Publications by authors named "Radoslaw Charkiewicz"

21 Publications

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[Corrigendum] Pituitary sex hormones enhance the pro‑metastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase‑1.

Int J Oncol 2019 03 3;54(3):1134. Epub 2019 Jan 3.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

After the publication of the article, the authors realize that they overlooked stating that the author Magda Kucia was the recipient of an OPUS grant (grant no. UMO‑2016/21/B/NZ4/00201). Therefore, the Acknowledgements section of the paper should have read as follows (the added text is highlighted in bold): "This study was supported by NIH grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment, and NCN Harmonia grant UMO‑2014/14/M/NZ3/00475 to M.Z.R., and OPUS grant UMO‑2016/21/B/NZ4/00201 to M.K." The authors regret their oversight in failing to include this information in the Acknowledgements section of their paper. [the original article was published in International Journal of Oncology 50: 317-328, 2017; DOI: 10.3892/ijo.2016.3787].
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http://dx.doi.org/10.3892/ijo.2019.4670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365021PMC
March 2019

Systematic biobanking, novel imaging techniques, and advanced molecular analysis for precise tumor diagnosis and therapy: The Polish MOBIT project.

Adv Med Sci 2017 Sep 21;62(2):405-413. Epub 2017 Jun 21.

Indivumed GmbH, Falkenreid 88, Hamburg, Germany.

Personalized and precision medicine is gaining recognition due to the limitations by standard diagnosis and treatment; many areas of medicine, from cancer to psychiatry, are moving towards tailored and individualized treatment for patients based on their clinical characteristics and genetic signatures as well as novel imaging techniques. Advances in whole genome sequencing have led to identification of genes involved in a variety of diseases. Moreover, biomarkers indicating severity of disease or susceptibility to treatment are increasingly being characterized. The continued identification of new genes and biomarkers specific to disease subtypes and individual patients is essential and inevitable for translation into personalized medicine, in estimating both, disease risk and response to therapy. Taking into consideration the mostly unsolved necessity of tailored therapy in oncology the innovative project MOBIT (molecular biomarkers for individualized therapy) was designed. The aims of the project are: (i) establishing integrative management of precise tumor diagnosis and therapy including systematic biobanking, novel imaging techniques, and advanced molecular analysis by collecting comprehensive tumor tissues, liquid biopsies (whole blood, serum, plasma), and urine specimens (supernatant; sediment) as well as (ii) developing personalized lung cancer diagnostics based on tumor heterogeneity and integrated genomics, transcriptomics, metabolomics, and radiomics PET/MRI analysis. It will consist of 5 work packages. In this paper the rationale of the Polish MOBIT project as well as its design is presented. (iii) The project is to draw interest in and to invite national and international, private and public, preclinical and clinical initiatives to establish individualized and precise procedures for integrating novel targeted therapies and advanced imaging techniques.
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http://dx.doi.org/10.1016/j.advms.2017.05.002DOI Listing
September 2017

Gene Expression Signature Differentiates Histology But Not Progression Status of Early-Stage NSCLC.

Transl Oncol 2017 Jun 26;10(3):450-458. Epub 2017 Apr 26.

Department of Histology and Embryology, Medical University of Bialystok, Waszyngtona 13, Bialystok 15-269, Poland. Electronic address:

Advances in molecular analyses based on high-throughput technologies can contribute to a more accurate classification of non-small cell lung cancer (NSCLC), as well as a better prediction of both the disease course and the efficacy of targeted therapies. Here we set out to analyze whether global gene expression profiling performed in a group of early-stage NSCLC patients can contribute to classifying tumor subtypes and predicting the disease prognosis. Gene expression profiling was performed with the use of the microarray technology in a training set of 108 NSCLC samples. Subsequently, the recorded findings were validated further in an independent cohort of 44 samples. We demonstrated that the specific gene patterns differed significantly between lung adenocarcinoma (AC) and squamous cell lung carcinoma (SCC) samples. Furthermore, we developed and validated a novel 53-gene signature distinguishing SCC from AC with 93% accuracy. Evaluation of the classifier performance in the validation set showed that our predictor classified the AC patients with 100% sensitivity and 88% specificity. We revealed that gene expression patterns observed in the early stages of NSCLC may help elucidate the histological distinctions of tumors through identification of different gene-mediated biological processes involved in the pathogenesis of histologically distinct tumors. However, we showed here that the gene expression profiles did not provide additional value in predicting the progression status of the early-stage NSCLC. Nevertheless, the gene expression signature analysis enabled us to perform a reliable subclassification of NSCLC tumors, and it can therefore become a useful diagnostic tool for a more accurate selection of patients for targeted therapies.
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http://dx.doi.org/10.1016/j.tranon.2017.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408153PMC
June 2017

Profiling of selected angiogenesis-related genes in serous ovarian cancer patients.

Adv Med Sci 2017 Mar 21;62(1):116-120. Epub 2017 Feb 21.

Department of Perinatology, Medical University of Bialystok, Bialystok, Poland.

Purpose: Since angiogenesis plays an important role in the pathogenesis of ovarian cancer the aim of the study was to compare the expression of the most relevant angiogenesis-related genes in serous ovarian cancer samples. Genes were divided into 5 subgroups according to their angiogenic potential: growth factors and their receptors; cytokines/chemokines; adhesion molecules and other matrix related proteins; transcriptions factors and signaling molecules; morphogenic factors, and angiogenesis inhibitors.

Materials/methods: Twenty-nine patients were involved in the study: 20 with serous ovarian cancer and 9 healthy controls. All neoplasms were confirmed by histopathological examination. Healthy ovarian control samples were obtained from women diagnosed with fibroids and had previously scheduled operations. Real-time PCR gene arrays were used to examine the expression of 84 human angiogenesis-related genes and expression of selected proteins was assessed with ELISA.

Results: Significantly higher expressions of 46 genes were found in the ovarian cancer group compared to the healthy control group. By the use of ELISA we confirmed the expression of three proteins i.e.: angiopoietin-2, angiopoietin-like protein 3, and angiopoietin receptor 2. Only angiopoietin-2 and angiopoietin receptor 2 showed significant differences between ovarian cancer and healthy controls.

Conclusions: Changes in the expression of selected genes associated with angiogenesis may add new information to the pathogenesis of ovarian cancer. Although the angiopoietin-2 signaling pathway may play an important role in neovascularization in ovarian cancer, the role of angiopoietin-like protein 3 is yet to be established.
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http://dx.doi.org/10.1016/j.advms.2016.11.005DOI Listing
March 2017

Prognostic significance of Notch ligands in patients with non-small cell lung cancer.

Oncol Lett 2017 Jan 23;13(1):506-510. Epub 2016 Nov 23.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland.

The Notch signaling pathway is deregulated in numerous solid types of cancer including non-small cell lung cancer (NSCLC). However, the profile of Notch ligand expression remains unclear. Therefore, the present study aimed to determine the profile of Notch ligands in NSCLC patients and to investigate whether quantitative assessment of Notch ligand expression may have prognostic significance in NSCLC patients. The study was performed in 61 pairs of tumor and matched unaffected lung tissue specimens obtained from patients with various stages of NSCLC, which were analyzed by reverse transcription-polymerase chain reaction. The marked expression levels of certain analyzed genes were detected in NSCLC samples and in noncancerous lung samples. Of the five Notch ligands, jagged 1 (), jagged 2, delta-like protein 1 and delta-like protein 4 were expressed in the majority of tissues, but their expression levels were reduced in NSCLC when compared with noncancerous lung tissue (P<0.001). Delta-like protein 3 expression was consistently low and was observed only in 21/61 tumor tissue samples. Taken together, Notch ligands are expressed in NSCLC. However, the expression level is reduced when compared to noncancerous tissue. Furthermore, the present study revealed that quantitative assessment of expression in NSCLC may improve prognostication of patient survival.
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http://dx.doi.org/10.3892/ol.2016.5420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244844PMC
January 2017

Pituitary sex hormones enhance the pro‑metastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase‑1.

Int J Oncol 2017 Jan 2;50(1):317-328. Epub 2016 Dec 2.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

We report that human lung cancer cell lines express functional receptors for pituitary sex hormones (SexHs) and respond to stimulation by follicle‑stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL). Expression of these receptors has also been confirmed in patient lung cancer samples at the mRNA level. Stimulation of human lung cancer cell lines with FSH, LH, or PRL stimulated migration and chemotaxis, and some cell lines responded by enhanced proliferation. Moreover, priming of human lung cancer cells by exposing them to pituitary SexHs resulted in enhanced seeding efficiency of injected human lung cancer cells into bone marrow, liver, and lungs in an immunodeficient mouse model. The chemotaxis of lung cancer cell lines corresponded with the activity of heme oxygenase‑1 (HO‑1), as stimulation of these cells by FSH, LH, and PRL downregulated its expression in a p38 MAPK‑dependent manner. Moreover, while downregulation of HO‑1 by the small‑molecule inhibitor tin protoporphyrin (SnPP) promoted migration, upregulation of HO‑1 by the small‑molecule activator cobalt protoporphyrin (CoPP) showed the opposite effect. Based on this finding, we propose that pituitary SexHs play a significant role in the pathogenesis of lung cancer, particularly when the blood level of FSH increases due to gonadal dysfunction with advanced age. Finally, we propose that upregulation of HO‑1 expression by a small‑molecule activator may be effective in controlling SexH‑induced cell migration in lung cancer.
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http://dx.doi.org/10.3892/ijo.2016.3787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182010PMC
January 2017

Lipid mediators involved in the oxidative stress and antioxidant defence of human lung cancer cells.

Redox Biol 2016 10 20;9:210-219. Epub 2016 Aug 20.

Departments of Analytical Chemistry, Medical University of Białystok, Białystok, Poland. Electronic address:

Background: The oxidative modifications of bioactive macromolecules have important roles in carcinogenesis. Of particular interest are lipid peroxidation products, which are involved in the activation of Nrf2 and endocannabinoids that affect cancer progression.

Methods: In lung cancer tissues (squamous cell lung carcinoma - SCC and adenocarcinoma - AC), the glutathione peroxidase and catalase activity and glutathione level, together with the expression of Nrf2 and its activators/inhibitors were estimated. The oxidative modifications of DNA (8-hydroxy-2'-deoxyguanosine and N7-methylguanine), endocannabinoids (anandamide and 2- arachidonylglyceriol), their receptors (CB1/2, TRV1, GPR55), phospholipid fatty acids (arachidonic, linoleic and docosahexaenoic), and reactive aldehydes (4-hydroxynonenal, 4-oxononenal and malondialdehyde) were determined.

Results: Tumour tissues showed lower antioxidant capacity than healthy tissues, which was accompanied by lower levels of fatty acids and higher levels of reactive aldehydes. Disturbances in antioxidant capacity and enhanced DNA oxidative modifications were observed in 88% of AC patients and 81% of SCC patients. The 4-hydroxynonenal-Histidine adducts were detected in the necrotic and stromal cells in all tumours. These findings were associated with the enhanced Nrf2 activity, especially in AC. The strong difference between the cancer subtypes was evident in the levels of endocannabinoids, with an increase in 89% of SCC and a decrease in 85% of AC patients being observed. Additionally, the increase in the expression of CB1/2 receptors was observed only in 82% of AC, while the expression of VR1 and GPR55 was enhanced in 79% of SCC and 82% of AC patients.

Conclusions: This study shows significant differences in the redox status, Nrf2 pathway and endocannabinoid system between SCC and AC tissues. Understanding the relation between the various lipid mediators and antioxidants in different lung cancer subtypes may be beginning for further research on the effective anticancer therapy.
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http://dx.doi.org/10.1016/j.redox.2016.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007445PMC
October 2016

Effects of different omeprazole dosing on gastric pH in non-variceal upper gastrointestinal bleeding: A randomized prospective study.

J Dig Dis 2016 Sep;17(9):588-599

Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.

Objective: We aimed to identify the best method of omeprazole (OME) application with respect to intragastric pH, cytochrome P450 2C19 (CYP2C19) genotype and phenotype.

Methods: The patients with non-variceal upper gastrointestinal bleeding (NVUGIB) were prospectively enrolled. After the achievement of endoscopic hemostasis, the patients were randomized to 40-mg intravenous (i.v.) OME bolus injection every 12 h or 8-mg/h continuous i.v. infusion for 72 h after an 80-mg i.v. OME bolus administration. The intragastric pH was recorded for 72 h. The CYP2C19 variant alleles (*2, *3, *17) were analyzed and the serum concentrations of OME and 5-hydroxyomeprazole (5-OH OME) were determined.

Results: Altogether 41 Caucasians (18 in the OME infusion [OI] group and 23 in the OME bolus [OB] group) were analyzed. The median percentage of time with an intragastric pH > 4.0 was higher in the infusion group than in the OB group over 48 h (100% vs 96.6%, P = 0.009) and 72 h (100% vs 87.6%, P = 0.006), and that at an intragastric pH >6.0 was higher in the OI group than the OB group over 72 h (97.9% vs 63.5%, P = 0.04). Helicobacter pylori infection was correlated with the fastest increase in intragastric pH, especially in the OI group. In both groups, CYP2C19 genotypes (*1/*1, *1/*17, *17/*17) had no essential effect on intragastric pH.

Conclusions: In patients with NVUGIB, OME i.v. bolus followed by continuous infusion is more effective than OME i.v. bolus every 12 h in maintaining higher intragastric pH, regardless of CYP2C19 genetic polymorphisms. H. pylori infection accelerates the initial elevation of intragastric pH.
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http://dx.doi.org/10.1111/1751-2980.12393DOI Listing
September 2016

Are anti-Müllerian hormone and its receptor polymorphism associated with the hormonal condition of undescended testes?

Adv Med Sci 2016 Sep 26;61(2):288-292. Epub 2016 Mar 26.

Department of Pediatric Surgery, Medical University of Bialystok, Bialystok, Poland. Electronic address:

Purpose: Numerous genetic and endocrine factors are involved in the process of testicular descent, but only a few genetic causes have been reported in human. The aim of this study was to investigate the density and distribution of single nucleotide polymorphisms (SNPs) anti-Müllerian hormone (AMH) and AMHRII receptors in cryptorchid patients and determine potential hormone imbalance connected with undescended testes by assessing the levels of AMH, Insulin-like factor 3 (INSL3) and inhibin B.

Materials And Methods: The serum hormone levels (AMH, INSL3 and inhibin B) were compared in the two groups - cryptorchidism (n=105) and control group (n=58). The frequency of AMHRII -482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5-6 C>T, and AMH Ile49Ser polymorphisms among cryptorchid boys were compared with the control group.

Results: None of the hormones levels were different between the cryptorchid and the control groups. All cases of IVS 5-6 C>T homozygote and heterozygote mutation were accompanied by an IVS 10+77 A>G and 482 A>G homozygote and heterozygote mutation. Interestingly, in most cases of all four polymorphisms, homozygote recessive genotype was associated with cases of cryptorchidism. However, the groups of patients were too small to draw definite conclusions.

Conclusion: The AMHRII -482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5-6 C>T and AMH Ile49Ser genotypes should be determined in a much larger group of boys with cryptorchidism.
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http://dx.doi.org/10.1016/j.advms.2016.03.004DOI Listing
September 2016

Mutation of the gene as a prognostic factor in patients with colorectal cancer.

Oncol Lett 2015 Sep 19;10(3):1423-1429. Epub 2015 Jun 19.

Department of Oncology, Military Institute of Medicine, Warsaw 04-141, Poland.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with ~700,000 mortalities occurring due to CRC in 2012. The treatment options are effective in a small percentage of patients, and it is important to identify specific biomarkers in order to determine patients for whom the available therapies will be beneficial. It has been hypothesised that the gene mutation may affect the response to therapy of patients with metastatic CRC. In the present study, primary tumour specimens were collected from 156 patients with CRC who were treated in the Military Institute of Medicine in Warsaw (Warsaw, Poland). Codons 12 and 13 of exon 1 of , exons 11 and 15 of and exons 9 and 20 of were analysed for mutation using direct sequencing. The prognostic value of each mutation and the clinical and pathological variables of these tumours were estimated. The results revealed that mutations were present in 15 patients (9.6%), of whom seven (46.7%) possessed mutations in codon 9 and eight (53.3%) possessed mutations in codon 20. Mutation in the gene was detected in six patients with gene mutations, which accounted for 40% of -mutated tumours, and in one patient with mutations, which accounted for 6.6% of -mutated tumours. No significant differences were identified between the overall survival (OS) rates of patients with mutations (median OS, 56.7 months) and those with wild-type genes (median OS, 47.6 months) (P=0.1270). Univariate analysis identified that the following prognostic factors affected the OS rate in the current patient cohort: Gender, female patients survived for 57.5 months compared with 39.3 months for male patients (P=0.0111); and lymph node involvement grade, as survival of patients without lymph node metastases was 61.4 months compared with 45.4 months in patients presenting with metastases (P=0.0122). The findings of the present analysis indicate that mutation status is not a prognostic factor in CRC patients. In addition, no statistically significant association exists between tumours with mutations and clinical or pathological factors.
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http://dx.doi.org/10.3892/ol.2015.3398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533752PMC
September 2015

Relationships between level of lipid peroxidation products and expression of Nrf2 and its activators/ inhibitors in non-small cell lung cancer tissue.

Free Radic Biol Med 2014 Oct 10;75 Suppl 1:S31. Epub 2014 Dec 10.

Medical University of Bialystok, Department of Analytical Chemistry, Poland.

Lung cancer development is characterized by oxidative stress that leads to the oxidative modifications of cellular components, including phospholipid and protein. Lipid peroxidation products may be involved in intracellular signaling pathways or in the activity of transcription factors (Nrf2). Therefore, the aim of this study has been to evaluate the relationship between the level of reactive aldehydes and the activity of the transcription factor and a comparison of these parameters in different histological types and stages of non-small cell lung cancer. Lung cancer tissues and tissues without morphological changes were received during operation from patients with squamous cell lung carcinoma (SqCC), lung adenocarcinoma (AC) and large cell lung carcinoma (LCC). In the tissue homogenates the level of reactive aldehydes [4-HNE, MDA, 4-ONE] was determined by GCMS, while Nrf2 and its activators/inhibitors were evaluated by Western immunobloting. Tumor tissues showed several times higher reactive aldehydes level and those changes were accompanied by overexpression of Nrf2. The highest increase of 4-HNE and MDA level was observed in the SqCC and it was correlated with the highest increase in Nrf2 expression. Moreover, the aldehydes level and Nrf2 phosphorylation were significantly higher in the stage I than in the stage II. The level of Nrf2 inhibitor - Bach1 was lower in all histological types of tumor, but in AC was the most reduced, what is correlated with the lowest level of reactive aldehydes. The highest expression of p62 and p21 - Nrf2 activators was observed also in adenocarcinoma of the lung. However, the level of another Nrf2 activator - KAP1 was decreased in all histological types of tumor. Additionally, the cJun amount in the tumor tissue was increased, whereas reduction of its phosphorylated form in AC and LCC was observed. Understanding the relation between reactive aldehydes level and the Nrf2 activity may be applied in anticancer therapies.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.761DOI Listing
October 2014

Validation for histology-driven diagnosis in non-small cell lung cancer using hsa-miR-205 and hsa-miR-21 expression by two different normalization strategies.

Int J Cancer 2016 Feb 10;138(3):689-97. Epub 2015 Sep 10.

Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland.

Targeted therapy of non-small cell lung cancer (NSCLC) demands a more accurate tumor classification that is crucial for patient selection in personalized treatment. MicroRNAs constitute a promising class of biomarkers and a helpful tool for the distinction between lung adenocarcinoma (AC) and squamous cell lung carcinoma (SCC). The aim of this study was to evaluate the impact of two different normalization strategies, using U6 snRNA and hsa-miR-103 as reference genes, on hsa-miR-205 and hsa-miR-21 expression levels, in terms of the classification of subtypes of NSCLC. By means of a quantitative real-time polymerase chain reaction (qRT-PCR) microRNA expression levels were evaluated in a classification set of 98 surgically resected NSCLC fresh-frozen samples, and validated findings in an independent set of 42 NSCLC samples. The microRNA expression levels were exploited to develop a diagnostic test using two data normalization strategies. The performance of microRNA profiling in different normalization methods was compared. We revealed the microRNA-based qRT-PCR tests to be appropriate measures for distinguishing between AC and SCC (the concordance of histologic diagnoses and molecular methods greater than 88%). Performance evaluation of microRNA tests, based on the two normalization strategies, showed that the procedure using hsa-miR-103 as reference target has a slight advantage (sensitivity 83.33 and 100% in classification and validation set, respectively) compared to U6 snRNA. Molecular tests based on microRNA expression allow a reliable classification of subtypes for NSCLC and can constitute a useful diagnostic strategy in patient selection for targeted therapy.
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http://dx.doi.org/10.1002/ijc.29816DOI Listing
February 2016

Erratum: MicroRNAs expression profiling of eutopic proliferative endometrium in women with ovarian endometriosis.

Reprod Biol Endocrinol 2015 May 27;13:50. Epub 2015 May 27.

Department of Clinical Molecular Biology, Medical University of Bialystok, ul. Waszyngtona 13, 15-276, Bialystok, Poland.

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http://dx.doi.org/10.1186/s12958-015-0040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446104PMC
May 2015

Maternal plasma and amniotic fluid chemokines screening in fetal Down syndrome.

Mediators Inflamm 2014 16;2014:835837. Epub 2014 Nov 16.

Department of Clinical Molecular Biology, Medical University of Bialystok, Waszyngtona 12, 15-269 Bialystok, Poland.

Objective: Chemokines exert different inflammatory responses which can potentially be related to certain fetal chromosomal abnormalities. The aim of the study was to determine the concentration of selected chemokines in plasma and amniotic fluid of women with fetal Down syndrome.

Method: Out of 171 amniocentesis, we had 7 patients with confirmed fetal Down syndrome (15th-18th weeks of gestation). For the purpose of our control, we chose 14 women without confirmed chromosomal aberration. To assess the concentration of chemokines in the blood plasma and amniotic fluid, we used a protein macroarray, which allows the simultaneous determination of 40 chemokines per sample.

Results: We showed significant decrease in the concentration of 4 chemokines, HCC-4, IL-28A, IL-31, and MCP-2, and increase in the concentration of CXCL7 (NAP-2) in plasma of women with fetal Down syndrome. Furthermore, we showed decrease in concentration of 3 chemokines, ITAC, MCP-3, MIF, and increase in concentration of 4 chemokines, IP-10, MPIF-1, CXCL7, and 6Ckine, in amniotic fluid of women with fetal Down syndrome.

Conclusion: On the basis of our findings, our hypothesis is that the chemokines may play role in the pathogenesis of Down syndrome. Defining their potential as biochemical markers of Down syndrome requires further investigation on larger group of patients.
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http://dx.doi.org/10.1155/2014/835837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248337PMC
July 2015

MicroRNAs expression profiling of eutopic proliferative endometrium in women with ovarian endometriosis.

Reprod Biol Endocrinol 2013 Aug 15;11:78. Epub 2013 Aug 15.

Department of Perinatology, Medical University of Bialystok, ul, Marii Sklodowskiej-Curie 24a, 15-276, Bialystok, Poland.

Background: The eutopic endometrium of women with endometriosis, compared with disease-free individuals, contains certain molecular alterations, including the differential expression of microRNA (miRNA). The aim of the study was to compare the expression of the most relevant miRNAs in the eutopic endometrium of women with and without ovarian endometriosis.

Methods: A total of 46 regularly menstruating patients, 21 patients with ovarian endometriosis and 25 controls, underwent surgery in the proliferative phase of the cycle. The eutopic endometrium was collected through aspirating biopsy prior to laparoscopy. Only patients with advanced (stage III and IV) histopathologically confirmed ovarian endometriosis were included. TaqMan MicroRNA Array Cards were applied to examine the expression of 667 human miRNAs in 10 patients with endometriosis and 10 controls. Custom-made, low-density real-time PCR arrays were used to confirm the expression of 15 selected molecules in 21 endometriosis patients and 25 disease-free individuals.

Results: Of 667 miRNAs, 2 were highly likely to be upregulated and 13 were downregulated in the eutopic endometrium of patients with endometriosis compared with the controls. Validation using real-time PCR showed that hsa-miR-483-5p (p = 0.012) and hsa-miR-629* (p = 0.02) are significantly downregulated in patients with endometriosis.

Conclusions: Changes in the expression of select miRNAs might lead to or be a consequence of an early defect in the physiological activity of the proliferative endometrium, ultimately resulting in the overgrowth of this tissue outside the uterus.
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http://dx.doi.org/10.1186/1477-7827-11-78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766175PMC
August 2013

Overexpression of epidermal growth factor receptor as a prognostic factor in colorectal cancer on the basis of the Allred scoring system.

Onco Targets Ther 2013 24;6:967-76. Epub 2013 Jul 24.

Department of Oncology, Military Institute of Medicine, Central Teaching Hospital, Warsaw Poland.

Background: Overexpression of epidermal growth factor receptor (EGFR) is found in many types of neoplasms. The aim of the study was to evaluate EGFR expression in colorectal cancer (CRC) specimens and to determine whether EGFR expression correlates with clinicopathological data and overall survival.

Patients And Methods: Tissue specimens from 181 consecutive CRC patients treated at the Military Institute of Medicine in 2006-2010 were collected and examined for EGFR expression, by immunohistochemistry staining. The staining intensity and percentage of cells with membranous EGFR expression were scored and then grouped according to the parameters of the Allred Scoring system. Cutoff values were subjected to further statistical analysis. Univariate tests and a multivariate Cox proportional hazards model were used in data analysis.

Results: EGFR was overexpressed in 96 of 181 CRC specimens (53%). EGFR expression was not correlated with other clinicopathological variables. On univariate analysis, overexpression of EGFR, determined by PS (percentage score) (>3) and total score (sum of PS and intensity score) (>4), was associated with poor overall survival. On multivariate analysis, EGFR overexpression (PS > 3) was an independent adverse prognostic factor (hazard ratio [HR] 1.62; 95% confidence interval [CI]: 1.03-2.53). Elevated carcinoembryonic antigen (CEA) serum concentration before treatment, performance status (Word Health Organization [WHO]-2), and tumor localized in colon and liver metastases were also independent unfavorable prognostic factors.

Conclusion: EGFR overexpression (PS > 3) in a CRC patient population was an independent adverse prognostic factor. Implementation of the Allred Scoring system criteria into clinical practice might facilitate treatment decisions in CRC patients.
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http://dx.doi.org/10.2147/OTT.S42446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729248PMC
August 2013

Determination of cathepsins B, D and G concentration in eutopic proliferative endometrium of women with endometriosis by the surface plasmon resonance imaging (SPRI) technique.

Eur J Obstet Gynecol Reprod Biol 2013 Jul 7;169(1):80-3. Epub 2013 Mar 7.

Department of Perinatology, Medical University of Bialystok, ul. Marii Sklodowskiej-Curie 24a, Bialystok, Poland.

Objective: To determine the concentrations of cathepsins B, D and G in proliferative eutopic endometrium of patients with and without endometriosis, by use of the surface plasmon resonance imaging (SPRI) technique.

Study Design: A total of 55 patients were recruited in the study: 31 patients with endometriosis (stages I-IV) and 24 controls. Endometrial samples were obtained in the first phase of the menstrual cycle from regularly menstruating premenopausal women, prior to laparoscopy, by the use of aspiration biopsy. Endometriosis was appropriately classified according to the Revised American Fertility Society classification and confirmed by histopathology in every case. The SPRI technique was used to determine the concentration of cathepsins B, D and G. To compare the two groups for quantitative data, Mann-Whitney-Wilcoxon's test was used due to the non-normal distribution of the tested variables and normality of distribution was assessed using Shapiro-Wilk W test.

Results: The concentration of the three examined cathepsins was higher in the proliferative eutopic endometrium of patients with endometriosis, especially in advanced stages, e.g. III and IV, when compared to healthy individuals. Corresponding median values were, for cathepsin B: [7.93 pmol/mg (min-max 2.82-15.71) vs 1.2 pmol/mg (min-max 0.7-15.49) p=0.0014], for cathepsin D: [1.86 pmol/mg (min-max 0.51-5.4) vs 1.03 pmol/mg (min-max 0.4-2.72) p=0.00041] and for cathepsin G: [0.6 pmol/mg (min-max 0.33-2.51) vs 0.3 pmol/mg (min-max 0.16-1.29) p=0.00051].

Conclusions: Increased concentrations of cathepsins B, D and G in the proliferative eutopic endometrium may play a role in the implantation of endometrial tissue outside the uterine cavity.
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http://dx.doi.org/10.1016/j.ejogrb.2013.01.024DOI Listing
July 2013

Cytological picture of the oral mucosa in patients with gastric and colon cancer.

Folia Histochem Cytobiol 2012 Oct 8;50(3):375-80. Epub 2012 Oct 8.

Department of Periodontal and Oral Mucosa Diseases, Medical University of Bialystok, Poland.

The incidence of malignant gastrointestinal cancers in Poland has been constantly growing, which has led to an intensification of the search for new markers of the early clinical stage of this disease. The oral cavity,as the first part of the gastrointestinal tract, has a very important role. The oral cavity presents symptoms of both typically stomatological and systemic diseases. Oral cancers, benign or malignant, may originate and grow in any of the tissues of the mouth, and within this small area they may be of varied clinical, histological and biological features. These can be lesions typically observed in the oral cavity, but also characteristic of cases where the symptoms occur both in the mouth and in other body parts. The aim of this study was to present a cytological picture of the oral mucosa in patients with gastric and colon cancer and to compare the cytological picture with that obtained from a group of patients with no cancer, using the Papanicolaou classification and the Bethesda system. The study was conducted in 126 patients treated surgically in the II General and Gastroenterological Surgery Clinic between 2006 and 2008. All patients were divided into two groups based on the type of lesions. In both of the studied groups, more than half of the patients did not present any abnormalities in the mucosa of the mouth, lips and cheeks in the physical examination. None of the patients had erosion, ulceration or lesions typical of leukoplakia or lichen planus. No malignant cells were detected in either of the studied groups, and there were no well-defined lesions found in the oral cavity that would distinguish the patients with gastrointestinal cancer.
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http://dx.doi.org/10.5603/19746DOI Listing
October 2012

K-Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan- or oxaliplatin-based chemotherapy.

Cancer Biol Ther 2012 Nov 22;13(13):1235-43. Epub 2012 Aug 22.

Department of Oncology, Military Institute of Medicine in Warsaw, Warsaw, Poland.

Background: CRC caused more than 600,000 estimated deaths in 2008. Dysregulated signaling through the RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway due to mutations in K-Ras and B-Raf are common events in CRC.

Methods: Incidence of mutations in codons 12 and 13 of K-Ras and exons 11 and 15 of B-Raf were analyzed in amplified PCR products from primary tumors of 273 patients with CRC, and their prognostic and predictive significance was assessed. The prognostic role of clinical and pathological factors was also examined.

Results: K-Ras mutations were present in 89 patients (32.6%), of whom 76 (85.4%) had mutations in codon 12 and 10 (11.2%) had mutations in codon 13. B-Raf gene mutations were present in 17 patients (6.9%), of whom 6 (35.3%) had mutations in exon 15. Multivariate analysis revealed a predictive significance for K-Ras mutations with respect to time to progression in patients treated with irinotecan and oxaliplatin as first-line chemotherapy. There was no predictive significance for B-Raf gene mutation status in these patients. The following risk factors were found to affect overall survival (OS) rates: primary tumor location, lymph node involvement grade, carcinoembryonic antigen (CEA) level before treatment, and performance status according to WHO criteria.

Conclusions: Based on the results of this study, K-Ras mutation status may be a suitable indicator of patient eligibility and a prognostic indicator for responsiveness to anti-EGFR therapy alone, or in combination with chemotherapy. Also, K-Ras mutation status may predict time to progression in patients treated with irinotecan and oxaliplatin.
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http://dx.doi.org/10.4161/cbt.21813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493430PMC
November 2012

Selective gene expression profiling of mTOR-associated tumor suppressor and oncogenes in ovarian cancer.

Folia Histochem Cytobiol 2011 ;49(2):317-24

Department of Perinatology, Medical University of Bialystok, Poland.

The aim of this study was to selectively profile the activation status of mammalian target of rapamycin (mTOR)-associated oncogenes and tumor suppressor genes (TSGs) in ovarian cancer specimens, healthy ovaries and benign ovarian tumors, including endometrial cysts. We used a novel type of microfluidic gene array to examine the expression of 15 human tumor suppressors and oncogenes in ovarian cancer specimens of 53 patients, benign ovarian cysts of 29 women (endometrial and simple) and 11 healthy ovaries of individuals in whom the material was obtained during total hysterectomies performed because of fibroid changes. The array was custom-designed to include the following genes: NF1, RHEB, mTOR1, AKT-1, PTEN, TSC1, TSC2, KRAS, RPS6KB1, 4EBP1, TP53, EIF4E, STK11, PIK3CA and BECN1. Confirmatory immunohistochemical detection was performed for a group of selected proteins. Particularly significant differences were observed as to the expression of PTEN (p < 0.0001), TP53 (p = 0.0003), PIK3CA (p = 0.0003) and BECN1 (p = 0.0014) which were shown to be downregulated in cancer patients when compared to healthy ovaries and benign ovarian cysts (endometrial and simple). These markers did not show association with grade or stage of the tumor. Immunohistochemistry showed that PTEN, TP53, PIK3CA and BECN1 proteins are expressed in ovarian cancer. Our results indicate that there are significant differences in the expression of some of the mTOR-related tumor suppressors and oncogenes which could be associated with the pathogenesis of ovarian cancer.
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http://dx.doi.org/10.5603/fhc.2011.0044DOI Listing
October 2011

Molecular differences in the KRAS gene mutation between a primary tumor and related metastatic sites - case report and a literature review.

Folia Histochem Cytobiol 2010 Dec;48(4):597-602

Department of Gastrointestinal Cancer, Cancer Center-Institute, Warsaw, Poland.

In recent years the the set of diagnostic tools in colorectal cancers has been extended by the assessment of the KRAS gene status. Currently it is a necessary step in order to qualify patients for the targeted therapy. The results of the analysis of several studies revealed a high rate of compliance of the KRAS gene mutational status in primary and metastatic tumors. In this paper we present a rare case of incompatibility of the KRAS mutations in the primary tumor located in the colon and metastatic changes in the liver.
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http://dx.doi.org/10.2478/v10042-010-0078-zDOI Listing
December 2010