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Estonia

Cancer Statistics
Population in 2012: 1.3m
People newly diagnosed with cancer (excluding NMSC) / yr: 6,100
Age-standardised rate, incidence per 100,000 people/yr: 242.8
Risk of getting cancer before age 75:25.2%
People dying from cancer /yr: 3,100
Data from IARC GlobalCan (2012)
Estonia Cancer Organisations and Resources
Latest Research Publications Related to Estonia

Estonia Cancer Organisations and Resources (9 links)


Latest Research Publications Related to Estonia

Padrik P, Valter A, Valter E, et al.
Trends in incidence and survival of cutaneous malignant melanoma in Estonia: a population-based study.
Acta Oncol. 2017; 56(1):52-58 [PubMed] Related Publications
BACKGROUND: Previous studies have shown an increase in the incidence of cutaneous melanoma (CM) in Estonia, but also poor survival in international comparisons, with a significant survival gap between the sexes. The aim of this study was to analyze the time trends in CM incidence and relative survival by age, TNM stage and anatomical subsite among men and women in Estonia.
MATERIALS AND METHODS: Data from the Estonian Cancer Registry were used to calculate age-standardized (World) and age-specific incidence of CM in 1995-2013, and five-year relative survival ratios (RSR) for cases diagnosed in 1995-2012 and followed through in 2014. Period hybrid analysis was used to calculate the most recent survival estimates for 2010-2014.
RESULTS: Between 1995 and 2013, the age-standardized incidence of CM increased significantly in Estonia among both sexes, at a rate of around 4% per year. Among women, the proportion of trunk melanomas increased from 26% in 1995-1999 to 39% in 2010-2012 and became the most common site. The proportion of stage I cases and T1 tumors increased considerably. Women had more favorable stage distribution and thinner tumors than men. The age-adjusted five-year RSR increased significantly, from 64% in 1995-1999 to 81% in 2010-2014. The latest age-adjusted RSRs were 76% among men and 84% among women. Survival gains were the largest in patients below 50 years, those with head and neck or trunk melanomas, and stage III cancer.
CONCLUSIONS: The proportion of stage I and T1 cases is lower in Estonia compared with the Scandinavian data and is likely a major contributor to the persisting overall survival deficit in Estonia. The apparent deficit in stage II survival also warrants further investigation. A public health program is necessary in Estonia to raise awareness of CM and to significantly increase early stage diagnosis.

Hulegårdh E, Punab M, Holmberg E, et al.
Acute de novo Leukemia in Estonia and Western Sweden 1982-2006: Positive Trend in the Survival of Acute Leukemia over 25 Years.
Acta Haematol. 2016; 136(3):167-73 [PubMed] Related Publications
This study focuses on the incidence, treatment, and survival of de novo acute leukemia in a 25-year perspective in western Sweden and Estonia. At the beginning of our study, Estonia was a part of the Eastern bloc with planned economy, but since 1991 it is a member of the European Union and transforming into a market economy. Survival rates have steadily increased in both countries. However, a gap between their survival curves remains. Based on our data, it is difficult to explain the big difference in the 5-year relative survival in favor of western Sweden (55 vs. 22%). In Germany, there was a big difference in overall cancer survival between East and West Germany after the fall of the iron curtain, but today no difference is seen. Differences in survival are probably due to a higher proportion of intense chemotherapy regimens and a higher rate of hematopoietic stem cell transplantations in Sweden. Other important factors might be better supportive care and diagnostics as well as better adjuvant therapy. Better staff training and conditions in wards are also factors that might play an essential role.

Kashyap D, Mittal S, Sak K, et al.
Molecular mechanisms of action of quercetin in cancer: recent advances.
Tumour Biol. 2016; 37(10):12927-12939 [PubMed] Related Publications
In the last few decades, the scientific community has discovered an immense potential of natural compounds in the treatment of dreadful diseases such as cancer. Besides the availability of a variety of natural bioactive molecules, efficacious cancer therapy still needs to be developed. So, to design an efficacious cancer treatment strategy, it is essential to understand the interactions of natural molecules with their respective cellular targets. Quercetin (Quer) is a naturally occurring flavonol present in many commonly consumed food items. It governs numerous intracellular targets, including the proteins involved in apoptosis, cell cycle, detoxification, antioxidant replication, and angiogenesis. The weight of available synergistic studies vigorously fortifies the utilization of Quer as a chemoprevention drug. This extensive review covers various therapeutic interactions of Quer with their recognized cellular targets involved in cancer treatment.

Baburin A, Aareleid T, Rahu M, et al.
Recent changes in breast cancer incidence and mortality in Estonia: Transition to the west.
Acta Oncol. 2016; 55(6):728-33 [PubMed] Related Publications
Background The aim of this study was to examine breast cancer (BC) incidence and mortality trends in Estonia during recent decades and to compare the pattern of these trends with other selected European countries and regions. We attempt to explain the findings in relation to changes in Estonian society and healthcare system. Methods BC incidence (1985-2012) and mortality (1985-2013) data for Estonia were obtained from the Estonian Cancer Registry and Statistics Estonia. Data for selected European countries were obtained from the EUREG database. Joinpoint regression was used to analyze age-standardized rates in Estonia by age. For international comparison of incidence and mortality rates, we used scatterplot with 95% confidence ellipses and the mortality to incidence ratio. Results The overall BC incidence continues to increase in Estonia, while mortality has been in decline since 2000. Both incidence and mortality trends varied considerably across age groups. Among women aged 60 years and older, BC incidence increased at a rate of nearly 3% per year. Significant decrease in mortality was seen only among women aged 50-59 years. Comparison of scatterplots between countries and regions revealed two clusters in Europe separated along the incidence axis. The correlation between incidence and mortality in Estonia changed its direction in the mid-1990s. Conclusion In recent years, the dynamics of BC burden in Estonia has transitioned towards the high incidence-low mortality type model, which is characteristic to Western, Northern and Southern Europe. Although overall BC incidence is much lower in Estonia than in more affluent European countries, mortality from BC is still relatively high, particularly among elderly women.

Sflomos G, Dormoy V, Metsalu T, et al.
A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response.
Cancer Cell. 2016; 29(3):407-22 [PubMed] Related Publications
Seventy-five percent of breast cancers are estrogen receptor α positive (ER⁺). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient-derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER⁺ tumor cells into mammary fat pads induces TGFβ/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER⁺ tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER⁺ PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis.

Paasonen L, Sharma S, Braun GB, et al.
New p32/gC1qR Ligands for Targeted Tumor Drug Delivery.
Chembiochem. 2016; 17(7):570-5 [PubMed] Related Publications
Cell surface p32, the target of LyP-1 homing peptide, is upregulated in tumors and atherosclerotic plaques and has been widely used as a receptor for systemic delivery of payloads. Here, we identified an improved LyP-1-mimicking peptide (TT1, CKRGARSTC). We used this peptide in a fluorescence polarization-based high-throughput screening of a 50,000-compound chemical library and identified a panel of compounds that bind p32 with low micromolar affinity. Among the hits identified in the screen, two compounds were shown to specifically bind to p32 in multiple assays. One of these compounds was chosen for an in vivo study. Nanoparticles surface-functionalized with this compound specifically adhered to surfaces coated with recombinant p32 and, when injected intravenously, homed to p32-expressing breast tumors in mice. This compound provides a lead for the development of p32-targeted affinity ligands that circumvent some of the limitations of peptide-based probes in guided drug delivery.

Sak K, Everaus H
Sulfotransferase 1A1 as a Biomarker for Susceptibility to Carcinogenesis: From Molecular Genetics to the Role of Dietary Flavonoids.
Curr Drug Metab. 2016; 17(6):528-41 [PubMed] Related Publications
BACKGROUND: Sulfotransferase (SULT) 1A1 is a phase II metabolic enzyme that catalyzes sulfate conjugation of various phenolic compounds, including endogenous substances, such as estrogens and thyroid hormones, but also different xenobiotics. Although sulfation is classically considered as a detoxification event facilitating the excretion of more water soluble metabolites from the body, in some cases such bioconversion may also lead to bioactivation of promutagens, producing highly reactive intermediates which are capable of damaging DNA and promoting carcinogenesis. The most common polymorphism in SULT1A1 (Arg213His) has an important functional impact by affecting the capacity to sulfate diverse substrates and numerous case-control studies have shown associations between SULT1A1 variants and susceptibility to different malignancies. Several factors may significantly influence such relationships, including ethnicity, gender, parity, menopausal status, use of estrogen replacement therapy, exposure to tobacco smoke or occupational chemicals.
RESULTS AND CONCLUSION: In this review article, we show that one more important determinant should be considered as a stratifying factor in studies of possible associations between SULT1A1 variants and cancer risk, i.e., the dietary intake of different flavonoids. As sulfation of bioactive plant polyphenols can change their potential anticancer activities and, on the other hand, these phytochemicals are capable to behave also as potent SULT1A1 inhibitors, the regular dietary exposure of humans to these compounds can make a great contribution to the impact of sulfation capacity on individual susceptibility to carcinogenesis. The effect of specific flavonoids as well as their interactions with other factors on associations between SULT1A1 alleles and cancer risk certainly needs further thorough studies.

Kumar G, Mittal S, Sak K, Tuli HS
Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives.
Life Sci. 2016; 148:313-28 [PubMed] Related Publications
In recent years, natural compounds have received considerable attention in preventing and curing most dreadful diseases including cancer. The reason behind the use of natural compounds in chemoprevention is associated with fewer numbers of side effects than conventional chemotherapeutics. Curcumin (diferuloylmethane, PubMed CID: 969516), a naturally occurring polyphenol, is derived from turmeric, which is used as a common Indian spice. It governs numerous intracellular targets, including proteins involved in antioxidant response, immune response, apoptosis, cell cycle regulation and tumor progression. A huge mass of available studies strongly supports the use of Curcumin as a chemopreventive drug. However, the main challenge encountered is the low bioavailability of Curcumin. This extensive review covers various therapeutic interactions of Curcumin with its recognized cellular targets involved in cancer treatment, strategies to overcome the bioavailability issue and adverse effects associated with Curcumin consumption.

Borghesan M, Fusilli C, Rappa F, et al.
DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression.
Cancer Res. 2016; 76(3):594-606 [PubMed] Free Access to Full Article Related Publications
Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression.

Vranken MJ, Lisman JA, Mantel-Teeuwisse AK, et al.
Barriers to access to opioid medicines: a review of national legislation and regulations of 11 central and eastern European countries.
Lancet Oncol. 2016; 17(1):e13-22 [PubMed] Related Publications
Control measures designed to prevent the misuse of opioid medicines can often unintentionally restrict legitimate medical use, leaving patients with cancer in pain. This study aimed to develop and validate an assessment instrument based on WHO policy guidelines to systematically identify legal and regulatory barriers to opioid access in 11 European countries (Bulgaria, Cyprus, Estonia, Greece, Hungary, Latvia, Lithuania, Serbia, Slovakia, Slovenia, and Turkey) as part of the Access to Opioid Medication in Europe project. Relevant legislation and regulations were independently assessed by three reviewers and potential barriers were identified within nine categories including prescribing, penalties, and others. Potential barriers were identified in all countries, ranging from 22 potential barriers (Cyprus) to 128 potential barriers (Lithuania). The total number of barriers in a single category varied from one (Slovenia, usage category) to 49 (Greece, prescribing category). Differences, such as prescription validity, varied within one category, ranging from 5 days (Hungary) to 13 weeks (Cyprus). The results of this Review should give rise to a national review and revision of provisions that impede access to opioids, disproportionate to their (intended) benefit in preventing misuse, in these 11 European countries.

Tuckuviene R, Ranta S, Albertsen BK, et al.
Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study.
J Thromb Haemost. 2016; 14(3):485-94 [PubMed] Related Publications
UNLABELLED: ESSENTIALS: Children with acute lymphoblastic leukemia (ALL) are at risk of thromboembolism (TE). This is a prospective evaluation of the incidence, risk factors and outcomes of TE in 1038 children with ALL. TE occurred in 6.1% of children, with the highest incidence (20.5%) among those aged 15-17 years. A TE-associated case fatality of 6.4% indicates that TE is a severe complication of ALL treatment.

Kurtenkov O, Klaamas K
Increased Avidity of the Sambucus nigra Lectin-Reactive Antibodies to the Thomsen-Friedenreich Antigen as a Potential Biomarker for Gastric Cancer.
Dis Markers. 2015; 2015:761908 [PubMed] Free Access to Full Article Related Publications
AIM: To determine whether the naturally occurring Thomsen-Friedenreich (TF) antigen-specific antibodies differ in avidity between cancer patients and controls to find a novel biomarker for stomach cancer.
METHODS: Serum samples were taken from patients with cancer and controls. The level of TF-specific antibodies and their sialylation were determined using ELISA with synthetic TF-polyacrylamide conjugate as antigen and sialic acid-specific Sambucus nigra agglutinin (SNA). The avidity was determined using ammonium thiocyanate as a chaotrope.
RESULTS: A significantly higher SNA lectin binding to anti-TF antibodies was found in cancer patients irrespective of disease stage. The avidity of only IgM TF-specific antibodies was significantly higher in cancer patients compared to controls. The SNA-positive anti-TF antibodies of cancer patients showed a significantly higher avidity, P < 0.001. The sensitivity and specificity of this increase for gastric cancer were 73.53% and 73.08%, respectively, with a 73.2% diagnostic accuracy. The higher avidity of SNA-reactive anti-TF antibodies was associated with a benefit in survival of stage 3 cancer patients.
CONCLUSION: The SNA-reactive TF-specific antibodies display a significantly higher avidity in gastric cancer patients compared to controls, which can be used as a potential serologic biomarker for gastric cancer. It appears that IgM is the main target responsible for the above changes.

Davies EJ, Dong M, Gutekunst M, et al.
Capturing complex tumour biology in vitro: histological and molecular characterisation of precision cut slices.
Sci Rep. 2015; 5:17187 [PubMed] Free Access to Full Article Related Publications
Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1α. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means.

Gravanis I, Tzogani K, van Hennik P, et al.
The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.
Oncologist. 2016; 21(1):102-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option.
MATERIALS AND METHODS: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
RESULTS: Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection.
CONCLUSION: The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).
IMPLICATIONS FOR PRACTICE: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.

Krebs K, Ruusmann A, Simonlatser G, Velling T
Expression of FLNa in human melanoma cells regulates the function of integrin α1β1 and phosphorylation and localisation of PKB/AKT/ERK1/2 kinases.
Eur J Cell Biol. 2015; 94(12):564-75 [PubMed] Related Publications
FLNa is a ubiquitous cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and functions as a signalling intermediate. We investigated FLNa's role in the function of integrin-type collagen receptors, EGF-EGFR signalling and regulation of PKB/Akt and ERK1/2. Using FLNa-deficient M2 human melanoma cells, and same cells expressing EGFP-FLNa (M2F) or its Ig-like repeats 1-8+24, 8-15+24 and 16-24, we found that in M2F and M2 8-15+24 cells, EGF induced the increased phosphorylation of PKB/Akt and ERK1/2. In M2F cells EGF induced the localisation of these kinases to cell nucleus and lamellipodia, respectively, and the ERK1/2 phosphorylation-dependent co-immunoprecipitation of FLNa with ERK1/2. Only M2F and M2 8-15+24 cells adhered to and spread on type I collagen whereas on fibronectin all cells behaved similarly. α1β1 and α2β1 were the integrin-type collagen receptors expressed on these cells with primarily α1β1 localising to focal contacts and affecting cell adhesion and migration in a manner dependent on FLNa or its Ig-like repeats 8-15. Our results suggest a role for FLNa repeats 8-15 in the α1-subunit-dependent regulation of integrin α1β1 function, EGF-EGFR signalling to PKB/Akt and ERK1/2, identify ERK1/2 in EGF-induced FLNa-associated protein complexes, and show that the function of different integrins is subjected to differential regulation by FLNa.

Traks T, Karelson M, Reimann E, et al.
Association analysis of class II cytokine and receptor genes in vitiligo patients.
Hum Immunol. 2016; 77(5):375-81 [PubMed] Related Publications
The loss of melanocytes in vitiligo is mainly attributed to defective autoimmune mechanisms and lately autoinflammatory mediators have become more emphasized. Among these, a number of class II cytokines and their receptors have displayed altered expression patterns in vitiligo. Thus, we selected 30 SNPs from the regions of respective genes to be genotyped in Estonian case-control sample (109 and 328 individuals, respectively). For more precise analyses, patients were divided into subgroups based on vitiligo progression activity, age of onset, sex, occurrence of vitiligo among relatives, extent of depigmented areas, appearance of Köbner's phenomenon, existence of halo nevi, occurrence of spontaneous repigmentation, and amount of thyroid peroxidase antibodies. No associations appeared in whole vitiligo group. In subgroups, several allelic and haplotype associations were found. The strongest involved SNPs rs12301088 (near IL26 gene), that was associated with familial vitiligo and existence of halo nevi, and rs2257167 (IFNAR1 gene), that was associated with female vitiligo. Additionally, haplotypes consisting of rs12301088 and rs12321603 alleles (IL26-IL22 genes), that were associated with familial vitiligo and existence of halo nevi. In conclusion, several genetic associations with vitiligo subphenotypes were revealed and functional explanations to these remain to be determined in respective studies.

Day FR, Ruth KS, Thompson DJ, et al.
Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.
Nat Genet. 2015; 47(11):1294-303 [PubMed] Free Access to Full Article Related Publications
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Samarin A, Hüllner M, Queiroz MA, et al.
18F-FDG-PET/MR increases diagnostic confidence in detection of bone metastases compared with 18F-FDG-PET/CT.
Nucl Med Commun. 2015; 36(12):1165-73 [PubMed] Related Publications
PURPOSE: The aim of this study was to compare detection, lesion conspicuity and reader confidence of F-fluorodeoxyglucose (F-FDG)-PET/MR and F-FDG-PET/computed tomography (CT) in patients with F-FDG avid bone metastases.
MATERIALS AND METHODS: In this prospective study, a total of 30 PET/CT and PET/MRI data sets were performed in 24 patients. Each examination was evaluated for the presence of PET-positive bone lesions consistent with metastatic involvement. Conspicuity of PET-positive bone lesions was evaluated on the corresponding PET/CT and PET/MR images and compared using the Wilcoxon signed-ranks test. Reader confidence was determined to evaluate whether PET/CT or PET/MR was more useful for the assessment of the bone metastases and was compared using Student's t-test.
RESULTS: Overall, in both examinations, PET/CT and PET/MRI detected 86 F-FDG-positive bone lesions. On all 30 PET/MRI examinations, at least one morphological correlate for F-FDG-positive bone lesions was found on the MR component (82 out of 86 lesions). PET/CT imaging allowed identification of corresponding structural changes on the CT component in 23 out of 30 studies (65 out of 86 lesions). In lesion-by-lesion analysis, the mean lesion conspicuity was significantly better on T1 fat MR imaging compared with CT imaging (P=0.005). In seven out of 30 studies, a significant increase in reader confidence of PET/MRI compared with PET/CT was found.
CONCLUSION: PET/MRI offers higher reader confidence and improved conspicuity in bone metastases compared with PET/CT. However, the overall detection rate was not different. The highest possible clinical impact of PET/MRI appears to be in patients with limited, early bone metastatic disease.

Brenner DR, Amos CI, Brhane Y, et al.
Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia.
Carcinogenesis. 2015; 36(11):1314-26 [PubMed] Free Access to Full Article Related Publications
Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

Innos K, Valvere V, Padrik P, et al.
Mammography use and mode of detection among breast cancer patients in Estonia.
Women Health. 2016; 56(2):129-40 [PubMed] Related Publications
The aim of this study was to examine past mammography use and mode of detection among breast cancer (BC) patients in Estonia, a country that has low screening coverage and high BC mortality. Women newly diagnosed with primary BC in Estonia in 2008-2010 were interviewed. Determinants of past mammography use and the detection of BC by mammography were studied using multivariate logistic regression. Among 977 participants, almost half reported no mammograms prior to the detection of BC. Overall, 22% of the cases were detected by mammography (16% by screening mammography). Detection by mammography was strongly related to age, past mammography use, and obesity. Among cases detected by mammography, 10% were stage III/IV at diagnosis (32% among cases detected by other modes). This study showed low mammography utilization and high rate of self-detection of BC in Estonia. Increased detection by mammography would help diagnose the disease at an earlier stage and consequently avoid premature BC deaths. Efforts should be undertaken to increase participation in screening and improve the availability of mammography among older and high-risk women. The results are likely to be relevant for other countries and population groups with low screening coverage.

Mäemets-Allas K, Viil J, Jaks V
A Novel Inhibitor of AKT1-PDPK1 Interaction Efficiently Suppresses the Activity of AKT Pathway and Restricts Tumor Growth In Vivo.
Mol Cancer Ther. 2015; 14(11):2486-96 [PubMed] Related Publications
The serine/threonine kinase AKT/PKB has a critical role in the regulation of cell proliferation. Because AKT signaling is deregulated in numerous human malignancies, it has become an attractive anticancer drug target. A number of small molecule AKT kinase inhibitors have been developed; however, severe side effects have prevented their use in clinical trials. To find inhibitors of AKT1 signaling with principally novel mechanism of action, we carried out a live cell-based screen for small molecule inhibitors of physical interaction between AKT1 and its primary activator PDPK1. The screen revealed one molecule-NSC156529, which downregulated AKT1 signaling, efficiently decreased the proliferation of human cancer cells in vitro, and substantially inhibited the growth of prostate tumor xenografts in vivo. Interestingly, the treated tumor xenografts exhibited higher expression level of normal prostate differentiation markers but did not show augmented cell death, suggesting that the identified compound primarily enhances the differentiation of malignant cells toward normal prostate epithelium and thus poses as an attractive lead compound for developing novel antitumor agents with less cytotoxic side effects.

Sak K, Everaus H
Multi-Target Cytotoxic Actions of Flavonoids in Blood Cancer Cells.
Asian Pac J Cancer Prev. 2015; 16(12):4843-7 [PubMed] Related Publications
To date, cytotoxic effects of flavonoids in various cancer cells are well accepted. However, the intracellular signaling cascades triggered by these natural compounds remain largely unknown and elusive. In this mini- review, the multiplicity of molecular targets of flavonoids in blood cancer cells is discussed by demonstrating the involvement of various signaling pathways in induction of apoptotic responses. Although these data reveal a great potential of flavonoids for the development of novel agents against different types of hematological malignancies, the pleiotropic nature of these compounds in modulation of cellular processes and their interactions certainly need unraveling and further investigation.

Örd T, Örd D, Adler P, et al.
TRIB3 enhances cell viability during glucose deprivation in HEK293-derived cells by upregulating IGFBP2, a novel nutrient deficiency survival factor.
Biochim Biophys Acta. 2015; 1853(10 Pt A):2492-505 [PubMed] Related Publications
Glucose deprivation occurs in several human diseases, including infarctions and solid tumors, and leads to cell death. In this article, we investigate the role of the pseudokinase Tribbles homolog 3 (TRIB3) in the cellular stress response to glucose starvation using cell lines derived from HEK293, which is highly glycolytic under standard conditions. Our results show that TRIB3 mRNA and protein levels are strongly upregulated in glucose-deprived cells via the induction of activating transcription factor 4 (ATF4) by the endoplasmic reticulum (ER) stress sensor kinase PERK. Cell survival in glucose-deficient conditions is enhanced by TRIB3 overexpression and reduced by TRIB3 knockdown. Genome-wide gene expression profiling uncovered approximately 40 glucose deprivation-responsive genes that are affected by TRIB3, including several genes involved in signaling processes and metabolism. Based on transcription factor motif analysis, the majority of TRIB3-downregulated genes are target genes of ATF4, which TRIB3 is known to inhibit. The gene most substantially upregulated by TRIB3 is insulin-like growth factor binding protein 2 (IGFBP2). IGFBP2 mRNA and protein levels are downregulated in cells subjected to glucose deprivation, and reduced IGFBP2 expression aggravates cell death during glucose deficiency, while overexpression of IGFBP2 prolongs cell survival. Moreover, IGFBP2 silencing abrogates the pro-survival effect of TRIB3. Since TRIB3 augments IGFBP2 expression in glucose-starved cells, the data indicate that IGFBP2 contributes to the attenuation of cell death by TRIB3. These results implicate TRIB3 and IGFBP2, both of which are known to be overexpressed in several types of cancers, as pro-survival modulators of cell viability in nutrient-deficient microenvironments.

Sugahara KN, Scodeller P, Braun GB, et al.
A tumor-penetrating peptide enhances circulation-independent targeting of peritoneal carcinomatosis.
J Control Release. 2015; 212:59-69 [PubMed] Free Access to Full Article Related Publications
Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis.

Wang L, Xu Y, Luo C, et al.
MAGEA10 gene expression in non-small cell lung cancer and A549 cells, and the affinity of epitopes with the complex of HLA-A(∗)0201 alleles.
Cell Immunol. 2015; 297(1):10-8 [PubMed] Related Publications
MAGEA10, a cancer/testis antigens expressed in tumors but not in normal tissues with the exception of testis and placenta, represents an attractive target for cancer immunotherapy. However, suppressive cytoenvironment and requirement of specific HLA-alleles presentation frequently led to immunotherapy failure. In this study MAGEA10 was scarcely expressed in cancer patients, but enhanced by viili polysaccharides, which indicates a possibility of increasing epitopes presentation. Furthermore the correlation of gene expression with methylation, indicated by R(2) value for MAGEA10 that was 3 times higher than the value for other MAGE genes tested, provides an explanation of why MAGEA10 was highly inhibited, this is also seen by Kaplan-Meier analysis because MAGEA10 did not change the patients' lifespan. By using Molecular-Docking method, 3 MAGEA10 peptides were found binding to the groove position of HLA-A(∗)0210 as same as MAGEA4 peptide co-crystallized with HLA-A(∗)0210, which indicates that they could be promising for HLA-A(∗)0201 presentation in immunotherapy.

Zarovni N, Corrado A, Guazzi P, et al.
Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches.
Methods. 2015; 87:46-58 [PubMed] Related Publications
Clinical implementation of exosome based diagnostic and therapeutic applications is still limited by the lack of standardized technologies that integrate efficient isolation of exosomes with comprehensive detection of relevant biomarkers. Conventional methods for exosome isolation based on their physical properties such as size and density (filtration, ultracentrifugation or density gradient), or relying on their differential solubility (chemical precipitation) are established primarily for processing of cell supernatants and later adjusted to complex biological samples such as plasma. Though still representing gold standard in the field, these methods are clearly suboptimal for processing of routine clinical samples and have intrinsic limits that impair their use in biomarker discovery and development of novel diagnostics. Immunoisolation (IA) offers unique advantages for the recovery of exosomes from complex and viscous fluids, in terms of increased efficiency and specificity of exosome capture, integrity and selective origin of isolated vesicles. We have evaluated several commercially available solutions for immunoplate- and immunobead-based affinity isolation and have further optimized protocols to decrease non-specific binding due to exosomes complexity and matrix contaminants. In order to identify best molecular targets for total exosome capture from diverse biological sources, as well as for selective enrichment in populations of interest (e.g. tumor derived exosomes) several exosome displayed proteins and respective antibodies have been evaluated for plate and bead functionalisation. Moreover, we have optimized and directly implemented downstream steps allowing on-line quantification and characterization of bound exosome markers, namely proteins and RNAs. Thus assembled assays enabled rapid overall quantification and validation of specific exosome associated targets in/on plasma exosomes, with multifold increased yield and enrichment ratio over benchmarking technologies. Assays directly coupling selective immobilization of exosomes to a solid phase and their immune- and or molecular profiling through conventional ELISA and PCR analysis, resulted in easy-to-elaborate, quantitative readouts, with high low-end sensitivity and dynamic range, low costs and hands-on time, minimal sample handling and downscaling of a working plasma volumes to as few as 100 μl.

Viil J, Maasalu K, Mäemets-Allas K, et al.
Laminin-rich blood vessels display activated growth factor signaling and act as the proliferation centers in Dupuytren's contracture.
Arthritis Res Ther. 2015; 17:144 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Dupuytren's contracture (DC) is a chronic fibroproliferative disease of the hand, which is characterized by uncontrolled proliferation of atypical myofibroblasts at the cellular level. We hypothesized that specific areas of the DC tissue are sustaining the cell proliferation and studied the potential molecular determinants that might contribute to the formation of such niches.
METHODS: We studied the expression pattern of cell proliferation marker Ki67, phosphorylated AKT (Ak mouse strain thymoma) kinase, DC-associated growth factors (connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), insulin-like growth factor 2 (IGF-2)) and extracellular matrix components (laminins, fibronectin, collagen IV) in DC tissue and normal palmar fascia using immunofluorescence microscopy and quantitative real-time polymerase chain reaction (qPCR).
RESULTS: We found that proliferative cells in the DC nodules were concentrated in the immediate vicinity of small blood vessels and localized predominantly in the myofibroblast layer. Correspondingly, the DC-associated blood vessels contained increased levels of phosphorylated AKT, a hallmark of activated growth factor signaling. When studying the expression of potential activators of AKT signaling we found that the expression of bFGF was confined to the endothelium of the small blood vessels, IGF-2 was present uniformly in the DC tissue and CTGF was expressed in the DC-associated sweat gland acini. In addition, the blood vessels in DC nodules contained increased amounts of laminins 511 and 521, which have been previously shown to promote the proliferation and stem cell properties of different cell types.
CONCLUSIONS: Based on our findings, we propose that in the DC-associated small blood vessels the presence of growth factors in combination with favorable extracellular matrix composition provide a supportive environment for sustained proliferation of myofibroblasts and thus the blood vessels play an important role in DC pathogenesis.

Thrift AP, Gong J, Peters U, et al.
Mendelian randomization study of height and risk of colorectal cancer.
Int J Epidemiol. 2015; 44(2):662-72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: For men and women, taller height is associated with increased risk of all cancers combined. For colorectal cancer (CRC), it is unclear whether the differential association of height by sex is real or is due to confounding or bias inherent in observational studies. We performed a Mendelian randomization study to examine the association between height and CRC risk.
METHODS: To minimize confounding and bias, we derived a weighted genetic risk score predicting height (using 696 genetic variants associated with height) in 10,226 CRC cases and 10,286 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height, genetically predicted height and CRC.
RESULTS: Using conventional methods, increased height (per 10-cm increment) was associated with increased CRC risk (OR = 1.08, 95% CI = 1.02-1.15). In sex-specific analyses, height was associated with CRC risk for women (OR = 1.15, 95% CI = 1.05-1.26), but not men (OR = 0.98, 95% CI = 0.92-1.05). Consistent with these results, carrying greater numbers of (weighted) height-increasing alleles (per 1-unit increase) was associated with higher CRC risk for women and men combined (OR = 1.07, 95% CI = 1.01-1.14) and for women (OR = 1.09, 95% CI =  .01-1.19). There was weaker evidence of an association for men (OR = 1.05, 95% CI = 0.96-1.15).
CONCLUSION: We provide evidence for a causal association between height and CRC for women. The CRC-height association for men remains unclear and warrants further investigation in other large studies.

Sak K, Everaus H
Chemomodulating Effects of Flavonoids in Human Leukemia Cells.
Anticancer Agents Med Chem. 2015; 15(9):1112-26 [PubMed] Related Publications
Flavonoids, a diverse class of polyphenolic compounds, are well known for their anticancer properties. Moreover, it is generally accepted that these plant secondary metabolites can also sensitize malignant cells to conventional chemotherapeutic drugs and could thus be considered as potential adjunctive agents in cancer treatment. In this review article we show that besides potentiating the anticancer activity of standard chemotherapeutics by modifying the molecular events that are involved in cell growth, differentiation and apoptosis, flavonoids might also act as inhibitory modulators in human leukemia cells. The specific behavior of a certain flavonoid in such combination treatments is multifactorial being dependent on various aspects, including cellular context, molecular mechanisms of clinical drugs, temporal regimen of administration, as well as doses of agents. Based on the highly complex nature of leukemogenesis it is feasible that a multifaceted therapeutic approach is also required to cure this disease and therefore, combined chemotherapeutic schemes incorporating natural plant metabolites as chemosensitizing agents can represent a new attractive strategy for more successful treatment of leukemia patients in the future. However, as highlighted in this review, caution should be taken when affecting malignant cells concurrently with chemotherapeutic drugs and flavonoids as unwisely chosen combinations can lead to inadvisable results and sometimes even deteriorate the clinical outcomes.

Veiman KL, Künnapuu K, Lehto T, et al.
PEG shielded MMP sensitive CPPs for efficient and tumor specific gene delivery in vivo.
J Control Release. 2015; 209:238-47 [PubMed] Related Publications
Gene therapy has great potential to treat a range of different diseases, such as cancer. For that therapeutic gene can be inserted into a plasmid vector and delivered specifically to tumor cells. The most frequently used applications utilize lipoplex and polyplex approaches where DNA is non-covalently condensed into nanoparticles. However, lack of in vivo efficacy is the major concern that hinders translation of such gene therapeutic applications into clinics. In this work we introduce a novel method for in vivo delivery of plasmid DNA (pDNA) and efficient tumor-specific gene induction using intravenous (i.v) administration route. To achieve this, we utilize a cell penetrating peptide (CPP), PepFect14 (PF14), double functionalized with polyethylene glycol (PEG) and a matrix metalloprotease (MMP) substrate. We show that this delivery vector effectively forms nanoparticles, where the condensed CPP and pDNA are shielded by the PEG, in an MMP-reversible manner. Administration of the complexes results in efficient induction of gene expression specifically in tumors, avoiding normal tissues. This strategy is a potent gene delivery platform that can be used for tumor-specific induction of a therapeutic gene.

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