Browsing by Subject "BIOMARKERS"

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  • Posti, Jussi P.; Takala, Riikka S. K.; Raj, Rahul; Luoto, Teemu M.; Azurmendi, Leire; Lagerstedt, Linnea; Mohammadian, Mehrbod; Hossain, Iftakher; Gill, Jessica; Frantzen, Janek; van Gils, Mark; Hutchinson, Peter J.; Katila, Ari J.; Koivikko, Pia; Maanpää, Henna-Riikka; Menon, David K.; Newcombe, Virginia F.; Tallus, Jussi; Blennow, Kaj; Tenovuo, Olli; Zetterberg, Henrik; Sanchez, Jean-Charles (2020)
    Background: Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). Objective: To investigate whether admission levels of eight different protein biomarkers can improve the outcome prediction performance of the Helsinki computed tomography score (HCTS) without clinical covariates in TBI. Materials and methods: Eighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of beta-amyloid isoforms 1-40 (A beta 40) and 1-42 (A beta 42), glial fibrillary acidic protein, heart fatty acid-binding protein, interleukin 10 (IL-10), neurofilament light, S100 calcium-binding protein B, and total tau were measured within 24 h from admission. The patients were divided into favorable (Glasgow Outcome Scale-Extended 5-8, n = 49) and unfavorable (Glasgow Outcome Scale-Extended 1-4, n = 33) groups. The outcome was assessed 6-12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90-100%. Results: The HCTS alone yielded a sensitivity of 97.0% (95% CI: 90.9-100) and specificity of 22.4% (95% CI: 10.2-32.7) and partial area under the curve of the receiver operating characteristic of 2.5% (95% CI: 1.1-4.7), in discriminating patients with favorable and unfavorable outcomes. The threshold to detect a patient with unfavorable outcome was an HCTS > 1. The three best individually performing biomarkers in outcome prediction were A beta 40, A beta 42, and neurofilament light. The optimal panel included IL-10, A beta 40, and the HCTS reaching a partial area under the curve of the receiver operating characteristic of 3.4% (95% CI: 1.7-6.2) with a sensitivity of 90.9% (95% CI: 81.8-100) and specificity of 59.2% (95% CI: 40.8-69.4). Conclusion: Admission plasma levels of IL-10 and A beta 40 significantly improve the prognostication ability of the HCTS after TBI.
  • Lähteenmäki, Hanna; Umeizudike, Kehinde A.; Heikkinen, Anna Maria; Räisänen, Ismo T.; Rathnayake, Nilminie; Johannsen, Gunnar; Tervahartiala, Taina; Nwhator, Solomon O.; Sorsa, Timo (2020)
    This communication article addresses currently available rapid non-invasive methods to screen and detect periodontitis and dental peri-implantitis. In this regard, oral fluid biomarkers have been researched extensively but self-reported oral health (SROH)-questionnaires have also been developed. Both alternatives may offer a quick and easy way to screen and detect diseased patients. Active matrix metalloproteinase (aMMP-8) is one of the most validated biomarkers for screening and detecting periodontal breakdown related to periodontitis and peri-implantitis and monitoring their treatment effects revealing successful, less- and non-successful treatment results. Currently available aMMP-8 lateral-flow technologies allow this kind of analysis, as demonstrated here, to be conducted quantitatively online and real-time as point-of-care/chairside testing in dental and even medical care settings. In this study, an aMMP-8 peri-implant sulcular fluid point-of-care-test diagnosed peri-implantitis and healthy implants far more accurately than bleeding-on-probing or the other biomarkers, such as polymorphonuclear (PMN)/neutrophil elastase, myeloperoxidase and MMP-9. Although, SROH-questionnaires allow screening in similar settings but they lack the information about the current disease activity of periodontitis and peri-implantitis, which is of essential value in periodontal diagnostics and treatment monitoring. Thus, both methods can be considered as adjunct methods for periodontitis and peri-implant diagnostics, but the value of oral fluid biomarkers analysis does not seem to be substitutable.
  • Int League Against Epilepsy Consor; Stevelink, Remi; Pangilinan, Faith; Jansen, Floor E.; Eriksson, Johan G.; Kälviäinen, Reetta; Kantanen, Anne-Mari; Lehesjoki, Anna-Elina; Palotie, Aarno (2019)
    Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.
  • Heikkinen, Ilkka; Bello, Ibrahim O.; Wahab, Awais; Hagström, Jaana; Haglund, Caj; Coletta, Ricardo D.; Nieminen, Pentti; Makitie, Antti A.; Salo, Tuula; Leivo, Ilmo; Almangush, Alhadi (2019)
    Tumor-infiltrating lymphocytes (TILs) have shown a promising prognostic value in many epithelial cancers. We sought to assess the prognostic value of TILs in a multicenter cohort of early oral tongue squamous cell carcinoma (OTSCC). The percentage of TILs was assessed on the surgical resection slides stained with hematoxylin and eosin. The assessment of TILs was performed in the stromal compartment and in the intraepithelial compartment (at the invasive front and at the center of the tumor). We followed the method that was described recently by the International Immuno-Oncology Biomarker Working Group for the assessment of TILs. A total of 308 cases from the 5 Finnish university hospitals and from A.C. Camargo Cancer Center, Sao Paulo, Brazil, were included. We found a promising prognostic value for stromal TILs at the invasive front in the multivariable analysis with a hazard ratio of 2.61 (95% confidence interval [CI], 1.77-3.83; P
  • Koulaouzidis, Anastasios; Sipponen, Taina; Nemeth, Artur; Makins, Richard; Kopylov, Uri; Nadler, Moshe; Giannakou, Andry; Yung, Diana E.; Johansson, Gabriele Wurm; Bartzis, Leonidas; Thorlacius, Henrik; Seidman, Ernest G.; Eliakim, Rami; Plevris, John N.; Toth, Ervin (2016)
    Accurate inflammation reporting in capsule endoscopy (CE) is important for diagnosis and monitoring of treatment of inflammatory bowel disease (IBD). Fecal calprotectin (FC) is a highly specific biomarker of gut inflammation. Lewis score (LS) was developed to standardize quantification of inflammation in small-bowel (SB) CE images. Multicenter retrospective study aiming to investigate correlation between LS and FC in a large group of patients undergoing CE for suspected or known small-bowel IBD, and to develop a model for prediction of CE results (LS) based on FC levels. Five academic centers and a district general hospital offering CE in UK, Finland, Sweden, Canada, and Israel. In total, 333 patients were recruited. They had small-bowel CE and FC done within 3 months. Overall, correlation between FC and LS was weak (r (s): 0.232, P <0.001). When two clinically significant FC thresholds (100 and 250 mu g/g) were examined, the r (s) between FC and LS was 0.247 (weak) and 0.337 (moderate), respectively (P = 0.307). For clinically significant (LS a parts per thousand yen 135) or negative (LS <135) for SB inflammation, ROC curves gave an optimum cutoff point of FC 76 mu g/g with sensitivity 0.59 and specificity 0.41. Limitations: Retrospective design. LS appears to show low correlation with FC as well as other serology markers of inflammation. FC does not appear to be a reliable biomarker for significant small-bowel inflammation. Nevertheless, FC level a parts per thousand yen 76 mu g/g may be associated with appreciable visual inflammation on small-bowel CE in patients with negative prior diagnostic workup.
  • Rautiola, Juhana; Lampinen, Anita; Mirtti, Tuomas; Ristimaki, Ari; Joensuu, Heikki; Bono, Petri; Saharinen, Pipsa (2016)
    The Angiopoietin-2 (Ang2, Angpt2) growth factor is a context-dependent antagonist/agonist ligand of the endothelial Tie2 receptor tyrosine kinase and known to promote tumour angiogenesis and metastasis. Angiopoietin antagonists have been tested in clinical cancer trials in combination with VEGF-based anti-angiogenic therapy, including sunitinib, which is widely used as a first-line therapy for metastatic renal cell carcinoma (mRCC). However, little is known about Ang2 protein expression in human tumours and the correlation of tumour Ang2 expression with tumour vascularization, tumour cell proliferation and response to anti-angiogenic therapies. Here, we evaluated, using immunohistochemistry, the expression of Ang2, CD31 and the cell proliferation marker Ki-67 in the primary kidney cancer from 136 mRCC patients, who received first-line sunitinib after nephrectomy. Ang2 protein expression was restrained to RCC tumour vessels, and correlated with tumour vascularization and response to sunitinib. High pre-therapeutic Ang2 expression, and more strongly, combined high expression of both Ang2 and CD31, were associated with a high clinical benefit rate (CBR). Low cancer Ki-67 expression, but not Ang2 or CD31 expression, was associated with favourable progression-free (PFS) and overall survival (OS) as compared to patients with high Ki-67 expression (PFS 6.5 vs. 10.6 months, P = 0.009; OS, 15.7 vs. 28.5 months, P = 0.015). In summary, in this study to investigate endothelial Ang2 in mRCC patients treated with first-line sunitinib, high cancer Ang2 expression was associated with the CBR, but not PFS or OS, whereas low Ki-67 expression was significantly associated with long PFS and OS.
  • Karhula, Kati; Harma, Mikko; Sallinen, Mikael; Lindholm, Harri; Hirvonen, Ari; Elovainio, Marko; Kivimaki, Mika; Vahtera, Jussi; Puttonen, Sampsa (2016)
    Although the prevalence of work-related stress has increased, knowledge on the contributions of that stress to long-term adverse health effects is still lacking. Stress biomarkers can reveal early signs of negative health effects, but no previous studies have measured both acute stress reactions and long-term exposure to job strain using both salivary cortisol and -amylase (AA). The present study examines the association between job strain and these biomarkers among shift-working female health care professionals in the laboratory and the field. The 95 participants were recruited from hospital wards categorized in either the top (high job strain [HJS] group, n = 42) or the bottom quartile of job strain (low job strain [LJS] group, n = 53), as rated by survey responses. Participants' self-perceived job strain was at least as high or low as the ward's average estimation. Saliva samples were collected during the Trier Social Stress Test (TSST), preselected morning and night shifts, and a day off. There was a larger increase in the cortisol concentration of participants in the HJS than in the LJS group (2.27- vs. 1.48-fold, respectively, nonsignificant) during the TSST. Participants in the HJS group also had higher salivary AA levels 30 min after awakening on the morning-shift day than those in the LJS group (p = .02), whereas the salivary cortisol awakening response on the day off was higher in the LJS group (p = .05, education as a covariate). The remaining stress-biomarker results did not differ significantly between groups. These data suggest that HJS in shift-working health care professionals is weakly associated with changes in stress biomarkers.
  • Fedirko, Veronika; Jenab, Mazda; Meplan, Catherine; Jones, Jeb S.; Zhu, Wanzhe; Schomburg, Lutz; Siddiq, Afshan; Hybsier, Sandra; Overvad, Kim; Tjonneland, Anne; Omichessan, Hanane; Perduca, Vittorio; Boutron-Ruault, Marie-Christine; Kuehn, Tilman; Katzke, Verena; Aleksandrova, Krasimira; Trichopoulou, Antonia; Karakatsani, Anna; Kotanidou, Anastasia; Tumino, Rosario; Panico, Salvatore; Masala, Giovanna; Agnoli, Claudia; Naccarati, Alessio; Bueno-de-Mesquita, Bas; Vermeulen, Roel C. H.; Weiderpass, Elisabete; Skeie, Guri; Nost, Therese Haugdahl; Lujan-Barroso, Leila; Ramon Quiros, J.; Maria Huerta, Jose; Rodriguez-Barranco, Miguel; Barricarte, Aurelio; Gylling, Bjoern; Harlid, Sophia; Bradbury, Kathryn E.; Wareham, Nick; Khaw, Kay-Tee; Gunter, Marc; Murphy, Neil; Freisling, Heinz; Tsilidis, Kostas; Aune, Dagfinn; Riboli, Elio; Hesketh, John E.; Hughes, David J. (2019)
    Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (P-ACT = 0.10; P-ACT significance threshold was P <0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.
  • Palviainen, Mari; Laukkanen, Kirsi; Tavukcuoglu, Zeynep; Velagapudi, Vidya; Kärkkäinen, Olli; Hanhineva, Kati; Auriola, Seppo; Ranki, Annamari; Siljander, Pia (2020)
    Cancer alters cell metabolism. How these changes are manifested in the metabolite cargo of cancer-derived extracellular vesicles (EVs) remains poorly understood. To explore these changes, EVs from prostate, cutaneous T-cell lymphoma (CTCL), colon cancer cell lines, and control EVs from their noncancerous counterparts were isolated by differential ultracentrifugation and analyzed by nanoparticle tracking analysis (NTA), electron microscopy (EM), Western blotting, and liquid chromatography-mass spectrometry (LC-MS). Although minor differences between the cancerous and non-cancerous cell-derived EVs were observed by NTA and Western blotting, the largest differences were detected in their metabolite cargo. Compared to EVs from noncancerous cells, cancer EVs contained elevated levels of soluble metabolites, e.g., amino acids and B vitamins. Two metabolites, proline and succinate, were elevated in the EV samples of all three cancer types. In addition, folate and creatinine were elevated in the EVs from prostate and CTCL cancer cell lines. In conclusion, we present the first evidence in vitro that the altered metabolism of different cancer cells is reflected in common metabolite changes in their EVs. These results warrant further studies on the significance and usability of this metabolic fingerprint in cancer.
  • Ahola-Olli, Ari V.; Mustelin, Linda; Kalimeri, Maria; Kettunen, Johannes; Jokelainen, Jari; Auvinen, Juha; Puukka, Katri; Havulinna, Aki S.; Lehtimäki, Terho; Kähönen, Mika; Juonala, Markus; Keinänen-Kiukaanniemi, Sirkka; Salomaa, Veikko; Perola, Markus; Järvelin, Marjo-Riitta; Ala-Korpela, Mika; Raitakari, Olli; Wurtz, Peter (2019)
    Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.
  • Paajanen, Juuso; Laaksonen, Sanna; Ilonen, Ilkka; Vehmas, Tapio; Mäyränpää, Mikko I.; Sutinen, Eva; Kettunen, Eeva; Salo, Jarmo A.; Räsänen, Jari; Wolff, Henrik; Myllärniemi, Marjukka (2020)
    Within a larger national malignant pleural mesothelioma cohort, we identified 43 patients with unusually long survival times. This study aimed to evaluate the diagnostic accuracy in this subgroup, and the diagnosis was confirmed to be correct in most cases. In addition, we searched for clinical factors related to the prolonged survival time. Introduction: Malignant pleural mesothelioma (MPM) is a fatal malignancy strongly associated with previous asbestos exposure. Overall survival remains dismal, partly owing to poor response to available treatment. The aims of this study were to evaluate diagnostic accuracy in a group of patients with MPM with an unusually long survival time and to assess the factors related to this prolonged survival. Materials and Methods: Forty-three patients with overall survival exceeding 5 years were accepted to the long-term survivor (LTS) group, and these patients were compared with 84 patients with epithelial MPM. Data were collected from various national registries and electronic medical records. In addition, all available histopathologic diagnostic samples and computed tomography studies were re-evaluated by experienced specialists. Results: Our study showed a good diagnostic accuracy, with only 1 (0.5%) patient having an incorrect MPM diagnosis. Two (0.9%) localized malignant mesotheliomas and 2 (0.9%) well-differentiated papillary mesotheliomas were also found. LTS patients were younger, more frequently female, had a better performance status at time of diagnosis, and had less evidence of prior asbestos exposure. In multivariate analysis, we showed tumor size, Eastern Cooperative Oncology Group performance status, and first-line treatment (both surgery and chemotherapy) to be associated with survival time. Conclusion: We confirmed the diagnosis of MPM in an overwhelming majority of patients in the LTS group. An epithelial subtype of MPM behaving clinically more indolently seems to exist, but further tumor and genetic characterization is needed. The prolonged survival time is most likely explained by a combination of tumor-, patient-, and treatment-related factors. (C) 2020 Elsevier Inc. All rights reserved.
  • Zamora-Ros, Raul; Cayssials, Valerie; Jenab, Mazda; Rothwell, Joseph A.; Fedirko, Veronika; Aleksandrova, Krasimira; Tjonneland, Anne; Kyro, Cecilie; Overvad, Kim; Boutron-Ruault, Marie-Christine; Carbonnel, Franck; Mahamat-Saleh, Yahya; Kaaks, Rudolf; Kuehn, Tilman; Boeing, Heiner; Trichopoulou, Antonia; Valanou, Elissavet; Vasilopoulou, Effie; Masala, Giovanna; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Ricceri, Fulvio; Weiderpass, Elisabete; Lukic, Marko; Sandanger, Torkjel M.; Lasheras, Cristina; Agudo, Antonio; Sanchez, Maria-Jose; Amiano, Pilar; Navarro, Carmen; Ardanaz, Eva; Sonestedt, Emily; Ohlsson, Bodil; Nilsson, Lena Maria; Rutegard, Martin; Bueno-de-Mesquita, Bas; Peeters, Petra H.; Khaw, Kay-Thee; Wareham, Nicholas J.; Bradbury, Kathryn; Freisling, Heinz; Romieu, Isabelle; Cross, Amanda J.; Vineis, Paolo; Scalbert, Augustin (2018)
    Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HRlog2=1.06, 95% CI 0.99-1.14) or in men (HRlog2=0.97, 95% CI 0.90-1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HRlog2=0.91, 95% CI 0.85-0.97) and positively associated with rectal cancer in women (HRlog2=1.10, 95% CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.
  • Hanson, Linda L. Magnusson; Virtanen, Marianna; Rod, Naja H.; Steptoe, Andrew; Head, Jenny; Batty, G. D.; Kivimäki, Mika; Westerlund, Hugo (2019)
    Objective: Inflammation may underlie the association between psychological stress and cardiometabolic diseases, but this proposition has not been tested longitudinally. We investigated whether the circulating inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) mediate the relationship between psychosocial work characteristics and diabetes. Methods: We used three phases of data at 5 years intervals from the Whitehall II cohort study, originally recruiting 10,308 civil service employees aged 35-55 years. The data included repeat self-reports of job demands, control and social support, IL-6 from plasma samples, CRP from serum samples, and diabetes, ascertained through oral glucose tolerance test, medications, and self-reports of doctor-diagnosed diabetes. Results: Structural equation models with age, sex and occupational position considering men and women combined, showed that low social support at work, but not high job demands or low job control, was prospectively associated with diabetes (standardized beta = 0.05, 95% confidence interval (CI) 0.01-0.09) and higher levels of IL-6 (beta = 0.03, CI 0.00-0.06). The inflammatory markers and diabetes were bidirectionally associated over time. A mediation model including workplace social support, IL-6 and diabetes further showed that 10% of the association between social support and diabetes over the three repeat examinations (total effect beta = 0.08, CI 0.01-0.15) was attributable to a weak indirect effect through IL-6 (beta = 0.01, CI 0.00-0.02). A similar indirect effect was observed for CRP in men only, while job control was prospectively associated with IL-6 among women. Conclusions: This study indicates an association between poor workplace support and diabetes that is partially ascribed to an inflammatory response.
  • Spjuth, Ola; Karlsson, Andreas; Clements, Mark; Humphreys, Keith; Ivansson, Emma; Dowling, Jim; Eklund, Martin; Jauhiainen, Alexandra; Czene, Kamila; Gronberg, Henrik; Sparen, Par; Wiklund, Fredrik; Cheddad, Abbas; Palsdottir, Porgerodur; Rantalainen, Mattias; Abrahamsson, Linda; Laure, Erwin; Litton, Jan-Eric; Palmgren, Juni (2017)
    Objective: We provide an e-Science perspective on the workflow from risk factor discovery and classification of disease to evaluation of personalized intervention programs. As case studies, we use personalized prostate and breast cancer screenings. Materials and Methods: We describe an e-Science initiative in Sweden, e-Science for Cancer Prevention and Control (eCPC), which supports biomarker discovery and offers decision support for personalized intervention strategies. The generic eCPC contribution is a workflow with 4 nodes applied iteratively, and the concept of e-Science signifies systematic use of tools from the mathematical, statistical, data, and computer sciences. Results: The eCPC workflow is illustrated through 2 case studies. For prostate cancer, an in-house personalized screening tool, the Stockholm-3 model (S3M), is presented as an alternative to prostate-specific antigen testing alone. S3M is evaluated in a trial setting and plans for rollout in the population are discussed. For breast cancer, new biomarkers based on breast density and molecular profiles are developed and the US multicenter Women Informed to Screen Depending on Measures (WISDOM) trial is referred to for evaluation. While current eCPC data management uses a traditional data warehouse model, we discuss eCPC-developed features of a coherent data integration platform. Discussion and Conclusion: E-Science tools are a key part of an evidence-based process for personalized medicine. This paper provides a structured workflow from data and models to evaluation of new personalized intervention strategies. The importance of multidisciplinary collaboration is emphasized. Importantly, the generic concepts of the suggested eCPC workflow are transferrable to other disease domains, although each disease will require tailored solutions.
  • Peddinti, Gopal; Cobb, Jeff; Yengo, Loic; Froguel, Philippe; Kravic, Jasmina; Balkau, Beverley; Tuomi, Tiinamaija; Aittokallio, Tero; Groop, Leif (2017)
    Aims/hypothesis The aims of this study were to evaluate systematically the predictive power of comprehensive metabolomics profiles in predicting the future risk of type 2 diabetes, and to identify a panel of the most predictive metabolic markers. Methods We applied an unbiased systems medicine approach to mine metabolite combinations that provide added value in predicting the future incidence of type 2 diabetes beyond known risk factors. We performed mass spectrometry-based targeted, as well as global untargeted, metabolomics, measuring a total of 568 metabolites, in a Finnish cohort of 543 nondiabetic individuals from the Botnia Prospective Study, which included 146 individuals who progressed to type 2 diabetes by the end of a 10 year follow-up period. Multivariate logistic regression was used to assess statistical associations, and regularised least-squares modelling was used to perform machine learning-based risk classification and marker selection. The predictive performance of the machine learning models and marker panels was evaluated using repeated nested cross-validation, and replicated in an independent French cohort of 1044 individuals including 231 participants who progressed to type 2 diabetes during a 9 year follow-up period in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study. Results Nine metabolites were negatively associated (potentially protective) and 25 were positively associated with progression to type 2 diabetes. Machine learning models based on the entire metabolome predicted progression to type 2 diabetes (area under the receiver operating characteristic curve, AUC = 0.77) significantly better than the reference model based on clinical risk factors alone (AUC = 0.68; DeLong's p = 0.0009). The panel of metabolic markers selected by the machine learning-based feature selection also significantly improved the predictive performance over the reference model (AUC = 0.78; p = 0.00019; integrated discrimination improvement, IDI = 66.7%). This approach identified novel predictive biomarkers, such as alpha-tocopherol, bradykinin hydroxyproline, X-12063 and X-13435, which showed added value in predicting progression to type 2 diabetes when combined with known biomarkers such as glucose, mannose and alpha-hydroxybutyrate and routinely used clinical risk factors. Conclusions/interpretation This study provides a panel of novel metabolic markers for future efforts aimed at the prevention of type 2 diabetes.
  • Perpetuo, Ines P.; Raposeiro, Rita; Caetano-Lopes, Joana; Vieira-Sousa, Elsa; Campanilho-Marques, Raquel; Ponte, Cristina; Canhao, Helena; Ainola, Mari; Fonseca, Joao E. (2015)
    Introduction Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients. Methods 13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed. Results RANKL(+) circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-beta levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline. Conclusion In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli.
  • Paajanen, Juuso; Ilonen, Ilkka; Lauri, Helena; Järvinen, Tommi; Sutinen, Eva; Ollila, Hely; Rouvinen, Eeva; Lemström, Karl; Räsänen, Jari; Ritvos, Olli; Koli, Katri; Myllärniemi, Marjukka (2020)
    Activin A has previously been associated with cancer cachexia and in vitro resistance to platinum-based chemotherapy. We studied circulating activin A concentrations as well as activin B and their antagonists' follistatin/follistatin-like 3 in presurgical patients with non-small-cell lung cancer and malignant pleural mesothelioma. We found that circulating activing A levels were elevated in malignant pleural mesothelioma and associated with cancer cachexia and poor response to platinum-based chemotherapy. Circulating activing A separated non-small-cell lung cancer from benign lung lesion. Background: Previous preclinical studies have shown that activin A is overexpressed in malignant pleural mesothelioma (MPM), associates with cancer cachexia, and is observed in in vitro resistance to platinum-based chemotherapy. We evaluated circulating activin levels and their endogenous antagonists' follistatin/follistatin-like 3 in intrathoracic tumors. Materials and Methods: Patients suspected of thoracic malignancy were recruited prior to surgery. Serum samples were collected from 21 patients with MPM, 59 patients with non-small-cell lung cancer (NSCLC), and 22 patients with benign lung lesions. Circulating activin/follistatin levels were measured using enzymelinked immunosorbent assay and compared with clinicopathologic parameters. Results: Circulating activin A levels were elevated in patients with MPM when compared with patients with NSCLC or benign lung lesion samples (P <.0001). Also, follistatin and follistatin-like 3 levels were the highest in MPM, although with less difference compared with activin A. Receiver operating characteristic analysis for activin A for separating NSCLC from benign lung lesion showed an area under the curve of 0.856 (95% confidence interval, 0.77-0.94). Activin A levels were higher in patients with cachexia (P <.001). In patients with MPM, activin A levels correlated positively with computed tomographybased baseline tumor size (R = 0.549; P = .010) and the change in tumor size after chemotherapy (R = 0.743; P = .0006). Patients with partial response or stable disease had lower circulating activin A levels than the ones with progressive disease (P = .028). Conclusion: Activin A serum level could be used as a biomarker in differentiating malignant and benign lung tumors. Circulating activin A levels were elevated in MPM and associates with cancer cachexia and reduced chemotherapy response. (C) 2019 The Author(s). Published by Elsevier Inc.
  • Penttila, P.; Donskov, F.; Rautiola, J.; Peltola, K.; Laukka, M.; Bono, P. (2017)
    Background: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. Patients and methods: Eighty-five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan-Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation. Results: In cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P <0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12-0.44; P <0.001), PFS (HR 0.37; 95% CI 0.21-0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42-11.95; P = 0.01). In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P <0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36-0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39-0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10-15.18; P = 0.001). In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46-0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01). Conclusions: Everolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy. (C) 2017 Elsevier Ltd. All rights reserved.
  • Mäkitie, Antti A.; Almangush, Alhadi; Youssef, Omar; Metsälä, Markus; Silen, Suvi; Nixon, Iain J.; Haigentz, Missak; Rodrigo, Juan P.; Saba, Nabil F.; Vander Poorten, Vincent; Ferlito, Alfio (2020)
    Head and neck cancer (HNC) comprises a heterogeneous group of upper aerodigestive tract malignant neoplasms, the most frequent of which is squamous cell carcinoma. HNC forms the eighth most common cancer type and the incidence is increasing. However, survival has improved only moderately during the past decades. Currently, early diagnosis remains the mainstay for improving treatment outcomes in this patient population. Unfortunately, screening methods to allow early detection of HNC are not yet established. Therefore, many cases are still diagnosed at advanced stage, compromising outcomes. Exhaled breath analysis (EBA) is a diagnostic tool that has been recently introduced for many cancers. Breath analysis is non-invasive, cost-effective, time-saving, and can potentially be applied for cancer screening. Here, we provide a summary of the accumulated evidence on the feasibility of EBA in the diagnosis of HNC.
  • Dourado, Mauricio Rocha; Korvala, Johanna; Åström, Pirjo; De Oliveira, Carine Ervolino; Cervigne, Nilva K.; Mofatto, Luciana Souto; Bastos, Debora Campanella; Pereira Messetti, Ana Camila; Graner, Edgard; Paes Leme, Adriana Franco; Coletta, Ricardo D.; Salo, Tuula (2019)
    As one of the most abundant constituents of the tumour microenvironment (TME), cancer-associated fibroblasts (CAF) display critical roles during tumour progression and metastasis. Multiple classes of molecules including growth factors, cytokines, proteases and extracellular matrix proteins, are produced by CAF to act as mediators of the stroma-tumour interactions. One of the main channels for this communication is associated with extracellular vesicles (EV), which are secreted particles loaded with protein and genetic information. In this study, we evaluated the effects of EV derived from CAF primary human cell lines (n = 5) on proliferation, survival, migration, and invasion of oral squamous cell carcinoma (OSCC) cells. As controls, EV from human primary-established normal oral fibroblasts (NOF, n = 5) were used. Our in vitro assays showed that CAF-EV significantly induces migration and invasion of OSCC cells and promote a disseminated pattern of HSC-3 cell invasion in the 3D organotypic assay. Furthermore, gene expression analysis of EV-treated cancer cells revealed changes in the pathways associated with tumour metabolism and up-regulation of tumour invasion genes. Our findings suggest a significant role of CAF-EV in promoting the migration and invasion of OSCC cells, which are related to the activation of cancer-related pathways.