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Innos K.,National Institute for Health Development | Padrik P.,University of Tartu | Valvere V.,North Estonia Medical Center | Valvere V.,Competence Center for Cancer Research | Aareleid T.,National Institute for Health Development
BMC Cancer | Year: 2015

Background: In Estonia, women have much longer life expectancy than men. The aim of this study was to examine sex differences in cancer survival in Estonia and to explore the role of age at diagnosis, stage at diagnosis and tumour subsite. Methods: Using data from the population-based Estonian Cancer Registry, we examined the relative survival of adult patients diagnosed with nine common cancers in Estonia in 1995-2006 and followed up through 2011. Excess hazard ratios (EHR) of death associated with female gender adjusted for age, stage at diagnosis and tumour subsite were estimated. Results: A total of 20 828 male and 13 166 female cases were analysed. The main data quality indicators were similar between men and women. Women had more cases with unknown extent of disease at diagnosis. Overall, the age-adjusted 5-year relative survival ratio was higher among women than men for all studied sites, but the difference was significant for cancers of mouth and pharynx (22% units), lung (5% units), skin melanoma (17% units) and kidney (8% units). The increase in survival over time was larger for women than men for cancers of mouth and pharynx, colon, rectum, kidney and skin melanoma. In multivariate analysis, women had a significantly lower EHR of death within five years after diagnosis for five of the nine cancers studied (cancers of mouth and pharynx, stomach, lung, skin melanoma and kidney). Adjustment for stage and subsite explained some, but not all of the women's advantage. Conclusions: We found a significant female survival advantage in Estonia for cancers of mouth and pharynx, stomach, lung, kidney and skin melanoma. The differences in favour of women tended to increase over time as from the 1990s to the 2000s, survival improved more among women than among men. A large part of the women's advantage is likely attributable to biological factors, but other factors, such as co-morbidities, treatment compliance or health behaviour, are also probable contributors to gender survival disparities in Estonia and merit further investigation. Our findings have implications for public health, early detection and cancer care in Estonia. © 2015 Innos et al.; licensee BioMed Central.


Innos K.,National Institute for Health Development | Padrik P.,University of Tartu | Valvere V.,North Estonia Medical Center | Valvere V.,Competence Center for Cancer Research | And 4 more authors.
BMC Public Health | Year: 2013

Background: Survival from breast cancer remains lower in Estonia than in most other European countries. More advanced stage and larger tumors that have impact on survival may be a result of delay in seeking help for breast cancer symptoms. The aim of this study was to identify determinants of delayed presentation among breast cancer patients in Estonia. Methods. The study population included women with primary breast cancer diagnosed in Estonia in 2008-2010. All data were collected using structured personal interviews carried out by trained nurses in the hospital setting. Only patients with self-discovered symptoms were included in this analysis. Patient delay was measured as time elapsing from symptom self-discovery to first medical consultation. The effect of different factors on the likelihood of prolonged delay (>90 days) was evaluated using logistic regression. Results: Among 703 eligible patients, median patient delay was 16 days (interquartile range 5-54 days). Seventeen percent of the patients had their first medical consultation more than three months after self-detection of symptoms. In multivariate analysis, the risk of prolonged delay was significantly associated with age 65 years and over (OR 2.27, 95% CI 1.23-4.20), current smoking (OR 2.09, 95% CI 1.21-3.61), symptoms other than painless breast lump or breast pain (OR 1.84, 95% CI 1.08-3.16), no history of mammograms (OR 1.83, 95% CI 1.13-2.95), having received no information on breast cancer during past year (OR 1.77, 95% CI 1.05-2.99), and previous benign breast problems (OR 1.65, 95% CI 1.01-2.67). Non-significant risk increase was seen with lower education. Conclusions: This study provides evidence that factors associated with delayed presentation of breast cancer in Eastern Europe are similar to those observed in Western countries. The results suggest that educational messages to general population should aim at increasing awareness of "non-lump" symptoms of breast cancer and encouraging women of all ages to present in a timely manner. Women at risk for delayed presentation such as smokers and women with no history of mammograms could be identified in the primary care setting. © 2013 Innos et al.; licensee BioMed Central Ltd.


Baburin A.,National Institute for Health Development | Aareleid T.,National Institute for Health Development | Padrik P.,University of Tartu | Valvere V.,North Estonia Medical Center | And 2 more authors.
Acta Oncologica | Year: 2014

Background. Survival from breast cancer (BC) in Estonia has been consistently among the lowest in Europe. The aim of this study was to examine most recent trends in BC survival in Estonia by age and stage. The trends in overall BC incidence and mortality are also shown in the paper. Material and methods. Estonian Cancer Registry data on all cases of BC, diagnosed in women in Estonia during 1995-2007 (n = 7424) and followed up for vital status through 2009, were used to estimate relative survival ratios (RSR). Period hybrid approach was used to obtain the most recent estimates (2005-2009). Stage was classified as localized, local/regional spread or distant. Results. BC incidence continued to rise throughout the study period, but mortality has been in steady decline since 2000. The distribution of patients shifted towards older age and earlier stage at diagnosis. Overall age-standardized five-year RSR increased from 63% in 1995-1999 to 74% in 2005-2009. Younger age groups experienced a more rapid improvement compared to women over 60. Significant survival increase was observed for both localized and locally/regionally spread BC with five-year RSRs reaching 96% and 70% in 2005-2009, respectively; the latest five-year RSR for distant BC was 11%. Survival for T4 tumors was poor and large age difference was seen for locally/regionally spread BC. Conclusions. Considerable improvement in BC survival was observed over the study period. Women under 60 benefited most from both earlier diagnosis and treatment advances of locally/regionally spread cancers. However, the survival gap with more developed countries persists. Further increase in survival, but also decline in BC mortality in Estonia could be achieved by facilitating early diagnosis in all age groups, but particularly among women over 60. Investigations should continue to clarify the underlying mechanisms of the stage-specific survival deficit in Estonia. © 2014 Informa Healthcare.


Kaambre T.,Estonian National Institute of Chemical Physics and Biophysics | Chekulayev V.,Estonian National Institute of Chemical Physics and Biophysics | Shevchuk I.,Estonian National Institute of Chemical Physics and Biophysics | Karu-Varikmaa M.,Estonian National Institute of Chemical Physics and Biophysics | And 9 more authors.
Journal of Bioenergetics and Biomembranes | Year: 2012

The aim of this study was to analyze quantitatively cellular respiration in intraoperational tissue samples taken from human breast cancer (BC) patients. We used oxygraphy and the permeabilized cell techniques in combination with Metabolic Control Analysis (MCA) to measure a corresponding flux control coefficient (FCC). The activity of all components of ATP synthasome, and respiratory chain complexes was found to be significantly increased in human BC cells in situ as compared to the adjacent control tissue. FCC(s) were determined upon direct activation of respiration with exogenously-added ADP and by titrating the complexes with their specific inhibitors to stepwise decrease their activity. MCA showed very high sensitivity of all complexes and carriers studied in human BC cells to inhibition as compared to mitochondria in normal oxidative tissues. The sum of FCC (s) for all ATP synthasome and respiratory chain components was found to be around 4, and the value exceeded significantly that for normal tissue (close to 1). In BC cells, the key sites of the regulation of respiration are Complex IV (FCC=0.74), ATP synthase (FCC=0.61), and phosphate carrier (FCC= 0.60); these FCC(s) exceed considerably (∼10-fold) those for normal oxidative tissues. In human BC cells, the outer mitochondrial membrane is characterized by an increased permeability towards adenine nucleotides, the mean value of the apparent Km for ADP being equal to 114.8±13.6 μM. Our data support the two-compartment hypothesis of tumor metabolism, the high sum of FCC(s) showing structural and functional organization of mitochondrial respiratory chain and ATP synthasome as supercomplexes in human BC. © Springer Science+Business Media, LLC 2012.


Laht P.,Tallinn University of Technology | Laht P.,Competence Center for Cancer Research | Pill K.,Tallinn University of Technology | Haller E.,Tallinn University of Technology | And 2 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2012

Background: Plexins are transmembrane receptors that are highly expressed in the central nervous system. They participate in the patterning of neural connections and regulation of cell adhesion and motility in many cell types. The aim of this study was to characterize novel protein-protein interactions of plexin-B3 intracellular portion. Methods: To identify new interactors of plexin-B3 yeast two-hybrid screen was performed. We used GST pull-down and co-immunoprecipitation to verify those results. Deletion mutants were used to map the interacting regions. The physiological relevance of this interaction was assessed with neurite outgrowth assay in Neuro2A cell line. Results: We show that the N-terminal segment of intracellular domain of plexin-B3 interacts with microtubule plus end-binding proteins EB1, EB2 and EB3. The corresponding region in human plexin-A2, B1 and B3 contains the conserved EB-binding motif SxIP and these plexins also associate with EBs indicating the specificity of plexin-EB binding. As to the EB proteins, their N-terminal microtubule-binding domain is dispensable for plexin interaction. Plexin-EB interaction is involved in neurite growth as the synthetic peptide corresponding to the EB-binding region of plexin-B1 increases significantly the number of neurite tips in Neuro2A cells. Conclusions: Microtubule end-binding proteins EB1, EB2 and EB3 interact with plexin-A2, B1 and B3 through a conserved EB-binding motif, which is located in their intracellular domain N-terminal segment. General significance: The observed interaction between plexin intracellular domain and EBs suggests a novel function for plexins in regulating EB-mediated changes in microtubule dynamics and neurite growth. © 2012 Elsevier B.V. All rights reserved.


Luberg K.,Tallinn University of Technology | Luberg K.,Competence Center for Cancer Research | Wong J.,Schizophrenia Research Institute | Wong J.,Prince of Wales Medical Research Institute | And 6 more authors.
Journal of Neurochemistry | Year: 2010

Brain-derived neurotrophic factor and neurotrophin-4 high-affinity receptor tropomyosine related kinase (Trk) B is required for the differentiation and maintenance of specific neuron populations. Misregulation of TrkB has been reported in many human diseases, including cancer, obesity and neurological and psychiatric disorders. Alternative splicing that generates receptor isoforms with different functional properties also regulates TrkB function. Here, we describe numerous novel isoforms of TrkB proteins, including isoforms generated by alternative splicing of cassette exons in the regions encoding both the extracellular and intracellular domain and also N-terminally truncated isoforms encoded by novel 5′ exon-containing transcripts. We also characterize the intracellular localization and phosphorylation potential of novel TrkB isoforms and find that these proteins have unique properties. In addition, we describe the expression profiles of all the known human TrkB transcripts in adult tissues and also during postnatal development in the human prefrontal cortex. We show that transcripts encoding the full-length TrkB receptor and the C-terminally truncated TrkB-T1 have different expression profiles as compared to the proteins they encode. Identification of 36 potential TrkB protein isoforms suggests high complexity in the synthesis, regulation and function of this important neurotrophin receptor emphasizing the need for further study of these novel TrkB variants. © 2010 International Society for Neurochemistry.


Laht P.,Tallinn University of Technology | Laht P.,Competence Center for Cancer Research | Otsus M.,Competence Center for Cancer Research | Remm J.,University of Tartu | And 2 more authors.
Experimental Cell Research | Year: 2014

Semaphorins and their receptors plexins are implicated in various processes in the nervous system, but how B-plexins regulate the growth of dendrites remains poorly characterized. We had previously observed that Plexin-B1 and B3 interact with microtubule end-binding proteins (EBs) that are central adapters at growing microtubule tips, and this interaction is involved in neurite growth. Therefore, we hypothesized that plexins regulate microtubule dynamics and through that also dendritogenesis. The role of all three B-plexins was systematically examined in these processes. B-plexins and their ligand Semaphorin-4D influence the dynamics of microtubule tips both EB-dependently and independendently. EB3 as well as Plexin-B1, B2 and B3 turned out to have a significant role in the development of dendritic arbor of rat hippocampal neurons. Our results clearly indicate that semaphorin-plexin-EB pathway is one molecular mechanism how extracellular guidance cues are translated into intracellular mechanics. Taken together, Semaphorin-4D and B-plexins modulate the dynamic behavior of microtubule tips, and are therefore important in neurite growth. © 2014 Elsevier Inc.


Pall T.,Tallinn University of Technology | Pall T.,Competence Center for Cancer Research | Pink A.,Tallinn University of Technology | Pink A.,Competence Center for Cancer Research | And 8 more authors.
PLoS ONE | Year: 2011

CD44 is a cell surface glycoprotein that functions as hyaluronan receptor. Mouse and human serum contain substantial amounts of soluble CD44, generated either by shedding or alternative splicing. During inflammation and in cancer patients serum levels of soluble CD44 are significantly increased. Experimentally, soluble CD44 overexpression blocks cancer cell adhesion to HA. We have previously found that recombinant CD44 hyaluronan binding domain (CD44HABD) and its non-HA-binding mutant inhibited tumor xenograft growth, angiogenesis, and endothelial cell proliferation. These data suggested an additional target other than HA for CD44HABD. By using non-HA-binding CD44HABD Arg41Ala, Arg78Ser, and Tyr79Ser-triple mutant (CD443MUT) we have identified intermediate filament protein vimentin as a novel interaction partner of CD44. We found that vimentin is expressed on the cell surface of human umbilical vein endothelial cells (HUVEC). Endogenous CD44 and vimentin coprecipitate from HUVECs, and when overexpressed in vimentin-negative MCF-7 cells. By using deletion mutants, we found that CD44HABD and CD443MUT bind vimentin N-terminal head domain. CD443MUT binds vimentin in solution with a Kd in range of 12-37 nM, and immobilised vimentin with Kd of 74 nM. CD443MUT binds to HUVEC and recombinant vimentin displaces CD443MUT from its binding sites. CD44HABD and CD443MUT were internalized by wild-type endothelial cells, but not by lung endothelial cells isolated from vimentin knock-out mice. Together, these data suggest that vimentin provides a specific binding site for soluble CD44 on endothelial cells. © 2011 Päll et al.


Tints K.,Protobios LLC | Prink M.,Protobios LLC | Prink M.,Competence Center for Cancer Research | Neuman T.,Protobios LLC | And 2 more authors.
International Journal of Molecular Sciences | Year: 2014

Degenerate expression of transcription coregulator proteins is observed in most human cancers. Therefore, in targeted anti-cancer therapy development, intervention at the level of cancer-specific transcription is of high interest. The steroid receptor coactivator-1 (SRC-1) is highly expressed in breast, endometrial, and prostate cancer. It is present in various transcription complexes, including those containing nuclear hormone receptors. We examined the effects of a peptide that contains the LXXLL-motif of the human SRC-1 nuclear receptor box 1 linked to the cell-penetrating transportan 10 (TP10), hereafter referred to as TP10-SRC1LXXLL, on proliferation and estrogen-mediated transcription of breast cancer cells in vitro. Our data show that TP10-SRC1LXXLL induced dose-dependent cell death of breast cancer cells, and that this effect was not affected by estrogen receptor (ER) status. Surprisingly TP10-SRC1LXXLL severely reduced the viability and proliferation of hormone-unresponsive breast cancer MDA-MB-231 cells. In addition, the regulation of the endogenous ERα direct target gene pS2 was not affected by TP10-SRC1LXXLL in estrogen-stimulated MCF-7 cells. Dermal fibroblasts were similarly affected by treatment with higher concentrations of TP10-SRC1LXXLL and this effect was significantly delayed. These results suggest that the TP10-SRC1LXXLL peptide may be an effective drug candidate in the treatment of cancers with minimal therapeutic options, for example ER-negative tumors. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


PubMed | Competence Center for Cancer Research and Tallinn University of Technology
Type: Journal Article | Journal: Experimental cell research | Year: 2015

Molecular mechanisms underlying synaptogenesis and synaptic plasticity have become one of the main topics in neurobiology. Increasing evidence suggests that axon guidance molecules including semaphorins and plexins participate in synapse formation and elimination. Although class B plexins are widely expressed in the brain, their role in the nervous system remains poorly characterized. We previously identified that B-plexins modulate microtubule dynamics and through this impact dendrite growth in rat hippocampal neurons. Here, we demonstrate that Plexin-B2 and Plexin-B3 are present in dendrites, but do not localize in synapses. We find that overexpression of all B-plexins leads to decreased volume of excitatory synapses, and at the same time Plexin-B1 and Plexin-B3 promote inhibitory synapse assembly. Plexin-B3 mutants revealed that these processes use different downstream pathways. While elimination of excitatory synapses is the result of Plexin-B3 binding to microtubule end binding proteins EB1 and EB3, the increase in inhibitory synapses is mediated by regulation of Ras and Rho GTPases. Overall, our findings demonstrate that Plexin-B3 contributes to regulating synapse formation.

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