66 results on '"Niemira, M."'
Search Results
2. The antitumour derivative, C-1748, affects CYP3A4: crosstalk between drug metabolism, CYP3A4 expression and enzymatic activity: B1.35
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Niemira, M., Brillowska-Dabrowska, A., Konopa, J., and Mazerska, Z.
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- 2010
3. Metabolism of antitumor 9-amino-1-nitroacridine derivatives in HepG2 cells and its influence on cytochrome P450 enzymes: YSF-67
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Niemira, M., Wisniewska, A., Konopa, J., and Mazerska, Z.
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- 2009
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4. Glucose metabolism dysregulation affects the transcriptome of skeletal muscle and responds to three-month exercise intervention in humans
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Szczerbinski, L., Niemira, M., Szczerbinski, K., Puchta, U., Taylor, M., Citko, A., Siewiec, E., Zapolska, J., Larsen, S., Gorska, M., Kretowski, A., Szczerbinski, L., Niemira, M., Szczerbinski, K., Puchta, U., Taylor, M., Citko, A., Siewiec, E., Zapolska, J., Larsen, S., Gorska, M., and Kretowski, A.
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- 2019
5. The type 2 diabetes susceptibility TCF7L2 gene variants affect postprandial glucose and fat utilization in non-diabetic subjects
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Adamska, E., Kretowski, A., Goscik, J., Citko, A., Bauer, W., Waszczeniuk, M., Maliszewska, K., Paczkowska-Abdulsalam, M., Niemira, M., Szczerbinski, L., Ciborowski, M., and Gorska, M.
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- 2018
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6. P13.04 Transcriptional profiling differentiates spinal cord ependymal tumours from other glial tumours in children
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Sobocińska, A A, primary, Niemira, M, additional, Szałkowska, A, additional, Wojtaś, B, additional, Trubicka, J, additional, Grajkowska, W, additional, Matyja, E, additional, and Łastowska, M, additional
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- 2019
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7. Muscle mass decline as a significant risk factor for type 2 diabetes development in middle-age subjects during the prospective 1000PLUS cohort study
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Maliszewska, K., Goscik, J., Szczerbinski, L., Citko, A., Paczkowska, M., Niemira, M., Adamska, E., Ciborowski, M., Adam Kretowski, and Gorska, M.
8. The antitumour derivative, C-1748, affects CYP3A4: crosstalk between drug metabolism, CYP3A4 expression and enzymatic activity
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Niemira, M., Brillowska-Dabrowska, A., Konopa, J., and Zofia Mazerska
9. Low Tumor-to-Stroma Ratio Reflects Protective Role of Stroma against Prostate Cancer Progression
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Paulina Nastały, Elke Eltze, Burkhard Brandt, Marcin Matuszewski, Axel Semjonow, Natalia Bednarz-Knoll, Emanuele Martini, Marek Sowa, Marta Popęda, Magdalena Niemira, Paolo Maiuri, Jolanta Szade, Leszek Kalinowski, Julia Smentoch, Anna J. Żaczek, Nastały, P, Smentoch, J, Popęda, M, Martini, E, Maiuri, P, Żaczek, Aj, Sowa, M, Matuszewski, M, Szade, J, Kalinowski, L, Niemira, M, Brandt, B, Eltze, E, Semjonow, A, and Bednarz-Knoll, N.
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Biochemical recurrence ,Oncology ,medicine.medical_specialty ,Medicine (miscellaneous) ,tumor progression ,Article ,Extracellular matrix ,chemistry.chemical_compound ,Prostate cancer ,Stroma ,Internal medicine ,medicine ,biochemical recurrence ,Tissue microarray ,business.industry ,fungi ,Epithelial cell adhesion molecule ,medicine.disease ,prostate cancer ,chemistry ,tumor-to-stroma ratio ,Tumor progression ,Cohort ,Medicine ,business ,digital pathology - Abstract
Tumor-to-stroma ratio (TSR) is a prognostic factor that expresses the relative amounts of tumor and intratumoral stroma. In this study, its clinical and molecular relevance was evaluated in prostate cancer (PCa). The feasibility of automated quantification was tested in digital scans of tissue microarrays containing 128 primary tumors from 72 PCa patients stained immunohistochemically for epithelial cell adhesion molecule (EpCAM), followed by validation in a cohort of 310 primary tumors from 209 PCa patients. In order to investigate the gene expression differences between tumors with low and high TSR, we applied multigene expression analysis (nCounter® PanCancer Progression Panel, NanoString) of 42 tissue samples. TSR scores were categorized into low (<, 1 TSR) and high (≥1 TSR). In the pilot cohort, 31 patients (43.1%) were categorized as low and 41 (56.9%) as high TSR score, whereas 48 (23.0%) patients from the validation cohort were classified as low TSR and 161 (77.0%) as high. In both cohorts, high TSR appeared to indicate the shorter time to biochemical recurrence in PCa patients (Log-rank test, p = 0.04 and p = 0.01 for the pilot and validation cohort, respectively). Additionally, in the multivariate analysis of the validation cohort, TSR predicted BR independent of other factors, i.e., pT, pN, and age (p = 0.04, HR 2.75, 95%CI 1.07–7.03). Our data revealed that tumors categorized into low and high TSR score show differential expression of various genes, the genes upregulated in tumors with low TSR score were mostly associated with extracellular matrix and cell adhesion regulation. Taken together, this study shows that high stroma content can play a protective role in PCa. Automatic EpCAM-based quantification of TSR might improve prognostication in personalized medicine for PCa.
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- 2021
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10. Mesenchymal stromal cells effectively limit house dust mite extract-induced mixed granulocytic lung inflammation.
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Tynecka M, Janucik A, Tarasik A, Zbikowski A, Niemira M, Kulczynska-Przybik A, Zeller A, Stocker N, Reszec-Gielazyn J, Mroczko B, Kretowski A, Akdis CA, Sokolowska M, Moniuszko M, and Eljaszewicz A
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- 2024
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11. Identification of MicroRNA Profiles in Fetal Spina Bifida: The Role in Pathomechanism and Diagnostic Significance.
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Buczyńska A, Sidorkiewicz I, Niemira M, Krętowski AJ, Węgrzyn P, Kosiński P, and Zbucka-Krętowska M
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- Pregnancy, Humans, Female, Down-Regulation, Up-Regulation, MicroRNAs genetics, Spinal Diseases, Spinal Dysraphism
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Distinct miRNA expression patterns may reflect anomalies related to fetal congenital malformations such as spinal bifida (SB). The aim of this preliminary study was to determine the maternal miRNA expression profile of women carrying fetuses with SB. Therefore, six women carrying fetuses with SB and twenty women with euploid healthy fetuses were enrolled in this study. Using NanoString technology, we evaluated the expression level of 798 miRNAs in both plasma and amniotic fluid samples. A downregulation of miR-1253, miR-1290, miR-194-5p, miR-302d-3p, miR-3144-3p, miR-4536-5p, miR-548aa + miR-548t-3p, miR-548ar-5p, miR-548n, miR-590-5p, miR-612, miR-627-5p, miR-644a, and miR-122-5p, and an upregulation of miR-320e, let-7b-5p, miR-23a-3p, miR-873-3p, and miR-30d-5p were identified in maternal amniotic fluid samples in SB when compared to the control group. The target genes of these miRNAs play a predominant role in regulating the synthesis of several biological compounds related to signaling pathways such as those regulating the pluripotency of stem cells. Moreover, the maternal plasma expression of miR-320e was increased in pregnancies with SB, and this marker could serve as a valuable non-invasive screening tool. Our results highlight the SB-specific miRNA signature and the differentially expressed miRNAs that may be involved in SB pathogenesis. Our findings emphasize the role of miRNA as a predictive factor that could potentially be useful in prenatal genetic screening for SB.
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- 2024
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12. Circulating serum miR-362-3p and miR-6721-5p as potential biomarkers for classification patients with adult-type diffuse glioma.
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Niemira M, Bielska A, Chwialkowska K, Raczkowska J, Skwarska A, Erol A, Zeller A, Sokolowska G, Toczydlowski D, Sidorkiewicz I, Mariak Z, Reszec J, Lyson T, Moniuszko M, and Kretowski A
- Abstract
According to the fifth edition of the WHO Classification of Tumours of the Central Nervous System (CNS) published in 2021, grade 4 gliomas classification includes IDH-mutant astrocytomas and wild-type IDH glioblastomas. Unfortunately, despite precision oncology development, the prognosis for patients with grade 4 glioma remains poor, indicating an urgent need for better diagnostic and therapeutic strategies. Circulating miRNAs besides being important regulators of cancer development could serve as promising diagnostic biomarkers for patients with grade 4 glioma. Here, we propose a two-miRNA miR-362-3p and miR-6721-5p screening signature for serum for non-invasive classification of identified glioma cases into the highest-grade 4 and lower-grade gliomas. A total of 102 samples were included in this study, comprising 78 grade 4 glioma cases and 24 grade 2-3 glioma subjects. Using the NanoString platform, seven miRNAs were identified as differentially expressed (DE), which was subsequently confirmed via RT-qPCR analysis. Next, numerous combinations of DE miRNAs were employed to develop classification models. The dual panel of miR-362-3p and miR-6721-5p displayed the highest diagnostic value to differentiate grade 4 patients and lower grade cases with an AUC of 0.867. Additionally, this signature also had a high AUC = 0.854 in the verification cohorts by RT-qPCR and an AUC = 0.842 using external data from the GEO public database. The functional annotation analyses of predicted DE miRNA target genes showed their primary involvement in the STAT3 and HIF-1 signalling pathways and the signalling pathway of pluripotency of stem cells and glioblastoma-related pathways. For additional exploration of miRNA expression patterns correlated with glioma, we performed the Weighted Gene-Co Expression Network Analysis (WGCNA). We showed that the modules most associated with glioma grade contained as many as six DE miRNAs. In conclusion, this study presents the first evidence of serum miRNA expression profiling in adult-type diffuse glioma using a classification based on the WHO 2021 guidelines. We expect that the discovered dual miR-362-3p and miR-6721-5p signatures have the potential to be utilised for grading gliomas in clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Niemira, Bielska, Chwialkowska, Raczkowska, Skwarska, Erol, Zeller, Sokolowska, Toczydlowski, Sidorkiewicz, Mariak, Reszec, Lyson, Moniuszko and Kretowski.)
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- 2024
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13. High tumour-infiltrating lymphocytes correlate with distinct gene expression profile and favourable survival in single hormone receptor-positive breast cancer.
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Ciarka A, Kunc M, Popęda M, Łacko A, Radecka B, Braun M, Pikiel J, Litwiniuk M, Pogoda K, Iżycka-Świeszewska E, Zeller A, Niemira M, Pęksa R, Biernat W, and Senkus E
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Introduction: This study aimed to evaluate the impact of tumour-infiltrating lymphocytes (TILs) on the expression of immune-related genes and prognosis in single hormone receptor-positive breast cancer. Material and methods: Tumour-infiltrating lymphocytes were analysed according to the guidelines of the International TILs Working Group in a cohort of 206 patients with single hormone receptor-positive breast cancer. Of these, 44.7% were classified as ER+/PgR-/HER2-, 18.4% as ER+/PgR-/HER2+, 26.2% as ER-/PgR+/HER2-, and 10.7% as ER-/PgR+/HER2+. Moreover, in 52 samples the analysis of gene expression profiling was performed using nCounter technology., Results: Most cases (74.3%) showed at least 1% of stromal TILs, with a median of 4%, mean of 16.3%, and interquartile range of 0-20%. ER-/PgR+ tumours displayed significantly higher TILs density than ER+/PgR- cases (p < 0.001, Wilcoxon test), regardless of HER2 status. The abundance of TILs was positively associated with ER-/PgR+ phenotype, higher Ki-67, and higher grade, but not with age, tumour size, or regional and distant metastases at diagnosis. Additionally, in ER+/PgR- subgroup higher TILs were associated with HER2-positive status. Stromal TILs > 5% were associated with better survival in the whole group, but this effect was less prominent in ER-/PgR+ patients. We identified 50 differentially expressed genes (DEGs) between single hormone receptor-positive breast tumours with high and low TILs, including 39 up-regulated and 11 down-regulated genes in the high TILs group., Conclusions: The up-regulated expression of immune-related genes was consistent also among separately analysed single hormone receptor-positive groups (ER+/PgR- and ER-/PgR+)., Competing Interests: None., (Copyright © 2024 Termedia.)
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- 2024
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14. Identification of serum miR-1246 and miR-150-5p as novel diagnostic biomarkers for high-grade serous ovarian cancer.
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Niemira M, Erol A, Bielska A, Zeller A, Skwarska A, Chwialkowska K, Kuzmicki M, Szamatowicz J, Reszec J, Knapp P, Moniuszko M, and Kretowski A
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- Humans, Female, Carcinoma, Ovarian Epithelial diagnosis, Carcinoma, Ovarian Epithelial genetics, Biomarkers, Tumor, MicroRNAs, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Cystadenocarcinoma, Serous diagnosis, Cystadenocarcinoma, Serous genetics, Cystadenocarcinoma, Serous pathology
- Abstract
Epithelial ovarian cancer (EOC) is one of the leading cancers in women, with high-grade serous ovarian cancer (HGSOC) being the most common and lethal subtype of this disease. A vast majority of HGSOC are diagnosed at the late stage of the disease when the treatment and total recovery chances are low. Thus, there is an urgent need for novel, more sensitive and specific methods for early and routine HGSOC clinical diagnosis. In this study, we performed miRNA expression profiling using the NanoString miRNA assay in 34 serum samples from patients with HGSOC and 36 healthy women. We identified 13 miRNAs that were differentially expressed (DE). For additional exploration of expression patterns correlated with HGSOC, we performed weighted gene co-expression network analysis (WGCNA). As a result, we showed that the module most correlated with tumour size, nodule and metastasis contained 8 DE miRNAs. The panel including miR-1246 and miR-150-5p was identified as a signature that could discriminate HGSOC patients with AUCs of 0.98 and 1 for the training and test sets, respectively. Furthermore, the above two-miRNA panel had an AUC = 0.946 in the verification cohorts of RT-qPCR data and an AUC = 0.895 using external data from the GEO public database. Thus, the model we developed has the potential to markedly improve the diagnosis of ovarian cancer., (© 2023. The Author(s).)
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- 2023
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15. Identification and subsequent validation of transcriptomic signature associated with metabolic status in endometrial cancer.
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Sidorkiewicz I, Jóźwik M, Buczyńska A, Erol A, Jóźwik M, Moniuszko M, Jarząbek K, Niemira M, and Krętowski A
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- Female, Humans, Prospective Studies, Gene Expression Profiling, Genes, cdc, Carbon, Transcriptome, Endometrial Neoplasms genetics
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Aberrant metabolism has been identified as a main driver of cancer. Profiling of metabolism-related pathways in cancer furthers the understanding of tumor plasticity and identification of potential metabolic vulnerabilities. In this prospective controlled study, we established transcriptomic profiles of metabolism-related pathways in endometrial cancer (EC) using a novel method, NanoString nCounter Technology. Fifty-seven ECs and 30 normal endometrial specimens were studied using the NanoString Metabolic Panel, further validated by qRT-PCR with a very high similarity. Statistical analyses were by GraphPad PRISM and Weka software. The analysis identified 11 deregulated genes (FDR ≤ 0.05; |FC|≥ 1.5) in EC: SLC7A11; SLC7A5; RUNX1; LAMA4; COL6A3; PDK1; CCNA1; ENO1; PKM; NR2F1; and NAALAD2. Gene ontology showed direct association of these genes with 'central carbon metabolism (CCM) in cancer'. Thus, 'CCM in cancer' appears to create one of the main metabolic axes in EC. Further, transcriptomic data were functionally validated with drug repurposing on three EC cell lines, with several drug candidates suggested. These results lay the foundation for personalized therapeutic strategies in this cancer. Metabolic plasticity represents a promising diagnostic and therapeutic option in EC., (© 2023. Springer Nature Limited.)
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- 2023
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16. Extracellular circulating miRNAs as potential non-invasive biomarkers in non-small cell lung cancer patients.
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Raczkowska J, Bielska A, Krętowski A, and Niemira M
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Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancers and is a malignant condition resistant to advanced-stage treatment. Despite the advancement in detection and treatment techniques, the disease is taking a deadly toll worldwide, being the leading cause of cancer death every year. Current diagnostic methods do not ensure the detection of the disease at an early stage, nor can they predict the risk of its development. There is an urgent need to identify biomarkers that can help predict an individual's risk of developing NSCLC, distinguish NSCLC subtype, allow monitor disease and treatment progression which can improve patient survival. Micro RNAs (miRNAs) represent the class of small and non-coding RNAs involved in gene expression regulation, influencing many biological processes such as proliferation, differentiation, and carcinogenesis. Research reports significant differences in miRNA profiles between healthy and neoplastic tissues in NSCLC. Its abundant presence in biofluids, such as serum, blood, urine, and saliva, makes them easily detectable and does not require invasive collection techniques. Many studies support miRNAs' importance in detecting, predicting, and prognosis of NSCLC, indicating their utility as a promising biomarker. In this work, we reviewed up-to-date research focusing on biofluid miRNAs' role as a diagnostic tool in NSCLC cases. We also discussed the limitations of applying miRNAs as biomarkers and highlighted future areas of interest., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Raczkowska, Bielska, Krętowski and Niemira.)
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- 2023
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17. Pharmacovariome scanning using whole pharmacogene resequencing coupled with deep computational analysis and machine learning for clinical pharmacogenomics.
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Tafazoli A, Mikros J, Khaghani F, Alimardani M, Rafigh M, Hemmati M, Siamoglou S, Golińska AK, Kamiński KA, Niemira M, Miltyk W, and Patrinos GP
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- Pilot Projects, Machine Learning, Sequence Analysis, DNA methods, Algorithms, Artificial Intelligence, Pharmacogenetics
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Background: This pilot study aims to identify and functionally assess pharmacovariants in whole exome sequencing data. While detection of known variants has benefited from pharmacogenomic-dedicated bioinformatics tools before, in this paper we have tested novel deep computational analysis in addition to artificial intelligence as possible approaches for functional analysis of unknown markers within less studied drug-related genes., Methods: Pharmacovariants from 1800 drug-related genes from 100 WES data files underwent (a) deep computational analysis by eight bioinformatic algorithms (overall containing 23 tools) and (b) random forest (RF) classifier as the machine learning (ML) approach separately. ML model efficiency was calculated by internal and external cross-validation during recursive feature elimination. Protein modelling was also performed for predicted highly damaging variants with lower frequencies. Genotype-phenotype correlations were implemented for top selected variants in terms of highest possibility of being damaging., Results: Five deleterious pharmacovariants in the RYR1, POLG, ANXA11, CCNH, and CDH23 genes identified in step (a) and subsequent analysis displayed high impact on drug-related phenotypes. Also, the utilization of recursive feature elimination achieved a subset of 175 malfunction pharmacovariants in 135 drug-related genes that were used by the RF model with fivefold internal cross-validation, resulting in an area under the curve of 0.9736842 with an average accuracy of 0.9818 (95% CI: 0.89, 0.99) on predicting whether a carrying individuals will develop adverse drug reactions or not. However, the external cross-validation of the same model indicated a possible false positive result when dealing with a low number of observations, as only 60 important variants in 49 genes were displayed, giving an AUC of 0.5384848 with an average accuracy of 0.9512 (95% CI: 0.83, 0.99)., Conclusion: While there are some technologies for functionally assess not-interpreted pharmacovariants, there is still an essential need for the development of tools, methods, and algorithms which are able to provide a functional prediction for every single pharmacovariant in both large-scale datasets and small cohorts. Our approaches may bring new insights for choosing the right computational assessment algorithms out of high throughput DNA sequencing data from small cohorts to be used for personalized drug therapy implementation., (© 2023. The Author(s).)
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- 2023
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18. Implementation of the web-based calculator estimating odds ratio of severe COVID-19 for unvaccinated individuals in a country with high coronavirus-related death toll.
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Kwasniewski M, Korotko U, Chwialkowska K, Niemira M, Jaroszewicz J, Sobala-Szczygiel B, Puzanowska B, Moniuszko-Malinowska A, Pancewicz S, Parfieniuk-Kowerda A, Martonik D, Zarebska-Michaluk D, Simon K, Pazgan-Simon M, Mozer-Lisewska I, Bura M, Adamek A, Tomasiewicz K, Pawłowska M, Piekarska A, Berkan-Kawinska A, Horban A, Kowalska J, Podlasin R, Wasilewski P, Azzadin A, Czuczwar M, Borys M, Piwowarczyk P, Czaban S, Bogocz J, Ochab M, Kruk A, Uszok S, Bielska A, Szałkowska A, Raczkowska J, Sokołowska G, Chorostowska-Wynimko J, Jezela-Stanek A, Rozy A, Lechowicz U, Połowianiuk U, Tycinska A, Grubczak K, Starosz A, Izdebska W, Krzemiński TF, Bousqet J, Franchini G, Hadlock J, Kretowski A, Akdis M, Akdis CA, Sokolowska M, Eljaszewicz A, Flisiak R, and Moniuszko M
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- Humans, Odds Ratio, Internet, COVID-19
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- 2023
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19. BCOR expression in paediatric pineoblastoma.
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Trubicka J, Łastowska M, Karkucińska-Więckowska A, Niemira M, Ejmont M, Sowińska A, Pronicki M, Matyja E, and Grajkowska W
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- Humans, Child, RNA, Proto-Oncogene Proteins, Repressor Proteins genetics, Pinealoma diagnosis, Pinealoma genetics, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Germinoma, Rhabdoid Tumor, Pineal Gland
- Abstract
BCOR is expressed in a new brain tumour entity, i.e. 'CNS tumour with BCOR internal tandem duplication' (HGNET BCOR) but not in several other high grade paediatric brain tumours investigated. Immunohistochemical detection of BCOR expression may therefore serve as a potential diagnostic marker. Nevertheless, in rare paediatric glioma cases recurrent EP300-BCOR fusions were detected, which resulted in strong BCOR immunopositivity. We have therefore examined other, not analysed so far, types of central nervous system (CNS) tumours, pineoblastoma and germinoma, to assess a potential involvement of BCOR in these tumours. Levels of BCOR RNA expression were investigated by NanoString nCounter system analysis in a series of altogether 66 high grade paediatric tumours, including four pineoblastoma cases. Immunohistological detection of BCOR was performed in eight pineoblastoma, five germinoma and four atypical teratoid rhabdoid tumours (ATRTs), all located in the pineal region. We detected BCOR expression in all pineoblastomas, at the RNA and protein levels, but not in germinomas and ATRTs. Further analysis of pineoblastoma samples did not reveal the presence of either BCOR internal tandem duplication or BCOR fusion involvement. Positive immunohistological BCOR nuclear reaction in pineoblastoma may therefore differentiate this type of tumour from other high grade tumours located in the pineal region.
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- 2023
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20. Human Gut Microbiota in Coronary Artery Disease: A Systematic Review and Meta-Analysis.
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Choroszy M, Litwinowicz K, Bednarz R, Roleder T, Lerman A, Toya T, Kamiński K, Sawicka-Śmiarowska E, Niemira M, and Sobieszczańska B
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In recent years, the importance of the gut microbiome in human health and disease has increased. Growing evidence suggests that gut dysbiosis might be a crucial risk factor for coronary artery disease (CAD). Therefore, we conducted a systematic review and meta-analysis to determine whether or not CAD is associated with specific changes in the gut microbiome. The V3-V4 regions of the 16S rDNA from fecal samples were analyzed to compare the gut microbiome composition between CAD patients and controls. Our search yielded 1181 articles, of which 21 met inclusion criteria for systematic review and 7 for meta-analysis. The alpha-diversity, including observed OTUs, Shannon and Simpson indices, was significantly decreased in CAD, indicating the reduced richness of the gut microbiome. The most consistent results in a systematic review and meta-analysis pointed out the reduced abundance of Bacteroidetes and Lachnospiraceae in CAD patients. Moreover, Enterobacteriaceae , Lactobacillus , and Streptococcus taxa demonstrated an increased trend in CAD patients. The alterations in the gut microbiota composition are associated with qualitative and quantitative changes in bacterial metabolites, many of which have pro-atherogenic effects on endothelial cells, increasing the risk of developing and progressing CAD., Competing Interests: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the manuscript’s contents, and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. The authors have no competing interests to declare.
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- 2022
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21. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.
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Butler-Laporte G, Povysil G, Kosmicki JA, Cirulli ET, Drivas T, Furini S, Saad C, Schmidt A, Olszewski P, Korotko U, Quinodoz M, Çelik E, Kundu K, Walter K, Jung J, Stockwell AD, Sloofman LG, Jordan DM, Thompson RC, Del Valle D, Simons N, Cheng E, Sebra R, Schadt EE, Kim-Schulze S, Gnjatic S, Merad M, Buxbaum JD, Beckmann ND, Charney AW, Przychodzen B, Chang T, Pottinger TD, Shang N, Brand F, Fava F, Mari F, Chwialkowska K, Niemira M, Pula S, Baillie JK, Stuckey A, Salas A, Bello X, Pardo-Seco J, Gómez-Carballa A, Rivero-Calle I, Martinón-Torres F, Ganna A, Karczewski KJ, Veerapen K, Bourgey M, Bourque G, Eveleigh RJ, Forgetta V, Morrison D, Langlais D, Lathrop M, Mooser V, Nakanishi T, Frithiof R, Hultström M, Lipcsey M, Marincevic-Zuniga Y, Nordlund J, Schiabor Barrett KM, Lee W, Bolze A, White S, Riffle S, Tanudjaja F, Sandoval E, Neveux I, Dabe S, Casadei N, Motameny S, Alaamery M, Massadeh S, Aljawini N, Almutairi MS, Arabi YM, Alqahtani SA, Al Harthi FS, Almutairi A, Alqubaishi F, Alotaibi S, Binowayn A, Alsolm EA, El Bardisy H, Fawzy M, Cai F, Soranzo N, Butterworth A, Geschwind DH, Arteaga S, Stephens A, Butte MJ, Boutros PC, Yamaguchi TN, Tao S, Eng S, Sanders T, Tung PJ, Broudy ME, Pan Y, Gonzalez A, Chavan N, Johnson R, Pasaniuc B, Yaspan B, Smieszek S, Rivolta C, Bibert S, Bochud PY, Dabrowski M, Zawadzki P, Sypniewski M, Kaja E, Chariyavilaskul P, Nilaratanakul V, Hirankarn N, Shotelersuk V, Pongpanich M, Phokaew C, Chetruengchai W, Tokunaga K, Sugiyama M, Kawai Y, Hasegawa T, Naito T, Namkoong H, Edahiro R, Kimura A, Ogawa S, Kanai T, Fukunaga K, Okada Y, Imoto S, Miyano S, Mangul S, Abedalthagafi MS, Zeberg H, Grzymski JJ, Washington NL, Ossowski S, Ludwig KU, Schulte EC, Riess O, Moniuszko M, Kwasniewski M, Mbarek H, Ismail SI, Verma A, Goldstein DB, Kiryluk K, Renieri A, Ferreira MAR, and Richards JB
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- Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Toll-Like Receptor 7 genetics, SARS-CoV-2 genetics, Exome genetics, COVID-19 genetics
- Abstract
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Biobanque Québécoise de la Covid-19: Brent Richards’s institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. He is the CEO of 5 Prime Sciences Inc (www.5primesciences.com). DeCOI: Oliver Witzke has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Köhler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, Takeda, TEVA and UCB. Kerstin U. Ludwig is co-founder and holds equity in the LAMPseq Diagnostics GmbH. UP serves as ad hoc advisor for Sanofi-Pasteur, BioNtech and Sobi and is member of the SAB of Leukocare. Christoph D. Spinner reports grants, personal fees from AstraZeneca, personal fees and non-financial support from BBraun Melsungen, grants, personal fees and non-financial support from Gilead Sciences, grants and personal fees from Janssen-Cilag, personal fees from Eli Lilly, personal fees from Formycon, personal fees from Roche, other from Apeiron, grants and personal fees from MSD, grants from Cepheid, personal fees from GSK, personal fees from Molecular partners, other from Eli Lilly, personal fees from SOBI during the conduct of the study; personal fees from AbbVie, personal fees from MSD, grants and personal fees from ViiV Healthcare, outside the submitted work. Jochen Schneider received grants and/or personal fees from Gilead Sciences, Janssen-Cilag, and from AbbVie outside the submitted work. Philipp Koehler reports grants or contracts from German Federal Ministry of Research and Education (BMBF) B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and NAPKON (Nationales Pandemie Kohorten Netz, German National Pandemic Cohort Network) of the Network University Medicine (NUM) and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited and Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. Oliver A. Cornely reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley. Genentech: Amy D Stockwell, Fang Cai, and Brian L Yaspan are, or were at the execution of the study, full time employees of Genentech with stock and stock options in Roche. Helix Exome+ and Healthy Nevada Project COVID-19 Phenotypes: Alexandre Bolze, Kelly M Schiabor Barrett, Simon White, Nicole L Washington, Francisco Tanudjaja, Stephen Riffle, Efren Sandoval, and Elizabeth T Cirulli are employees of Helix. Regeneron: Jack A Kosmicki and Manuel AR Ferreira are current employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. Vanda CALYPSO COVID-19: Bartlomiej Przychodzen and Sandra Smieszek are employees of Vanda Pharmaceuticals Inc.
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- 2022
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22. The short-term and long-term effects of intranasal mesenchymal stem cell administration to noninflamed mice lung.
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Tynecka M, Janucik A, Niemira M, Zbikowski A, Stocker N, Tarasik A, Starosz A, Grubczak K, Szalkowska A, Korotko U, Reszec J, Kwasniewski M, Kretowski A, Akdis C, Sokolowska M, Moniuszko M, and Eljaszewicz A
- Subjects
- Animals, Claudin-3 metabolism, Humans, Lung, Mice, Occludin metabolism, COVID-19 therapy, Mesenchymal Stem Cells metabolism
- Abstract
Mesenchymal stem cells (mesenchymal stromal cells; MSC)-based therapies remain a promising approach to treat degenerative and inflammatory diseases. Their beneficial effects were confirmed in numerous experimental models and clinical trials. However, safety issues concerning MSCs' stability and their long-term effects limit their implementation in clinical practice, including treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, and COVID-19. Here, we aimed to investigate the safety of intranasal application of human adipose tissue-derived MSCs in a preclinical experimental mice model and elucidate their effects on the lungs. We assessed short-term (two days) and long-term (nine days) effects of MSCs administration on lung morphology, immune responses, epithelial barrier function, and transcriptomic profiles. We observed an increased frequency of IFNγ- producing T cells and a decrease in occludin and claudin 3 as a long-term effect of MSCs administration. We also found changes in the lung transcriptomic profiles, reflecting redox imbalance and hypoxia signaling pathway. Additionally, we found dysregulation in genes clustered in pattern recognition receptors, macrophage activation, oxidative stress, and phagocytosis. Our results suggest that i.n. MSCs administration to noninflamed healthy lungs induces, in the late stages, low-grade inflammatory responses aiming at the clearance of MSCs graft., Competing Interests: MT reports grant from National Science Centre, Poland, during the conduct of the study, grants from European Union funds, POWER 2014-2020, grants from National Centre for Research and Development, outside the submitted work. AJ and AZ reports grants and non-financial support from Ministry of Education and Science, Poland. CA reports research grants from the Swiss National Science Foundation, European Union (EU CURE), Novartis Research Institutes (Basel, Switzerland), Stanford University (Redwood City, Calif), and SciBase (Stockholm, Sweden), he is the Co-Chair for EAACI Guidelines on Environmental Science in Allergic diseases and Asthma, and serves on the Advisory Boards of Sanofi/Regeneron, Novartis, GlaxoSmithKline, and SciBase, and is the Editor-in-Chief of Allergy, outside the submitted work. MS reports grants from Swiss National Science Foundation, grants from GSK, grants from Novartis, personal fees from AstraZeneca, outside the submitted work. MM reports grants from National Centre for Research and Development, grant from Medical Research Agency, lecture fees from Astra Zeneca, Berlin-Chemie/Menarini, GSK, Takeda, Shire, Teva, Lek-Am, Celon, Sandoz, Pfizer, Hal Allergy, and had reimbursed conference costs and travel by Berlin-Chemie/Menarini, outside the submitted work. AE reports grant from National Science Centre, during the conduct of the study, grants from National Centre for Research and Development. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tynecka, Janucik, Niemira, Zbikowski, Stocker, Tarasik, Starosz, Grubczak, Szalkowska, Korotko, Reszec, Kwasniewski, Kretowski, Akdis, Sokolowska, Moniuszko and Eljaszewicz.)
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- 2022
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23. Alpha-smooth muscle actin-positive cancer-associated fibroblasts secreting osteopontin promote growth of luminal breast cancer.
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Muchlińska A, Nagel A, Popęda M, Szade J, Niemira M, Zieliński J, Skokowski J, Bednarz-Knoll N, and Żaczek AJ
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- Actins metabolism, Cell Line, Tumor, Culture Media, Conditioned pharmacology, Female, Fibroblasts metabolism, Humans, Muscle, Smooth chemistry, Muscle, Smooth metabolism, Muscle, Smooth pathology, Osteopontin genetics, Osteopontin metabolism, Breast Neoplasms pathology, Cancer-Associated Fibroblasts chemistry, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology
- Abstract
Background: Cancer-associated fibroblasts (CAFs) have been shown to support tumor development in a variety of cancers. Different markers were applied to classify CAFs in order to elucidate their impact on tumor progression. However, the exact mechanism by which CAFs enhance cancer development and metastasis is yet unknown., Methods: Alpha-smooth muscle actin (α-SMA) was examined immunohistochemically in intratumoral CAFs of nonmetastatic breast cancers and correlated with clinicopathological data. Four CAF cell lines were isolated from patients with luminal breast cancer (lumBC) and classified according to the presence of α-SMA protein. Conditioned medium (CM) from CAF cultures was used to assess the influence of CAFs on lumBC cell lines: MCF7 and T47D cells using Matrigel 3D culture assay. To identify potential factors accounting for promotion of tumor growth by α-SMA
high CAFs, nCounter PanCancer Immune Profiling Panel (NanoString) was used., Results: In luminal breast cancer, presence of intratumoral CAFs expressing high level of α-SMA (13% of lumBC group) correlated with poor prognosis (p = 0.019). In in vitro conditions, conditioned medium obtained from primary cultures of α-SMA-positive CAFs isolated from luminal tumors was observed to enhance growth of lumBC cell line colonies in 3D Matrigel, in contrast to CM derived from α-SMA-negative CAFs. Multigene expression analysis indicated that osteopontin (OPN) was overexpressed in α-SMA-positive CAFs in both clinical samples and in vitro models. OPN expression was associated with higher percentage of Ki67-positive cells in clinical material (p = 0.012), while OPN blocking in α-SMA-positive CAF-derived CM attenuated growth of lumBC cell line colonies in 3D Matrigel., Conclusions: Our findings demonstrate that α-SMA-positive CAFs might enhance tumor growth via secretion of OPN., (© 2022. The Author(s).)- Published
- 2022
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24. Expression Profile and Diagnostic Significance of MicroRNAs in Papillary Thyroid Cancer.
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Rogucki M, Sidorkiewicz I, Niemira M, Dzięcioł JB, Buczyńska A, Adamska A, Siewko K, Kościuszko M, Maliszewska K, Wójcicka A, Supronik J, Szelachowska M, Reszeć J, Krętowski AJ, and Popławska-Kita A
- Abstract
The incidence of papillary thyroid cancer (PTC) has increased in recent years. To improve the diagnostic management of PTC, we propose the use of microRNAs (miRNAs) as a biomarker. Our aim in this study was to evaluate the miRNA expression pattern in PTC using NanoString technology. We identified ten miRNAs deregulated in PTC compared with reference tissue: miR-146b-5p, miR-221-3p, miR-221-5p, miR-34-5p, miR-551b-3p, miR-152-3p, miR-15a-5p, miR-31-5p, and miR-7-5p (FDR < 0.05; |fold change (FC)| ≥ 1.5). The gene ontology (GO) analysis of differentially expressed miRNA (DEM) target genes identified the predominant involvement of epidermal growth factor receptor (EGFR), tyrosine kinase inhibitor resistance, and pathways in cancer in PTC. The highest area under the receiver operating characteristic (ROC) curve (AUC) for DEMs was found for miR-146-5p (AUC = 0.770) expression, indicating possible clinical applicability in PTC diagnosis. The combination of four miRNAs (miR-152-3p, miR-221-3p, miR-551b-3p, and miR-7-5p) showed an AUC of 0.841. Validation by real-time quantitative polymerase chain reactions (qRT-PCRs) confirmed our findings. The introduction of an miRNA diagnostic panel based on the results of our study may help to improve therapeutic decision making for questionable cases. The use of miRNAs as biomarkers of PTC may become an aspect of personalized medicine.
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- 2022
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25. Serum miRNA Profile in Diabetic Patients With Ischemic Heart Disease as a Promising Non-Invasive Biomarker.
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Bielska A, Niemira M, Bauer W, Sidorkiewicz I, Szałkowska A, Skwarska A, Raczkowska J, Ostrowski D, Gugała K, Dobrzycki S, and Krętowski A
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- Biomarkers, Gene Expression Profiling, Humans, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 genetics, MicroRNAs genetics, Myocardial Ischemia complications, Myocardial Ischemia diagnosis, Myocardial Ischemia genetics
- Abstract
The increasing morbidity and mortality of type 2 diabetic mellitus (T2DM) patients with ischemic heart disease (IHD) highlight an urgent need to identify early biomarkers, which would help to predict individual risk of development of IHD. Here, we postulate that circulating serum-derived micro RNAs (miRNAs) may serve as potential biomarkers for early IHD diagnosis and support the identification of diabetic individuals with a predisposition to undergo IHD. We obtained serum samples from T2DM patients either with IHD or IHD-free and analysed the expression levels of 798 miRNAs using the NanoString nCounter technology platform. The prediction of the putative miRNAs targets was performed using the Ingenuity Pathway Analysis (IPA) software. Gene Ontology (GO) analysis was used to identify the biological function and signalling pathways associated with miRNA target genes. Hub genes of protein-protein interaction (PPI) network were identified by STRING database and Cytotoscape tool. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic value of identified miRNAs. Real-time quantitative polymerase chain reaction (qRT-PCR) was used for nCounter platform data validation. Our data showed that six miRNAs (miR-615-3p, miR-3147, miR-1224-5p, miR-5196-3p, miR-6732-3p, and miR-548b-3p) were significantly upregulated in T2DM IHD patients compared to T2DM patients without IHD. Further analysis indicated that 489 putative target genes mainly affected the endothelin-1 signalling pathway, glucocorticoid biosynthesis, and apelin cardiomyocyte signalling pathway. All tested miRNAs showed high diagnostic value (AUC = 0.779 - 0.877). Taken together, our research suggests that circulating miRNAs might have a crucial role in the development of IHD in diabetic patients and may be used as a potential biomarker for early diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bielska, Niemira, Bauer, Sidorkiewicz, Szałkowska, Skwarska, Raczkowska, Ostrowski, Gugała, Dobrzycki and Krętowski.)
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- 2022
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26. ERα36-High Cancer-Associated Fibroblasts as an Unfavorable Factor in Triple-Negative Breast Cancer.
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Nagel A, Popeda M, Muchlinska A, Sadej R, Szade J, Zielinski J, Skokowski J, Niemira M, Kretowski A, Markiewicz A, and Zaczek AJ
- Abstract
Background: Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor microenvironment (TME). Estrogen receptor alpha 36 (ERα36), the alternatively spliced variant of ERα, is described as an unfavorable factor when expressed in cancer cells. ERα can be expressed also in CAFs; however, the role of ERα36 in CAFs is unknown. Methods: Four CAF cultures were isolated from chemotherapy-naïve BC patients and characterized for ERα36 expression and the NanoString gene expression panel using isolated RNA. Conditioned media from CAF cultures were used to assess the influence of CAFs on triple-negative breast cancer (TNBC) cells using a matrigel 3D culture assay. Results: We found that ERα36high CAFs significantly induced the branching of TNBC cells in vitro (p < 0.001). They also produced a set of pro-tumorigenic cytokines compared to ERα36low CAFs, among which hepatocyte growth factor (HGF) was the main inducer of TNBC cell invasive phenotype in vitro (p < 0.001). Tumor stroma rich in ERα36high CAFs was correlated with high Ki67 expression (p = 0.041) and tumor-associated macrophages markers (CD68 and CD163, p = 0.041 for both). HGF was found to be an unfavorable prognostic factor in TCGA database analysis (p = 0.03 for DFS and p = 0.04 for OS). Conclusions: Breast cancer-associated fibroblasts represent distinct subtypes based on ERα36 expression. We propose that ERα36high CAFs could account for an unfavorable prognosis for TNBC patients.
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- 2022
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27. miRNAs as Predictive Factors in Early Diagnosis of Gestational Diabetes Mellitus.
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Juchnicka I, Kuźmicki M, Niemira M, Bielska A, Sidorkiewicz I, Zbucka-Krętowska M, Krętowski AJ, and Szamatowicz J
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- Early Diagnosis, Female, Humans, Pregnancy, Prospective Studies, Circulating MicroRNA, Diabetes, Gestational diagnosis, Diabetes, Gestational genetics, MicroRNAs metabolism
- Abstract
Introduction: Circulating miRNAs are important mediators in epigenetic changes. These non-coding molecules regulate post-transcriptional gene expression by binding to mRNA. As a result, they influence the development of many diseases, such as gestational diabetes mellitus (GDM). Therefore, this study investigates the changes in the miRNA profile in GDM patients before hyperglycemia appears., Materials and Methods: The study group consisted of 24 patients with GDM, and the control group was 24 normoglycemic pregnant women who were matched for body mass index (BMI), age, and gestational age. GDM was diagnosed with an oral glucose tolerance test between the 24th and 26th weeks of pregnancy. The study had a prospective design, and serum for analysis was obtained in the first trimester of pregnancy. Circulating miRNAs were measured using the NanoString quantitative assay platform. Validation with real time-polymerase chain reaction (RT-PCR) was performed on the same group of patients. Mann-Whitney U-test and Spearman correlation were done to assess the significance of the results., Results: Among the 800 miRNAs, 221 miRNAs were not detected, and 439 were close to background noise. The remaining miRNAs were carefully investigated for their average counts, fold changes, p-values, and false discovery rate (FDR) scores. We selected four miRNAs for further validation: miR-16-5p, miR-142-3p, miR-144-3p, and miR-320e, which showed the most prominent changes between the studied groups. The validation showed up-regulation of miR-16-5p (p<0.0001), miR-142-3p (p=0.001), and miR-144-3p (p=0.003)., Conclusion: We present changes in miRNA profile in the serum of GDM women, which may indicate significance in the pathophysiology of GDM. These findings emphasize the role of miRNAs as a predictive factor that could potentially be useful in early diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Juchnicka, Kuźmicki, Niemira, Bielska, Sidorkiewicz, Zbucka-Krętowska, Krętowski and Szamatowicz.)
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- 2022
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28. MicroRNA Profile Alterations in Parathyroid Carcinoma: Latest Updates and Perspectives.
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Wielogórska M, Podgórska B, Niemira M, Szelachowska M, Krętowski A, and Siewko K
- Abstract
Parathyroid tumors are a genetically heterogenous group with a significant variability in clinical features. Due to a lack of specific signs and symptoms and uncertain histopathological criteria, parathyroid carcinomas (PCs) are challenging to diagnose, both before and after surgery. There is a great interest in searching for accurate molecular biomarkers for early detection, disease monitoring, and clinical management. Due to improvements in molecular pathology, the latest studies have reported that PC tumorigenesis is strongly linked to the epigenetic regulation of gene expression. MicroRNA (miRNA) profiling may serve as a helpful adjunct in distinguishing parathyroid adenoma (PAd) from PC and provide further insight into regulatory pathways involved in PTH release and parathyroid tumorigenesis. So far, only a few studies have attempted to show the miRNA signature for PC, and very few overlaps could be found between these relatively similar studies. A global miRNA downregulation was detected in PC compared with normal glands among differentially expressed miRNAs. This review summarizes changes in miRNA expression in PC and discusses the future research directions in this area.
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- 2022
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29. Exploring microRNAs as predictive biomarkers for type 2 diabetes mellitus remission after sleeve gastrectomy: A pilot study.
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Wojciechowska G, Szczerbinski L, Kretowski M, Niemira M, Hady HR, and Kretowski A
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- Biomarkers, Gastrectomy, Humans, Pilot Projects, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 surgery, MicroRNAs metabolism
- Abstract
Objective: This study aimed to evaluate microRNAs (miRNAs) as predictive biomarkers for type 2 diabetes (T2D) remission 12 months after sleeve gastrectomy (SG)., Methods: A total of 179 serum miRNAs were profiled, and 26 clinical variables were collected from 46 patients. Two patients were later excluded because of hemolysis, and six patients with unclear remission status were set aside to evaluate the prediction models. The remaining 38 patients were included for model building. Variable selection was done using different approaches, including Least Absolute Shrinkage and Selection Operator (LASSO). Prediction models were then developed using LASSO and assessed in the validation set., Results: A total of 26 out of 38 patients achieved T2D remission 12 months after SG. The prediction model with only clinical variables misclassified two patients, which were correctly classified using miRNAs. Two miRNA-only models achieved an accuracy of one but performed poorly for the validation set. The best miRNA model was a mixed model (accuracy: 0.974) containing four miRNAs (hsa-miR-32-5p, hsa-miR-382-5p, hsa-miR-1-3p, and hsa-miR-21-5p) and four clinical variables (T2D medication, sex, age, and fasting blood glucose). These miRNAs are involved in pathways related to obesity and insulin resistance., Conclusions: This study suggests that four serum miRNAs might be predictive biomarkers for T2D remission 12 months after SG, but further validation studies are needed., (© 2022 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)
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- 2022
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30. The Role of Androgen Receptor and microRNA Interactions in Androgen-Dependent Diseases.
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Bielska A, Skwarska A, Kretowski A, and Niemira M
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- Biomarkers, Tumor genetics, Early Detection of Cancer, Gene Expression Regulation, Neoplastic, Humans, Neoplasms diagnosis, MicroRNAs genetics, Neoplasms genetics, Receptors, Androgen genetics
- Abstract
The androgen receptor (AR) is a member of the steroid hormone receptor family of nuclear transcription factors. It is present in the primary/secondary sexual organs, kidneys, skeletal muscles, adrenal glands, skin, nervous system, and breast. Abnormal AR functioning has been identified in numerous diseases, specifically in prostate cancer (PCa). Interestingly, recent studies have indicated a relationship between the AR and microRNA (miRNA) crosstalk and cancer progression. MiRNAs are small, endogenous, non-coding molecules that are involved in crucial cellular processes, such as proliferation, apoptosis, or differentiation. On the one hand, AR may be responsible for the downregulation or upregulation of specific miRNA, while on the other hand, AR is often a target of miRNAs due to their regulatory function on AR gene expression. A deeper understanding of the AR-miRNA interactions may contribute to the development of better diagnostic tools as well as to providing new therapeutic approaches. While most studies usually focus on the role of miRNAs and AR in PCa, in this review, we go beyond PCa and provide insight into the most recent discoveries about the interplay between AR and miRNAs, as well as about other AR-associated and AR-independent diseases.
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- 2022
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31. Transcriptional profiling of paediatric ependymomas identifies prognostically significant groups.
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Łastowska M, Matyja E, Sobocińska A, Wojtaś B, Niemira M, Szałkowska A, Krętowski A, Karkucińska-Więckowska A, Kaleta M, Ejmont M, Tarasińska M, Perek-Polnik M, Dembowska-Bagińska B, Pronicki M, Grajkowska W, and Trubicka J
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- Age Factors, Cluster Analysis, Ependymoma mortality, Ependymoma pathology, Ependymoma therapy, Humans, Infratentorial Neoplasms mortality, Infratentorial Neoplasms pathology, Infratentorial Neoplasms therapy, Predictive Value of Tests, Prognosis, Retrospective Studies, Supratentorial Neoplasms mortality, Supratentorial Neoplasms pathology, Supratentorial Neoplasms therapy, Biomarkers, Tumor genetics, Ependymoma genetics, Gene Expression Profiling, Infratentorial Neoplasms genetics, Supratentorial Neoplasms genetics, Transcriptome
- Abstract
The majority of supratentorial ependymomas in children contain oncogenic fusions, such as ZFTA-RELA or YAP1-MAMLD1. In contrast, posterior fossa (PF) ependymomas lack recurrent somatic mutations and are classified based on gene expression or methylation profiling into group A (PFA) and group B (PFB). We have applied a novel method, NanoString nCounter Technology, to identify four molecular groups among 16 supratentorial and 50 PF paediatric ependymomas, using 4-5 group-specific signature genes. Clustering analysis of 16 supratentorial ependymomas revealed 9 tumours with a RELA fusion-positive signature (RELA+), 1 tumour with a YAP1 fusion-positive signature (YAP1+), and 6 not-classified tumours. Additionally, we identified one RELA+ tumour among historically diagnosed CNS primitive neuroectodermal tumour samples. Overall, 9 of 10 tumours with the RELA+ signature possessed the ZFTA-RELA fusion as detected by next-generation sequencing (p = 0.005). Similarly, the only tumour with a YAP1+ signature exhibited the YAP1-MAMLD1 fusion. Among the remaining unclassified ependymomas, which did not exhibit the ZFTA-RELA fusion, the ZFTA-MAML2 fusion was detected in one case. Notably, among nine ependymoma patients with the RELA+ signature, eight survived at least 5 years after diagnosis. Clustering analysis of PF tumours revealed 42 samples with PFA signatures and 7 samples with PFB signatures. Clinical characteristics of patients with PFA and PFB ependymomas corroborated the previous findings. In conclusion, we confirm here that the NanoString method is a useful single tool for the diagnosis of all four main molecular groups of ependymoma. The differences in reported survival rates warrant further clinical investigation of patients with the ZFTA-RELA fusion., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)
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- 2021
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32. Gut Microbiome in Chronic Coronary Syndrome Patients.
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Sawicka-Smiarowska E, Bondarczuk K, Bauer W, Niemira M, Szalkowska A, Raczkowska J, Kwasniewski M, Tarasiuk E, Dubatowka M, Lapinska M, Szpakowicz M, Stachurska Z, Szpakowicz A, Sowa P, Raczkowski A, Kondraciuk M, Gierej M, Motyka J, Jamiolkowski J, Bondarczuk M, Chlabicz M, Bucko J, Kozuch M, Dobrzycki S, Bychowski J, Musial WJ, Godlewski A, Ciborowski M, Gyenesei A, Kretowski A, and Kaminski KA
- Abstract
Despite knowledge of classical coronary artery disease (CAD) risk factors, the morbidity and mortality associated with this disease remain high. Therefore, new factors that may affect the development of CAD, such as the gut microbiome, are extensively investigated. This study aimed to evaluate gut microbiome composition in CAD patients in relation to the control group. We examined 169 CAD patients and 166 people in the control group, without CAD, matched in terms of age and sex to the study group. Both populations underwent a detailed health assessment. The microbiome analysis was based on the V3-V4 region of the 16S rRNA gene (NGS method). Among 4074 identified taxonomic units in the whole population, 1070 differed between study groups. The most common bacterial types were Firmicutes , Bacteroidetes , Proteobacteria, and Actinobacteria . Furthermore, a higher Firmicutes/Bacteroidetes ratio in the CAD group compared with the control was demonstrated. Firmicutes/Bacteroidetes ratio, independent of age, sex, CAD status, LDL cholesterol concentration, and statins treatment, was related to altered phosphatidylcholine concentrations obtained in targeted metabolomics. Altered alpha-biodiversity (Kruskal-Wallis test, p = 0.001) and beta-biodiversity (Bray-Curtis metric, p < 0.001) in the CAD group were observed. Moreover, a predicted functional analysis revealed some taxonomic units, metabolic pathways, and proteins that might be characteristic of the CAD patients' microbiome, such as increased expressions of 6-phospho-β-glucosidase and protein-N(pi)-phosphohistidine-sugar phosphotransferase and decreased expressions of DNA topoisomerase, oxaloacetate decarboxylase, and 6-beta-glucosidase. In summary, CAD is associated with altered gut microbiome composition and function.
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- 2021
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33. Low Tumor-to-Stroma Ratio Reflects Protective Role of Stroma against Prostate Cancer Progression.
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Nastały P, Smentoch J, Popęda M, Martini E, Maiuri P, Żaczek AJ, Sowa M, Matuszewski M, Szade J, Kalinowski L, Niemira M, Brandt B, Eltze E, Semjonow A, and Bednarz-Knoll N
- Abstract
Tumor-to-stroma ratio (TSR) is a prognostic factor that expresses the relative amounts of tumor and intratumoral stroma. In this study, its clinical and molecular relevance was evaluated in prostate cancer (PCa). The feasibility of automated quantification was tested in digital scans of tissue microarrays containing 128 primary tumors from 72 PCa patients stained immunohistochemically for epithelial cell adhesion molecule (EpCAM), followed by validation in a cohort of 310 primary tumors from 209 PCa patients. In order to investigate the gene expression differences between tumors with low and high TSR, we applied multigene expression analysis (nCounter
® PanCancer Progression Panel, NanoString) of 42 tissue samples. TSR scores were categorized into low (<1 TSR) and high (≥1 TSR). In the pilot cohort, 31 patients (43.1%) were categorized as low and 41 (56.9%) as high TSR score, whereas 48 (23.0%) patients from the validation cohort were classified as low TSR and 161 (77.0%) as high. In both cohorts, high TSR appeared to indicate the shorter time to biochemical recurrence in PCa patients (Log-rank test, p = 0.04 and p = 0.01 for the pilot and validation cohort, respectively). Additionally, in the multivariate analysis of the validation cohort, TSR predicted BR independent of other factors, i.e., pT, pN, and age ( p = 0.04, HR 2.75, 95%CI 1.07-7.03). Our data revealed that tumors categorized into low and high TSR score show differential expression of various genes; the genes upregulated in tumors with low TSR score were mostly associated with extracellular matrix and cell adhesion regulation. Taken together, this study shows that high stroma content can play a protective role in PCa. Automatic EpCAM-based quantification of TSR might improve prognostication in personalized medicine for PCa.- Published
- 2021
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34. Aluminum or Low pH - Which Is the Bigger Enemy of Barley? Transcriptome Analysis of Barley Root Meristem Under Al and Low pH Stress.
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Szurman-Zubrzycka M, Chwiałkowska K, Niemira M, Kwaśniewski M, Nawrot M, Gajecka M, Larsen PB, and Szarejko I
- Abstract
Aluminum (Al) toxicity is considered to be the most harmful abiotic stress in acidic soils that today comprise more than 50% of the world's arable lands. Barley belongs to a group of crops that are most sensitive to Al in low pH soils. We present the RNA-seq analysis of root meristems of barley seedlings grown in hydroponics at optimal pH (6.0), low pH (4.0), and low pH with Al (10 μM of bioavailable Al
3+ ions). Two independent experiments were conducted: with short-term (24 h) and long-term (7 days) Al treatment. In the short-term experiment, more genes were differentially expressed (DEGs) between root meristems grown at pH = 6.0 and pH = 4.0, than between those grown at pH = 4.0 with and without Al treatment. The genes upregulated by low pH were associated mainly with response to oxidative stress, cell wall organization, and iron ion binding. Among genes upregulated by Al, overrepresented were those related to response to stress condition and calcium ion binding. In the long-term experiment, the number of DEGs between hydroponics at pH = 4.0 and 6.0 were lower than in the short-term experiment, which suggests that plants partially adapted to the low pH. Interestingly, 7 days Al treatment caused massive changes in the transcriptome profile. Over 4,000 genes were upregulated and almost 2,000 genes were downregulated by long-term Al stress. These DEGs were related to stress response, cell wall development and metal ion transport. Based on our results we can assume that both, Al3+ ions and low pH are harmful to barley plants. Additionally, we phenotyped the root system of barley seedlings grown in the same hydroponic conditions for 7 days at pH = 6.0, pH = 4.0, and pH = 4.0 with Al. The results correspond to transcriptomic data and show that low pH itself is a stress factor that causes a significant reduction of root growth and the addition of aluminum further increases this reduction. It should be noted that in acidic arable lands, plants are exposed simultaneously to both of these stresses. The presented transcriptome analysis may help to find potential targets for breeding barley plants that are more tolerant to such conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the authors MS-Z and IS., (Copyright © 2021 Szurman-Zubrzycka, Chwiałkowska, Niemira, Kwaśniewski, Nawrot, Gajecka, Larsen and Szarejko.)- Published
- 2021
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35. Recent Highlights of Research on miRNAs as Early Potential Biomarkers for Cardiovascular Complications of Type 2 Diabetes Mellitus.
- Author
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Bielska A, Niemira M, and Kretowski A
- Subjects
- Animals, Gene Expression Regulation, Humans, Prognosis, Transcription, Genetic, Biomarkers, Cardiovascular Diseases diagnosis, Cardiovascular Diseases etiology, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, MicroRNAs genetics
- Abstract
Type 2 diabetes mellitus (T2DM) and its complications pose a serious threat to the life and health of patients around the world. The most dangerous complications of this disease are vascular complications. Microvascular complications of T2DM include retinopathy, nephropathy, and neuropathy. In turn, macrovascular complications include coronary artery disease, peripheral artery disease, and cerebrovascular disease. The currently used diagnostic methods do not ensure detection of the disease at an early stage, and they also do not predict the risk of developing specific complications. MicroRNAs (miRNAs) are small, endogenous, noncoding molecules that are involved in key processes, such as cell proliferation, differentiation, and apoptosis. Recent research has assigned them an important role as potential biomarkers for detecting complications related to diabetes. We suggest that utilizing miRNAs can be a routine approach for early diagnosis and prognosis of diseases and may enable the development of better therapeutic approaches. In this paper, we conduct a review of the latest reports demonstrating the usefulness of miRNAs as biomarkers in the vascular complications of T2DM.
- Published
- 2021
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36. Reduced expression of innate immunity-related genes in lymph node metastases of luminal breast cancer patients.
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Popeda M, Markiewicz A, Stokowy T, Szade J, Niemira M, Kretowski A, Bednarz-Knoll N, and Zaczek AJ
- Subjects
- Biomarkers, Tumor genetics, Cohort Studies, Complement C3 genetics, Complement C3 metabolism, Female, Humans, Immunohistochemistry, Prognosis, Transcriptome, Breast Neoplasms pathology, Down-Regulation genetics, Gene Expression Regulation, Neoplastic, Genes immunology, Immunity, Innate genetics, Lymph Nodes pathology, Lymphatic Metastasis genetics
- Abstract
Immune system plays a dual role in cancer by either targeting or supporting neoplastic cells at various stages of disease, including metastasis. Yet, the exact immune-related transcriptome profiles of primary tumours (PT) and lymph node metastases (LNM) and their evolution during luminal breast cancer (BCa) dissemination remain undiscovered. In order to identify the immune-related transcriptome changes that accompany lymphatic spread, we analysed PT-LNM pairs of luminal BCa using NanoString technology. Decrease in complement C3-one of the top-downregulated genes, in LNM was validated at the protein level using immunohistochemistry. Thirty-three of 360 analysed genes were downregulated (9%), whereas only 3 (0.8%) upregulated in LNM when compared to the corresponding PT. In LNM, reduced expression was observed in genes related to innate immunity, particularly to the complement system (C1QB, C1S, C1R, C4B, CFB, C3, SERPING1 and C3AR1). In validation cohort, complement C3 protein was less frequently expressed in LNM than in PT and it was associated with worse prognosis. To conclude, local expression of the complement system components declines during lymphatic spread of non-metastatic luminal BCa, whilst further reduction of tumoral complement C3 in LNM is indicative for poor survival. This points to context-dependent role of complement C3 in BCa dissemination.
- Published
- 2021
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37. In search for interplay between stool microRNAs, microbiota and short chain fatty acids in Crohn's disease - a preliminary study.
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Ambrozkiewicz F, Karczmarski J, Kulecka M, Paziewska A, Niemira M, Zeber-Lubecka N, Zagorowicz E, Kretowski A, and Ostrowski J
- Subjects
- Fatty Acids, Volatile, Feces, Humans, RNA, Ribosomal, 16S genetics, Crohn Disease genetics, MicroRNAs, Microbiota
- Abstract
Background: Inflammatory bowel diseases are classic polygenic disorders, with genetic loads that reflect immunopathological processes in response to the intestinal microbiota. Herein we performed the multiomics analysis by combining the large scale surveys of gut bacterial community, stool microRNA (miRNA) and short chain fatty acid (SCFA) signatures to correlate their association with the activity of Crohn's disease (CD)., Methods: DNA, miRNA, and metabolites were extracted from stool samples of 15 CD patients, eight with active disease and seven in remission, and nine healthy individuals. Microbial, miRNA and SCFA profiles were assessed using datasets from 16S rRNA sequencing, Nanostring miRNA and GC-MS targeted analysis, respectively., Results: Pairwise comparisons showed that 9 and 23 taxa differed between controls and CD patients with active and inactive disease, respectively. Six taxa were common to both comparisons, whereas four taxa differed in CD patients. α-Diversity was lower in both CD groups than in controls. The levels of 13 miRNAs differed (p-value < 0.05; FC > 1.5) in CD patients and controls before FDR correction and 4 after. Of six SCFAs, the levels of two differed significantly (p-value < 0.05, FC > 1.5) in CD patients and controls, and the levels of four differed in patients with active and inactive CD. PLS-DA revealed models with smallest error rate for controls in bacterial component and inactive disease in metabolites., Conclusion: A complex interrelationship may exist between gut dysbiosis, miRNA profiling and SCFA level in response to intestinal inflammation.
- Published
- 2020
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38. Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA.
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Sidorkiewicz I, Jóźwik M, Niemira M, and Krętowski A
- Abstract
Endometrial cancer (EC) remains one of the most common cancers of the female reproductive system. Epidemiological and clinical data implicate insulin resistance (IR) and its accompanying hyperinsulinemia as key factors in the development of EC. MicroRNAs (miRNAs) are short molecules of non-coding endogenous RNA that function as post-transcriptional regulators. Accumulating evidence has shown that the miRNA expression pattern is also likely to be associated with EC risk factors. The aim of this work was the verification of the relationships between IR, EC, and miRNA, and, as based on the literature data, elucidation of miRNA's potential utility for EC prevention in IR patients. The pathways affected in IR relate to the insulin receptors, insulin-like growth factors and their receptors, insulin-like growth factor binding proteins, sex hormone-binding globulin, and estrogens. Herein, we present and discuss arguments for miRNAs as a plausible molecular link between IR and EC development. Specifically, our careful literature search indicated that dysregulation of at least 13 miRNAs has been ascribed to both conditions. We conclude that there is a reasonable possibility for miRNAs to become a predictive factor of future EC in IR patients.
- Published
- 2020
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39. microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers is Mainly Dependent on HER2 Status-A Pilot Study.
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Kunc M, Popęda M, Niemira M, Szałkowska A, Bieńkowski M, Pęksa R, Łacko A, Radecka BS, Braun M, Pikiel J, Litwiniuk M, Pogoda K, Iżycka-Świeszewska E, Krętowski A, Żaczek AJ, Biernat W, and Senkus-Konefka E
- Abstract
Estrogen (ER) and progesterone (PgR) receptors and HER2 are crucial in the assessment of breast cancer specimens due to their prognostic and predictive significance. Single hormone receptor-positive breast cancers are less common and their clinical course is less favorable than ER(+)/PgR(+) tumors. Their molecular features, especially microRNA (miRNA) profiles, have not been investigated to date. Tumor specimens from 36 chemonaive breast cancer patients with known ER and PgR status (18 ER(+)/PgR(-) and 18 ER(-)/PgR(+) cases) were enrolled to the study. The expression of 829 miRNAs was evaluated with nCounter Human v3 miRNA expression Assay (NanoString). miRNAs differentiating between ER/PgR/HER2 phenotypes were selected based on fold change (FC) calculated for the mean normalized counts of each probe in compared groups. The differences were estimated with Student's T -test or Two-Way ANOVA (considering also the HER2 status). The results were validated using The Cancer Genome Atlas (TCGA) dataset. Following quality control of raw data, fourcases were excluded due to low sample quality, leaving 14 ER(+)/PgR(-) and 18 ER(-)/PgR(+) cases. After correction for multiple comparisons, we did not find miRNA signature differentiating between ER(-)/PgR(+) and ER(+)/PgR(-) breast cancers. However, a trend for differing expression ( p -value ≤ 0.05; FDR > 0.2; ANOVA) in eight miRNAs was observed. The ER(+)/PgR(-) group demonstrated elevated levels of four miRNAs-miR-30a-5p, miR-29c-3p, miR-141-3p and miR-423-5p-while the ER(-)/PgR(+) tumors were enriched in another four miRNAs-miR-514b-5p, miR-424-5p, miR-495-3p, and miR-92a-3p. For one of the miRNAs-miR-29c-3p-the association with the ER(+)/PgR(-) phenotype was confirmed in the TCGA cohort ( p -value = 0.024; T -test). HER2 amplification/overexpression in the NanoString cohort was related to significant differences observed in 33 miRNA expression levels (FDR ≤ 0.2; ANOVA). The association with HER2 status was confirmed in the TCGA cohort for four miRNAs (miR-1180-3p, miR-223-3p, miR-30d-5p, and miR-195-5p). The main differences in miRNA expression amongst single hormone receptor-positive tumors were identified according to their HER2 status. However, ER(+)/PgR(-) cases tended to express higher levels of miRNAs associated with ER-positivity (miR-30a-5p, miR-29c-3p, miR-141-3p), whereas ER(-)/PgR(+) cancers showed elevated levels of miRNAs characteristic for double- and triple-negative tumors (miR-92a-3p, miR-424-5p). Further studies are necessary to comprehensively analyze miRNA signatures characteristic of ER(-)/PgR(+) and ER(+)/PgR(-) tumors.
- Published
- 2020
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40. Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells.
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Niemira M, Borowa-Mazgaj B, Bader SB, Moszyńska A, Ratajewski M, Karaś K, Kwaśniewski M, Krętowski A, Mazerska Z, Hammond EM, and Skwarska A
- Abstract
The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen ( PSA ) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa.
- Published
- 2020
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41. Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes.
- Author
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Łastowska M, Trubicka J, Sobocińska A, Wojtas B, Niemira M, Szałkowska A, Krętowski A, Karkucińska-Więckowska A, Kaleta M, Ejmont M, Perek-Polnik M, Dembowska-Bagińska B, Grajkowska W, and Matyja E
- Subjects
- Brain Neoplasms genetics, Child, Child, Preschool, Female, Forkhead Transcription Factors genetics, Humans, Infant, Male, Neoplasms, Neuroepithelial genetics, Neuroblastoma genetics, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Sarcoma, Ewing genetics, Trans-Activators genetics, Transcriptome, Tumor Suppressor Proteins genetics, Brain Neoplasms diagnosis, Gene Expression Profiling methods, Neoplasms, Neuroepithelial diagnosis, Neuroblastoma diagnosis, Sarcoma, Ewing diagnosis
- Abstract
Four molecular types of rare central nervous system (CNS) tumors have been recently identified by gene methylation profiling: CNS Neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing Sarcoma Family Tumor with CIC alteration (CNS EFT-CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Although they are not represented in 2016 updated WHO classification of CNS tumors, their diagnostic recognition is important because of clinical consequences. We have introduced a diagnostic method based on transcription profiling of tumor specific signature genes from formalin-fixed, paraffin-embedded tumor blocks using NanoString nCounter Technology. Altogether, 14 out of 187 (7.4%) high grade pediatric brain tumors were diagnosed with either of four new CNS categories. Histopathological examination of the tumors confirmed, that they demonstrate a spectrum of morphology mimicking other CNS high grade tumors. However, they also exhibit some suggestive histopathological and immunohistochemical features that allow for a presumptive diagnosis prior to molecular assessment. Clinical characteristics of patients corroborated with the previous findings for CNS EFT-CIC, CNS NB-FOXR2 and CNS HGNET-MN1 patients, with a favorable survival rate for the latter two groups. Among six CNS HGNET-BCOR patients, three patients are long term survivors, suggesting possible heterogeneity within this molecular category of tumors. In summary, we confirmed the effectiveness of NanoString method using a single, multi-gene tumor specific signature and recommend this novel approach for identification of either one of the four newly described CNS tumor entities.
- Published
- 2020
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42. Circulating miRNAs as a Predictive Biomarker of the Progression from Prediabetes to Diabetes: Outcomes of a 5-Year Prospective Observational Study.
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Sidorkiewicz I, Niemira M, Maliszewska K, Erol A, Bielska A, Szalkowska A, Adamska-Patruno E, Szczerbinski L, Gorska M, and Kretowski A
- Abstract
Due to a global increase in the prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need for early identification of prediabetes, as these people have the highest risk of developing diabetes. Circulating miRNAs have shown potential as progression biomarkers in other diseases. This study aimed to conduct a baseline comparison of serum-circulating miRNAs in prediabetic individuals, with the distinction between those who later progressed to T2DM and those who did not. The expression levels of 798 miRNAs using NanoString technology were examined. Spearman correlation, receiver operating characteristic (ROC) curve analysis, and logistic regression modeling were performed. Gene ontology (GO) and canonical pathway analysis were used to explore the biological functions of the miRNA target genes. The study revealed that three miRNAs were upregulated in the serum samples of patients who later progressed to T2DM. Pathway analysis showed that the miRNA target genes were mainly significantly enriched in neuronal NO synthase (nNOS) signaling in neurons, amyloid processing, and hepatic cholestasis. ROC analysis demonstrated that miR-491-5p, miR-1307-3p, and miR-298 can be introduced as a diagnostic tool for the prediction of T2DM (area under the curve (AUC) = 94.0%, 88.0%, and 84.0%, respectively). Validation by real-time quantitative polymerase chain reaction (qRT-PCR) confirmed our findings. The results suggest that circulating miRNAs can potentially be used as predictive biomarkers of T2DM in prediabetic patients.
- Published
- 2020
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43. Evaluation of Transcriptomic Regulations behind Metabolic Syndrome in Obese and Lean Subjects.
- Author
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Paczkowska-Abdulsalam M, Niemira M, Bielska A, Szałkowska A, Raczkowska BA, Junttila S, Gyenesei A, Adamska-Patruno E, Maliszewska K, Citko A, Szczerbiński Ł, and Krętowski A
- Subjects
- Adult, Biomarkers metabolism, Body Mass Index, Female, Humans, Male, Metabolic Syndrome genetics, Middle Aged, Obesity genetics, Gene Expression Profiling, Gene Expression Regulation, Metabolic Syndrome metabolism, Obesity metabolism, Transcriptome
- Abstract
Multiple mechanisms have been suggested to confer to the pathophysiology of metabolic syndrome (MetS), however despite great interest from the scientific community, the exact contribution of each of MetS risk factors still remains unclear. The present study aimed to investigate molecular signatures in peripheral blood of individuals affected by MetS and different degrees of obesity. Metabolic health of 1204 individuals from 1000PLUS cohort was assessed, and 32 subjects were recruited to four study groups: MetS lean, MetS obese, "healthy obese", and healthy lean. Whole-blood transcriptome next generation sequencing with functional data analysis were carried out. MetS obese and MetS lean study participants showed the upregulation of genes involved in inflammation and coagulation processes: granulocyte adhesion and diapedesis ( p < 0.0001, p = 0.0063), prothrombin activation pathway ( p = 0.0032, p = 0.0091), coagulation system ( p = 0.0010, p = 0.0155). The results for "healthy obese" indicate enrichment in molecules associated with protein synthesis ( p < 0.0001), mitochondrial dysfunction ( p < 0.0001), and oxidative phosphorylation ( p < 0.0001). Our results suggest that MetS is related to the state of inflammation and vascular system changes independent of excess body weight. Furthermore, "healthy obese", despite not fulfilling the criteria for MetS diagnosis, seems to display an intermediate state with a lower degree of metabolic abnormalities, before they proceed to a full blown MetS.
- Published
- 2020
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44. Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA).
- Author
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Niemira M, Collin F, Szalkowska A, Bielska A, Chwialkowska K, Reszec J, Niklinski J, Kwasniewski M, and Kretowski A
- Abstract
Non-small-cell lung cancer (NSCLC) represents a heterogeneous group of malignancies consisting essentially of adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although the diagnosis and treatment of ADC and SCC have been greatly improved in recent decades, there is still an urgent need to identify accurate transcriptome profile associated with the histological subtypes of NSCLC. The present study aims to identify the key dysregulated pathways and genes involved in the development of lung ADC and SCC and to relate them with the clinical traits. The transcriptional changes between tumour and normal lung tissues were investigated by RNA-seq. Gene ontology (GO), canonical pathways analysis with the prediction of upstream regulators, and weighted gene co-expression network analysis (WGCNA) to identify co-expressed modules and hub genes were used to explore the biological functions of the identified dysregulated genes. It was indicated that specific gene signatures differed significantly between ADC and SCC related to the distinct pathways. Of identified modules, four and two modules were the most related to clinical features in ADC and SCC, respectively. CTLA4 , MZB1 , NIP7 , and BUB1B in ADC, as well as GNG11 and CCNB2 in SCC, are novel top hub genes in modules associated with tumour size, SUV
max , and recurrence-free survival. Our research provides a more effective understanding of the importance of biological pathways and the relationships between major genes in NSCLC in the perspective of searching for new molecular targets., Competing Interests: The authors declare no conflicts of interest.- Published
- 2019
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45. NF-kappa B Signaling-Related Signatures Are Connected with the Mesenchymal Phenotype of Circulating Tumor Cells in Non-Metastatic Breast Cancer.
- Author
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Popeda M, Stokowy T, Bednarz-Knoll N, Jurek A, Niemira M, Bielska A, Kretowski A, Kalinowski L, Szade J, Markiewicz A, and Zaczek AJ
- Abstract
The role of circulating tumor cells (CTCs), tumor microenvironment (TME), and the immune system in the formation of metastasis is evident, yet the details of their interactions remain unknown. This study aimed at exploring the immunotranscriptome of primary tumors associated with the status of CTCs in breast cancer (BCa) patients. The expression of 730 immune-related genes in formalin-fixed paraffin-embedded samples was analyzed using the multigenomic NanoString technology and correlated with the presence and the phenotype of CTCs. Upregulation of 37 genes and downregulation of 1 gene were observed in patients characterized by a mesenchymal phenotype of CTCs when compared to patients with epithelial CTCs. The upregulated genes were involved in NF-kappa B signaling and in the production of type I interferons. The clinical significance of the differentially expressed genes was evaluated using The Cancer Genome Atlas (TCGA) data of a breast invasive carcinoma (BRCA) cohort. Five of the upregulated genes- PSMD7 , C2, IFNAR1 , CD84 , and CYLD -were independent prognostic factors in terms of overall and disease-free survival. To conclude, our data identify a group of genes that are upregulated in BCa patients with mesenchymal CTCs and reveal their prognostic potential, thus indicating that they merit further investigation.
- Published
- 2019
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46. Sex-Specific Glucose Homeostasis and Anthropometric Responses to Sleeve Gastrectomy in Obese Patients.
- Author
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Taylor MA, Szczerbinski L, Citko A, Niemira M, Gorska M, Hady HR, and Kretowski A
- Subjects
- Adult, Anthropometry, Blood Glucose analysis, Body Mass Index, Cohort Studies, Diabetes Mellitus blood, Fasting, Female, Glucose Tolerance Test, Humans, Longitudinal Studies, Male, Middle Aged, Obesity blood, Prospective Studies, Blood Glucose metabolism, Gastrectomy methods, Homeostasis, Obesity surgery, Sex Factors
- Abstract
Bariatric surgery rapidly and effectively treats obesity and its comorbidities like dysregulated glucose homeostasis. Despite the sex-balanced incidence of obesity in most human populations, women have sought this intervention more frequently than men. However, as the number of bariatric surgeries rapidly rises, it is increasingly urgent to understand how sex-specific differences may emerge in metabolic and anthropometric parameters. Hundred fifty-four obese patients (47% men and 53% women) from the Bialystok Bariatric Surgery Study underwent sleeve gastrectomy and were measured for 25 parameters at baseline (immediately prior to surgery) and at four follow-up visits over one year. We used generalized linear mixed models to detect sex-specific differences in the time series of responses parameters. Unlike most previous studies with older cross-sections of men than women, our cohort was age-matched, and men were less healthy at baseline. Of parameters that showed a significant cohort-wide (across-sex) response, 14 (56%) also showed sex-specific responses with men improving more than women. In particular, men remitted in diabetes symptoms more strongly, rapidly, and durably than women. Taken together, our results indicate that men may benefit more from sleeve gastrectomy and that this difference in improvement may be related to more progressed morbidity prior to surgery independent of age.
- Published
- 2019
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47. Efficacy of family history, genetic risk score, and physical activity in assessing the prevalence of type 2 diabetes.
- Author
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Szczerbiński Ł, Gościk J, Bauer W, Wawrusiewicz-Kurylonek N, Paczkowska-Abdulsalam M, Niemira M, Citko A, Adamska-Patruno E, Górska M, and Krętowski A
- Subjects
- Adult, Body Mass Index, Diabetes Mellitus, Type 2 epidemiology, Female, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Humans, Male, Middle Aged, Poland, Prevalence, Risk Factors, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 prevention & control, Exercise, Genetic Predisposition to Disease epidemiology
- Abstract
Introduction: Environmental and genetic factors play an important role in the development of type 2 diabetes (T2D). One of the most important lifestyle factors is a low level of physical activity (PA), but no studies have explicitly compared the amount of variation in diabetes prevalence explained by variation in PA compared with the amount explained by genetic variation., Objectives: We examined associations between PA and patients stratified by the levels of genetic susceptibility to T2D and the prevalence of the disease., Patients and Methods: We assessed the level of PA and family history (FH) of T2D in first‑degree relatives as well as calculated the genetic risk score (GRS). We examined associations of PA, GRS, and FH with the prevalence of T2D among 1195 individuals enrolled in the 1000 Polish Longitudinal University Study (1000‑PLUS) by stratifying the sample according to GRS, FH, and PA., Results: We found that FH, in contrast to GRS, was positively associated with a higher prevalence of T2D (23.4% in patients with positive FH [FH+], 11.6% in those with negative [FH-]; P <0.001), with the association being stronger in men than in women. The prevalence of T2D was slightly lower among physically active individuals in the FH- group (10.6% in high PA vs 14.7% in low PA) as well as in the FH+ group (19.2% in high PA vs 34.0% in low PA), but the differences were not significant. Similar results were found for high and low GRSs., Conclusions: We confirmed that PA is significantly associated with glucose homeostasis parameters and T2D prevalence, and that this association may be stronger in individuals who are more genetically predisposed to diabetes.
- Published
- 2019
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48. Novel Approaches in Ovarian Cancer Research against Heterogeneity, Late Diagnosis, Drug Resistance, and Transcoelomic Metastases.
- Author
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Erol A, Niemira M, and Krętowski AJ
- Subjects
- Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Female, Humans, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Drug Resistance, Neoplasm genetics, Early Detection of Cancer methods, Genomics methods, Ovarian Neoplasms genetics
- Abstract
The development of modern technologies has revolutionised science and has had a huge impact on biomedical studies. This review focuses on possible tools that scientists can use to face the challenges of fighting ovarian cancer. Ovarian cancer is the deadliest gynaecologic malignancy and, even after years of study, the mortality has not decreased significantly. In the era of sequencing and personalised and precision medicine, we are now closer than ever to helping patients and physicians in regard to treatment and diagnosis of this disease. This work summarises the newest findings in the development of ovarian cancer research.
- Published
- 2019
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49. Prenatal circulating microRNA signatures of foetal Down syndrome.
- Author
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Zbucka-Kretowska M, Niemira M, Paczkowska-Abdulsalam M, Bielska A, Szalkowska A, Parfieniuk E, Ciborowski M, Wolczynski S, and Kretowski A
- Subjects
- Adult, Biomarkers metabolism, Down-Regulation, Female, Gene Expression Profiling methods, Humans, Pregnancy, Up-Regulation, Amniocentesis, Amniotic Fluid metabolism, Circulating MicroRNA metabolism, Down Syndrome diagnosis
- Abstract
The altered expression pattern of miRNAs might potentially reflect anomalies related to foetal chromosomal aberrations. The aim of the study was to determine the expression level of miRNAs in plasma of pregnant women with foetal Down syndrome (DS). Out of 198 amniocentesis performed at 15-18 weeks of gestation, within a group of 12 patients with foetal DS and 12 patients with uncomplicated pregnancies, who delivered healthy newborns at term, we examined the expression level of 800 miRNAs using the NanoString technology. Our study revealed that there are 6 miRNAs were upregulated (hsa-miR-15a, hsa-let-7d, hsa-miR-142, hsa-miR-23a, hsa-miR-199, hsa-miR-191) and 7 were downregulated (hsa-miR-1290, hsa-miR-1915, hsa-miR30e, hsa-miR-1260, hsa-miR-483, hsa-miR-548, hsa-miR-590) in plasma samples of women with foetal DS syndrome. The genes regulated by identified miRNAs are involved in central nervous system development, congenital abnormalities and heart defects. The results of the present study yielded information on DS-specific miRNA expression signature, which can further help to design a panel of miRNAs as a non-invasive test for DS diagnosis. We believe that identified miRNAs may attend in the pathogenesis of DS and would potentially make a significant role for the future preventive therapies.
- Published
- 2019
- Full Text
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50. Maternal plasma metabolic fingerprint indicative for fetal Down syndrome.
- Author
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Parfieniuk E, Samczuk P, Kowalczyk T, Pietrowska K, Niemira M, Paczkowska-Abdulsalam M, Wolczynski S, Kretowski A, Ciborowski M, and Zbucka-Kretowska M
- Subjects
- Adult, Case-Control Studies, Female, Humans, Pregnancy, Down Syndrome, Fetal Diseases metabolism, Metabolome, Plasma metabolism
- Abstract
Objective: The objective of the study was to perform maternal plasma metabolic fingerprinting to evaluate differences in plasma metabolites between healthy and Down syndrome (DS) pregnancies and to indicate novel non-invasive markers for DS prenatal diagnostics., Methods: This was a case-control study of pregnancies between 15th and 18th gestational week. LC-MS-based metabolic fingerprinting of plasma samples was performed., Results: Levels of five metabolites were significantly lower in the plasma of DS pregnancies. The majority of the statistically significant metabolites may be connected with fetal brain and central nervous system development (eg, fatty acid amides). According to the receiver operating characteristic (ROC), the combination of linoleamide and piperine has the highest diagnostic potential: area under the curve (AUC) = 0.878, sensitivity of 100%, and specificity of 73.3%., Conclusions: The study indicates disturbances in maternal metabolic pathways evoked by fetal DS. Novel potential maternal plasma metabolomic markers for non-invasive prenatal diagnostics of fetal DS are proposed., (© 2018 John Wiley & Sons, Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
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