: 2.37 95%; CI 1.19-4.73). A diagnosis of acne classified as severe conferred a 6-fold increased risk of prostate cancer (HR: 5.70 95% CI 1.42-22.85). Data from this large prospective population-based cohort add new evidence supporting a role of P acnes infection in prostate cancer.

  • 24.
    Ugge, Henrik
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Appendicitis before age 20 years is associated with an increased risk of later prostate cancer2018In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 27, no 6, p. 660-664Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Appendicitis before age 20 years has been observed to influence the risk of several inflammatory conditions, possibly through underlying immunological mechanisms. Inflammation has further been suggested to be involved in prostate cancer development. We therefore hypothesized that immunological characteristics signaled by appendicitis before late adolescence might influence the risk of later prostate cancer, and aimed to evaluate this association in a population-based study.

    METHODS: We identified a large cohort of Swedish men who underwent assessment for military conscription around the age of 18 years (n= 242,573). Medical diagnoses at time of conscription were available through the Swedish Military Conscription Register. The Swedish Cancer Register was used to identify diagnoses of prostate cancer. Multivariable adjusted Cox regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between appendicitis and prostate cancer.

    RESULTS: During a median of 36.7 years of follow-up, 1,684 diagnoses of prostate cancer occurred. We found a statistically significant association between appendicitis and overall prostate cancer (adjusted HR: 1.70; 95% CI: 1.08-2.67). The risk was notably increased for advanced (HR: 4.42; 95% CI: 1.74-11.22) and lethal (HR: 8.95; 95% CI: 2.98-26.91) prostate cancer.

    CONCLUSION: These results suggest that a diagnosis of appendicitis before adulthood potentially signals underlying immune characteristics and a pattern of inflammatory response relevant to prostate cancer risk.

    IMPACT: The study lends support to the proposed role of inflammation in prostate carcinogenesis, and adds another area of investigation potentially relevant to prostate cancer development.

  • 25.
    Zelic, Renata
    et al.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Zugna, Daniela
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy ; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Bottai, Matteo
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden .
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Fridfeldt, Jonna
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden .
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    Fiano, Valentina
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Fiorentino, Michelangelo
    Pathology Service, Addarii Institute of Oncology, Sant’ Orsola-Malpighi Hospital, Bologna, Italy.
    Giunchi, Francesca
    Pathology Service, Addarii Institute of Oncology, Sant’ Orsola-Malpighi Hospital, Bologna, Italy.
    Grasso, Chiara
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Lianas, Luca
    Data-Intensive Com puting Division, Center for Advanced Studies, Research and Development in Sardinia, Pula, Italy.
    Mascia, Cecilia
    Data-Intensive Com puting Division, Center for Advanced Studies, Research and Development in Sardinia, Pula, Italy.
    Molinaro, Luca
    Division of Pathology, Azienda Os pedaliero-Universitaria Città della Salute e della Scienza Hospital, Turin, Italy .
    Zanetti, Gianluigi
    Data-Intensive Com puting Division, Center for Advanced Studies, Research and Development in Sardinia, Pula, Italy.
    Richiardi, Lorenzo
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Pettersson, Andreas
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Akre, Olof
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
    Estimation of Relative and Absolute Risks in a Competing-Risks Setting Using a Nested Case-Control Study Design: Example From the ProMort Study2019In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, no 6, p. 1165-1173Article in journal (Refereed)
    Abstract [en]

    In this paper, we describe the Prognostic Factors for Mortality in Prostate Cancer (ProMort) study and use it to demonstrate how the weighted likelihood method can be used in nested case-control studies to estimate both relative and absolute risks in the competing-risks setting. ProMort is a case-control study nested within the National Prostate Cancer Register (NPCR) of Sweden, comprising 1,710 men diagnosed with low- or intermediate-risk prostate cancer between 1998 and 2011 who died from prostate cancer (cases) and 1,710 matched controls. Cause-specific hazard ratios and cumulative incidence functions (CIFs) for prostate cancer death were estimated in ProMort using weighted flexible parametric models and compared with the corresponding estimates from the NPCR cohort. We further drew 1,500 random nested case-control subsamples of the NPCR cohort and quantified the bias in the hazard ratio and CIF estimates. Finally, we compared the ProMort estimates with those obtained by augmenting competing-risks cases and by augmenting both competing-risks cases and controls. The hazard ratios for prostate cancer death estimated in ProMort were comparable to those in the NPCR. The hazard ratios for dying from other causes were biased, which introduced bias in the CIFs estimated in the competing-risks setting. When augmenting both competing-risks cases and controls, the bias was reduced.

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