Browsing by Subject "Biomarker"

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  • Nakken, Sigrid; Eikrem, Oystein; Marti, Hans-Peter; Beisland, Christian; Bostad, Leif; Scherer, Andreas; Flatberg, Arnar; Beisvag, Vidar; Skandalou, Eleni; Furriol, Jessica; Strauss, Philipp (2021)
    Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in "low-risk" patients who were potentially eligible for adjuvant treatments or more intensive follow-up. Methods We assembled a cohort of ccRCC patients (n = 443) and identified all "low-risk" patients who later developed progressing tumors (n = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these "low-risk" patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas. Results Principal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p = 2.44E-7). Conclusion AGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as "low risk" at the time of surgery.
  • Knight, Anna K.; Craig, Jeffrey M.; Theda, Christiane; Baekvad-Hansen, Marie; Bybjerg-Grauholm, Jonas; Hansen, Christine S.; Hollegaard, Mads V.; Hougaard, David M.; Mortensen, Preben B.; Weinsheimer, Shantel M.; Werge, Thomas M.; Brennan, Patricia A.; Cubells, Joseph F.; Newport, D. Jeffrey; Stowe, Zachary N.; Cheong, Jeanie L. Y.; Dalach, Philippa; Doyle, Lex W.; Loke, Yuk J.; Baccarelli, Andrea A.; Just, Allan C.; Wright, Robert O.; Tellez-Rojo, Mara M.; Svensson, Katherine; Trevisi, Letizia; Kennedy, Elizabeth M.; Binder, Elisabeth B.; Iurato, Stella; Räikkönen, Katri; Lahti, Jari M. T.; Pesonen, Anu-Katriina; Kajantie, Eero; Villa, Pia M.; Laivuori, Hannele; Hämäläinen, Esa; Park, Hea Jin; Bailey, Lynn B.; Parets, Sasha E.; Kilaru, Varun; Menon, Ramkumar; Horvath, Steve; Bush, Nicole R.; LeWinn, Kaja Z.; Tylavsky, Frances A.; Conneely, Karen N.; Smith, Alicia K. (2016)
    Background: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.
  • Inkinen, Nina; Pettilä, Ville; Lakkisto, Päivi; Kuitunen, Anne; Jukarainen, Sakari; Bendel, Stepani; Inkinen, Outi; Ala-Kokko, Tero; Vaara, Suvi T. (Springer International Publishing, 2019)
    Abstract Background Injury to endothelium and glycocalyx predisposes to vascular leak, which may subsequently lead to increased fluid requirements and worse outcomes. In this post hoc study of the prospective multicenter observational Finnish Acute Kidney Injury (FINNAKI) cohort study conducted in 17 Finnish intensive care units, we studied the association of Syndecan-1 (SDC-1), Angiopoetin-2 (Ang-2), soluble thrombomodulin (sTM), vascular adhesion protein-1 (VAP-1) and interleukin-6 (IL-6) with fluid administration and balance among septic critical care patients and their association with development of acute kidney injury (AKI) and 90-day mortality. Results SDC-1, Ang-2, sTM, VAP-1 and IL-6 levels were measured at ICU admission from 619 patients with sepsis. VAP-1 decreased (p < 0.001) and IL-6 increased (p < 0.001) with increasing amounts of administered fluid, but other biomarkers did not show differences according to fluid administration. In linear regression models adjusted for IL-6, only VAP-1 was significantly associated with fluid administration on day 1 (p < 0.001) and the cumulative fluid balance on day 5/ICU discharge (p = 0.001). Of 415 patients admitted without AKI, altogether 112 patients (27.0%) developed AKI > 12 h from ICU admission (AKI>12 h). They had higher sTM levels than patients without AKI, and after multivariable adjustment log, sTM level was associated with AKI>12 h with OR (95% CI) of 12.71 (2.96–54.67), p = 0.001). Ninety-day non-survivors (n = 180; 29.1%) had higher SDC-1 and sTM levels compared to survivors. After adjustment for known confounders, log SDC-1 (OR [95% CI] 2.13 [1.31–3.49], p = 0.002), log sTM (OR [95% CI] 7.35 [2.29–23.57], p < 0.001), and log Ang-2 (OR [95% CI] 2.47 [1.44–4.14], p = 0.001) associated with an increased risk for 90-day mortality. Finally, patients who had high levels of all three markers, namely, SDC-1, Ang-2 and sTM, had an adjusted OR of 5.61 (95% CI 2.67–11.79; p < 0.001) for 90-day mortality. Conclusions VAP-1 and IL-6 associated with fluid administration on the first ICU day. After adjusting for confounders, sTM was associated with development of AKI after 12 h from ICU admission. SDC-1, Ang-2 and sTM were independently associated with an increased risk for 90-day mortality.
  • FINNAKI Study Grp (2019)
    Background Injury to endothelium and glycocalyx predisposes to vascular leak, which may subsequently lead to increased fluid requirements and worse outcomes. In this post hoc study of the prospective multicenter observational Finnish Acute Kidney Injury (FINNAKI) cohort study conducted in 17 Finnish intensive care units, we studied the association of Syndecan-1 (SDC-1), Angiopoetin-2 (Ang-2), soluble thrombomodulin (sTM), vascular adhesion protein-1 (VAP-1) and interleukin-6 (IL-6) with fluid administration and balance among septic critical care patients and their association with development of acute kidney injury (AKI) and 90-day mortality. Results SDC-1, Ang-2, sTM, VAP-1 and IL-6 levels were measured at ICU admission from 619 patients with sepsis. VAP-1 decreased (p <0.001) and IL-6 increased (p <0.001) with increasing amounts of administered fluid, but other biomarkers did not show differences according to fluid administration. In linear regression models adjusted for IL-6, only VAP-1 was significantly associated with fluid administration on day 1 (p <0.001) and the cumulative fluid balance on day 5/ICU discharge (p = 0.001). Of 415 patients admitted without AKI, altogether 112 patients (27.0%) developed AKI > 12 h from ICU admission (AKI(>12 h)). They had higher sTM levels than patients without AKI, and after multivariable adjustment log, sTM level was associated with AKI(>12 h) with OR (95% CI) of 12.71 (2.96-54.67), p = 0.001). Ninety-day non-survivors (n = 180; 29.1%) had higher SDC-1 and sTM levels compared to survivors. After adjustment for known confounders, log SDC-1 (OR [95% CI] 2.13 [1.31-3.49], p = 0.002), log sTM (OR [95% CI] 7.35 [2.29-23.57], p <0.001), and log Ang-2 (OR [95% CI] 2.47 [1.44-4.14], p = 0.001) associated with an increased risk for 90-day mortality. Finally, patients who had high levels of all three markers, namely, SDC-1, Ang-2 and sTM, had an adjusted OR of 5.61 (95% CI 2.67-11.79; p <0.001) for 90-day mortality. Conclusions VAP-1 and IL-6 associated with fluid administration on the first ICU day. After adjusting for confounders, sTM was associated with development of AKI after 12 h from ICU admission. SDC-1, Ang-2 and sTM were independently associated with an increased risk for 90-day mortality.
  • Strandberg, Timo E.; Levinson, Susan L.; DiNubile, Mark J.; Jyväkorpi, Satu; Kivimäki, Mika (2022)
    Background Biomarkers are needed for frailty, a common phenotype often associated with muscle loss in older people. Plasma gelsolin (pGSN) is a protein largely synthesized and secreted by skeletal muscle. Aims To investigate whether pGSN could be a biomarker of the frailty phenotype and predict mortality. Methods A homogenous cohort of males (born 1919-1934, baseline n = 3490) has been followed since the 1960s. In 2010/11, frailty phenotypes by modified Fried criteria were assessed. pGSN was measured in a convenience subset (n = 469, mean age 83) and re-measured in survivors (n = 127) in 2017. Mortality through December 31, 2018 was retrieved from national registers. Regression models were used for analyses. Results Of 469 males, 152 (32.4%) were robust, 284 (60.6%) prefrail, and 33 (7.0%) frail in 2010/11. There was a graded (p = 0.018) association between pGSN (mean 58.1 ug/mL, SD 9.3) and frailty. After multivariable adjustment, higher pGSN levels were associated with lower odds of having contemporaneous phenotypic prefrailty (OR per 1 SD 0.73, 95% CI 0.58-0.92) and frailty (OR per 1 SD 0.70, 95% CI 0.44-1.11). By 2018, 179 males (38.2%) had died, and higher baseline pGSN predicted a lower 7-year mortality rate (HR per 1 SD 0.85, 95% CI 0.72-1.00). pGSN concentrations in 2010/11 and 2017 were correlated (n = 127, r = 0.34, p < 0.001). Discussion Higher baseline pGSN concentrations were associated with a persistently robust phenotype and lower mortality rate over 7 years in a cohort of octogenarian males with high socioeconomic status and may be a promising laboratory biomarker for the development of a frailty phenotype.
  • Kuuliala, Krista; Kuuliala, Antti; Koivuniemi, Riitta; Kautiainen, Hannu; Repo, Heikki; Leirisalo-Repo, Marjatta (2017)
    Background: We found recently that baseline signal transducer and activator of transcription 3 phosphorylation in peripheral blood CD4(+) T cells of patients with early rheumatoid arthritis (RA) is associated with treatment response to synthetic disease-modifying antirheumatic drugs (DMARDs). This prompted us to study the baseline phosphorylation profiles of Janus kinases (JAKs) in blood leukocytes with respect to treatment response in early RA. Methods: Thirty-five DMARD-naive patients with early RA provided blood samples for whole blood flow cytometric determination of phosphorylation of JAKs in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes. Treatment response was determined after 1 year of treatment with synthetic DMARDs, with remission defined as absence of tender and swollen joints and normal erythrocyte sedimentation rate. Exact logistic regression was used to investigate the association of baseline variables with treatment response. Ninety-five percent CIs of means were estimated by bias-corrected bootstrapping. Results: High JAK3 phosphorylation in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes and low JAK2 phosphorylation in CD14(+) monocytes were significantly associated with remission following treatment with synthetic DMARDs. Conclusions: Baseline JAK phosphorylation profile in peripheral blood leukocytes may provide a means to predict treatment response achieved by synthetic DMARDs among patients with early RA.
  • Kuuliala, Krista; Kuuliala, Antti; Koivuniemi, Riitta; Kautiainen, Hannu; Repo, Heikki; Leirisalo-Repo, Marjatta (BioMed Central, 2017)
    Abstract Background We found recently that baseline signal transducer and activator of transcription 3 phosphorylation in peripheral blood CD4+ T cells of patients with early rheumatoid arthritis (RA) is associated with treatment response to synthetic disease-modifying antirheumatic drugs (DMARDs). This prompted us to study the baseline phosphorylation profiles of Janus kinases (JAKs) in blood leukocytes with respect to treatment response in early RA. Methods Thirty-five DMARD-naïve patients with early RA provided blood samples for whole blood flow cytometric determination of phosphorylation of JAKs in CD4+ and CD8+ T cells, CD19+ B cells, and CD14+ monocytes. Treatment response was determined after 1 year of treatment with synthetic DMARDs, with remission defined as absence of tender and swollen joints and normal erythrocyte sedimentation rate. Exact logistic regression was used to investigate the association of baseline variables with treatment response. Ninety-five percent CIs of means were estimated by bias-corrected bootstrapping. Results High JAK3 phosphorylation in CD4+ and CD8+ T cells, CD19+ B cells, and CD14+ monocytes and low JAK2 phosphorylation in CD14+ monocytes were significantly associated with remission following treatment with synthetic DMARDs. Conclusions Baseline JAK phosphorylation profile in peripheral blood leukocytes may provide a means to predict treatment response achieved by synthetic DMARDs among patients with early RA.
  • Friedland, Barbara A.; Stoner, Marie; Chau, Michelle M.; Plagianos, Marlena Gehret; Govender, Sumen; Morar, Neetha; Altini, Lydia; Skoler-Karpoff, Stephanie; Ahmed, Khatija; Ramjee, Gita; Monedi, Constance; Maguire, Robin; Lähteenmäki, Pekka (2016)
    A randomized, placebo-controlled, efficacy trial of Carraguard was unable to demonstrate a reduction in women's risk of HIV infection, which may have been due, in part, to low adherence (gel used in 42 % of vaginal sex acts, on average). A secondary analysis was undertaken to understand baseline factors associated with high adherence (gel used in aeyen85 % of sex acts). Women who reported aeyen1 vaginal sex act, returned aeyen1 opened applicator, and had aeyen1 conclusive post-enrollment HIV test (N = 5990) were included. Adherence was estimated as the ratio of average weekly applicator insertions (based on a dye stain assay indicating vaginal insertion)/average weekly sex acts (by self-report). Multivariate logistic regression modeling indicated that coital frequency, site, contraception, and partner age difference had a significant impact on adherence. Women reporting > 1 and aecurrency sign2 vaginal sex acts per week, on average, were half as likely to be adherent as those reporting 1 vaginal sex act per week or less [adjusted odds ratio (AOR): 0.48; 95 % CI 0.38-0.61]; women from the Western Cape had one-third the odds of being adherent compared to women from KZN (AOR: 0.31; 95 % CI 0.23-0.41); compared to women using injectable contraception, women using any other or no method were more likely to be adherent (AOR: 1.30; 95 % CI 1.04-1.63); and women who had a larger age gap from their partners were more likely to be adherent (AOR: 1.03; 95 % CI 1.01-1.05; p = 0.001). Despite low adherence, overall, 13 % of participants achieved nearly perfect adherence, indicating a potential niche for a coitally dependent microbicide. More research is needed on the impact of sexual patterns and HIV risk perception on product acceptability and adherence to improve counseling in ongoing trials and when products are eventually introduced.
  • Benvik, Eva (Helsingin yliopisto, 2018)
    Perinatal asphyxia is a main cause of neonatal deaths worldwide. Asphyxia can lead to hypoxic ischemic encephalopathy, which may cause severe neurological impairment to infants. The consequences of hypoxic ischemic encephalopathy can have a significant impact on the life of affected children and their families. Neonates with hypoxic ischemic encephalopathy can be treated with therapeutic hypothermia. Therapeutic hypothermia is to be initiated within 6 hours after birth. Biomarkers of asphyxia used at present are cord blood pH and Apgar score. The severity of hypoxic ischemic encephalopathy is evaluated with the help of clinical assessment, magnetic resonance imaging and amplitude integrated electroencephalography. Currently there is a need for new biomarkers of asphyxia in order to identify adequate candidates for treatment, for the estimation of prognosis and planning of follow up. The purpose of this review is to present and evaluate studies concerning biomarkers of perinatal asphyxia. Biomarkers discussed are erythropoietin, activin a, S-100, nucleated red blood cells, lactate, lactate dehydrogenase, neuron specific enolase, cytokines, free radicals, glial fibrillar acidic protein, copeptin, metabolomics, magnetic resonance techniques (magnetic resonance imaging and magnetic resonance spectroscopy) and neurophysiology (electroencephalography, amplitude integrated electroencephalography and near-infrared spectroscopy. Based on this review, copeptin and glial fibrillary acidic protein may be potential biomarkers. Metabolomics show a new promising field. Further research is, however, required to find new biomarkers that can be validated into clinical use. (226 words)
  • Nurmi, Anna Maria; Mustonen, Harri; Haglund, Caj; Seppänen, Hanna (2021)
    Introduction: Tumor and systemic inflammatory markers predict survival. This retrospective study aimed to explore the changes in CRP, CA19-9, and other routine laboratory tests during preoperative oncological therapy as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). Methods: Between 2000 and 2016, 68 borderline resectable PDAC patients received preoperative oncological therapy and underwent subsequent surgery at Helsinki University Hospital, Finland. We investigated changes in CRP, CA19-9, CEA, albumin, leukocytes, bilirubin, and platelets and examined the impact on survival. Results: In the multivariate analysis, CRP remaining at >= 3 mg/L after preoperative oncological therapy predicted a poorer postoperative outcome when compared to CRP decreasing to or remaining at 90% during preoperative treatment predicted a favorable postoperative outcome (HR 0.297, 95% CI: 0.124-0.708, p = 0.006). In the Kaplan-Meier analysis, the median survival for patients with CRP remaining at = 3 mg/L (42 months vs. 24 months, p = 0.001). Patients with a CA19-9 decrease >90% or level normalization (to
  • Joo, SeoJeong (Helsingin yliopisto, 2019)
    Although lung transplantation has become a routine procedure and is optimal therapy for patients with end-stage pulmonary diseases, the lifespan of lung allografts is still shorter than that of other organ transplants. As acute allograft rejection is one of the main risk factors for the development of chronic lung allograft dysfunction (CLAD) which threatens the long-term survival rate of the recipients, it is crucial to predict and diagnose acute lung allograft rejection. However, there are no specific methods established so far to predict acute rejection (AR). Even though the histopathological evaluation of transbronchial biopsies (TBBs) is used as the gold standard to ensure the diagnosis of AR, it is essential to discover novel biomarkers for AR to overcome the limitations of the TBB-based invasive diagnostics. Recently extracellular vesicles (EVs) got noticed as potential biomarkers in various fields of medicine based on the findings that they exist in high concentration in body fluids and deliver functional genetic molecules which can modulate gene expression in target cells. In that regard, this preliminary study was designed with two different approaches; a time-point analysis and a case analysis of rejection and non-rejection episodes to validate their potentials as diagnostic and predictive biomarkers for acute lung allograft rejection. To discover biomarkers, EV RNA was isolated from the plasma of four patients that was collected at different time points, and whole EV mRNA transcriptome sequencing was performed on the Illumina platform to obtain at least 15 million reads. The time-point analysis showed that the mRNA contents of EVs changed according to the time points and clinical presentations of the patients. At the same time, gene expression profiles showed that mRNA molecules inside the EVs change from innate immunity to adaptive immunity related signatures with the time after transplantation. Furthermore, the case analysis identified that EVs contain RNA molecules that are closely related to the migration of leukocytes and adaptive immune system during acute rejection episodes. In conclusion, the profiles of EV RNA may reflect the immune responses that are taking place in the recipient’s body. Therefore, it is speculated that EVs may play an essential role in the development of AR by transferring functional mRNA molecules to the allograft, immune cells, and endothelial cells. On that account, EV transcriptome profiling could be used as a diagnostic tool for AR in the future, as well as a therapeutic tool by engineering EVs to target specific genes that may be involved in the development of AR. Keywords: extracellular vesicles, lung transplantation, transplantation immunology, RNA sequencing, acute lung allograft rejection, biomarkers
  • Konev, Alexey A.; Kharitonov, Alexey; Rozov, Fedor N.; Altshuler, Evgeny P.; Serebryanaya, Daria; Lassus, Johan; Harjola, Veli-Pekka; Katrukha, Alexey G.; Postnikov, Alexander B. (2020)
    Aims Insulin-like growth factor binding protein-4 (IGFBP-4) fragments have been shown to predict the risk of major adverse cardiovascular events, including segment-elevation myocardial infarction, in patients with acute coronary syndrome. We evaluated the prognostic value of the carboxy-terminal fragment of IGFBP-4 (CT-IGFBP-4) for all-cause mortality in emergency room patients with acute heart failure (AHF). Methods and results CT-IGFBP-4, N-terminal pro brain natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) were measured at admission from the lithium-heparin plasma of 156 patients with AHF. All-cause mortality was recorded for 1 year. Receiver operator characteristic (ROC) curves, Kaplan-Meier, and Cox proportional hazard ratio analyses were performed to evaluate the prognostic value of the various clinical variables, CT-IGFBP-4, NT-proBNP, CRP, and their combinations. During 1 year of follow-up, 52 (33.3%) patients died. CT-IGFBP-4 only weakly correlated with NT-proBNP (Pearson correlation coefficient r = 0.16, P = 0.044) and did not correlate with CRP (r = 0.08, P = 0.35), emphasizing the different nature of these biomarkers. The receiver operator characteristic area under the curve (ROC AUC) of CT-IGFBP-4 for the prediction of all-cause mortality (0.727) was significantly higher than that of NT-proBNP (0.680, P = 0.045) and CRP (0.669, P = 0.016). The combination of CT-IGFBP-4, NT-proBNP, and CRP predicted mortality significantly better (ROC AUC = 0.788) than any of the biomarkers alone (P <0.01 for all). The addition of CT-IGFBP-4 to a clinical prediction model that included age, gender, systolic blood pressure, creatinine, and sodium levels, as well as the history of previous heart failure, coronary artery disease, and hypertension significantly improved the mortality risk prediction (ROC AUC 0.774 vs. 0.699, P = 0.025). Cox hazard analysis indicated that elevated CT-IGFBP-4 was independently associated with 1 year mortality (hazard ratio 3.26, P = 0.0008) after adjustment for age, gender, history of previous heart failure, coronary artery disease, hypertension, chronic kidney failure, history of diabetes, heart rate, haemoglobin, plasma sodium, NT-proBNP, CRP, cystatin C, and elevated cardiac troponin I or T. Patients with increased levels of either two or three of the biomarkers CT-IGFBP-4, NT-proBNP, and CRP had significantly higher mortality risk (adjusted hazard ratio 10.04, P <0.0001) than patients with increased levels of one or none of the biomarkers. Conclusions CT-IGFBP-4 was independently associated with all-cause mortality in patients with AHF. Compared with single biomarkers, the combination of CT-IGFBP-4, NT-proBNP, and CRP improved the prediction of all-cause mortality in patients with AHF.
  • Gursoy, Ulvi Kahraman; Pussinen, Pirkko J.; Salomaa, Veikko; Syrjalainen, Sanna; Kononen, Eija (2018)
    Objective: Aim was to analyze the diagnostic ability of cumulative risk score (CRS), which uses salivary levels of Porphyromonas gingivalis, interleukin (IL)-1 beta, and matrix metalloproteinase (MMP)-8 in an adaptive design, compared to previously reported thresholds of each marker alone. Materials and Methods: Oral and general health information of 463 participants were included in the analysis. Having the percentage of bleeding on probing (BOP) > 25%, having at least two sites with probing pocket depth (PPD) of 4-5 mm or having at least one tooth with alveolar bone loss (ABL) of at least 1/3 of the root length were accepted as outcome variables. Being above the salivary threshold concentrations of P. gingivalis, IL-1 beta, and MMP-8 and CRS values were used as explanatory variables. Receiver operating characteristics (ROC) producing an area under the curve (AUC) and multinomial regression analysis were used in statistical analysis. Results: CRS provided AUCs larger than any other tested biomarker threshold. Sensitivity and specificity of CRS for detecting clinical markers of periodontitis were acceptable, and a strong association was observed between the highest CRS score and having at least two sites with PPD of 4-5 mm. Conclusion: CRS brings additional power over fixed thresholds of single biomarkers in detecting periodontitis.
  • Hoglund, K.; Lequarre, A. -S.; Ljungvall, I.; Mc Entee, K.; Merveille, A. -C.; Wiberg, M.; Gouni, V.; Willesen, J. Lundgren; Hanas, S.; Wess, G.; Sorensen, L. Mejer; Tiret, L.; Kierczak, M.; Forsberg, S. K. G.; Seppälä, E.; Lindblad-Toh, K.; Lohi, H.; Chetboul, V.; Fredholm, M.; Haggstrom, J. (2016)
    BackgroundThere are breed differences in several blood variables in healthy dogs. ObjectiveInvestigate breed variation in plasma endothelin-1 (ET-1) concentration, plasma renin activity, and serum cortisol concentration. AnimalsFive-hundred and thirty-one healthy dogs of 9 breeds examined at 5 centers (2-4 breeds/center). MethodsProspective observational study. Circulating concentrations of ET-1 and cortisol, and renin activity, were measured using commercially available assays. Absence of organ-related or systemic disease was ensured by thorough clinical investigations, including blood pressure measurement, echocardiography, ECG, blood and urine analysis. ResultsMedian ET-1 concentration was 1.29 (interquartile range [IQR], 0.97-1.82) pg/mL, median cortisol concentration 46.0 (IQR, 29.0-80.8) nmol/L, and median renin activity 0.73 (IQR, 0.48-1.10) ng/mL/h in all dogs. Overall, breed differences were found in ET-1 and cortisol concentrations, and renin activity (P <.0001 for all). Pair-wise comparisons between breeds differed in 67% of comparisons for ET-1, 22% for cortisol, and 19% for renin activity, respectively. Within centers, breed differences were found at 5/5 centers for ET-1, 4/5 centers for cortisol, and 2/5 centers for renin activity. Newfoundlands had highest median ET-1 concentration, 3 times higher than Cavalier King Charles Spaniels, Doberman Pinschers, and Dachshunds. Median renin activity was highest in Dachshunds, twice the median value in Newfoundlands and Boxers. Median cortisol concentration was highest in Finnish Lapphunds, almost 3 times higher than in Boxers. Conclusions and Clinical ImportanceBreed variation might be important to take into consideration when interpreting test results in clinical studies.
  • 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.
  • Smirnov, Petr; Smith, Ian; Safikhani, Zhaleh; Ba-alawi, Wail; Khodakarami, Farnoosh; Lin, Eva; Yu, Yihong; Martin, Scott; Ortmann, Janosch; Aittokallio, Tero; Hafner, Marc; Haibe-Kains, Benjamin (2022)
    Background Identifying associations among biological variables is a major challenge in modern quantitative biological research, particularly given the systemic and statistical noise endemic to biological systems. Drug sensitivity data has proven to be a particularly challenging field for identifying associations to inform patient treatment. Results To address this, we introduce two semi-parametric variations on the commonly used concordance index: the robust concordance index and the kernelized concordance index (rCI, kCI), which incorporate measurements about the noise distribution from the data. We demonstrate that common statistical tests applied to the concordance index and its variations fail to control for false positives, and introduce efficient implementations to compute p-values using adaptive permutation testing. We then evaluate the statistical power of these coefficients under simulation and compare with Pearson and Spearman correlation coefficients. Finally, we evaluate the various statistics in matching drugs across pharmacogenomic datasets. Conclusions We observe that the rCI and kCI are better powered than the concordance index in simulation and show some improvement on real data. Surprisingly, we observe that the Pearson correlation was the most robust to measurement noise among the different metrics.
  • Rodrigues, Andre A. Nimtz; Lopes-Santos, Lucilene; Lacerda, Pammela A.; Juste, Mariana F.; Mariz, Bruno Augusto; Cajazeiro, Debora C.; Giacobbe, Victoria; Borges, Rafael; Casarim, Andre; Callegari, Giovanna De Sanctis; Arcadipane, Fernando Antonio M. Claret; Aprahamian, Ivan; Salo, Tuula Anneli; De Oliveira, Carine Ervolino; Coletta, Ricardo D.; Augusto, Taize M.; Cervigne, Nilva K. (2022)
    Background: Oral cavity cancer is still an important public health problem throughout the world. Oral squamous cell carcinomas (OSCCs) can be quite aggressive and metastatic, with a low survival rate and poor prognosis. However, this is usually related to the clinical stage and histological grade, and molecular prognostic markers for clinical practice are yet to be defined. Heparanase (HPSE1) is an endoglycosidase associated with extracellular matrix remodeling, and although involved in several malignancies, the clinical implications of HPSE1 expression in OSCCs are still unknown.Methods: We sought to investigate HPSE1 expression in a series of primary OSCCs and further explore whether its overexpression plays a relevant role in OSCC tumorigenesis. mRNA and protein expression analyses were performed in OSCC tissue samples and cell lines. A loss-of-function strategy using shRNA and a gain-of-function strategy using an ORF vector targeting HPSE1 were employed to investigate the endogenous modulation of HPSE1 and its effects on proliferation, apoptosis, adhesion, epithelial-mesenchymal transition (EMT), angiogenesis, migration, and invasion of oral cancer in vitro.Results: We demonstrated that HPSE1 is frequently upregulated in OSCC samples and cell lines and is an unfavorable prognostic indicator of disease-specific survival when combined with advanced pT stages. Moreover, abrogation of HPSE1 in OSCC cells significantly promoted apoptosis and inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition by significantly decreasing the expression of N-cadherin and vimentin. Furthermore, a conditioned medium of HPSE1-downregulated cells resulted in reduced vascular endothelial growth.Conclusion: Our results confirm the overexpression of HPSE1 in OSCCs, suggest that HPSE1 expression correlates with disease progression as it is associated with several important biological processes for oral tumorigenesis, and can be managed as a prognostic marker for patients with OSCC.
  • Tverring, Jonas; Vaara, Suvi T.; Fisher, Jane; Poukkanen, Meri; Pettila, Ville; Linder, Adam; FINNAKI Study Grp (2017)
    Background: Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-binding protein (HBP)is a promising biomarker in predicting development and prognosis of severe sepsis and septic shock that has recently been proposed to be involved in the pathophysiology of AKI. The objective of this study was to investigate the added predictive value of measuring plasma HBP on admission to the intensive care unit (ICU) regarding the development of septic AKI. Methods: We included 601 patients with severe sepsis or septic shock from the prospective, observational FINNAKI study conducted in seventeen Finnish ICUs during a 5-month period (1 September 2011-1 February 2012). The main outcome measure was the development of KDIGO AKI stages 2-3 from 12 h after admission up to 5 days. Statistical analysis for the primary endpoint included construction of a clinical risk model, area under the receiver operating curve (ROC area), category-free net reclassification index (cfNRI) and integrated discrimination improvement (IDI) with 95% confidence intervals (95% CI). Results: Out of 511 eligible patients, 101 (20%) reached the primary endpoint. The addition of plasma HBP to a clinical risk model significantly increased ROC area (0.82 vs. 0.78, p = 0.03) and risk classification scores: cfNRI 62.0% (95% CI 40.5-82.4%) and IDI 0.053 (95% CI 0.029-0.075). Conclusions: Plasma HBP adds predictive value to known clinical risk factors in septic AKI. Further studies are warranted to compare the predictive performance of plasma HBP to other novel AKI biomarkers.
  • Höglund, K.; Häggström, J.; Hanås, S.; Merveille, A. -C.; Gouni, V.; Wiberg, M.; Willesen, J. Lundgren; Mc Entee, K.; Sorensen, L. Mejer; Tiret, L.; Seppälä, E. H.; Lohi, H.; Chetboul, V.; Fredholm, M.; Lequarre, A. -S.; Ljungvall, I. (2018)
    Introduction: Serotonin (5-hydroxytryptamine [5-HT]) has several biological functions. In different species, excessive 5-HT has been linked to valvular lesions, similar to those seen in dogs with myxomatous mitral valve disease. Previous studies suggest higher 5-HT in healthy Cavalier King Charles Spaniels (CKCSs), a breed highly affected by myxomatous mitral valve disease, compared to other breeds. Objective: To investigate potential interbreed variation in serum 5-HT in healthy dogs. Animals: 483 healthy dogs of nine breeds aged 1-7 years. Methods: Dogs were examined at five European centers. Absence of cardiovascular, organ-related, or systemic diseases was ensured by thorough clinical investigations including echocardiography. Serum was frozen and later analyzed by enzyme-linked immunosorbent assay (ELISA). Results: Median 5-HT concentration was 252.5 (interquartile range = 145.5-390.6) ng/mL. Overall breed difference was found (p Conclusions: Interbreed variation in serum 5-HT concentration was found in healthy dogs aged 1-7 years. These differences should be taken into account when designing clinical studies. (C) 2018 Elsevier B.V. All rights reserved.
  • Naafs, B. D. A.; Inglis, G. N.; Zheng, Y.; Amesbury, M. J.; Biester, H.; Bindler, R.; Blewett, J.; Burrows, M. A.; del Castillo Torres, D.; Chambers, F. M.; Cohen, A. D.; Evershed, R. P.; Feakins, S. J.; Galka, M.; Gallego-Sala, A.; Gandois, L.; Gray, D. M.; Hatcher, P. G.; Honorio Coronado, E. N.; Hughes, P. D. M.; Huguet, A.; Kononen, M.; Laggoun-Defarge, F.; Lahteenoja, O.; Lamentowicz, M.; Marchant, R.; McClymont, E.; Pontevedra-Pombal, X.; Ponton, C.; Pourmand, A.; Rizzuti, A. M.; Rochefort, L.; Schellekens, J.; De Vleeschouwer, F.; Pancost, R. D. (2017)
    Glycerol dialkyl glycerol tetraethers (GDGTs) are membrane-spanning lipids from Bacteria and Archaea that are ubiquitous in a range of natural archives and especially abundant in peat. Previous work demonstrated that the distribution of bacterial branched GDGTs (brGDGTs) in mineral soils is correlated to environmental factors such as mean annual air temperature (MAAT) and soil pH. However, the influence of these parameters on brGDGT distributions in peat is largely unknown. Here we investigate the distribution of brGDGTs in 470 samples from 96 peatlands around the world with a broad mean annual air temperature (-8 to 27 degrees C) and pH (3-8) range and present the first peat-specific brGDGT-based temperature and pH calibrations. Our results demonstrate that the degree of cyclisation of brGDGTs in peat is positively correlated with pH, pH = 2.49 x CBTpeat + 8.07 (n = 51, R-2 = 0.58, RMSE = 0.8) and the degree of methylation of brGDGTs is positively correlated with MAAT, MAAT(peat) (degrees C) = 52.18 x MBT'(5me) - 23.05 (n = 96, R-2 = 0.76, RMSE = 4.7 degrees C). These peat-specific calibrations are distinct from the available mineral soil calibrations. In light of the error in the temperature calibration (similar to 4.7 degrees C), we urge caution in any application to reconstruct late Holocene climate variability, where the climatic signals are relatively small, and the duration of excursions could be brief. Instead, these proxies are well-suited to reconstruct large amplitude, longer-term shifts in climate such as deglacial transitions. Indeed, when applied to a peat deposit spanning the late glacial period (similar to 15.2 kyr), we demonstrate that MAAT(peat) yields absolute temperatures and relative temperature changes that are consistent with those from other proxies. In addition, the application of MAAT(peat) to fossil peat (i.e. lignites) has the potential to reconstruct terrestrial climate during the Cenozoic. We conclude that there is clear potential to use brGDGTs in peats and lignites to reconstruct past terrestrial climate. (C) 2017 The Authors. Published by Elsevier Ltd.