Browsing by Subject "PROGRESSION"

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  • Kauppinen, S.; Karhula, S. S.; Thevenot, J.; Ylitalo, T.; Rieppo, L.; Kestilä, I.; Haapea, M.; Hadjab, I.; Finnilä, M. A.; Quenneville, E.; Garon, M.; Gahunia, H. K.; Pritzker, K. P. H.; Buschmann, M. D.; Saarakkala, S.; Nieminen, H. J. (2019)
    Objective: Our aim is to establish methods for quantifying morphometric properties of calcified cartilage (CC) from micro-computed tomography (mu CT). Furthermore, we evaluated the feasibility of these methods in investigating relationships between osteoarthritis (OA), tidemark surface morphology and open subchondral channels (OSCCs). Method: Samples (n = 15) used in this study were harvested from human lateral tibial plateau (n = 8). Conventional roughness and parameters assessing local 3-dimensional (3D) surface variations were used to quantify the surface morphology of the CC. Subchondral channel properties (percentage, density, size) were also calculated. As a reference, histological sections were evaluated using Histopathological osteoarthritis grading (OARSI) and thickness of CC and subchondral bone (SCB) was quantified. Results: OARSI grade correlated with a decrease in local 3D variations of the tidemark surface (amount of different surface patterns (r(s) = -0.600, P = 0.018), entropy of patterns (EP) (r(s) = -0.648, P = 0.018), homogeneity index (HI) (r(s) = 0.555, P = 0.032)) and tidemark roughness (TMR) (r(s) = -0.579, P = 0.024). Amount of different patterns (ADP) and EP associated with channel area fraction (CAF) (r(p) = 0.876, P <0.0001; r(p) = 0.665, P = 0.007, respectively) and channel density (CD) (r(p) = 0.680, P = 0.011; r(p) = 0.582, P = 0.023, respectively). TMR was associated with CAF (r(p) = 0.926, P <0.0001) and average channel size (r(p) = 0.574, P = 0.025). CC topography differed statistically significantly in early OA vs healthy samples. Conclusion: We introduced a mu-CT image method to quantify 3D CC topography and perforations through CC. CC topography was associated with OARSI grade and OSCC properties; this suggests that the established methods can detect topographical changes in tidemark and CC perforations associated with OA. (c) 2018 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
  • Lindbohm, Joni; Sipilä, Pyry N.; Mars, Nina J.; Pentti, Jaana; Ahmadi-Abhari, Sara; Brunner, Eric J.; Shipley, Martin J.; Singh-Manoux, Archana; Tabak, Adam G.; Kivimäki, Mika (2019)
    Background Clinical guidelines suggest preventive interventions such as statin therapy for individuals with a high estimated 10-year risk of major cardiovascular events. For those with a low or intermediate estimated risk, risk-factor screenings are recommended at 5-year intervals; this interval is based on expert opinion rather than on direct research evidence. Using longitudinal data on the progression of cardiovascular disease risk over time, we compared different screening intervals in terms of timely detection of high-risk individuals, cardiovascular events prevented, and health-care costs. Methods We used data from participants in the British Whitehall II study (aged 40-64 years at baseline) who had repeated biomedical screenings at 5-year intervals and linked these data to electronic health records between baseline (Aug 7, 1991, to May 10, 1993) and June 30, 2015. We estimated participants' 10-year risk of a major cardiovascular event (myocardial infarction, cardiac death, and fatal or non-fatal stroke) using the revised Atherosclerotic Cardiovascular Disease (ASCVD) calculator. We used multistate Markov modelling to estimate optimum screening intervals on the basis of progression rates from low-risk and intermediate-risk categories to the high-risk category (ie, >= 7.5% 10-year risk of a major cardiovascular event). Our assessment criteria included person-years spent in a high-risk category before detection, the number of major cardiovascular events prevented and quality-adjusted life-years (QALYs) gained, and screening costs. Findings Of 6964 participants (mean age 50.0 years [ SD 6.0] at baseline) with 152 700 person-years of follow-up (mean follow-up 22.0 years [SD 5.0]), 1686 participants progressed to the high-risk category and 617 had a major cardiovascular event. With the 5-year screening intervals, participants spent 7866 (95% CI 7130-8658) person-years unrecognised in the high-risk group. For individuals in the low, intermediate-low, and intermediate-high risk categories, 21 alternative risk category-based screening intervals outperformed the 5-yearly screening protocol. Screening intervals at 7 years, 4 years, and 1 year for those in the low, intermediate-low, and intermediate-high-risk category would reduce the number of person-years spent unrecognised in the high-risk group by 62% (95% CI 57-66; 4894 person-years), reduce the number of major cardiovascular events by 8% (7-9; 49 events), and raise 44 QALYs (40-49) for the study population. Interpretation In terms of timely preventive interventions, the 5-year screening intervals were unnecessarily frequent for low-risk individuals and insufficiently frequent for intermediate-risk individuals. Screening intervals based on risk-category-specific progression rates would perform better in terms of preventing major cardiovascular disease events and improving cost-effectiveness. (C) 2019 The Author(s). Published by Elsevier Ltd.
  • Rantala, Juha K.; Makela, Rami; Aaltola, Anna-Riina; Laasola, Petra; Mpindi, John-Patrick; Nees, Matthias; Saviranta, Petri; Kallioniemi, Olli (2011)
  • Surrogate Markers Micro-Macro-Vasc (2018)
    Purpose Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. Methods Results A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 x 10(-9). Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 x 10(-8) and 1.23 x 10(-8), respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). Conclusion This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
  • Salminen, Liina; Nadeem, Nimrah; Jain, Shruti; Grènman, Seija; Carpén, Olli; Hietanen, Sakari; Oksa, Sinikka; Lamminmäki, Urpo; Pettersson, Kim; Gidwani, Kamlesh; Huhtinen, Kaisa; Hynninen, Johanna (2020)
    Objective. Cancer antigen 125 (CM 25) is generally considered the gold standard of biomarkers in the diagnosis and monitoring of high grade serous ovarian carcinoma (HGSC). We recently reported, that two CM 25 glycoforms (CA125-STn and CA125-MGL) have a high specificity to HGSC and further hypothesized, that these cancer specific glycoforms are feasible candidates as biomarkers in HGSC treatment and follow up. Methods. Our cohort consisted of 122 patients diagnosed with HGSC. Serum samples were collected longitudinally at the time of diagnosis, during treatment and follow up. Serum levels of CA125, CM 25-STn and CA125MGL were determined and compared or correlated with different end points (tumor load assessed intraoperatively, residual disease, treatment response, progression free survival). Results. Serum CA125-STn levels at diagnosis differentiated patients with low tumor load and high tumor load (p = 0,030), indicating a favorable detection of tumor volume. Similarly, the CA125-STn levels at diagnosis were significantly lower in patients with subsequent complete cytoreduction than in patients with suboptimal cytoreduction (p = 0,025). Conventional CA125 did not differentiate these patients (p = 0,363 and p = 0,154). The CA125-STn nadir value predicted the progression free survival of patients. The detection of disease relapse was improved with CA125-STn, which presented higher fold increase in 80,0% of patients and earlier increase in 37,0% of patients. Conclusions. CA125-STn showed promise as a useful biomarker in the monitoring and follow up of patients with HGSC utilizing a robust and affordable technique. Our findings are topical as a suitable indicator of tumor load facilitates patient selection in an era of new targeted therapies. (C) 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
  • Limonte, Christine P.; Valo, Erkka; Montemayor, Daniel; Afshinnia, Farsad; Ahluwalia, Tarunveer S.; Costacou, Tina; Darshi, Manjula; Forsblom, Carol; Hoofnagle, Andrew N.; Groop, Per-Henrik; Miller, Rachel G.; Orchard, Trevor J.; Pennathur, Subramaniam; Rossing, Peter; Sandholm, Niina; Snell-Bergeon, Janet K.; Ye, Hongping; Zhang, Jing; Natarajan, Loki; de Boer, Ian H.; Sharma, Kumar (2020)
    Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict. Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of >= 3 and
  • Mattila, Kalle E.; Laajala, Teemu D.; Tornberg, Sara V.; Kilpeläinen, Tuomas P.; Vainio, Paula; Ettala, Otto; Bostrom, Peter J.; Nisen, Harry; Elo, Laura L.; Jaakkola, Panu M. (2021)
    After surgery of localized renal cell carcinoma, over 20% of the patients will develop distant metastases. Our aim was to develop an easy-to-use prognostic model for predicting metastasis-free survival after radical or partial nephrectomy of localized clear cell RCC. Model training was performed on 196 patients. Right-censored metastasis-free survival was analysed using LASSO-regularized Cox regression, which identified three key prediction features. The model was validated in an external cohort of 714 patients. 55 (28%) and 134 (19%) patients developed distant metastases during the median postoperative follow-up of 6.3 years (interquartile range 3.4-8.6) and 5.4 years (4.0-7.6) in the training and validation cohort, respectively. Patients were stratified into clinically meaningful risk categories using only three features: tumor size, tumor grade and microvascular invasion, and a representative nomogram and a visual prediction surface were constructed using these features in Cox proportional hazards model. Concordance indices in the training and validation cohorts were 0.755 +/- 0.029 and 0.836 +/- 0.015 for our novel model, which were comparable to the C-indices of the original Leibovich prediction model (0.734 +/- 0.035 and 0.848 +/- 0.017, respectively). Thus, the presented model retains high accuracy while requiring only three features that are routinely collected and widely available.
  • Rademakers, Timo; van der Vorst, Emiel P. C.; Daissormont, Isabelle T. M. N.; Otten, Jeroen J. T.; Theodorou, Kosta; Theelen, Thomas L.; Gijbels, Marion; Anisimov, Andrey; Nurmi, Harri; Lindeman, Jan H. N.; Schober, Andreas; Heeneman, Sylvia; Alitalo, Kari; Biessen, Erik A. L. (2017)
    During plaque progression, inflammatory cells progressively accumulate in the adventitia, paralleled by an increased presence of leaky vasa vasorum. We here show that next to vasa vasorum, also the adventitial lymphatic capillary bed is expanding during plaque development in humans and mouse models of atherosclerosis. Furthermore, we investigated the role of lymphatics in atherosclerosis progression. Dissection of plaque draining lymph node and lymphatic vessel in atherosclerotic ApoE(-/-)mice aggravated plaque formation, which was accompanied by increased intimal and adventitial CD3(+) T cell numbers. Likewise, inhibition of VEGF-C/D dependent lymphangiogenesis by AAV aided gene transfer of hVEGFR3-Ig fusion protein resulted in CD3(+) T cell enrichment in plaque intima and adventitia. hVEGFR3-Ig gene transfer did not compromise adventitial lymphatic density, pointing to VEGF-C/D independent lymphangiogenesis. We were able to identify the CXCL12/CXCR4 axis, which has previously been shown to indirectly activate VEGFR3, as a likely pathway, in that its focal silencing attenuated lymphangiogenesis and augmented T cell presence. Taken together, our study not only shows profound, partly CXCL12/CXCR4 mediated, expansion of lymph capillaries in the adventitia of atherosclerotic plaque in humans and mice, but also is the first to attribute an important role of lymphatics in plaque T cell accumulation and development.
  • Kokko, Eeva; Nevalainen, Pasi; Choudhary, Manoj Kumar; Koskela, Jenni; Tikkakoski, Antti; Huhtala, Heini; Niemelä, Onni; Viukari, Marianna; Mustonen, Jukka; Matikainen, Niina; Pörsti, Ilkka (2020)
    Aldosterone-to-renin ratio (ARR) is a screening tool for primary aldosteronism (PA), but the significance of ARR when the PA criteria are not met remains largely unknown. In this cross-sectional study we investigated the association of ARR with haemodynamic variables in 545 normotensive and never-medicated hypertensive subjects (267 men, 278 women, age range 19-72 years) without suspicion of PA. Supine haemodynamic data was recorded using whole-body impedance cardiography and radial tonometric pulse wave analysis. In sex-adjusted quartiles of ARR, determined as serum aldosterone to plasma renin activity ratio, the mean values were 282, 504, 744 and 1467 pmol/mu g of angiotensin I/h, respectively. The only difference in haemodynamic variables between the ARR quartiles was higher pulse wave velocity (PWV) in the highest quartile versus other quartiles (p=0.004), while no differences in blood pressure (BP), heart rate, wave reflections, cardiac output or systemic vascular resistance were observed between the quartiles. In linear regression analysis with stepwise elimination, ARR was an independent explanatory factor for PWV (beta =0.146, p
  • Pereira, Renata C.; Valta, Helena; Tumber, Navdeep; Salusky, Isidro B.; Jalanko, Hannu; Makitie, Outi; Perry, Katherine Wesseling (2015)
    Background Bone fragility is common post solid organ transplantation but little is known about bone pathology on a tissue level. Abnormal osteocytic protein expression has been linked to compromised bone health in chronic kidney disease (CKD) and immunosuppressant medications may impact osteocyte function. Methods Transiliac bone biopsies were obtained from 22 pediatric solid organ allograft recipients (average age 15.6 years) an average of 6.3 +/- 1.2 years after transplantation and from 12 pediatric pre-dialysis CKD patients (average age 13.2 years). Histomorphometry and immunohistochemistry for FGF23, DMP1, sclerostin, and osteopontin were performed on all biopsies. Results FGF23 and sclerostin were increased in transplant recipients relative to non-transplant CKD, regardless of the type of allograft received and despite, in the case of liver and heart recipients, a higher GFR. Bone DMP1 expression was higher in liver or heart than in kidney recipients, concomitant with higher serum phosphate values. Osteopontin expression was higher in CKD than in transplant recipients (p Conclusions Solid-organ transplantation is associated with increased FGF23 and sclerostin expression. The contribution of these findings to compromised bone health post transplantation warrants further evaluation.
  • Berntson, Lillemor; Nordal, Ellen; Fasth, Anders; Aalto, Kristiina; Herlin, Troels; Nielsen, Susan; Rygg, Marite; Zak, Marek; Ronnelid, Johan; Nordic Study Grp Pediat Rheumatolo (2014)
  • Knuuttila, Matias; Mehmood, Arfa; Huhtaniemi, Riikka; Yatkin, Emrah; Häkkinen, Merja R.; Oksala, Riikka; Laajala, Teemu D.; Ryberg, Henrik; Handelsman, David J.; Aittokallio, Tero; Auriola, Seppo; Ohlsson, Claes; Laiho, Asta; Elo, Laura L.; Sipila, Petra; Makela, Sari I.; Poutanen, Matti (2018)
    The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P <0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P <0.05) and the AR splice variants 1 (threefold, P <0.05) and 7 (threefold, P <0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.
  • Utz, Begüm; Turpin, Rita; Lampe, Johanna; Pouwels, Jeroen; Klefström, Juha (2020)
    Breast cancer is the most common form of cancer in women. Despite significant therapeutic advances in recent years, breast cancer also still causes the greatest number of cancer-related deaths in women, the vast majority of which (>90%) are caused by metastases. However, very few mouse mammary cancer models exist that faithfully recapitulate the multistep metastatic process in human patients. Here we assessed the suitability of a syngrafting protocol for a Myc-driven mammary tumor model (WAP-Myc) to study autochthonous metastasis. A moderate but robust spontaneous lung metastasis rate of around 25% was attained. In addition, increased T cell infiltration was observed in metastatic tumors compared to donor and syngrafted primary tumors. Thus, the WAP-Myc syngrafting protocol is a suitable tool to study the mechanisms of metastasis in MYC-driven breast cancer.
  • TRIGR Investigators; Pacaud, Daniele; Nucci, Anita M.; Cuthbertson, David; Becker, Dorothy J.; Virtanen, Suvi M.; Ludvigsson, Johnny; Ilonen, Jorma; Knip, Mikael (2021)
    Aims/hypothesis The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. Methods In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. Results Multiple autoantibodies (>= 2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p <0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046,p <0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722,p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator groupn = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (zscore/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70],p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity. Conclusions/interpretation The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.
  • Finndiane Study Grp (2018)
    Background and aims: In the general population, habitual coffee consumption is inversely associated with the metabolic syndrome, a syndrome that is rather common also in patients with type 1 diabetes. However, whether coffee intake is beneficially related to the metabolic syndrome also in type 1 diabetes, is not known. We, therefore, studied the potential association between coffee consumption and the metabolic syndrome in a large population of individuals with type 1 diabetes. Furthermore, we investigated whether coffee consumption is associated with insulin resistance (estimated glucose disposal rate, eGDR), kidney function (estimated glomerular filtration rate, eGFR), and low-grade chronic inflammation (high-sensitivity C-reactive protein, hsCRP). Methods and results: Data from 1040 participants in the Finnish Diabetic Nephropathy Study were included in these cross-sectional analyses. Metabolic syndrome was assumed if at least 3 of the following cardiovascular risk factors were present: central obesity, high blood pressure, low HDL-cholesterol concentration, high triglyceride concentration, and hyperglycaemia. Subjects were categorized based on self-reported daily coffee intake: non-consumers (= 1 cups/d <3), moderate (>= 3 cups/d <5), and high coffee consumption (>= 5 cups/d). In multivariable logistic regression analysis, moderate and high coffee consumption was associated with increased odds of the metabolic syndrome. Moreover, any level of coffee consumption was associated with increased risk of the blood pressure-component. An increasing trend was observed in the eGFR with increasing coffee consumption. Conclusions: In type 1 diabetes, high coffee intake is associated with the metabolic syndrome, and especially its blood pressure-component. (C) 2018 Published by Elsevier B.V.
  • Tynkkynen, Juho; Chouraki, Vincent; van der Lee, Sven J.; Hernesniemi, Jussi; Yang, Qiong; Li, Shuo; Beiser, Alexa; Larson, Martin G.; Sääksjärvi, Katri; Shipley, Martin J.; Singh-Manoux, Archana; Gerszten, Robert E.; Wang, Thomas J.; Havulinna, Aki S.; Würtz, Peter; Fischer, Krista; Demirkan, Ayse; Ikram, M. Arfan; Amin, Najaf; Lehtimäki, Terho; Kähönen, Mika; Perola, Markus; Metspalu, Andres; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mika; Vasan, Ramachandran S.; Kivimäki, Mika; van Duijn, Cornelia M.; Seshadri, Sudha; Salomaa, Veikko (2018)
    Introduction: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. Methods: We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented. Results: Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk. Discussion: Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
  • NBCS Collaborators; ABCTB Investigators; kConFab Investigators; Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Muranen, Taru A.; Nevanlinna, Heli (2021)
    Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
  • Nukarinen, Eija; Lindstrom, Outi; Kuuliala, Krista; Kylänpää, Leena; Pettilä, Ville; Puolakkainen, Pauli; Kuuliala, Antti; Hamalainen, Mari; Moilanen, Eeva; Repo, Heikki; Hästbacka, Johanna (2016)
    Objectives Several biomarkers for early detection of severe acute pancreatitis (SAP) have been presented. Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are released early in inflammation. We aimed to assess levels of MMP-7, -8, -9 and TIMP-1 in acute pancreatitis (AP) and explore their ability to detect disease severity. Our second aim was to find an association between MMPs, TIMP and creatinine. Methods We collected plasma samples for MMP-7, -8, -9 and TIMP-1 analyses from 176 patients presenting within 96 h from onset of acute pancreatitis (AP) symptoms. We used samples from 32 control subjects as comparison. The revised Atlanta Classification was utilised to assess severity of disease. Receiver operating characteristic curve analysis and Spearman's Rho-test were utilised for statistical calculations. Results Compared with controls, patients showed higher levels of all studied markers. MMP-8 was higher in moderately severe AP than in mild AP (p = 0.005) and MMP-8, -9 and TIMP-1 were higher in severe than in mild AP (p
  • Raykhel, Irina; Moafi, Fazeh; Myllymaki, Satu M.; Greciano, Patricia G.; Matlin, Karl S.; Moyano, Jose V.; Manninen, Aki; Myllyharju, Johanna (2018)
    Hypoxia and loss of cell polarity are common features of malignant carcinomas. Hypoxia-inducible factor 1 (HIF1) is the major regulator of cellular hypoxia response and mediates the activation of similar to 300 genes. Increased HIF1 signaling is known to be associated with epithelial-mesenchymal transformation. Here, we report that hypoxia disrupts polarized epithelial morphogenesis of MDCK cells in a HIF1 alpha-dependent manner by modulating the transforming growth factor-beta (TGF beta) signaling pathway. Analysis of potential HIF1 targets in the TGF beta pathway identified the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a transmembrane glycoprotein related to the type I receptors of the TGF beta family, whose expression was essentially lost in HIF1-depleted cells. Similar to what was observed in HIF1-deficient cells, BAMBI-depleted cells failed to efficiently activate TGF beta signaling and retained epithelial polarity during hypoxia. Taken together, we show that hypoxic conditions promote TGF beta signaling in a HIF1-dependent manner and BAMBI is identified in this pathway as a novel HIF1-regulated gene that contributes to hypoxia-induced loss of epithelial polarity.
  • Kallio, Pauliina; Jokinen, Elina; Högström, Jenny; Das, Suvendu; Heino, Sarika; Lähde, Marianne; Brodkin, Jefim; Korhonen, Emilia A.; Alitalo, Kari (2020)
    Abnormal vasculature in tumors leads to poor tissue perfusion and cytostatic drug delivery. Although drugs inducing vascular normalization, for example, angiopoietin-2 (Ang2)-blocking antibodies, have shown promising results in preclinical tumor models, clinical studies have so far shown only little efficacy. Because Ang2 is known to play a protective role in stressed endothelial cells, we tested here whether Ang2 blocking could enhance radiation-induced tumor vascular damage. Tumor-bearing mice were treated with anti-Ang2 antibodies every 3 or 4 days starting 3 days before 3 x 2 Gy or 4 x 0.5 Gy whole-body or tumor-focused radiation. Combination treatment with anti-Ang2 and radiation improved tumor growth inhibition and extended the survival of mice with melanoma or colorectal tumors. Single-cell RNA-sequencing revealed that Ang2 blocking rescued radiation-induced decreases inT cells and cells of the monocyte/macrophage lineage. In addition, anti-Ang2 enhanced radiation-induced apoptosis in cultured endothelial cells. In vivo, combination treatment decreased tumor vasculature and increased tumor necrosis in comparison with tumors treated with monotherapies. These results suggest that a combination of Ang2-blocking antibodies with radiation increases tumor growth inhibition and extends the survival of tumor-bearing mice. Significance: These findings offer a preclinical rationale for further testing of the use of radiation in combination with Ang2-blocking antibodies to improve the overall outcome of cancer treatment.