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  • 1. Arkestal, Kurt
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Enocson, Anders
    Linton, Ludvig
    Marits, Per
    Glise, Hans
    Andersson, John
    Winqvist, Ola
    CCR2 upregulated on peripheral T cells in osteoarthritis but not in bone marrow2018In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 88, no 6, article id UNSP e12722Article in journal (Refereed)
    Abstract [en]

    Osteoarthritis (OA) is a condition affecting millions of patients around the world, causing pain and disability and often resulting in joint replacement surgery. The aetiology of OA has long been attributed to mechanical wear mainly due to the increased prevalence of OA in load bearing joints among older patients. However, recent studies reveal a complex molecular disease causality in which inflammation, nutritional deficit and angiogenesis lead to the destruction of the joint structure. The aim of this study was to examine chemokine receptor expression in peripheral blood and bone marrow in OA patients. We devised a protocol for extracting healthy bone marrow from patients undergoing hip arthroplasty due to coxarthrosis. Flow cytometry was used to determine the expression of 18 chemokine receptors on CD4 and CD8 T cells from bone marrow and blood from 7 osteoarthritis patients and peripheral blood from 9 healthy controls. We found a significantly increased fraction of CCR2 expressing CD4 and CD8 T cell in peripheral blood compared to healthy controls. Also, there was a significant decrease in CXCR3 (Th1) (P < 0.01) expressing T cells in peripheral blood from OA patients. Finally, multivariate analysis was used to separate T cell profiles from healthy controls and OA patients and demonstrate that the divergence of chemokine receptor expression occurs in the mature T cell subsets. In conclusion, we find increased CCR2 expression in peripheral blood from OA patients that possibly may be targeted in future clinical studies.

  • 2. Bersani, Cinzia
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Tertipis, Nikolaos
    Haeggblom, Linnea
    Näsman, Anders
    Romanitan, Mircea
    Dalianis, Tina
    Ramqvist, Torbjörn
    MicroRNA-155,-185 and-193b as biomarkers in human papillomavirus positive and negative tonsillar and base of tongue squamous cell carcinoma2018In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 82, p. 8-16Article in journal (Refereed)
    Abstract [en]

    Objective: Three-year disease-free survival (DFS) is 80% for human papillomavirus (HPV) positive tonsillar and base of tongue cancer (TSCC/BOTSCC) treated with radiotherapy alone, and today's intensified therapy does not improve prognosis. More markers are therefore needed to more accurately identify patients with good prognosis or in need of alternative therapy. Here, microRNAs (miRs) 155, 185 and 193b were examined as potential prognostic markers in TSCC/BOTSCC.

    Material and methods: 168 TSCC/BOTSCC patients diagnosed 2000-2013, with known data on HPV-status, CD8(+) tumour infiltrating lymphocytes, tumour staging and survival were examined for expression of miR-155, -185 and -193b using Real-Time PCR. Associations between miR expression and patient and tumour characteristics were analysed using univariate testing and multivariate regression.

    Results: Tumours compared to normal tonsils showed decreased miR-155 and increased miR-193b expression. miR-155 expression was associated with HPV-positivity, low T-stage, high CD8(+) TIL counts and improved survival. miR-185 expression was associated with HPV-negativity and a tendency towards decreased survival, while miR-193b expression was associated with higher T-stage, male gender and lower CD8(+) TIL counts, but not with outcome. Upon Cox regression, miR-185 was the only miR significantly associated with survival. Combining miR-155 and miR-185 to predict outcome in HPV+ patients yielded an area under curve (AUC) of 71%.

    Conclusion: Increased miR-155 expression was found as a positive predictor of survival, with the effect mainly due to its association with high CD8(+) TIL numbers, while miR-185 independently associated with decreased survival. Addition of these miRs to previously validated prognostic biomarkers could improve patient stratification accuracy.

  • 3. Bersani, Cinzia
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Dept. of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Tertipis, Nikolaos
    Haeggblom, Linnea
    Sivars, Lars
    Ährlund-Richter, Andreas
    Vlastos, Andrea
    Smedberg, Cecilia
    Grün, Nathalie
    Munck-Wikland, Eva
    Näsman, Anders
    Ramqvist, Torbjörn
    Dalianis, Tina
    A model using concomitant markers for predicting outcome in human papillomavirus positive oropharyngeal cancer2017In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 68, p. 53-59Article in journal (Refereed)
    Abstract [en]

    Objective: Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. Material and methods: TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8(+) TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. Results: 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8(+) TIL counts and young age were the strongest predictors of survival, followed by T-stage <3 and presence of HPV16 E2 mRNA. The model had an area under curve (AUC) of 76%. A model where the presence of three of four of these markers defined good prognosis captured 56% of non-relapsing patients with a positive predictive value of 98% in the validation set. Furthermore, the model identified 35% of our cohort that was over-treated and could safely have received de-escalated therapy. Conclusion: CD8(+) TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.

  • 4. Bersani, Cinzia
    et al.
    Sivars, Lars
    Haeggblom, Linnea
    DiLorenzo, Sebastian
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahrlund-Richter, Andreas
    Tertipis, Nikolaos
    Munck-Wikland, Eva
    Nasman, Anders
    Ramqvist, Torbjorn
    Dalianis, Tina
    Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR32017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 21, p. 35339-35350Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes.

    PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants.

    RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed.

    CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.

  • 5.
    Mints, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Hiltbrunner, Stefanie
    Eldh, Maria
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Holmström, Benny
    Alamdari, Farhood
    Johansson, Markus
    Hansson, Johan
    Vasko, Jonas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Winqvist, Ola
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Gabrielsson, Susanne
    Exosomes in urine retain a malignant protein profile after primary tumour ablation in patients with invasive urinary bladder cancer2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 38-39Article in journal (Other academic)
  • 6.
    Mints, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Krantz, David
    Johansson, Markus
    Hansson, Johan
    Vasko, Jonas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Winerdal, Malin
    Zirakzadeh, Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Riklund, Katrin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Zubarev, Roman
    Rutishauser, Dorothea
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Winqvist, Ola
    Individual immunoproteomics identifies il-16 processing in tregs as a factor in bladder cancer tumour immunity2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 36-37Article in journal (Other academic)
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