Browsing by Author "Miklasevics, Edvins"
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Item BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families(2013-06-14) Berzina, Dace; Nakazawa-Miklasevica, Miki; Zestkova, Jekaterina; Aksenoka, Karina; Irmejs, Arvids; Gardovskis, Andris; Kalniete, Dagnija; Gardovskis, Janis; Miklasevics, Edvins; Onkoloģijas institūtsBackground: The estimated ratio of hereditary breast/ovarian cancer (HBOC) based on family history is 1.5% in Latvia. This is significantly lower than the European average of 5-10%. Molecular markers like mutations and SNPs can help distinguish HBOC patients in the sporadic breast and ovarian cancer group.Methods: 50 patients diagnosed with HBOC in the Latvian Cancer Registry from January 2005 to December 2008 were screened for BRCA1 founder mutation-negatives and subjected to targeted resequencing of BRCA1 and BRCA2 genes. The newly found mutations were screened for in the breast and ovarian cancer group of 1075 patients by Real Time-PCR/HRM analysis and RFLP.Results: Four BRCA2 mutations including three novel BRCA2 frameshift mutations and one previously known BRCA2 frameshift mutation and one BRCA1 splicing mutation were identified. Two of the BRCA2 mutations were found in a group of consecutive breast cancer patients with a frequency of 0.51% and 0.38%.Conclusions: Molecular screening of sequential cancer patients is an important tool to identify HBOC families.Item Can We Predict Differentiated Thyroid Cancer Behavior? : Role of Genetic and Molecular Markers(2021-10-19) Niciporuka, Rita; Nazarovs, Jurijs; Ozolins, Arturs; Narbuts, Zenons; Miklasevics, Edvins; Gardovskis, Janis; Department of Surgery; Onkoloģijas institūtsThyroid cancer is ranked in ninth place among all the newly diagnosed cancer cases in 2020. Differentiated thyroid cancer behavior can vary from indolent to extremely aggressive. Currently, predictions of cancer prognosis are mainly based on clinicopathological features, which are direct consequences of cell and tissue microenvironment alterations. These alterations include genetic changes, cell cycle disorders, estrogen receptor expression abnormalities, enhanced epithelial-mesenchymal transition, extracellular matrix degradation, increased hypoxia, and consecutive neovascularization. All these processes are represented by specific genetic and molecular markers, which can further predict thyroid cancer development, progression, and prognosis. In conclusion, evaluation of cancer genetic and molecular patterns, in addition to clinicopathological features, can contribute to the identification of patients with a potentially worse prognosis. It is essential since it plays a crucial role in decision-making regarding initial surgery, postoperative treatment, and follow-up. To date, there is a large diversity in methodologies used in different studies, frequently leading to contradictory results. To evaluate the true significance of predictive markers, more comparable studies should be conducted.Item Chromothripsis and progression-free survival in metastatic colorectal cancer(2017-02) Skuja, Elina; Kalniete, Dagnija; Nakazawa-Miklaševiča, Miki; Daneberga, Zanda; Abolins, Arnis; Purkalne, Gunta; Miklasevics, Edvins; Onkoloģijas institūtsMetastatic dissemination of the primary tumor is the major cause of death in colorectal cancer (CRC) patients. Multiple chromosomal breaks and chromothripsis, a phenomenon involving multiple chromosomal fragmentations occurring in a single catastrophic event, are associated with cancer genesis, progression and developing of metastases. The aim of this study was to evaluate the effect of chromothripsis and total breakpoint count (breakpoint instability index) on progression-free survival (PFS). A total of 19 patients with metastatic CRC (mCRC) receiving FOLFOX first‑line palliative chemotherapy between August, 2011 and October, 2012 were selected for this study. The results indicated that the highest breakpoint count was observed in chromosomes 1, 2 and 6. Chromothripsis was detected in 52.6% of the study patients. Furthermore, chromothripsis was associated with an increased median PFS (mPFS; 14 vs. 8 months, respectively; P=0.03), but an association with overall survival was not identified. The present study demonstrated that chromothripsis affected CRC patient survival, suggesting a role for this event as a prognostic and predictive marker in mCRC treatment.Item Dissemination of a carbapenem-resistant acinetobacter baumannii strain belonging to international clone II/sequence type 2 and harboring a novel abar4-like resistance Island in Latvia(2013-02) Saule, Mara; Samuelsen, Orjan; Dumpis, Uga; Sundsfjord, Arnfinn; Karlsone, Aija; Balode, Arta; Miklasevics, Edvins; Karah, Nabil; Rīga Stradiņš UniversityAn outbreak of hospital-acquired Acinetobacter baumannii infections, caused by a blaOXA-23-positive carbapenem-resistant strain belonging to international clone II/ST2, was detected in Latvia. The strain was partially equipped with the armA gene and the intI1-aacA4-catB8-aadA1-qacE=1 class 1 integron. In addition, the strain carried AbaR25, a novel AbaR4-like resistance island of̃46,500 bp containing structures similar to the previously described AbaR22 and Tn6167 islands. AbaR25 was characterized by the occurrence of a second copy of Tn6022a interrupted by Tn2006 carrying the blaOXA-23 gene.Item An effect of culture media on epithelial differentiation markers in breast cancer cell lines MCF7, MDA-MB-436 and SkBr3(2018-05) Pirsko, Valdis; Cakstina, Inese; Priedite, Marta; Dortane, Rasma; Feldmane, Linda; Nakazawa-Miklasevica, Miki; Daneberga, Zanda; Gardovskis, Janis; Miklasevics, Edvins; Onkoloģijas institūtsBackground and objectives: Cell culture is one of the mainstays in the research of breast cancer biology, although the extent to which this approach allows to preserve the original characteristics of originating tumor and implications of cell culture findings to real life situations have been widely debated in the literature. The aim of this study was to determine the role of three cell culture media on transcriptional expression of breast cancer markers in three breast cancer reference cell lines (MCF7, SkBr3 and MDA-MB-436). Materials and methods: Cell lines were conditioned in three studied media (all containing 5% fetal bovine serum (FBS) + hormones/growth factors; different composition of basal media) for four passages. Population growth was characterized by cumulative population doubling levels, average generation time, cell yield and viability at the fourth passage. Transcriptional expression of breast cancer differentiation markers and regulatory transcriptional programs was measured by qPCR. Results: Differences in the composition of growth media significantly influenced the growth of studied cell lines and the expression of mammary lineage governing transcriptional programs and luminal/basal markers. Effects of media on transcriptional expression were more pronounced in luminal cell lines (MCF7, SkBr3), than in the basal cell line (MDA-MB-436). Changes in growth media in terms of supplementation and basal medium delayed growth of cells, but improved cell yields. Conclusions: The expression of breast cancer cell differentiation phenotypic markers depends on the composition of cell growth medium, therefore cell culture as a tool in phenotypic studies should be used considering this effect. The findings of such studies should always be interpreted with caution. The formulation of cell growth media has greater effect on the expression of phenotypic markers in luminal, rather than basal cell lines. Media containing mitogens and higher vitamin content improved efficacy of cell culture in terms of cell yields, although greatly increased growth times.Item Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia(2011-10-27) Plakhins, Grigorijs; Irmejs, Arvids; Gardovskis, Andris; Subatniece, Signe; Rozite, Santa; Bitina, Marianna; Keire, Guntars; Purkalne, Gunta; Teibe, Uldis; Trofimovics, Genadijs; Miklasevics, Edvins; Gardovskis, Janis; Pārmantotā vēža pētniecības nodaļaBackground: Mutations in the high penetrance breast and ovarian cancer susceptibility gene BRCA1 account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of BRCA1 mutations located in different parts of the BRCA1 gene have been described previously; however, phenotypic differences of specific BRCA1 mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the BRCA1 c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers.Methods: We investigated the prevalence of the BRCA1 founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the BRCA1 mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers.Results: We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1st and 2nd degree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation.Conclusions: Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.Item Geographic distribution of Staphylococcus aureus causing invasive infections in Europe : A molecular-epidemiological analysis(2010-01) European Staphylococcal Reference Laboratory Working Group; Miklasevics, Edvins; Balode, Arta; Onkoloģijas institūtsBackground: Staphylococcus aureus is one of the most important human pathogens and methicillin-resistant variants (MRSAs) are a major cause of hospital and community-acquired infection. We aimed to map the geographic distribution of the dominant clones that cause invasive infections in Europe. Methods and Findings: In each country, staphylococcal reference laboratories secured the participation of a sufficient number of hospital laboratories to achieve national geo-demographic representation. Participating laboratories collected successive methicillin-susceptible (MSSA) and MRSA isolates from patients with invasive S. aureus infection using an agreed protocol. All isolates were sent to the respective national reference laboratories and characterised by quality-controlled sequence typing of the variable region of the staphylococcal spa gene (spa typing), and data were uploaded to a central database. Relevant genetic and phenotypic information was assembled for interactive interrogation by a purpose-built Web-based mapping application. Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 countries collected 2,890 MSSA and MRSA isolates from patients with invasive S. aureus infection. A wide geographical distribution of spa types was found with some prevalent in all European countries. MSSA were more diverse than MRSA. Genetic diversity of MRSA differed considerably between countries with dominant MRSA spa types forming distinctive geographical clusters. We provide evidence that a network approach consisting of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of MRSA populations such as early signalling of emerging strains, cross border spread, and importation by travel. Conclusions: In contrast to MSSA, MRSA spa types have a predominantly regional distribution in Europe. This finding is indicative of the selection and spread of a limited number of clones within health care networks, suggesting that control efforts aimed at interrupting the spread within and between health care institutions may not only be feasible but ultimately successful and should therefore be strongly encouraged.Item Methicillin Susceptible Panton - Valentine Leukocidin Positive S. Aureus Pneumonia in a Child with Novel Influenza H1N1 Infection(2010-01-01) Cupane, Liene; Pugacova, Nina; Aleksejevs, Girts; Berzina, Dace; Gardovska, Dace; Miklasevics, Edvins; Department of Paediatrics; Rīga Stradiņš UniversityThe first case in Latvia of Panton - Valentine leukocidin (PVL) positive methicillin susceptible Staphylococcus aureus (MSSA) pneumonia in an adolescent with novel influenza A H1N1 is described. A 15 year old boy was admitted to intensive care suffering from severe respiratory failure with bilateral necrotic pneumonia. The presence of influenza A H1N1 was confirmed by PCR. Invasive S. aureus was spa type t435 and Panton-Valentine leukocidin gene positive. He received therapy with ceftriaxone, oxacillin, clindamycin and oseltamivir phosphate and underwent two chest operations. He was discharged after 58 days in hospital.Item Neoadjuvant Chemoradiation in Patient with Localy Advanced Rectal Cancer(2013-12-01) Skuja, Elina; Sorubalko, Arturs; Purkalne, Gunta; Miklasevics, Edvins; Onkoloģijas institūtsItem Pathogenic APC variants in latvian familial adenomatous polyposis patients(2019) Daneberga, Zanda; Berzina, Dace; Borosenko, Viktors; Krumina, Zita; Kokaine-Sapovalova, Linda; Gardovskis, Andris; Berga-Svitina, Egija; Gardovskis, Janis; Miklasevics, Edvins; Onkoloģijas institūts; Department of Biology and Microbiology; Department of SurgeryBackground and objectives: Familial adenomatous polyposis is one of the APC-associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of symptoms. The purpose of this study was to determine sequence variants of the APC gene in patients with familial adenomatous polyposis (FAP) phenotype and positive or negative family history. Materials and Methods: Eight families with defined criteria of adenomatous polyposis underwent molecular genetic testing. Coding regions and flanking intron regions of the APC gene were analyzed by Sanger sequencing. Results: Eight allelic variants of the APC gene coding sequence were detected. All allelic variants of the APC gene were predicted to be pathogenic based on criteria according to the “Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology” (2015), four of them c.1586_1587insAT, c.2336delT, c.3066_3067insGA, and c.4303_4304insC, were considered novel. Conclusions: The timely molecular genetic analysis of APC germline variants and standardized interpretation of the pathogenicity of novel allelic variants has a high impact on choice for treatment, cancer prevention, and family genetic counseling.Item Pilot study on low penetrance breast and colorectal cancer predisposition markers in Latvia(2006-03-15) Irmejs, Arvids; Miklasevics, Edvins; Boroschenko, Viktors; Gardovskis, Andris; Vanags, Andrejs; Melbarde-Gorkusa, Inga; Bitina, Marianna; Suchy, Janina; Gardovskis, Janis; Pārmantotā vēža pētniecības nodaļaIntroduction: It has not been established whether CHEK2 and NOD2 variants are present in Latvia and whether inherited variation in these genes influences cancer risk in this population. Aim of the study: To evaluate the role of CHEK2 and NOD2 mutations in breast and colorectal cancers in the population of Latvia. Materials and methods: Peripheral venous blood samples were collected from 185 breast cancer and 235 colorectal cancer consecutive hospital-based cases from 11/2003 to 06/2005. The population control group included blood samples from the clamped distal part of the umbilical cord from 978 consecutive anonymous newborns born between 03/2005 and 08/2005. All cases and controls were tested for the presence of NOD2 3020insC mutation and CHEK2 I157T mutation. Results: NOD2 3020insC was present in 7.7% (18/235) of CRC cancers, in 9.2% (17/185) of breast cancers and in 7.7% (75/974) of controls. CHEK2 I157T variant was found in 7.6% (14/185) of breast cancer cases, 10.2% (24/235) of colon cancer cases and in 6.4% (63/978) of population controls. NOD2 3020insC variant was associated with increased risk of breast cancer (OR=2.5, p<0.05) for cases diagnosed at age between 51 and 60 years. CHEK2 I157T variant was associated with increased risk of colorectal cancer (OR=1.7, p<0.05) with the highest OR=2.0 for cases diagnosed at age >70 yrs. Conclusions: NOD2 3020insC and CHEK2 I157T variants may be associated with increased risk of colorectal and breast cancers in Latvia.Item Platinum-based neoadjuvant chemotherapy in BRCA1-positive breast cancer : A retrospective cohort analysis and literature review(2018-04-27) Sæther, Nikolai Havn; Skuja, Elina; Irmejs, Arvids; Maksimenko, Jelena; Miklasevics, Edvins; Purkalne, Gunta; Gardovskis, Janis; Rīga Stradiņš UniversityBackground: There is increasing evidence of high platinum sensitivity in BRCA-associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting. Methods: A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review. Results: Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies. Conclusion: The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer.Item Telomere length in Chernobyl accident recovery workers in the late period after the disaster(2014-11-01) Reste, Jelena; Zvigule, Gunda; Zvagule, Tija; Kurjane, Natalja; Eglite, Maija; Gabruseva, Natalija; Berzina, Dace; Plonis, Juris; Miklasevics, Edvins; Institute of Occupational Safety and Environmental Health; Rīga Stradiņš University; Onkoloģijas institūtsThe outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45-54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing radiation. Telomeres are important in aging processes and carcinogenesis. The aim of this study was to investigate the long-term effect of protracted ionizing radiation exposure on telomere length in CNPP clean-up workers. Relative telomere length (RTL) was measured in peripheral blood leukocytes of 595 CNPP clean-up workers and 236 gender- and agematched controls using real-time quantitative polymerase chain reaction (q-PCR). Close attention was paid to participation year and tasks performed during the worker's stay in Chernobyl, health status, and RTL differences between subgroups. Telomere shortening was not found in CNPP clean-up workers; on the contrary, their RTL was slightly greater than in controls (P = 0.001). Longer telomeres were found in people who worked during 1986, in those undertaking 'dirty' tasks (digging and deactivation), and in people with cancer. Shorter telomeres appeared frequently in those with cataract, osteoporosis, atherosclerosis, or coronary heart disease. We conclude that the longer telomeres revealed in people more heavily exposed to ionizing radiation probably indicate activation of telomerase as a chromosome healing mechanism following damage, and reflect defects in telomerase regulation that could potentiate carcinogenesis.