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  • 1.
    Almanza-Aguilera, Enrique
    et al.
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Guiñón-Fort, Daniel
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Perez-Cornago, Aurora
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Martínez-Huélamo, Miriam
    Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
    Andrés-Lacueva, Cristina
    Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
    Tjønneland, Anne
    Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark; Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
    Eriksen, Anne Kirstine
    Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
    Katzke, Verena
    Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Bajracharya, Rashmita
    Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Schulze, Matthias B.
    Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
    Masala, Giovanna
    Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network—ISPRO, Florence, Italy.
    Oliverio, Andreina
    Hyblean Association for Epidemiological Research (AIRE-ONLUS), Ragusa, Italy.
    Tumino, Rosario
    Hyblean Association for Epidemiological Research (AIRE-ONLUS), Ragusa, Italy.
    Manfredi, Luca
    Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
    Lasheras, Cristina
    Functional Biology Department, University of Oviedo, Oviedo, Spain.
    Crous-Bou, Marta
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Sánchez, Maria-José
    Granada Cancer Registry, Andalusian School of Public Health (EASP), Instituto de Investigación Biosanitaria Ibs. GRANADA, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
    Amiano, Pilar
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain; Epidemiology of Chronic and Communicable Diseases Group, BioGipuzkoa Health Research Institute, San Sebastian, Spain.
    Colorado-Yohar, Sandra M.
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain; Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
    Guevara, Marcela
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Navarra Public Health Institute, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
    Sonestedt, Emily
    Nutritional Epidemiology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Bjartell, Anders
    Department of Urology, Skåne University Hospital, Malmö, Sweden.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Weiderpass, Elisabete
    International Agency for Research on Cancer (IARC/WHO), Lyon, France.
    Aune, Dagfinn
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Nutrition, Oslo New University College, Oslo, Norway; Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
    Aglago, Elom K.
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Travis, Ruth C.
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Zamora-Ros, Raul
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Intake of the total, classes, and subclasses of (poly)phenols and risk of prostate cancer: a prospective analysis of the EPIC study2023Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 16, artikel-id 4067Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Existing epidemiological evidence regarding the potential role of (poly)phenol intake in prostate cancer (PCa) risk is scarce and, in the case of flavonoids, it has been suggested that their intake may increase PCa risk. We investigated the associations between the intake of the total and individual classes and subclasses of (poly)phenols and the risk of PCa, including clinically relevant subtypes. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort included 131,425 adult men from seven European countries. (Poly)phenol intake at baseline was assessed by combining validated center/country-specific dietary questionnaires and the Phenol-Explorer database. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). In total, 6939 incident PCa cases (including 3501 low-grade and 710 high-grade, 2446 localized and 1268 advanced, and 914 fatal Pca cases) were identified during a mean follow-up of 14 years. No associations were observed between the total intake of (poly)phenols and the risk of PCa, either overall (HRlog2 = 0.99, 95% CI 0.94–1.04) or according to PCa subtype. Null associations were also found between all classes (phenolic acids, flavonoids, lignans, and stilbenes) and subclasses of (poly)phenol intake and the risk of PCa, overall and according to PCa subtype. The results of the current large prospective cohort study do not support any association between (poly)phenol intake and PCa incidence.

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  • 2.
    Beyer, Sarah
    et al.
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden.
    Kimani, Martha
    Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und-prüfung (BAM), Richard-Willstätter Straße 11, Berlin, Germany.
    Zhang, Yuecheng
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Verhassel, Alejandra
    Institute of Biomedicine, University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku University Hospital, Turku, Finland.
    Sternbæk, Louise
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden; Phase Holographic Imaging AB, Lund, Sweden.
    Wang, Tianyan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Härkönen, Pirkko
    Institute of Biomedicine, University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku University Hospital, Turku, Finland.
    Johansson, Emil
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Caraballo, Remi
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Gawlitza, Kornelia
    Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und-prüfung (BAM), Richard-Willstätter Straße 11, Berlin, Germany.
    Rurack, Knut
    Chemical and Optical Sensing Division, Bundesanstalt für Materialforschung und-prüfung (BAM), Richard-Willstätter Straße 11, Berlin, Germany.
    Ohlsson, Lars
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    El-Schich, Zahra
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Wingren, Anette Gjörloff
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Stollenwerk, Maria M.
    Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, Malmö, Sweden; Biofilms-Research Center for Biointerfaces, Malmö University, Malmö, Sweden.
    Fluorescent Molecularly Imprinted Polymer Layers against Sialic Acid on Silica-Coated Polystyrene Cores — Assessment of the Binding Behavior to Cancer Cells2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 8, artikel-id 1875Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sialic acid (SA) is a monosaccharide usually linked to the terminus of glycan chains on the cell surface. It plays a crucial role in many biological processes, and hypersialylation is a common feature in cancer. Lectins are widely used to analyze the cell surface expression of SA. However, these protein molecules are usually expensive and easily denatured, which calls for the development of alternative glycan-specific receptors and cell imaging technologies. In this study, SA-imprinted fluorescent core-shell molecularly imprinted polymer particles (SA-MIPs) were employed to recognize SA on the cell surface of cancer cell lines. The SA-MIPs improved suspensibility and scattering properties compared with previously used core-shell SA-MIPs. Although SA-imprinting was performed using SA without preference for the α2,3-and α2,6-SA forms, we screened the cancer cell lines analyzed using the lectins Maackia Amurensis Lectin I (MAL I, α2,3-SA) and Sambucus Nigra Lectin (SNA, α2,6-SA). Our results show that the selected cancer cell lines in this study presented a varied binding behavior with the SA-MIPs. The binding pattern of the lectins was also demonstrated. Moreover, two different pentavalent SA conjugates were used to inhibit the binding of the SA-MIPs to breast, skin, and lung cancer cell lines, demonstrating the specificity of the SA-MIPs in both flow cytometry and confocal fluorescence microscopy. We concluded that the synthesized SA-MIPs might be a powerful future tool in the diagnostic analysis of various cancer cells.

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  • 3.
    Borgmästars, Emmy
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Lundberg, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nyström, Hanna
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Franklin, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Lundin, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sund, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi. Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Circulating tissue polypeptide-specific antigen in pre-diagnostic pancreatic cancer samples2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 21, artikel-id 5321Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Early detection of pancreatic ductal adenocarcinoma (PDAC) is challenging, and late diagnosis partly explains the low 5-year survival. Novel and sensitive biomarkers are needed to enable early PDAC detection and improve patient outcomes. Tissue polypeptide specific antigen (TPS) has been studied as a biomarker in PDAC diagnostics, and it has previously been shown to reflect clinical status better than the ‘golden standard’ biomarker carbohydrate antigen 19-9 (CA 19-9) that is most widely used in the clinical setting. In this cross-sectional case-control study using pre-diagnostic plasma samples, we aim to evaluate the potential of TPS as a biomarker for early PDAC detection. Furthermore, in a subset of individuals with multiple samples available at different time points before diagnosis, a longitudinal analysis was used. We assessed plasma TPS levels using enzyme-linked immunosorbent assay (ELISA) in 267 pre-diagnostic PDAC plasma samples taken up to 18.8 years before clinical PDAC diagnosis and in 320 matched healthy controls. TPS levels were also assessed in 25 samples at PDAC diagnosis. Circulating TPS levels were low both in pre-diagnostic samples of future PDAC patients and in healthy controls, whereas TPS levels at PDAC diagnosis were significantly increased (odds ratio 1.03; 95% confidence interval: 1.01–1.05) in a logistic regression model adjusted for age. In conclusion, TPS levels increase late in PDAC progression and hold no potential as a biomarker for early detection.

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  • 4.
    Calabrese, Alessandro
    et al.
    Department of Radiology, University of Rome “Sapienza”, Viale del Policlinico 155, Roma, Italy.
    Santucci, Domiziana
    Department of Radiology, Sant’Anna Hospital, Via Ravona, San Fermo della Battaglia, Italy; Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome “Campus Bio-Medico”, Via Alvaro del Portillo 21, Roma, Italy.
    Gravina, Michela
    Department of Electrical Engineering and Information Technology, University of Naples Federico II, Naples, Italy.
    Faiella, Eliodoro
    Department of Radiology, Sant’Anna Hospital, Via Ravona, San Fermo della Battaglia, Italy.
    Cordelli, Ermanno
    Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome “Campus Bio-Medico”, Via Alvaro del Portillo 21, Roma, Italy.
    Soda, Paolo
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik. Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome “Campus Bio-Medico”, Via Alvaro del Portillo 21, Roma, Italy.
    Iannello, Giulio
    Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome “Campus Bio-Medico”, Via Alvaro del Portillo 21, Roma, Italy.
    Sansone, Carlo
    Department of Electrical Engineering and Information Technology, University of Naples Federico II, Naples, Italy.
    Zobel, Bruno Beomonte
    Department of Radiology, University of Rome “Campus Bio-medico”, Via Alvaro del Portillo, 21, Rome, Italy.
    Catalano, Carlo
    Department of Radiology, University of Rome “Sapienza”, Viale del Policlinico 155, Roma, Italy.
    de Felice, Carlo
    Department of Radiology, University of Rome “Sapienza”, Viale del Policlinico 155, Roma, Italy.
    3t-mri artificial intelligence in patients with invasive breast cancer to predict distant metastasis status: a pilot study2023Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 1, artikel-id 36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The incidence of breast cancer metastasis has decreased over the years. However, 20–30% of patients with early breast cancer still die from metastases. The purpose of this study is to evaluate the performance of a Deep Learning Convolutional Neural Networks (CNN) model to predict the risk of distant metastasis using 3T-MRI DCE sequences (Dynamic Contrast-Enhanced). Methods: A total of 157 breast cancer patients who underwent staging 3T-MRI examinations from January 2011 to July 2022 were retrospectively examined. Patient data, tumor histological and MRI characteristics, and clinical and imaging follow-up examinations of up to 7 years were collected. Of the 157 MRI examinations, 39/157 patients (40 lesions) had distant metastases, while 118/157 patients (120 lesions) were negative for distant metastases (control group). We analyzed the role of the Deep Learning technique using a single variable size bounding box (SVB) option and employed a Voxel Based (VB) NET CNN model. The CNN performance was evaluated in terms of accuracy, sensitivity, specificity, and area under the ROC curve (AUC). Results: The VB-NET model obtained a sensitivity, specificity, accuracy, and AUC of 52.50%, 80.51%, 73.42%, and 68.56%, respectively. A significant correlation was found between the risk of distant metastasis and tumor size, and the expression of PgR and HER2. Conclusions: We demonstrated a currently insufficient ability of the Deep Learning approach in predicting a distant metastasis status in patients with BC using CNNs.

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  • 5. Chang, Rene Wei-Jung
    et al.
    Chuang, Shu-Lin
    Hsu, Chen-Yang
    Yen, Amy Ming-Fang
    Wu, Wendy Yi-Ying
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Chen, Sam Li-Sheng
    Fann, Jean Ching-Yuan
    Tabar, Laszlo
    Smith, Robert A.
    Duffy, Stephen W.
    Chiu, Sherry Yueh-Hsia
    Chen, Hsiu-Hsi
    Precision Science on Incidence and Progression of Early-Detected Small Breast Invasive Cancers by Mammographic Features2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 7, artikel-id 1855Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim was to evaluate how the inter-screening interval affected the performance of screening by mammographic appearances. This was a Swedish retrospective screening cohort study with information on screening history and mammography features in two periods (1977-1985 and 1996-2010). The pre-clinical incidence and the mean sojourn time (MST) for small breast cancer allowing for sensitivity by mammographic appearances were estimated. The percentage of interval cancer against background incidence (I/E ratio) was used to assess the performance of mammography screening by different inter-screening intervals. The sensitivity-adjusted MSTs (in years) were heterogeneous with mammographic features, being longer for powdery and crushed stone-like calcifications (4.26, (95% CI, 3.50-5.26)) and stellate masses (3.76, (95% CI, 3.15-4.53)) but shorter for circular masses (2.65, (95% CI, 2.06-3.55)) in 1996-2010. The similar trends, albeit longer MSTs, were also noted in 1977-1985. The I/E ratios for the stellate type were 23% and 32% for biennial and triennial screening, respectively. The corresponding figures were 32% and 43% for the circular type and 21% and 29% for powdery and crushed stone-like calcifications, respectively. Mammography-featured progressions of small invasive breast cancer provides a new insight into personalized quality assurance, surveillance, treatment and therapy of early-detected breast cancer.

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  • 6.
    Célind, Jimmy
    et al.
    Centre for Bone and Arthritis Research, Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bygdell, Maria
    Centre for Bone and Arthritis Research, Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Martikainen, Jari
    Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Styrke, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Damber, Jan-Erik
    Department of Urology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Kindblom, Jenny M.
    Centre for Bone and Arthritis Research, Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Pediatric Clinical Research Center, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Ohlsson, Claes
    Centre for Bone and Arthritis Research, Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Drug Treatment, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Timing of the pubertal growth spurt and prostate cancer2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 24, artikel-id 6238Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous studies of pubertal timing and the risk of prostate cancer have used self-reported markers of pubertal development, recalled in mid-life, and the results have been inconclusive. Our aim was to evaluate the age at the pubertal growth spurt, an objective marker of pubertal timing, and the risk of prostate cancer and high-risk prostate cancer. This population-based cohort study included 31,971 men with sufficient height measurements to calculate age at peak height velocity (PHV). Outcomes were accessed through national registers. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions with follow up starting at 20 years of age. In total, 1759 cases of prostate cancer including 449 high-risk were diagnosed during follow up. Mean follow up was 42 years (standard deviation 10.0). Compared to quintiles 2–4 (Q2–4), men in the highest age at PHV quintile (Q5) had lower risk of prostate cancer (HR 0.83, 95% CI 0.73–0.94), and of high-risk prostate cancer (0.73; 0.56–0.94). In an exploratory analysis with follow up starting at age at PHV, late pubertal timing was no longer associated with reduced risk of prostate cancer. Later pubertal timing was associated with reduced risk of prostate cancer and especially high-risk prostate cancer. We propose that the risk of prostate cancer might be influenced by the number of years with exposure to adult levels of sex steroids.

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  • 7.
    Eldh, Maria
    et al.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Mints, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Hiltbrunner, Stefanie
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Ladjevardi, Sam
    Department of Urology, Akademiska University Hospital, Uppsala, Sweden.
    Alamdari, Farhood
    Department of Urology, Västmanland Hospital, Västerås, Sweden.
    Johansson, Markus
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Jakubczyk, Tomasz
    Department of Urology, Länssjukhuset Ryhov, Jönköping, Sweden.
    Veerman, Rosanne E.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Winqvist, Ola
    Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Solna, Sweden.
    Sherif, Amir
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Gabrielsson, Susanne
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Proteomic profiling of tissue exosomes indicates continuous release of malignant exosomes in urinary bladder cancer patients, even with pathologically undetectable tumour2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 13, artikel-id 3242Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Invasive urothelial bladder cancer (UBC) has high recurrence rates even after radical cystectomy (RC). Exosomes are membrane-bound nanovesicles, which have been shown to contribute to carcinogenesis and metastasis. We previously showed that urinary exosomes display a malignant profile in UBC patients despite the absence of detectable tumour. Here, we investigated exosomes from sampling sites close to or distant from the former tumour, aiming to understand the effect of the tumour on the local milieu. Ten patients scheduled for cystectomy after transurethral bladder resection (TUR-B), without remaining detectable tumour, were included. Exosomes were isolated from tissue explants of both the previous tumour site and distant bladder tissue. Proteins were quantified by mass spectrometry in seven patients. Exosomes from the previous tumour site were enriched in inflammatory but not cancer-related pathways compared to distant tissue. However, the 69 most abundant proteins in tissue-derived exosomes regardless of site, 20 of which were also found in urinary exosomes from our previous study, were enriched for cancer-related metabolic pathways and associated with poor prognosis in an external mRNA dataset. The enrichment of cancer-related pathways in the most abundant proteins, regardless of sampling site, confirms our hypothesis that despite the absence of detectable tumour, the entire bladder releases exosomes that contribute to metastasis and highlights the need for early RC.

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  • 8.
    Engstrand, Jennie
    et al.
    Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Taflin, Helena
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden.
    Rystedt, Jenny Lundmark
    Department of Surgery, Skåne University Hospital, Lund University, Lund, Sweden.
    Hemmingsson, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Urdzik, Jozef
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Sandström, Per
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Björnsson, Bergthor
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Hasselgren, Kristina
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    The resection rate of synchronously detected liver and lung metastasis from colorectal cancer is low: a national registry-based study2023Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 5, artikel-id 1434Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Population-based data on the incidence and surgical treatment of patients with colorectal cancer (CRC) and synchronous liver and lung metastases are lacking as are real-life data on the frequency of metastasectomy for both sites and outcomes in this setting. This is a nationwide population-based study of all patients having liver and lung metastases diagnosed within 6 months of CRC between 2008 and 2016 in Sweden identified through the merging of data from the National Quality Registries on CRC, liver and thoracic surgery and the National Patient Registry. Among 60,734 patients diagnosed with CRC, 1923 (3.2%) had synchronous liver and lung metastases, of which 44 patients had complete metastasectomy. Surgery of liver and lung metastases yielded a 5-year OS of 74% (95% CI 57–85%) compared to 29% (95% CI 19–40%) if liver metastases were resected but not the lung metastases and 2.6% (95% CI 1.5–4%) if non-resected, p < 0.001. Complete resection rates ranged from 0.7% to 3.8% between the six healthcare regions of Sweden, p = 0.007. Synchronous liver and lung CRC metastases are rare, and a minority undergo the resection of both metastatic sites but with excellent survival. The reasons for differences in regional treatment approaches and the potential of increased resection rates should be studied further.

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  • 9. Fusee, Leila T. S.
    et al.
    Marin, Monica
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lopez, Ignacio
    Alternative Mechanisms of p53 Action During the Unfolded Protein Response2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 2, artikel-id 401Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The tumor suppressor protein p53 orchestrates cellular responses to a vast number of stresses, with DNA damage and oncogenic activation being some of the best described. The capacity of p53 to control cellular events such as cell cycle progression, DNA repair, and apoptosis, to mention some, has been mostly linked to its role as a transcription factor. However, how p53 integrates different signaling cascades to promote a particular pathway remains an open question. One way to broaden its capacity to respond to different stimuli is by the expression of isoforms that can modulate the activities of the full-length protein. One of these isoforms is p47 (p53/47, Delta 40p53, p53 Delta N40), an alternative translation initiation variant whose expression is specifically induced by the PERK kinase during the Unfolded Protein Response (UPR) following Endoplasmic Reticulum stress. Despite the increasing knowledge on the p53 pathway, its activity when the translation machinery is globally suppressed during the UPR remains poorly understood. Here, we focus on the expression of p47 and we propose that the alternative initiation of p53 mRNA translation offers a unique condition-dependent mechanism to differentiate p53 activity to control cell homeostasis during the UPR. We also discuss how the manipulation of these processes may influence cancer cell physiology in light of therapeutic approaches.

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  • 10. Gluud, Maria
    et al.
    Willerslev-Olsen, Andreas
    Gjerdrum, Lise Mette Rahbek
    Lindahl, Lise M.
    Buus, Terkild B.
    Andersen, Mads Hald
    Bonefeld, Charlotte Menne
    Krejsgaard, Thorbjorn
    Litvinov, Ivan V.
    Iversen, Lars
    Becker, Jürgen C.
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Koralov, Sergei B.
    Litman, Thomas
    Geisler, Carsten
    Woetmann, Anders
    Odum, Niels
    MicroRNAs in the Pathogenesis, Diagnosis, Prognosis and Targeted Treatment of Cutaneous T-Cell Lymphomas2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 5Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL.

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  • 11.
    Gu, Xiaolian
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wang, Lixiao
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Boldrup, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip J.
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; Équipe Labellisée Ligue Contre le Cancer, INSERM UMRS1162, Institut de Génétique Moléculaire, Université Paris 7, IUH Hôpital St. Louis, 75010 Paris, France.
    Sgaramella, Nicola
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wilms, Torben
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    AP001056.1, A Prognosis-Related Enhancer RNA in Squamous Cell Carcinoma of the Head and Neck2019Ingår i: Cancers, ISSN 2072-6694, Vol. 11, nr 3, artikel-id 347Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A growing number of long non-coding RNAs (lncRNAs) have been linked to squamous cell carcinoma of the head and neck (SCCHN). A subclass of lncRNAs, termed enhancer RNAs (eRNAs), are derived from enhancer regions and could contribute to enhancer function. In this study, we developed an integrated data analysis approach to identify key eRNAs in SCCHN. Tissue-specific enhancer-derived RNAs and their regulated genes previously predicted using the computational pipeline PreSTIGE, were considered as putative eRNA-target pairs. The interactive web servers, TANRIC (the Atlas of Noncoding RNAs in Cancer) and cBioPortal, were used to explore the RNA levels and clinical data from the Cancer Genome Atlas (TCGA) project. Requiring that key eRNAs should show significant associations with overall survival (Kaplan-Meier log-rank test, p < 0.05) and the predicted target (correlation coefficient r > 0.4, p < 0.001), we identified five key eRNA candidates. The most significant survival-associated eRNA was AP001056.1 with ICOSLG encoding an immune checkpoint protein as its regulated target. Another 1640 genes also showed significant correlation with AP001056.1 (r > 0.4, p < 0.001), with the "immune system process" being the most significantly enriched biological process (adjusted p < 0.001). Our results suggest that AP001056.1 is a key immune-related eRNA in SCCHN with a positive impact on clinical outcome.

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  • 12.
    Guan, Jikui
    et al.
    Institute of Biomedicine,Dept of Medical Biochem and Cell Biol, Sahlgrenska Academy, University of Gothenburg..
    Yamazaki, Yasuo
    Institute of Biomedicine,Dept of Medical Biochem and Cell Biol, Sahlgrenska Academy, University of Gothenburg..
    Chand, Damini
    Institute of Biomedicine,Dept of Medical Biochem and Cell Biol, Sahlgrenska Academy, University of Gothenburg..
    van Dijk, Jesper R.
    Institute of Biomedicine,Dept of Medical Biochem and Cell Biol, Sahlgrenska Academy, University of Gothenburg..
    Ruuth, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Palmer, Ruth H.
    Institute of Biomedicine,Dept of Medical Biochem and Cell Biol, Sahlgrenska Academy, University of Gothenburg..
    Hallberg, Bengt
    Institute of Biomedicine,Dept of Medical Biochem and Cell Biol, Sahlgrenska Academy, University of Gothenburg..
    Novel mechanisms of ALK activation revealed by analysis of the Y1278S neuroblastoma mutation2017Ingår i: Cancers, ISSN 2072-6694, Vol. 9, nr 11, artikel-id 149Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Numerous mutations have been observed in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) in both germline and sporadic neuroblastoma. Here, we have investigated the Y1278S mutation, observed in four patient cases, and its potential importance in the activation of the full length ALK receptor. Y1278S is located in the 1278-YRASYY-1283 motif of the ALK activation loop, which has previously been reported to be important in the activation of the ALK kinase domain. In this study, we have characterized activation loop mutations within the context of the full length ALK employing cell culture and Drosophila melanogaster model systems. Our results show that the Y1278S mutant observed in patients with neuroblastoma harbors gain-of-function activity. Secondly, we show that the suggested interaction between Y1278 and other amino acids might be of less importance in the activation process of the ALK kinase than previously proposed. Thirdly, of the three individual tyrosines in the 1278-YRASYY-1283 activation loop, we find that Y1283 is the critical tyrosine in the activation process. Taken together, our observations employing different model systems reveal new mechanistic insights on how the full length ALK receptor is activated and highlight differences with earlier described activation mechanisms observed in the NPM-ALK fusion protein, supporting a mechanism of activation more in line with those observed for the Insulin Receptor (InR).

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  • 13.
    Haigh, Daisy B.
    et al.
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Woodcock, Corinne L.
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Lothion-Roy, Jennifer
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Harris, Anna E.
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Metzler, Veronika M.
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Biomedical Sciences, Malmö Universitet, Malmö, Sweden.
    Robinson, Brian D.
    Department of Pathology, Weill Cornell Medicine, NY, New York, United States.
    Khani, Francesca
    Department of Pathology, Weill Cornell Medicine, NY, New York, United States.
    Alsaleem, Mansour
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Applied Medical Science, Applied College, Qassim University, Qassim, Unayzah, Saudi Arabia.
    Ntekim, Atara
    School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom; Department of Radiation Oncology, University College Hospital, University of Ibadan, Ibadan, Nigeria.
    Madhusudan, Srinivasan
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Medicine, University of Nottingham, Nottingham, United Kingdom.
    Davis, Melissa B.
    Department of Surgery, Weill Cornell Medicine, NY, New York, United States.
    Laursen, Kristian B.
    Department of Pharmacology, Weill Cornell Medicine, NY, New York, United States.
    Gudas, Lorraine J.
    Department of Pharmacology, Weill Cornell Medicine, NY, New York, United States.
    Rutland, Catrin S.
    School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Toss, Michael S.
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Medicine, University of Nottingham, Nottingham, United Kingdom.
    Archer, Nathan
    School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Bodi, Zsuzsanna
    School of Biosciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Rakha, Emad A.
    School of Medicine, University of Nottingham, Nottingham, United Kingdom.
    Fray, Rupert G.
    School of Biosciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Jeyapalan, Jennie N.
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom.
    Mongan, Nigel P.
    Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom; School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom; Department of Pharmacology, Weill Cornell Medicine, NY, New York, United States.
    The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 20, artikel-id 5148Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.

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  • 14.
    Harlid, Sophia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Gunter, Marc J.
    Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
    van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Risk‐predictive and diagnostic biomarkers for colorectal cancer: a systematic review of studies using pre‐diagnostic blood samples collected in prospective cohorts and screening settings2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 17, artikel-id 4406Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    This systematic review summarizes the evidence for blood‐based colorectal cancer biomarkers from studies conducted in pre‐diagnostic, asymptomatic settings. Of 1372 studies initially identified, the final selection included 30 studies from prospective cohorts and 23 studies from general screening settings. Overall, the investigations had high quality but considerable variability in data analysis and presentation of results, and few biomarkers demonstrated a clinically relevant discriminatory ability. One of the most promising biomarkers was the anti‐p53 antibody, with consistent findings in one screening cohort and in the 3–4 years prior to diagnosis in two prospective cohort studies. Proteins were the most common type of biomarker assessed, particularly carcinoembryonic antigen (CEA) and C‐reactive protein (CRP), with modest results. Other potentially promising biomarkers included proteins, such as AREG, MIC‐1/GDF15, LRG1 and FGF‐21, metabolites and/or metabolite profiles, non‐coding RNAs and DNA methylation, as well as re‐purposed routine lab tests, such as ferritin and the triglyceride–glucose index. Biomarker panels generally achieved higher discriminatory performance than single markers. In conclusion, this systematic review highlighted anti‐p53 antibodies as a promising blood‐based biomarker for use in colorectal cancer screening panels, together with other specific proteins. It also underscores the need for validation of promising biomarkers in independent pre‐diagnostic settings.

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  • 15.
    Hawranek, Carolina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Maxon, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Hajdarevic, Senada
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Numan Hellquist, Barbro
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rosén, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Cancer worry distribution and willingness to undergo colonoscopy at three levels of hypothetical cancer risk - a population-based survey in Sweden2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 4, artikel-id 918Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: We describe levels of cancer worry in the general population as measured with the Cancer Worry Scale (CWS) and investigate the association with colonoscopy screening intentions in three colorectal cancer risk scenarios. 

    Methods: The data were sourced through a population-based survey. Respondents (n = 943) completed an eight-item CWS and questions on colonoscopy screening interest at three hypothetical risk levels. 

    Results: Respondents without a personal cancer history (n = 853) scored 9.46 on the six-item CWS (mean, SD 2.72). Mean scores were significantly higher in women (9.91, SD 2.89) as compared to men (9.06, SD 2.49, p < 0.001). Linear regression showed higher cancer worry in women and those with children when controlling for education, age group, and country of birth. High cancer worry (six-item CWS mean >12) was identified in 25% of women and in 17% of men. Among those, 71% would attend a colonoscopy screening compared to 52% of those with low cancer worry (p < 0.001, 5% CRC-risk). 

    Conclusions: The distribution of cancer worry in a general population sample showed higher mean scores in women, and levels overlapped with earlier findings in cancer-affected samples. Respondents with high cancer worry were more inclined to undergo a colonoscopy screening, and intention increased with higher levels of hypothetical risk.

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  • 16. Hersi, Abdi-Fatah
    et al.
    Pistiolis, Lida
    Dussan Luberth, Carlos
    Vikhe-Patil, Eva
    Nilsson, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Mohammed, Imad
    Olofsson Bagge, Roger
    Wärnberg, Fredrik
    Eriksson, Staffan
    Karakatsanis, Andreas
    Optimizing Dose and Timing in Magnetic Tracer Techniques for Sentinel Lymph Node Detection in Early Breast Cancers: The Prospective Multicenter SentiDose Trial2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 4, artikel-id 693Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Superparamagnetic iron oxide nanoparticles (SPIO) are non-inferior to radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) detection. Previously, 2 mL SPIO (Sienna+®) in 3 mL NaCl was used. In this dose-optimizing study, lower doses of a new refined SPIO solution (Magtrace®) (1.5 vs. 1.0 mL) were tested in different timeframes (0-24 h perioperative vs. 1-7 days preoperative) and injections sites (subareolar vs. peritumoral). Two consecutive breast cancer cohorts (n = 328) scheduled for SLN-biopsy were included from 2017 to 2019. All patients received isotope ± blue dye as back-up. SLNs were identified primarily with the SentiMag® probe and thereafter a gamma-probe. The primary endpoint was SLN detection rate with SPIO. Analyses were performed as a one-step individual patient-level meta-analysis using patient-level data from the previously published Nordic Trial (n = 206) as a third, reference cohort. In 534 patients, the SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 and the 2.0 mL cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Lower SPIO volumes injected up to 7 days before the operation have comparable efficacy to standard SPIO dose and RI + BD for SLN detection.

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  • 17.
    Hägglöf, Christina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    The stroma: a key regulator in prostate function and malignancy2012Ingår i: Cancers, ISSN 2072-6694, Vol. 4, nr 2, s. 531-548Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Prostate cancer is a very common and highly unpredictable form of cancer. Whereas many prostate cancers are slow growing and could be left without treatment, others are very aggressive. Additionally, today there is no curative treatment for prostate cancer patients with local or distant metastasis. Identification of new, improved prognostic and diagnostic biomarkers for prostate cancer and the finding of better treatment strategies for metastatic prostate cancer is therefore highly warranted. Interactions between epithelium and stroma are known to be important already during prostate development and this interplay is critical also in development, progression of primary tumors and growth of metastases. It is therefore reasonable to expect that future biomarkers and therapeutic targets can be identified in the prostate tumor and metastasis stroma and this possibility should be further explored.

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  • 18.
    Johnson, Heather
    et al.
    Olympia Diagnostics, Inc., CA, Sunnyvale, United States.
    Amjad, Ali
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Zhang, Xuhui
    Department of Bio-Diagnosis, Institute of Basic Medical Sciences, Beijing, China.
    Wang, Tianyan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Simoulis, Athanasios
    Department of Clinical Pathology and Cytology, Skåne University Hospital, Malmö, Sweden.
    Gjörloff Wingren, Anette
    Department of Biomedical Sciences, Malmö University, Malmö, Sweden.
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Biomedical Sciences, Malmö University, Malmö, Sweden.
    K-RAS associated gene-mutation-based algorithm for prediction of treatment response of patients with subtypes of breast cancer and especially triple-negative cancer2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 21, artikel-id 5322Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality.

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  • 19. Johnson, Heather
    et al.
    El-Schich, Zahra
    Amjad, Ali
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Zhang, Xuhui
    Simoulis, Athanasios
    Gjörloff Wingren, Anette
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Biomedical Sciences, Malmö University, Malmö, Sweden.
    Gene-Mutation-Based Algorithm for Prediction of Treatment Response in Colorectal Cancer Patients2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 8, artikel-id 2045Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Despite the high mortality of metastatic colorectal cancer (mCRC), no new biomarker tools are available for predicting treatment response. We developed gene-mutation-based algorithms as a biomarker classifier to predict treatment response with better precision than the current predictive factors.

    METHODS: Random forest machine learning (ML) was applied to identify the candidate algorithms using the MSK Cohort (n = 471) as a training set and validated in the TCGA Cohort (n = 221). Logistic regression, progression-free survival (PFS), and univariate/multivariate Cox proportional hazard analyses were performed and the performance of the candidate algorithms was compared with the established risk parameters.

    RESULTS: A novel 7-Gene Algorithm based on mutation profiles of seven KRAS-associated genes was identified. The algorithm was able to distinguish non-progressed (responder) vs. progressed (non-responder) patients with AUC of 0.97 and had predictive power for PFS with a hazard ratio (HR) of 16.9 (p &lt; 0.001) in the MSK cohort. The predictive power of this algorithm for PFS was more pronounced in mCRC (HR = 16.9, p &lt; 0.001, n = 388). Similarly, in the TCGA validation cohort, the algorithm had AUC of 0.98 and a significant predictive power for PFS (p &lt; 0.001).

    CONCLUSION: The novel 7-Gene Algorithm can be further developed as a biomarker model for prediction of treatment response in mCRC patients to improve personalized therapies.

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  • 20.
    Jonsson, Pär
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Späth, Florentin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Björkblom, Benny
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Identification of Pre-Diagnostic Metabolic Patterns for Glioma Using Subset Analysis of Matched Repeated Time Points2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 11, artikel-id 3349Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Simple Summary: Reprogramming of cellular metabolism is a major hallmark of cancer cells, and play an important role in tumor initiation and progression. The aim of our study is to discover circulating early metabolic markers of brain tumors, as discovery and development of reliable predictive molecular markers are needed for precision oncology applications. We use a study design tailored to minimize confounding factors and a novel machine learning and visualization approach (SMART) to identify a panel of 15 interlinked metabolites related to glioma development. The presented SMART strategy facilitates early molecular marker discovery and can be used for many types of molecular data.

    Abstract: Here, we present a strategy for early molecular marker pattern detection-Subset analysis of Matched Repeated Time points (SMART)-used in a mass-spectrometry-based metabolomics study of repeated blood samples from future glioma patients and their matched controls. The outcome from SMART is a predictive time span when disease-related changes are detectable, defined by time to diagnosis and time between longitudinal sampling, and visualization of molecular marker patterns related to future disease. For glioma, we detect significant changes in metabolite levels as early as eight years before diagnosis, with longitudinal follow up within seven years. Elevated blood plasma levels of myo-inositol, cysteine, N-acetylglucosamine, creatinine, glycine, proline, erythronic-, 4-hydroxyphenylacetic-, uric-, and aceturic acid were particularly evident in glioma cases. We use data simulation to ensure non-random events and a separate data set for biomarker validation. The latent biomarker, consisting of 15 interlinked and significantly altered metabolites, shows a strong correlation to oxidative metabolism, glutathione biosynthesis and monosaccharide metabolism, linked to known early events in tumor development. This study highlights the benefits of progression pattern analysis and provide a tool for the discovery of early markers of disease.

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  • 21.
    Josefsson, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Larsson, Karin
    Freyhult, Eva
    Damber, Jan-Erik
    Welén, Karin
    Gene Expression Alterations during Development of Castration-Resistant Prostate Cancer Are Detected in Circulating Tumor Cells2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 1, artikel-id 39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC.

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  • 22.
    Järemo, Helena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Semenas, Julius
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Halin Bergström, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Investigating microRNA Profiles in Prostate Cancer Bone Metastases and Functional Effects of microRNA-23c and microRNA-43282023Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 9, artikel-id 2437Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    MicroRNAs (miRNAs) are aberrantly expressed in prostate cancer (PC), but comprehensive knowledge about their levels and function in metastatic PC is lacking. Here, we explored the differential expression of miRNA profiles during PC progression to bone metastasis, and further focused on the downregulation of miRNA-23c and -4328 and their impact on PC growth in experimental models. Using microarray screening, the levels of 1510 miRNAs were compared between bone metastases (n = 14), localized PC (n = 7) and benign prostate tissue (n = 7). Differentially expressed miRNAs (n = 4 increased and n = 75 decreased, p < 0.05) were identified, of which miRNA-1, -23c, -143-3p, -143-5p, -145-3p, -205-5p, -221-3p, -222-3p and -4328 showed consistent downregulation during disease progression (benign > localized PC > bone metastases). The downregulation of miRNA-23c and -4328 was confirmed by reverse transcription and quantitative polymerase chain reaction analysis of 67 metastasis, 12 localized PC and 12 benign prostate tissue samples. The stable overexpression of miRNA-23c and -4328 in the 22Rv1 and PC-3 cell lines resulted in reduced PC cell growth in vitro, and in the secretion of high levels of miRNA-23c (but not -4328) in extracellular vesicles. However, no tumor suppressive effects were observed from miRNA-23c overexpression in PC-3 cells subcutaneously grown in mice. In conclusion, bone metastases display a profound reduction of miRNA levels compared to localized PC and benign disease. The downregulation of those miRNAs, including miRNA-23c and -4328, may lead to a loss of tumor suppressive effects and provide biomarker and therapeutic possibilities that deserve to be further explored.

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  • 23.
    Karagiannakos, Alexandros
    et al.
    Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, Athens, Greece.
    Adamaki, Maria
    Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, Athens, Greece.
    Tsintarakis, Antonis
    Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, Athens, Greece.
    Vojtesek, Borek
    Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic; Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France; International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland.
    Zoumpourlis, Vassilis
    Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, Athens, Greece.
    Karakostis, Konstantinos
    Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Avenue, Athens, Greece; Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
    Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 3, artikel-id 664Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.

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  • 24.
    Karlsson, Richard
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
    Larsson, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Miftakhova, Regina R.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Genetics, Kazan Federal University, Kazan, Russia.
    Khaja, Azharuddin Sajid Syed
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Sarwar, Martuza
    Semenas, Julius
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
    Chen, Sa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Hedblom, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
    Wang, Tianyan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ekström-Holka, Kristina
    Simoulis, Athanasios
    Kumar, Anjani
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ødum, Nils
    Grundström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden; Department of Biomedical Sciences, Malmö University, Malmö, Sweden.
    Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 9, artikel-id 2719Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.

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  • 25. Khomiak, Andrii
    et al.
    Brunner, Marius
    Kordes, Maximilian
    Lindblad, Stina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Miksch, Rainer Christoph
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Regel, Ivonne
    Recent Discoveries of Diagnostic, Prognostic and Predictive Biomarkers for Pancreatic Cancer2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 11, artikel-id 3234Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Simple Summary Biomarkers for cancer diagnosis, prognosis and prediction are important tools and an urgent need in precision medicine for pancreatic cancer. In recent years, many experimental and clinical studies aimed at identifying new biomarkers for pancreatic ductal adenocarcinoma. In the review, we summarized current investigations on using novel protein markers, cell-free DNA, metabolome compounds, immune and stroma signatures and microbiome compositions as biomarkers for pancreatic cancer. Our comprehensive overview shows that although there are new promising biomarkers, CA 19-9 remains currently the only regularly used and validated biomarker for pancreatic cancer in clinical routine. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis that is frequently diagnosed at an advanced stage. Although less common than other malignant diseases, it currently ranks as the fourth most common cause of cancer-related death in the European Union with a five-year survival rate of below 9%. Surgical resection, followed by adjuvant chemotherapy, remains the only potentially curative treatment but only a minority of patients is diagnosed with locally resectable, non-metastatic disease. Patients with advanced disease are treated with chemotherapy but high rates of treatment resistance and unfavorable side-effect profiles of some of the used regimens remain major challenges. Biomarkers reflect pathophysiological or physiological processes linked to a disease and can be used as diagnostic, prognostic and predictive tools. Thus, accurate biomarkers can allow for better patient stratification and guide therapy choices. Currently, the only broadly used biomarker for PDAC, CA 19-9, has multiple limitations and the need for novel biomarkers is urgent. In this review, we highlight the current situation, recent discoveries and developments in the field of biomarkers of PDAC and their potential clinical applications.

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  • 26.
    Lawen, Tarek
    et al.
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Ilie, Gabriela
    Department of Urology, Dalhousie University, NS, Halifax, Canada; Department of Radiation Oncology, Dalhousie University, NS, Halifax, Canada; Department of Community Health and Epidemiology, Dalhousie University, NS, Halifax, Canada.
    Mason, Ross
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Rendon, Ricardo
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Spooner, Jesse
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Champion, Emmi
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Davis, Jessica
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    MacDonald, Cody
    Department of Community Health and Epidemiology, Dalhousie University, NS, Halifax, Canada.
    Kucharczyk, Michael J.
    Department of Oncology, Queens University, ON, Kingston, Canada.
    Patil, Nikhilesh
    Department of Radiation Oncology, Dalhousie University, NS, Halifax, Canada.
    Bowes, David
    Department of Radiation Oncology, Dalhousie University, NS, Halifax, Canada.
    Bailly, Greg
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Bell, David
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Lawen, Joseph
    Department of Urology, Dalhousie University, NS, Halifax, Canada.
    Wilke, Derek
    Department of Radiation Oncology, Dalhousie University, NS, Halifax, Canada.
    Kephart, George
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad. Department of Community Health and Epidemiology, Dalhousie University, NS, Halifax, Canada; School of Health Administration, Dalhousie University, NS, Halifax, Canada.
    Rutledge, Robert David Harold
    Department of Radiation Oncology, Dalhousie University, NS, Halifax, Canada.
    Six-month prostate cancer empowerment program (PC-PEP) improves urinary function: a randomized trial2024Ingår i: Cancers, ISSN 2072-6694, Vol. 16, nr 5, artikel-id 958Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: This is a secondary analysis examining a six-month home-based Prostate Cancer-Patient Empowerment Program (PC-PEP) on patient-reported urinary, bowel, sexual, and hormonal function in men with curative prostate cancer (PC) against standard of care.

    Methods: In a crossover clinical trial, 128 men scheduled for PC surgery (n = 62) or radiotherapy with/without hormones (n = 66) were randomized to PC-PEP (n = 66) or waitlist-control and received the standard of care for 6 months, and then PC-PEP to the end of the year. PC-PEP included daily emails with video instructions, aerobic and strength training, dietary guidance, stress management, and social support, with an initial PFMT nurse consultation. Over 6 months, participants in the PC-PEP received optional text alerts (up to three times daily) reminding them to follow the PFMT video program, encompassing relaxation, quick-twitch, and endurance exercises; compliance was assessed weekly. Participants completed baseline, 6, and 12-month International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC) questionnaires.

    Results: At 6 months, men in the PC-PEP reported improved urinary bother (IPSS, p = 0.004), continence (EPIC, p < 0.001), and irritation/obstruction function (p = 0.008) compared to controls, with sustained urinary continence benefits at 12 months (p = 0.002). Surgery patients in the waitlist-control group had 3.5 (95% CI: 1.2, 10, p = 0.024) times and 2.3 (95% CI: 0.82, 6.7, p = 0.11) times higher odds of moderate to severe urinary problems compared to PC-PEP at 6 and 12 months, respectively.

    Conclusions: PC-PEP significantly improves lower urinary tract symptoms, affirming its suitability for clinical integration alongside established mental health benefits in men with curative prostate cancer.

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  • 27.
    Li, Xingru
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Larsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Myte, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Löfgren Burström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zingmark, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ling, Agnes
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Edin, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ex Vivo Organoid Cultures Reveal the Importance of the Tumor Microenvironment for Maintenance of Colorectal Cancer Stem Cells2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 4, artikel-id 923Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Colorectal cancer (CRC) is a heterogeneous disease, with varying clinical presentations and patient prognosis. Different molecular subgroups of CRC should be treated differently and therefore, must be better characterized. Organoid culture has recently been suggested as a good model to reflect the heterogeneous nature of CRC. However, organoid cultures cannot be established from all CRC tumors. The study examines which CRC tumors are more likely to generate organoids and thus benefit from ex vivo organoid drug testing. Long-term organoid cultures from 22 out of 40 CRC tumor specimens were established. It was found that organoid cultures were more difficult to establish from tumors characterized as microsatellite instable (MSI), BRAF-mutated, poorly differentiated and/or of a mucinous type. This suggests that patients with such tumors are less likely to benefit from ex vivo organoid drug testing, but it may also suggest biological difference in tumor growth. RNA sequencing analysis of tumor sections revealed that the in vivo maintenance of these non-organoid-forming tumors depends on factors related to inflammation and pathogen exposure. Furthermore, using TCGA data we could show a trend towards a worse prognosis for patients with organoid-forming tumors, suggesting also clinical differences. Results suggest that organoids are more difficult to establish from tumors characterized as MSI, BRAF-mutated, poorly differentiated and/or of a mucinous type. We further suggest that the maintenance of cell growth of these tumors in vivo may be promoted by immune-related factors and other stromal components within the tumor microenvironment.

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  • 28.
    Li, Xingru
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ling, Agnes
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kellgren, Therese G.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Löfgren Burström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zingmark, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rutegård, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Edin, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 11, artikel-id 3440Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1+ T cells. No correlation was, however, found between MSI and the fraction of CTLA-4+ T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1+ T cells, but also CTLA-4+ T cells. Furthermore, no correlation was found between PD-1+ and CTLA-4+ T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients.

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  • 29.
    Lindgren, Moa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Rask, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Jonsson, Josefin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Berglund, Anette
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Lundin, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nyström, Hanna
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Type IV Collagen in Human Colorectal Liver Metastases—Cellular Origin and a Circulating Biomarker2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 14, artikel-id 3396Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Circulating type IV collagen (cCOL IV) is a potential biomarker for patients with colorectal liver metastases (CLM) who present with elevated levels of COL IV in both CLM tissue and circulation. This study aimed to establish the cellular origin of elevated levels of COL IV and analyze circulating COL IV in CLM patients. The cellular source was established through in situ hybridization, immunohistochemical staining, and morphological evaluation. Cellular expression in vitro was assessed by immunofluorescence. Tissue expression of COL IV-degrading matrix metalloproteinases (MMPs)-2, -7, -9, and -13 was studied with immunohistochemical staining. Plasma levels of COL IV in CLM patients and healthy controls were analyzed with ELISA. This study shows that cancer-associated fibroblasts (CAFs) express COL IV in the stroma of CLM and that COL IV is expressed in vitro by fibroblasts but not by tumor cells. MMP-2, -7, -9, and -13 are expressed in CLM tissue, mainly by hepatocytes and immune cells, and circulating COL IV is significantly elevated in CLM patients compared with healthy controls. Our study shows that stromal cells, not tumor cells, produce COL IV in CLM, and that circulating COL IV is elevated in patients with CLM.

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  • 30.
    Löwenmark, Thyra
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Löfgren Burström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zingmark, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dahlberg, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Edin, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Tumour colonisation of Parvimonas micra is associated with decreased survival in colorectal cancer patients2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 23, artikel-id 5937Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Increasing evidence suggests that the gut microbiota may impact colorectal cancer (CRC) development and progression. In this study, the tumour colonisation of two CRC-associated bacteria, Parvimonas micra and Fusobacterium nucleatum, was studied in relation to patient survival in a cohort of 257 CRC patients. Colonisation of P. micra and F. nucleatum was analysed in fresh frozen tumour tissue (n = 112) and in faeces (n = 250) by qPCR. When analysing tumour tissues, both P. micra and F. nucleatum were found to be associated with decreased five-year cancer-specific survival, an association that remained significant in multivariable analysis for P. micra. Furthermore, we found significant associations of high levels of P. micra and F. nucleatum with tumour molecular characteristics, i.e., tumours mutated in BRAFV600E, and tumours of the MSI subtype. The analysis of faecal samples showed weaker associations with prognosis and tumour molecular characteristics. In conclusion, our findings support a novel association of tumour colonisation of P. micra with decreased patient survival. A better understanding of the role of the gut microbiota in CRC might contribute to the advancement of prognostic tools and new targets for therapy.

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  • 31.
    Muthu, Magesh
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Kumar, Ranjeet
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Khaja, Azharuddin Sajid Syed
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Nordström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism2019Ingår i: Cancers, ISSN 2072-6694, Vol. 11, nr 12, artikel-id 1945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 μM in resistant GLUL KO A549 cells compared to 28 μM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.

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  • 32.
    Omran, Meis
    et al.
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; Cancer Theme, Karolinska University Hospital Solna, Stockholm, Sweden.
    Tham, Emma
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Clinical Genetics, Cancer Genetic Unit, Karolinska University Hospital Solna, Stockholm, Sweden.
    Brandberg, Yvonne
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Ahlström, Håkan
    Department of Surgical Sciences, Section of Radiology, Uppsala University, Uppsala, Sweden.
    Lundgren, Claudia
    Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Paulsson-Karlsson, Ylva
    Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Kuchinskaya, Ekaterina
    Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden.
    Silander, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rosén, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Persson, Fredrik
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Leonhardt, Henrik
    Department of Radiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Stenmark-Askmalm, Marie
    Division of Clinical Genetics, Department of Laboratory Medicine, Office for Medical Services, Skåne University Hospital, Lund, Sweden.
    Berg, Johanna
    Department of Translational Medicine, Radiology Diagnostics, Lund University, Malmö, Sweden; Centre for Medical and Imaging and Function, Lund, Sweden.
    van Westen, Danielle
    Centre for Medical and Imaging and Function, Lund, Sweden; Department of Diagnostic Radiology, Institution of Clinical Sciences, Lund University, Lund, Sweden.
    Bajalica-Lagercrantz, Svetlana
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; Cancer Theme, Karolinska University Hospital Solna, Stockholm, Sweden; Department of Clinical Genetics, Cancer Genetic Unit, Karolinska University Hospital Solna, Stockholm, Sweden.
    Blomqvist, Lennart
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Imaging and Physiology, Karolinska University Hospital Solna, Stockholm, Sweden.
    Whole-Body MRI Surveillance: Baseline Findings in the Swedish Multicentre Hereditary TP53-Related Cancer Syndrome Study (SWEP53)2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 2, artikel-id 380Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A surveillance strategy of the heritable TP53-related cancer syndrome (hTP53rc), commonly referred to as the Li–Fraumeni syndrome (LFS), is studied in a prospective observational nationwide multi-centre study in Sweden (SWEP53). The aim of this sub-study is to evaluate whole-body MRI (WB-MRI) regarding the rate of malignant, indeterminate, and benign imaging findings and the associated further workup generated by the baseline examination. Individuals with hTP53rc were enrolled in a surveillance program including annual whole-body MRI (WB-MRI), brain-MRI, and in female carriers, dedicated breast MRI. A total of 68 adults ≥18 years old have been enrolled to date. Of these, 61 fulfilled the inclusion criteria for the baseline MRI scan. In total, 42 showed a normal scan, while 19 (31%) needed further workup, of whom three individuals (3/19 = 16%) were diagnosed with asymptomatic malignant tumours (thyroid cancer, disseminated upper GI cancer, and liver metastasis from a previous breast cancer). Forty-three participants were women, of whom 21 had performed risk-reducing mastectomy prior to inclusion. The remaining were monitored with breast MRI, and no breast tumours were detected on baseline MRI. WB-MRI has the potential to identify asymptomatic tumours in individuals with hTP53rc syndrome. The challenge is to adequately and efficiently investigate all indeterminate findings. Thus, a multidisciplinary team should be considered in surveillance programs for individuals with hTP53rc syndrome.

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  • 33.
    Papadopetraki, Argyro
    et al.
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Giannopoulos, Antonios
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Avdelningen för idrottsmedicin. National Centre for Sport and Exercise Medicine (NCSEM), School of Sport, Exercise and Health Sciences, Loughborough University, Leicestershire, United Kingdom.
    Maridaki, Maria
    Faculty of Physical Education and Sport Science, National and Kapodistrian University of Athens, Dafne, Greece.
    Zagouri, Flora
    Department of Clinical Therapeutics, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Droufakou, Stavroula
    Medical Oncology Department, Iaso General Clinic, Athens, Greece.
    Koutsilieris, Michael
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Philippou, Anastassios
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    The role of exercise in cancer-related sarcopenia and sarcopenic obesity2023Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 24, artikel-id 5856Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    One of the most common adverse effects of cancer and its therapeutic strategies is sarcopenia, a condition which is characterised by excess muscle wasting and muscle strength loss due to the disrupted muscle homeostasis. Moreover, cancer-related sarcopenia may be combined with the increased deposition of fat mass, a syndrome called cancer-associated sarcopenic obesity. Both clinical conditions have significant clinical importance and can predict disease progression and survival. A growing body of evidence supports the claim that physical exercise is a safe and effective complementary therapy for oncology patients which can limit the cancer- and its treatment-related muscle catabolism and promote the maintenance of muscle mass. Moreover, even after the onset of sarcopenia, exercise interventions can counterbalance the muscle mass loss and improve the clinical appearance and quality of life of cancer patients. The aim of this narrative review was to describe the various pathophysiological mechanisms, such as protein synthesis, mitochondrial function, inflammatory response, and the hypothalamic–pituitary–adrenal axis, which are regulated by exercise and contribute to the management of sarcopenia and sarcopenic obesity. Moreover, myokines, factors produced by and released from exercising muscles, are being discussed as they appear to play an important role in mediating the beneficial effects of exercise against sarcopenia.

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  • 34. Papalampros, Alexandros
    et al.
    Vailas, Michail
    Ntostoglou, Konstantinos
    Chiloeches, maria
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Sakellariou, Stratigoula
    Chouliari, Niki, V
    Samaras, Menelaos G.
    Veltsista, Paraskevi D.
    Theodorou, Sofia D. P.
    Margetis, Aggelos T.
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Karydakis, Lysandros
    Hasemaki, Natasha
    Havaki, Sophia
    Moustakas, Ioannis I.
    Chatzigeorgiou, Antonios
    Karamitros, Timokratis
    Patsea, Eleni
    Kittas, Christos
    Lazaris, Andreas C.
    Felekouras, Evangelos
    Gorgoulis, Vassilis G.
    Frisan, Teresa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Pateras, Ioannis S.
    Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRP proportional to Expression2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 7, artikel-id 1825Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRP a axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.

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  • 35.
    Pham, Thu-Thi
    et al.
    Molecular Epidemiology Research Group, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
    Nimptsch, Katharina
    Molecular Epidemiology Research Group, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
    Aleksandrova, Krasimira
    Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology—BIPS, Bremen, Germany; Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany.
    Jenab, Mazda
    Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), World Health Organization, 150 Cours Albert Thomas, Lyon, France.
    Reichmann, Robin
    Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology—BIPS, Bremen, Germany.
    Wu, Kana
    Department of Nutrition, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Tjønneland, Anne
    Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
    Kyrø, Cecilie
    Danish Cancer Society Research Center, Copenhagen, Denmark.
    Schulze, Matthias B.
    Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
    Kaaks, Rudolf
    Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Katzke, Verena
    Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Palli, Domenico
    Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
    Pasanisi, Fabrizio
    Dipartimento di Medicina Clinica E Chirurgia, Federico Ii University, Naples, Italy.
    Ricceri, Fulvio
    Centre for Biostatistics, Epidemiology, and Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy; Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Italy.
    Tumino, Rosario
    Hyblean Association for Epidemiological Research, AIRE ONLUS, Ragusa, Italy.
    Krogh, Vittorio
    Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, Milan, Italy.
    Roodhart, Jeanine
    Department of Medical Oncology, UMC Utrecht, Utrecht, Netherlands.
    Castilla, Jesús
    Navarra Public Health Institute—IdiSNA, Pamplona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
    Sánchez, Maria-Jose
    CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
    Colorado-Yohar, Sandra Milena
    CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain; Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
    Harbs, Justin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rutegård, Martin
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Papier, Keren
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Aglago, Elom K.
    Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
    Dimou, Niki
    Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), World Health Organization, 150 Cours Albert Thomas, Lyon, France.
    Mayen-Chacon, Ana-Lucia
    Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), World Health Organization, 150 Cours Albert Thomas, Lyon, France.
    Weiderpass, Elisabete
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Pischon, Tobias
    Molecular Epidemiology Research Group, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Biobank Technology Platform, Berlin, Germany; Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Core Facility Biobank, Berlin, Germany.
    Pre-diagnostic circulating resistin concentrations are not associated with colorectal cancer risk in the european prospective investigation into cancer and nutrition study2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 22, artikel-id 5499Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Resistin is a polypeptide implicated in inflammatory processes, and as such could be linked to colorectal carcinogenesis. In case-control studies, higher resistin levels have been found in colorectal cancer (CRC) patients compared to healthy individuals. However, evidence for the association between pre-diagnostic resistin and CRC risk is scarce. We investigated pre-diagnostic resistin concentrations and CRC risk within the European Prospective Investigation into Cancer and Nutrition using a nested case-control study among 1293 incident CRC-diagnosed cases and 1293 incidence density-matched controls. Conditional logistic regression models controlled for matching factors (age, sex, study center, fasting status, and women-related factors in women) and potential confounders (education, dietary and lifestyle factors, body mass index (BMI), BMI-adjusted waist circumference residuals) were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for CRC. Higher circulating resistin concentrations were not associated with CRC (RR per doubling resistin, 1.11; 95% CI 0.94–1.30; p = 0.22). There were also no associations with CRC subgroups defined by tumor subsite or sex. However, resistin was marginally associated with a higher CRC risk among participants followed-up maximally two years, but not among those followed-up after more than two years. We observed no substantial correlation between baseline circulating resistin concentrations and adiposity measures (BMI, waist circumference), adipokines (adiponectin, leptin), or metabolic and inflammatory biomarkers (C-reactive protein, C-peptide, high-density lipoprotein cholesterol, reactive oxygen metabolites) among controls. In this large-scale prospective cohort, there was little evidence of an association between baseline circulating resistin concentrations and CRC risk in European men and women.

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  • 36.
    Provez, Lien
    et al.
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    Putteman, Tom
    Taghon Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roels, Juliette
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Taghon Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
    Reunes, Lindy
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    T’Sas, Sara
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
    Van Loocke, Wouter
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    Lintermans, Béatrice
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    De Coninck, Stien
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    Thenoz, Morgan
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    Sleeckx, Wouter
    Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium; Hematology Department, Ghent University Hospital (UZGent), Ghent, Belgium.
    Maćkowska-Maślak, Natalia
    Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland.
    Taghon, Tom
    Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Taghon Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
    Mansour, Marc R.
    Leukaemia Biology Research Group, Department of Heamatology, University College London Cancer Institute, London, United Kingdom; UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
    Farah, Nadine
    Leukaemia Biology Research Group, Department of Heamatology, University College London Cancer Institute, London, United Kingdom.
    Norga, Koen
    Paediatric Oncology at Antwerp University, Antwerp, Belgium.
    Vandenberghe, Peter
    Department of Human Genetics, Leuven University, Leuven, Belgium.
    Kotecha, Rishi S.
    Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia; Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, Australia; Curtin Medical School, Curtin University, Perth, Australia.
    Goossens, Steven
    Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    De Smedt, Renate
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    Van Vlierberghe, Pieter
    Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
    Pre-clinical evaluation of the hypomethylating agent decitabine for the treatment of t-cell lymphoblastic lymphoma2023Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 3, artikel-id 647Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10–20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL.

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  • 37.
    Razumova, Zoia
    et al.
    Division of Neonatology, Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Oda, Husam
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Govorov, Igor
    Division of Neonatology, Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Institute of Perinatology and Paediatrics, Almazov National Medical Research Centre, St. Petersburg, Russian Federation.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Östensson, Ellinor
    Division of Neonatology, Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Mints, Miriam
    Division of Neonatology, Obstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    The prognostic role of lrig proteins in endometrial cancer2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 6, s. 1-12, artikel-id 1361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Endometrial cancer (EC) is the most common gynecologic malignancy in Sweden and it has various prognostic factors. The LRIG family is a group of three integral surface proteins with a similar domain organization. The study aimed to explore LRIG family as prognostic factor proteins in EC. The initial study cohort included 100 women with EC who were treated at the Department of Women’s and Children’s Health, Karolinska University Hospital Solna, between 2007 and 2012. We assessed the associations between LRIG protein expression and type, grade, and stage of EC, as well as progression‐free and overall survival. Immunohistochemistry results revealed that most women in the analytical sample had >50% LRIG1‐, LRIG2‐ and LRIG3‐positive cells. A statistically significant association was observed between having a high number of LRIG3‐positive cells and superior overall survival (incidence rate ratio = 0.977; 95% confidence interval: 0.958–0.996, p = 0.019). Moreover, positive LRIG3 staining of the cell membrane was associated with reducing in the risk of death (hazard ratio = 0.23; 95% confidence interval: 0.09–0.57). Our results show that LRIG3 expression might be a prognostic factor in EC. The role of LRIG1 and LRIG2 expression remains to be further investigated.

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  • 38.
    Santucci, Domiziana
    et al.
    Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome, Campus Bio-medico”, Via Alvaro del Portillo, 21, Rome, Italy; Department of Radiology, Sant’Anna Hospital, Via Ravona, Como, Italy.
    Faiella, Eliodoro
    Department of Radiology, Sant’Anna Hospital, Via Ravona, Como, Italy.
    Gravina, Michela
    Department of Electrical Engineering and Information Technology, University of Naples Federico II, Naples, Italy.
    Cordelli, Ermanno
    Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome, Campus Bio-medico”, Via Alvaro del Portillo, 21, Rome, Italy.
    de Felice, Carlo
    Department of Radiology, University of Rome “Sapienza”, Viale del Policlinico, 155, Rome, Italy.
    Beomonte Zobel, Bruno
    Department of Radiology, University of Rome, Campus Bio-medico”, Via Alvaro del Portillo, 21, Rome, Italy.
    Iannello, Giulio
    Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome, Campus Bio-medico”, Via Alvaro del Portillo, 21, Rome, Italy.
    Sansone, Carlo
    Department of Electrical Engineering and Information Technology, University of Naples Federico II, Naples, Italy.
    Soda, Paolo
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik. Unit of Computer Systems and Bioinformatics, Department of Engineering, University of Rome, Campus Bio-medico”, Via Alvaro del Portillo, 21, Rome, Italy.
    CNN-Based Approaches with Different Tumor Bounding Options for Lymph Node Status Prediction in Breast DCE-MRI2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 19, artikel-id 4574Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The axillary lymph node status (ALNS) is one of the most important prognostic factors in breast cancer (BC) patients, and it is currently evaluated by invasive procedures. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), highlights the physiological and morphological characteristics of primary tumor tissue. Deep learning approaches (DL), such as convolutional neural networks (CNNs), are able to autonomously learn the set of features directly from images for a specific task.

    Materials and Methods: A total of 155 malignant BC lesions evaluated via DCE-MRI were included in the study. For each patient’s clinical data, the tumor histological and MRI characteristics and axillary lymph node status (ALNS) were assessed. LNS was considered to be the final label and dichotomized (LN+ (27 patients) vs. LN− (128 patients)). Based on the concept that peritumoral tissue contains valuable information about tumor aggressiveness, in this work, we analyze the contributions of six different tumor bounding options to predict the LNS using a CNN. These bounding boxes include a single fixed-size box (SFB), a single variable-size box (SVB), a single isotropic-size box (SIB), a single lesion variable-size box (SLVB), a single lesion isotropic-size box (SLIB), and a two-dimensional slice (2DS) option. According to the characteristics of the volumes considered as inputs, three different CNNs were investigated: the SFB-NET (for the SFB), the VB-NET (for the SVB, SIB, SLVB, and SLIB), and the 2DS-NET (for the 2DS). All the experiments were run in 10-fold cross-validation. The performance of each CNN was evaluated in terms of accuracy, sensitivity, specificity, the area under the ROC curve (AUC), and Cohen’s kappa coefficient (K).

    Results: The best accuracy and AUC are obtained by the 2DS-NET (78.63% and 77.86%, respectively). The 2DS-NET also showed the highest specificity, whilst the highest sensibility was attained by the VB-NET based on the SVB and SIB as bounding options.

    Conclusion: We have demonstrated that a selective inclusion of the DCE-MRI’s peritumoral tissue increases accuracy in the lymph node status prediction in BC patients using CNNs as a DL approach.

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  • 39. Saudi, Aws
    et al.
    Banday, Viqar Showkat
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Zirakzadeh, A. Ali
    Selinger, Martin
    Forsberg, Jon
    Holmbom, Martin
    Henriksson, Johan
    Waldén, Mauritz
    Alamdari, Farhood
    Aljabery, Firas
    Winqvist, Ola
    Sherif, Amir
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Immune-activated B cells are dominant in prostate cancer2023Ingår i: Cancers, ISSN 2072-6694, Vol. 15, nr 3, artikel-id 920Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    B cells are multifaceted immune cells responding robustly during immune surveillance against tumor antigens by presentation to T cells and switched immunoglobulin production. However, B cells are unstudied in prostate cancer (PCa). We used flow cytometry to analyze B-cell subpopulations in peripheral blood and lymph nodes from intermediate-high risk PCa patients. B-cell subpopulations were related to clinicopathological factors. B-cell-receptor single-cell sequencing and VDJ analysis identified clonal B-cell expansion in blood and lymph nodes. Pathological staging was pT2 in 16%, pT3a in 48%, and pT3b in 36%. Lymph node metastases occurred in 5/25 patients (20%). Compared to healthy donors, the peripheral blood CD19+ B-cell compartment was significantly decreased in PCa patients and dominated by naïve B cells. The nodal B-cell compartment had significantly increased fractions of CD19+ B cells and switched memory B cells. Plasmablasts were observed in tumor-draining sentinel lymph nodes (SNs). VDJ analysis revealed clonal expansion in lymph nodes. Thus, activated B cells are increased in SNs from PCa patients. The increased fraction of switched memory cells and plasmablasts together with the presence of clonally expanded B cells indicate tumor-specific T-cell-dependent responses from B cells, supporting an important role for B cells in the protection against tumors.

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  • 40. Sekhar, Sreeja C.
    et al.
    Venkatesh, Jaganathan
    Cheriyan, Vino T.
    Muthu, Magesh
    John D. Dingell Veterans Administration Medical Center, Detroit, USA; Department of Oncology, Karmanos Cancer Institute, Detroit, USA.
    Levi, Edi
    Assad, Hadeel
    Meister, Paul
    Undyala, Vishnu V.
    Gauld, James W.
    Rishi, Arun K.
    A H2AX-CARP-1 Interaction Regulates Apoptosis Signaling Following DNA Damage2019Ingår i: Cancers, ISSN 2072-6694, Vol. 11, nr 2, artikel-id 221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cell Cycle and Apoptosis Regulatory Protein (CARP-1/CCAR1) is a peri-nuclear phosphoprotein that regulates apoptosis via chemotherapeutic Adriamycin (doxorubicin) and a novel class of CARP-1 functional mimetic (CFM) compounds. Although Adriamycin causes DNA damage, data from Comet assays revealed that CFM-4.16 also induced DNA damage. Phosphorylation of histone 2AX (gamma H2AX) protein is involved in regulating DNA damage repair and apoptosis signaling. Adriamycin or CFM-4.16 treatments inhibited cell growth and caused elevated CARP-1 and gamma H2AX in human breast (HBC) and cervical cancer (HeLa) cells. In fact, a robust nuclear or peri-nuclear co-localization of CARP-1 and gamma H2AX occurred in cells undergoing apoptosis. Knock-down of CARP-1 diminished gamma H2AX, their co-localization, and apoptosis in CFM-4.16- or Adriamycin-treated cells. We found that CARP-1 directly binds with H2AX, and H2AX interacted with CARP-1, but not CARP-1 (Delta 600-652) mutant. Moreover, cells expressing CARP-1 (Delta 600-652) mutant were resistant to apoptosis, and had diminished levels of gamma H2AX, when compared with cells expressing wild-type CARP-1. Mutagenesis studies revealed that H2AX residues 1-35 harbored a CARP-1-binding epitope, while CARP-1 amino acids 636-650 contained an H2AX-interacting epitope. Surface plasmon resonance studies revealed that CARP-1 (636-650) peptide bound with H2AX (1-35) peptide with a dissociation constant (K-d) of 127 nM. Cells expressing enhanced GFP (EGFP)-tagged H2AX (1-35) peptide or EGFP-tagged CARP-1 (636-650) peptide were resistant to inhibition by Adriamycin or CFM-4.16. Treatment of cells with transactivator of transcription (TAT)-tagged CARP-1 (636-650) peptide resulted in a moderate, statistically significant abrogation of Adriamycin-induced growth inhibition of cancer cells. Our studies provide evidence for requirement of CARP-1 interaction with H2AX in apoptosis signaling by Adriamycin and CFM compounds.

  • 41. Vadivel, Chella Krishna
    et al.
    Gluud, Maria
    Torres-Rusillo, Sara
    Boding, Lasse
    Willerslev-Olsen, Andreas
    Buus, Terkild B.
    Nielsen, Tea Kirkegaard
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Biomedical Sciences, Malmö University, 21428 Malmö, Sweden.
    Bonefeld, Charlotte M.
    Geisler, Carsten
    Krejsgaard, Thorbjorn
    Fuglsang, Anja T.
    Odum, Niels
    Woetmann, Anders
    JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL).2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 2, artikel-id 280Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Perturbation in JAK-STAT signaling has been reported in the pathogenesis of cutaneous T cell lymphoma (CTCL). JAK3 is predominantly associated with the intra-cytoplasmic part of IL-2Rγc located in the plasma membrane of hematopoietic cells. Here we demonstrate that JAK3 is also ectopically expressed in the nucleus of malignant T cells. We detected nuclear JAK3 in various CTCL cell lines and primary malignant T cells from patients with Sézary syndrome, a leukemic variant of CTCL. Nuclear localization of JAK3 was independent of its kinase activity whereas STAT3 had a modest effect on nuclear JAK3 expression. Moreover, JAK3 nuclear localization was only weakly affected by blockage of nuclear export. An inhibitor of the nuclear export protein CRM1, Leptomycin B, induced an increased expression of SOCS3 in the nucleus, but only a weak increase in nuclear JAK3. Importantly, immunoprecipitation experiments indicated that JAK3 interacts with the nuclear protein POLR2A, the catalytic subunit of RNA Polymerase II. Kinase assays showed tyrosine phosphorylation of recombinant human Histone H3 by JAK3 in vitro-an effect which was blocked by the JAK inhibitor (Tofacitinib citrate). In conclusion, we provide the first evidence of nuclear localization of JAK3 in malignant T cells. Our findings suggest that JAK3 may have a cytokine-receptor independent function in the nucleus of malignant T cells, and thus a novel non-canonical role in CTCL.

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  • 42.
    Wikström, Pernilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Halin Bergström, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Josefsson, Andreas
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Semenas, Julius
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordstrand, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Thellenberg Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Epithelial and stromal characteristics of primary tumors predict the bone metastatic subtype of prostate cancer and patient survival after androgen-deprivation therapy2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 21, artikel-id 5195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prostate cancer (PC) bone metastases can be divided into transcriptomic subtypes, by us termed MetA-C. The MetB subtype, constituting about 20% of the cases, is characterized by high cell cycle activity, low androgen receptor (AR) activity, and a limited response to standard androgen deprivation therapy (ADT). Complementary treatments should preferably be introduced early on if the risk of developing metastases of the MetB subtype is predicted to behigh. In this study, we therefore examined if the bone metastatic subtype and patient outcome after ADT could be predicted by immunohistochemical analysis of epithelial and stromal cell markers in primary tumor biopsies obtained at diagnosis (n = 98). In this advanced patient group, primary tumor International Society of Urological Pathology (ISUP) grade was not associated with outcome or metastasis subtype. In contrast, high tumor cell Ki67 labeling (proliferation) in combination with low tumor cell immunoreactivity for PSA, and a low fraction of AR positive stroma cells in the primary tumors were prognostic for poor survival after ADT. Accordingly, the same tissue markers were associated with developing metastases enriched for the aggressive MetB subtype. The development of the contrasting MetA subtype, showing the best response to ADT, could be predicted by the opposite staining pattern. We conclude that outcome after ADT and metastasis subtype can, at least to some extent, be predicted by analysis of primary tumor characteristics, such as tumor cell proliferation and PSA expression, and AR expression in stromal cells.

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  • 43.
    Wu, Wendy Yi-Ying
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Malmström, Annika
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Bondy, Melissa L.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dahlin, Anna M.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes2019Ingår i: Cancers, ISSN 2072-6694, Vol. 11, nr 12, artikel-id 2001Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

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  • 44. Wu, Y. H. Andrew
    et al.
    Oba, Atsushi
    Beaty, Laurel
    Colborn, Kathryn L.
    Rodriguez Franco, Salvador
    Harnke, Ben
    Meguid, Cheryl
    Negrini, Daniel
    Valente, Roberto
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Ahrendt, Steven
    Schulick, Richard D.
    Del Chiaro, Marco
    Ductal Dilatation of ≥5 mm in Intraductal Papillary Mucinous Neoplasm Should Trigger the Consideration for Pancreatectomy: A Meta-Analysis and Systematic Review of Resected Cases2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 9, artikel-id 2031Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intraductal papillary mucinous neoplasms (IPMN) are common but difficult to manage since accurate tools for diagnosing malignancy are unavailable. This study tests the diagnostic value of the main pancreatic duct (MPD) diameter for detecting IPMN malignancy using a meta-analysis of published data of resected IPMNs. Collected from a comprehensive literature search, the articles included in this analysis must report malignancy cases (high-grade dysplasia (HGD) and invasive carcinoma (IC)) and MPD diameter so that two MPD cut-offs could be created. The sensitivity, specificity, and odds ratios of the two cutoffs for predicting malignancy were calculated. A review of 1493 articles yielded 20 retrospective studies with 3982 resected cases. A cutoff of ≥5 mm is more sensitive than the ≥10 mm cutoff and has pooled sensitivity of 72.20% and 75.60% for classification of HGD and IC, respectively. Both MPD cutoffs of ≥5 mm and ≥10 mm were associated with malignancy (OR = 4.36 (95% CI: 2.82, 6.75) vs. OR = 3.18 (95% CI: 2.25, 4.49), respectively). The odds of HGD and IC for patients with MPD ≥5 mm were 5.66 (95% CI: 3.02, 10.62) and 7.40 (95% CI: 4.95, 11.06), respectively. OR of HGD and IC for MPD ≥10 mm cutoff were 4.36 (95% CI: 3.20, 5.93) and 4.75 (95% CI: 2.39, 9.45), respectively. IPMN with MPD of >5 mm could very likely be malignant. In selected IPMN patients, pancreatectomy should be considered when MPD is >5 mm.

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  • 45.
    Ährlund-Richter, Andreas
    et al.
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Holzhauser, Stefan
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Dalianis, Tina
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Näsman, Anders
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Pathology, CCK R8:02, Karolinska University Hospital, Stockholm, Sweden.
    Mints, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
    Whole-exome sequencing of HPV positive tonsillar and base of tongue squamous cell carcinomas reveals a global mutational pattern along with relapse-specific somatic variants2022Ingår i: Cancers, ISSN 2072-6694, Vol. 14, nr 1, artikel-id 77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To identify predictive/targetable markers in human papillomavirus positive (HPV+) ton-sillar and base of tongue cancer (TSCC/BOTSCC), whole-exome sequencing (WES) of tumours of patients with/without recurrence was performed. Forty primary tumours and adjacent normal tissue were separated by micro-dissection from formalin-fixed paraffin-embedded tissue from patients treated with curative intent 2000–2014 at Karolinska University Hospital. Successful sequencing was obtained in primary tumours of 18 patients without and primaries of 17 with local or distant recurrence, as well as in 10 corresponding recurrences (i.e., five local relapses and five distant metas-tases) from these 17 patients. One variant—a high-impact deletion in the CDC27 gene—was observed only in primaries of 5/17 patients that had a recurrence after full treatment but in none of those without recurrence. In addition, 3 variants and 26 mutated genes, including CDC27, BCLAF1 and AQP7, were present in at least 30% of all primary tumours independent of prognosis. To conclude, a CDC27 deletion was specific and found in ~30% of samples from patients with a local relapse/distant metastasis and could, therefore, potentially be a prospective marker to predict prognosis. Commonly mutated genes, such as BCLAF1, should be further studied in the context of targeted therapy.

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  • 46.
    Åberg, Anna-Maja
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Halin Bergström, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Tjon-Kon-Fat, Lee-Ann
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nilsson, Jonas A.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Thellenberg-Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    High monocyte count and expression of s100a9 and s100a12 in peripheral blood mononuclear cells are associated with poor outcome in patients with metastatic prostate cancer2021Ingår i: Cancers, ISSN 2072-6694, Vol. 13, nr 10, artikel-id 2424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, S100A9 and S100A12, in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12, could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis.

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