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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. Source


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. Source


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. Source


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. Source


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. Source

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