Publications by authors named "Radzislaw Kordek"

125 Publications

New Class of Anti-Inflammatory Therapeutics Based on Gold (III) Complexes in Intestinal Inflammation-Proof of Concept Based on In Vitro and In Vivo Studies.

Int J Mol Sci 2021 Mar 18;22(6). Epub 2021 Mar 18.

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland.

Inflammatory bowel diseases (IBD) are at the top of the worldwide rankings for gastrointestinal diseases as regards occurrence, yet efficient and side-effect-free treatments are currently unavailable. In the current study, we proposed a new concept for anti-inflammatory treatment based on gold (III) complexes. A new gold (III) complex TGS 121 was designed and screened in the in vitro studies using a mouse macrophage cell line, RAW264.7, and in vivo, in the dextran sulphate sodium (DSS)-induced mouse model of colitis. Physicochemical studies showed that TGS 121 was highly water-soluble; it was stable in water, blood, and lymph, and impervious to sunlight. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, the complex showed a potent anti-inflammatory profile, as evidenced in neutral red uptake and Griess tests. In the DSS-induced mouse model of colitis, the complex administered in two doses (1.68 μg/kg, intragastrically, and 16.8 μg/kg, intragastrically, once daily) produced a significant (* < 0.05) anti-inflammatory effect, as shown by macroscopic score. The mechanism of action of TGS 121 was related to the enzymatic and non-enzymatic antioxidant system; moreover, TGS 121 induced changes in the tight junction complexes expression in the intestinal wall. This is the first study proving that gold (III) complexes may have therapeutic potential in the treatment of IBD.
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http://dx.doi.org/10.3390/ijms22063121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003307PMC
March 2021

Assessment of the Role of Selected and Genes Polymorphisms in the Development of Colorectal Cancer: Preliminary Research.

Pharmgenomics Pers Med 2021 29;14:167-178. Epub 2021 Jan 29.

Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Interfaculty Cathedral of Laboratory and Molecular Diagnostics, Medical University of Lodz, Lodz 90-151, Poland.

Background: Colon cancer is one of the most common types of malignant tumor worldwide. The molecular mechanism of colorectal carcinogenesis is very complex and not yet fully understood. The TGFβ (transforming growth factor β) signaling pathway plays a significant role in the development of many cancers, including colorectal cancer pathogenesis. Changes in TGFβ pathway are associated with increased colorectal cancer risk, because this pathway participates in the control of important cellular processes such as cell growth, proliferation, differentiation, or apoptosis. The family of SMAD (similar to mother against decapentaplegic) proteins is closely correlated to this pathway. genes expression affects modulation of the transcription of many genes, which leads to the inhibition of cell-growth and apoptosis in colon epithelial cells. The presence of SNPs (single nucleotide polymorphisms) in genes encoding proteins involved in the control of biological processes important for the cell may play a significant role in the predisposition to the development of colorectal cancer, or in the regulation of the severity of changes related to tumor growth. Extension of data in this field may provide clinically significant conclusions influencing the implementation of personalized treatment based on specific changes characteristic of a patient with colorectal cancer.

Purpose: The subject of this research was genotyping polymorphisms of (rs6494629) and (rs10502913, rs12968012, rs1057520801) genes in the group of patients with colorectal cancer and in the control group, and comparing the genotypic frequency distributions with clinical-pathological features within the study group and between the groups.

Materials And Methods: SNP genotyping analysis was performed on genomic DNA isolated from 84 frozen tissue sections of colorectal cancer and from 60 peripheral blood samples of patients without cancer. To evaluate the polymorphic variants of SMAD genes, the restricted fragment length of a polymorphism reaction (PCR-RFLP) was used.

Results: The results obtained in the study showed no significant association between the examined polymorphisms and the risk of developing colorectal cancer.

Conclusion: More extensive studies to confirm the results obtained in this study are needed. Further studies on a larger study group divided according to the clinical stage and histological differentiation may allow finding or excluding the significance of the studied SNPs as potential markers of colorectal cancer in relation to the clinico-pathological data.
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http://dx.doi.org/10.2147/PGPM.S281958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853629PMC
January 2021

A 'Real-Life' Experience on Automated Digital Image Analysis of FGFR2 Immunohistochemistry in Breast Cancer.

Diagnostics (Basel) 2020 Dec 7;10(12). Epub 2020 Dec 7.

Department of Pathology, Chair of Oncology, Medical University of Lodz, 92-213 Lodz, Poland.

We present here an assessment of a 'real-life' value of automated machine learning algorithm (AI) for examination of immunohistochemistry for fibroblast growth factor receptor-2 (FGFR2) in breast cancer (BC). Expression of FGFR2 in BC ( = 315) measured using a certified 3DHistech CaseViewer/QuantCenter software 2.3.0. was compared to the manual pathologic assessment in digital slides (PA). Results revealed: (i) substantial interrater agreement between AI and PA for dichotomized evaluation (Cohen's kappa = 0.61); (ii) strong correlation between AI and PA H-scores (Spearman r = 0.85, < 0.001); (iii) a small constant error and a significant proportional error (Passing-Bablok regression y = 0.51 × X + 29.9, < 0.001); (iv) discrepancies in H-score in cases of extreme (strongest/weakest) or heterogeneous FGFR2 expression and poor tissue quality. The time of AI was significantly longer (568 h) than that of the pathologist (32 h). This study shows that the described commercial machine learning algorithm can reliably execute a routine pathologic assessment, however, in some instances, human expertise is essential.
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http://dx.doi.org/10.3390/diagnostics10121060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762292PMC
December 2020

Anti-inflammatory and antibacterial effects of human cathelicidin active fragment KR-12 in the mouse models of colitis: a novel potential therapy of inflammatory bowel diseases.

Pharmacol Rep 2021 Feb 21;73(1):163-171. Epub 2020 Nov 21.

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.

Introduction: Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal tract disorders with complex etiology, with intestinal dysbiosis as the most prominent factor. In this study, we assessed the anti-inflammatory and antibacterial actions of the human cathelicidin LL-37 and its shortest active fragment, KR-12 in the mouse models of colitis.

Materials And Methods: Mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and dextran sulfate sodium (DSS) were used in the study. The extent of inflammation was evaluated based on the macro- and microscopic scores, quantification of myeloperoxidase (MPO) activity and microbiological analysis of stool samples.

Results: A preliminary study with LL-37 and KR-12 (1 mg/kg, ip, twice daily) showed a decrease in macroscopic and ulcer scores in the acute TNBS-induced model of colitis. We observed that KR-12 (5 mg/kg, ip, twice daily) reduced microscopic and ulcer scores in the semi-chronic and chronic TNBS-induced models of colitis compared with inflamed mice. Furthermore, qualitative and quantitative changes in colonic microbiota were observed: KR-12 (5 mg/kg, ip, twice daily) decreased the overall number of bacteria, Escherichia coli and coli group bacteria. In the semi-chronic DSS-induced model, KR-12 attenuated intestinal inflammation as demonstrated by a reduction in macroscopic score and colon damage score and MPO activity.

Conclusions: We demonstrated that KR-12 alleviates inflammation in four different mouse models of colitis what suggests KR-12 and cathelicidins as a whole are worth being considered as a potential therapeutic option in the treatment of IBD.
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http://dx.doi.org/10.1007/s43440-020-00190-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862075PMC
February 2021

Novel selective agonist of GPR18, PSB-KK-1415 exerts potent anti-inflammatory and anti-nociceptive activities in animal models of intestinal inflammation and inflammatory pain.

Neurogastroenterol Motil 2021 03 14;33(3):e14003. Epub 2020 Oct 14.

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.

Background: GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and inflammatory pain.

Methods: The anti-inflammatory activity of selective GPR18 agonist, PSB-KK-1415, and antagonist, PSB-CB5, was characterized in semi-chronic and chronic mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor-α (TNF-α) and interleukin-6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real-time PCR. The anti-nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain.

Key Results: In semi-chronic colitis, PSB-KK-1415 reduced macroscopic score (1.79 ± 0.22 vs. 2.61 ± 0.48), expression of TNF-α (1.89 ± 0.36 vs. 2.83 ± 0.64), and microscopic score (5.00 ± 0.33 vs. 6.45 ± 0.40), all compared to mice with colitis. In chronic colitis, PSB-KK-1415 decreased macroscopic score (3.33 ± 1.26 vs. 4.00 ± 1.32) and MPO activity (32.23 ± 8.51 vs. 41.33 ± 11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB-KK-1415 decreased the number of pain-induced behaviors in both, controls (32.60 ± 2.54 vs. 58.00 ± 6.24) and inflamed mice (60.83 ± 2.85 vs. 85.00 ± 5.77) compared to animals without treatment with PSB-KK-1415 (P < 0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77 ± 1.46 vs. 2.38 ± 0.66, p = 0.87).

Conclusions & Inferences: We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.
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http://dx.doi.org/10.1111/nmo.14003DOI Listing
March 2021

Upregulation of HIF1-α via an NF-κB/COX2 pathway confers proliferative dominance of HER2-negative ductal carcinoma in situ cells in response to inflammatory stimuli.

Neoplasia 2020 11 25;22(11):576-589. Epub 2020 Sep 25.

Department of Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland. Electronic address:

There are data to suggest that some ductal carcinoma in situ (DCIS) may evolve through an evolutionary bottleneck, where minor clones susceptible to the imposed selective pressure drive disease progression. Here, we tested the hypothesis that an impact of the inflammatory environment on DCIS evolution is HER2-dependent, conferring proliferative dominance of HER2-negative cells. In tissue samples, density of tumour-infiltrating immune cells (TIICs) was associated only with high tumour nuclear grade, but in 9% of predominantly HER2-negative cases, the presence of tumoral foci ('hot-spots') of basal-like cells with HIF1-α activity adjacent to the areas of dense stromal infiltration was noted. Results of in vitro analyses further demonstrated that IL-1β and TNF-α as well as macrophage-conditioned medium triggered phosphorylation of NF-κB and subsequent upregulation of COX2 and HIF1-α, exclusively in HER2-negative cells. Treatment with both IL-1β and TNF-α resulted in growth stimulation and inhibition of HER2-negative and HER2-positive cells, respectively. Moreover, ectopic overexpression of HIF1-α rescued HER2-positive cells from the negative effect of IL-1β and TNF-α on cell growth. Our data provide novel insight into the molecular basis of HER2-dependent proliferation of DCIS cells and indicate the NF-κB/COX2 → HIF1-α signalling axis as a dominant mechanism of DCIS evolution induced by inflammatory microenvironment. Presented findings also highlight the clinical significance of heterogeneity of DCIS tumours and suggest that HIF1-α might be considered as a predictive marker of disease progression.
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http://dx.doi.org/10.1016/j.neo.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522292PMC
November 2020

Hormonal Receptor Status Determines Prognostic Significance of FGFR2 in Invasive Breast Carcinoma.

Cancers (Basel) 2020 Sep 22;12(9). Epub 2020 Sep 22.

Department of Pathology, Chair of Oncology, Medical University of Lodz, 92-213 Lodz, Poland.

Interaction between fibroblast growth factor receptor 2 (FGFR2) and estrogen/progesterone receptors (ER/PR) affects resistance to anti-ER therapies, however the prognostic value of FGFR2 in breast cancer (BCa) remains largely unexplored. We have recently showed in vitro that FGFR2-mediated signaling alters PR activity and response to anti-ER treatment. Herein, prognostic significance of FGFR2 in BCa was evaluated in relation to both ER/PR protein status and a molecular signature designed to reflect PR transcriptional activity. FGFR2 was examined in 353 BCa cases using immunohistochemistry and Nanostring-based RNA quantification. FGFR2 expression was higher in ER+PR+ and ER+PR- compared to ER-PR- cases ( < 0.001). Low FGFR2 was associated with higher grade ( < 0.001), higher Ki67 proliferation index ( < 0.001), and worse overall and disease-free survival (HR = 2.34 (95% CI: 1.26-4.34), = 0.007 and HR = 2.22 (95% CI: 1.25-3.93), = 0.006, respectively). The poor prognostic value of low FGFR2 was apparent in ER+PR+, but not in ER+PR- patients, and it did not depend on the expression level of PR-dependent genes. Despite the functional link between FGFR2 and ER/PR revealed by preclinical studies, the data showed a link between FGFR2 expression and poor prognosis in BCa patients.
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http://dx.doi.org/10.3390/cancers12092713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564845PMC
September 2020

Cyclic derivative of morphiceptin Dmt-cyclo-(D-Lys-Phe-D-Pro-Asp)-NH2(P-317), a mixed agonist of MOP and KOP opioid receptors, exerts anti-inflammatory and anti-tumor activity in colitis and colitis-associated colorectal cancer in mice.

Eur J Pharmacol 2020 Oct 22;885:173463. Epub 2020 Aug 22.

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. Electronic address:

Endogenous opioid system is involved in the maintenance of the intestinal homeostasis. Recently, we proved that stimulation of opioid receptors using P-317, a cyclic morphiceptin analog, resulted in the alleviation of acute colitis in mice. The aim of the current study was to assess the effect of P-317 during colitis and colitis-associated colorectal cancer in mice. Colitis was induced by addition of dextran sodium sulfate (DSS) into drinking water. Colitis-associated colorectal cancer was induced by a single intraperitoneal injection of azoxymethane (AOM) and subsequent addition of DSS into drinking water (week 2, 5, 8). During macroscopic damage evaluation the samples were collected and used for biochemical (MPO activity assay), molecular (qPCR and western blot) and histological studies. In experimental colitis, P-317 induced an anti-inflammatory response as indicated by macroscopic and microscopic scores. In the colitis-associated colorectal cancer model, a significant difference in colorectal tumor development was observed between vehicle- and P-317-treated mice. P-317 decreased the total number of colonic tumors and inhibited MPO activity. Hematoxylin and eosin staining confirmed anti-tumor activity of P-317. The expression of TNF-α was decreased in P-317-treated mice as compared to the vehicle-treated group. P-317 decreased proliferation as well as β-catenin expression in tumors. P-317, a mixed MOP and KOP receptor agonist, induced an anti-inflammatory response in experimental colitis and decreased tumor development in colitis-associated colorectal cancer in mice.
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http://dx.doi.org/10.1016/j.ejphar.2020.173463DOI Listing
October 2020

Walnut Oil Alleviates Intestinal Inflammation and Restores Intestinal Barrier Function in Mice.

Nutrients 2020 May 2;12(5). Epub 2020 May 2.

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland.

Ulcerative colitis belongs to inflammatory bowel diseases, which is a group of chronic disorders of the gastrointestinal tract. It is a debilitating condition with a wide range of symptoms including rectal bleeding, diarrhea, and visceral pain. Current dietary habits often lead to imbalance in n-6/n-3 polyunsaturated fatty acids (PUFA) in favor of n-6 PUFA. Recent data showed the potential anti-inflammatory advantage of n-3 PUFA. Walnut oil (WO) is rich in those fatty acids and mainly consists of linoleic and linolenic acids that may act via free fatty acids receptors (FFARs). We assessed the anti-inflammatory effect of WO in the mouse model of dextran sulfate sodium (DSS)-induced colitis. Moreover, we examined changes in the expression of tight junction proteins (TJ), pro-inflammatory cytokines, and FFAR proteins in the inflamed mouse colon. WO improves the damage score in inflamed tissue, significantly restoring ion transport and colonic wall permeability. Inflammation caused changes in TJ, FFAR, and pro-inflammatory gene proteins expression, which WO was able to partially reverse. WO has anti-inflammatory properties; however, its exact mechanism of action remains unclear. This stems from the pleiotropic effects of n-3 PUFA ligands associated with receptor distribution and targeted signaling pathways.
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http://dx.doi.org/10.3390/nu12051302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284466PMC
May 2020

Benign-looking primary fibrosarcoma of the uterus.

Pol J Pathol 2019 ;70(2):148-152

Department of Pathology, Chair of Oncology, Medical University of Lodz, Poland.

Fibrosarcomas are placed among the most infrequent malignant tumors of the uterus. We present a case of a 38 years-old woman, whose benign looking uterine mass was primary diagnosed as a sclerosing leiomyoma. However, the tumor relapsed in two years with multisite metastases in the abdomen. The complex differential diagnosis excluded the most common mesenchymal tumors of the gynecological tract. Finally, we diagnosed the tumor as an epithelioid sclerosing fibrosarcoma arising from the uterine.
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http://dx.doi.org/10.5114/pjp.2019.87108DOI Listing
October 2019

A large single-institution retrospective analysis of aggressive B-cell lymphomas according to the 2016/2017 WHO classification.

Adv Clin Exp Med 2019 Oct;28(10):1359-1365

Department of Pathology, Chair of Oncology, Medical University of Lodz, Poland.

Background: High-grade B-cell lymphomas (HGBLs) comprise a new entity in the revised 2016/2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. The diagnosis of HGBL encompasses histopathology and immunohistochemistry, with additional molecular examination of the BCL2/MYC or BCL6/MYC rearrangement status.

Objectives: The aim of the study was to summarize our experience in the histopathological and immunohistochemical diagnosis of patients with aggressive B-cell lymphomas according to the revised 2016/2017 WHO classifications.

Material And Methods: We reviewed our single-institution experience with accurate diagnoses of HGBL and diffuse large B-cell lymphoma (DLBCL) using the available histopathological and immunohistochemical tools. The timeframe was from January 1, 2017 to April 18, 2018.

Results: Out of 265 patients, 217 (81.9%) were diagnosed with DLBCL, 43 (16.2%) with HGBL/DLBCL and 5 (1.9%) with not otherwise specified HGBL (HGBL-NOS). Regarding concurrent expression of MYC and BCL2 and/or BCL6 (double expressors (DE) and triple expressors (TE)), more DE and TE cases were found in the HGBL/DLBCL group than in the DLBCL group (25.53% vs 8.47%, p < 0.001, for DE cases and 55.32% vs 6.21%, p < 0.001, for TE cases). All 48 (100.00%) of the HGBL-NOS and HGBL/DLBCL patients, and 26 (11.98%) of the DLBCL-DE/TE cases were recommended for molecular analysis.

Conclusions: Our findings show that a comprehensive histopathological and immunohistochemical examination may identify potential HGBL cases. This study emphasizes the need to introduce a suitable molecular examination for patients with HGBL morphology and/or double/triple expression of BCL2/BCL6/MYC proteins.
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http://dx.doi.org/10.17219/acem/109200DOI Listing
October 2019

Ossifying fasciitis at an extraordinary site - a case report and analysis of diagnostic pitfalls.

Contemp Oncol (Pozn) 2019 13;23(2):121-125. Epub 2019 Jun 13.

Department of Pathology, Chair of Oncology, Medical University of Lodz, Poland.

Ossifying fasciitis is a very rare disease of reactive character; however, it can mimic malignant lesions, especially osteosarcoma. We report a case of a 30-year-old woman, who experienced a rapidly growing painful lesion of the left knee joint, preceded by a trauma. The tumor was resected, and the histopathological image suggested a malignant lesion with features of an osteosarcoma. A detailed correlation with a clinicopathological and radiological analysis led to the final diagnosis of ossifying fasciitis at an extraordinary site of patellar retinaculum. Our case shows that the close similarity between ossifying fasciitis and osteosarcoma may be challenging.
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http://dx.doi.org/10.5114/wo.2019.85884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630396PMC
June 2019

Analysis of Human Colon by Raman Spectroscopy and Imaging-Elucidation of Biochemical Changes in Carcinogenesis.

Int J Mol Sci 2019 Jul 10;20(14). Epub 2019 Jul 10.

Laboratory of Laser Molecular Spectroscopy, Institute of Applied Radiation Chemistry, Lodz University of Technology, Wroblewskiego 15, 93-590 Lodz, Poland.

Noninvasive Raman imaging of non-fixed and unstained human colon tissues based on vibrational properties of noncancerous and cancerous samples can effectively enable the differentiation between noncancerous and tumor tissues. This work aimed to evaluate the biochemical characteristics of colon cancer and the clinical merits of multivariate Raman image and spectroscopy analysis. Tissue samples were collected during routine surgery. The non-fixed, fresh samples were used to prepare micrometer sections from the tumor mass and the tissue from the safety margins outside of the tumor mass. Adjacent sections were used for typical histological analysis. We have found that the chemical composition identified by Raman spectroscopy of the cancerous and the noncancerous colon samples is sufficiently different to distinguish pathologically changed tissue from noncancerous tissue. We present a detailed analysis of Raman spectra for the human noncancerous and cancerous colon tissue. The multivariate analysis of the intensities of lipids/proteins/carotenoids Raman peaks shows that these classes of compounds can statistically divide analyzed samples into noncancerous and pathological groups, reaffirming that Raman imaging is a powerful technique for the histochemical analysis of human tissues. Raman biomarkers based on ratios for lipids/proteins/carotenoids content were found to be the most useful biomarkers in spectroscopic diagnostics.
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http://dx.doi.org/10.3390/ijms20143398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679107PMC
July 2019

FGFs/FGFRs-dependent signalling in regulation of steroid hormone receptors - implications for therapy of luminal breast cancer.

J Exp Clin Cancer Res 2019 May 29;38(1):230. Epub 2019 May 29.

Department of Pathology, Chair of Oncology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland.

Stromal stimuli mediated by growth factor receptors, leading to ligand-independent activation of steroid hormone receptors, have long been implicated in development of breast cancer resistance to endocrine therapy. Mutations in fibroblast growth factor receptor (FGFR) genes have been associated with a higher incidence and progression of breast cancer. Increasing evidence suggests that FGFR-mediated interaction between luminal invasive ductal breast carcinoma (IDC) and its microenvironment contributes to the progression to hormone-independence. Therapeutic strategies based on FGFR inhibitors hold promise for overcoming resistance to the ER-targeting treatment. A series of excellent reviews discuss a potential role of FGFR in development of IDC. Here, we provide a concise updated summary of existing literature on FGFR-mediated signalling with an emphasis on an interaction between FGFR and estrogen/progesterone receptors (ER/PR) in IDC. Focusing on the regulatory role of tumour microenvironment in the activity of steroid hormone receptors, we compile the available functional data on FGFRs-mediated signalling, as a fundamental mechanism of luminal IDC progression and failure of anti-ER treatment. We also highlight the translational value of the presented findings and summarize ongoing oncologic clinical trials investigating FGFRs inhibition in interventional studies in breast cancer.
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http://dx.doi.org/10.1186/s13046-019-1236-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542018PMC
May 2019

G protein-coupled estrogen receptor mediates anti-inflammatory action in Crohn's disease.

Sci Rep 2019 05 1;9(1):6749. Epub 2019 May 1.

Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236, Lodz, Poland.

Estrogens exert immunomodulatory action in many autoimmune diseases. Accumulating evidence highlights the meaningful impact of estrogen receptors in physiology and pathophysiology of the colon. However, the significance of G protein-coupled estrogen receptor (GPER) on Crohn's disease (CD), one of the inflammatory bowel disease (IBD) types, is still elusive. Our study revealed GPER overexpression at the mRNA and protein levels in patients with CD. To evaluate the effects of GPER activation/inhibition on colitis development, a murine 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced model of CD was used. We showed that activation of GPER reduces mortality, improves macroscopic and microscopic scores and lowers C-reactive protein (CRP) level. The impact of estrogen signaling on the suppression of the intestinal inflammation was proved by immunohistochemistry. It was demonstrated that GPER activation is accompanied by modulation of extracellular-signal regulated kinase (ERK) signaling pathway and expression level of genes involved in signal transmission and immune response as well as the expression of some microRNAs (miR-145, miR-148-5p and miR-592). Our study revealed that the membrane-bound estrogen receptor GPER mediates anti-inflammatory action and seems to be a potent therapeutic target in maintaining remission in CD.
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http://dx.doi.org/10.1038/s41598-019-43233-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494840PMC
May 2019

MiR-21, miR-34a, miR-125b, miR-181d and miR-648 levels inversely correlate with MGMT and TP53 expression in primary glioblastoma patients.

Arch Med Sci 2019 Mar 31;15(2):504-512. Epub 2017 Jul 31.

Department of Genetics, Chair of Molecular Medicine, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland.

Introduction: and alterations play a crucial role in glioblastoma (GB) pathogenesis. and function is affected by several pathologic mechanisms, such as point mutations or promoter methylation, which are well characterized. Expression of both genes can be regulated by other mechanisms as well, e.g., microRNAs (miRNAs). Moreover, cross-talk among various pathologic processes may occur, further affecting and functionality.

Material And Methods: In 49 GB patients, we analyzed the possible associations between and its miRNA regulators , , and , as well as and its miRNA regulators and . We evaluated the possible influence of mutational and methylation status on the pre-identified associations.

Results: In patients with immunohistochemistry-detected overexpression, expression levels of and were negatively correlated ( = -0.56, = 0.0195), and in patients with mutations, expression levels of and were negatively correlated ( = -0.67, = 0.0330). In patients with methylation, expression levels of were negatively correlated with and expression levels ( = -0.61, = 0.0269 and = -0.34, = 0.0727, respectively).

Conclusions: Our findings demonstrate that selected miRNAs are significantly correlated with and levels, but the extent of this correlation differs regarding the and mutational and promoter methylation status.
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http://dx.doi.org/10.5114/aoms.2017.69374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425218PMC
March 2019

Forms of diagnostic material as sources of miRNA biomarkers in hepatocellular carcinoma: a preliminary study.

Biomark Med 2019 05 11;13(7):523-534. Epub 2019 Mar 11.

Department of Medical Biochemistry, Medical University of Lodz, Mazowiecka Street 6/8 92-215 Lodz, Poland.

To assess the diagnostic value of selected miRNAs from various material collected from hepatocellular carcinoma (HCC) patients. Tissue, serum, urine and fecal samples from HCC patients and healthy individuals were screened for associated miRNAs using microarray analysis; the selected miRNAs were then validated by real time-quantitative PCR on 65 patients. Serum miR-122, a combination of serum miR-155 with miR-885-5p, a combination of urinary miR-532-3p with miR-765, and fecal miR-320a displayed 100% efficiency in discriminating patients from controls. A combination of urinary miR-532-3p and miR-765 allowed patients with neoplastic grade G3 to be distinguished from those with G1 and G2. Additionally to serum, urine and feces also appeared to be valuable source of potential HCC noninvasive miRNA biomarkers.
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http://dx.doi.org/10.2217/bmm-2018-0485DOI Listing
May 2019

Profiling of Invasive Breast Carcinoma Circulating Tumour Cells-Are We Ready for the 'Liquid' Revolution?

Cancers (Basel) 2019 Jan 25;11(2). Epub 2019 Jan 25.

Department of Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland.

As dissemination through blood and lymph is the critical step of the metastatic cascade, circulating tumour cells (CTCs) have attracted wide attention as a potential surrogate marker to monitor progression into metastatic disease and response to therapy. In patients with invasive breast carcinoma (IBC), CTCs are being considered nowadays as a valid counterpart for the assessment of known prognostic and predictive factors. Molecular characterization of CTCs using protein detection, genomic and transcriptomic panels allows to depict IBC biology. Such molecular profiling of circulating cells with increased metastatic abilities appears to be essential, especially after tumour resection, as well as in advanced disseminated disease, when information crucial for identification of therapeutic targets becomes unobtainable from the primary site. If CTCs are truly representative of primary tumours and metastases, characterization of the molecular profile of this easily accessible 'biopsy' might be of prime importance for clinical practice in IBC patients. This review summarizes available data on feasibility and documented benefits of monitoring of essential IBC biological features in CTCs, with special reference to multifactorial proteomic, genomic, and transcriptomic panels of known prognostic or predictive value.
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http://dx.doi.org/10.3390/cancers11020143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406427PMC
January 2019

Tetraspanin CD151 impairs heterodimerization of ErbB2/ErbB3 in breast cancer cells.

Transl Res 2019 05 28;207:44-55. Epub 2018 Dec 28.

Department of Pathology, Medical University of Lodz, Lodz, Poland. Electronic address:

CD151/Tspan24 (SFS-1, PETA3) is one of the best characterized members of the tetraspanin family, whose involvement in breast cancer (BCa) progression was demonstrated both in vitro and in vivo. We have recently reported that in ErbB2-overexpressing BCa cells grown in 3D laminin-rich extracellular matrix, CD151 regulated basal phosphorylation and homodimerization of ErbB2 and sensitized the cells to Herceptin (trastuzumab). Following from these data, we have here analyzed an involvement of CD151 in regulation of ErbB2/ErbB3 heterodimerization and its impact on cell response to Herceptin. CD151 was found to: (1) impair ErbB2/ErbB3 heterodimerization, (2) inhibit heregulin-dependent cell growth in 3D and signaling, and (3) counteract the protective effect of heregulin on Herceptin-mediated growth inhibition. Analysis of tissue samples demonstrated for the first time clinical significance of CD151 in patients with ErbB2-overexpressing BCa undergone trastuzumab-based therapy. Consistent with in vitro results, CD151 impact on disease outcome was ErbB3-dependent. In patients with ErbB3-negative tumors, CD151 significantly improved both overall survival (OS) (hazard ratio [HR] = 0.19, P = 0.034) and progression-free survival (PFS) (HR = 0.36, P = 0.043), while in ErbB3-positive cases it had no significant effect on patient survival (OS: HR = 3.33, P = 0.283; PFS: HR = 2.40, P = 0.208). These results support previous findings and show that CD151 acts as an important component of ErbB2 signaling axis in BCa cells, affecting their sensitivity to ErbB2-targeting therapy.
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http://dx.doi.org/10.1016/j.trsl.2018.12.007DOI Listing
May 2019

Systemic administration of serotonin exacerbates abdominal pain and colitis via interaction with the endocannabinoid system.

Biochem Pharmacol 2019 03 3;161:37-51. Epub 2019 Jan 3.

Department Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. Electronic address:

Background And Aims: Molecular basis of abdominal pain in IBD is not fully characterized. Serotonin (5-HT) increases visceral pain severity and contributes to exacerbation of inflammation. Moreover, it is well established that decreased anandamide (AEA) signaling in the gut increases visceral pain severity. The aim of this study was to investigate the interplay between 5-HT and endocannabinoid signaling in colitis.

Methods: We used 3% DSS in drinking water to induce colitis in mice. From day 3 5-HT was administered for 5 days and each day visceromotor response to colorectal distention (CRD) was measured. Expression of cannabinoid (CB) receptors as well as enzymes responsible of biosynthesis and degradation of endocannabinoids were investigated. Moreover, endocannabinoid levels were assessed by mass spectrometry. Additionally, we measured the expression of enzymes synthesizing 5-HT and AEA in the colon of IBD patients and healthy controls.

Results: Chronic exposure to 5-HT increased visceromotor response to CRD and worsened colitis, which was associated with decrease of AEA via 5-HT and 5-HT receptors. Moreover, exposure to 5-HT led to the downregulation of CB1 receptors. Colonic levels of N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which is responsible for synthesis of AEA, significantly declined after chronic treatment with 5-HT and this effect was reversed by the 5-HT and 5-HT receptor antagonists. NAPE-PLD was also downregulated in the colon of UC patients.

Conclusions: Our study shows a link between 5-HT and endocannabinoid signaling pathways in IBD. Thus, pharmacological blockade of 5-HT signaling or supplementation with endocannabinoids in the gut might be of benefit in severe cases of abdominal pain in IBD.
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http://dx.doi.org/10.1016/j.bcp.2019.01.001DOI Listing
March 2019

A malignant astrocytoma with uncommon angiocentric features and dot-like EMA expression.

Contemp Oncol (Pozn) 2018 30;22(3):205-208. Epub 2018 Sep 30.

Department of Pathology, Chair of Oncology, Medical University of Lodz, Poland.

Angiocentric features are uncommon in high-grade World Health Organisation (WHO) brain tumours, whilst they are typical for WHO grade I tumours, e.g. angiocentric gliomas. We present an unusual glial tumour that occurred in a 59-year-old man. The tumour had equivocal radiologic and histopathologic features, especially a characteristic angiocentric pattern, low-to-moderate Ki67, and dot-like epithelial membrane antigen expression. The tumour did not show features characteristic for glioblastoma; however, it recurred as glioblastoma four months later. Based on this case, we show that high-grade WHO brain tumours may show an angiocentric pattern typical for low-grade WHO brain tumours, such as angiocentric gliomas.
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http://dx.doi.org/10.5114/wo.2018.78944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238096PMC
September 2018

Intratumor heterogeneity and tissue distribution of KRAS mutation in non-small cell lung cancer: implications for detection of mutated KRAS oncogene in exhaled breath condensate.

J Cancer Res Clin Oncol 2019 Jan 27;145(1):241-251. Epub 2018 Oct 27.

Department of Clinical Physiology, Medical University of Lodz, Mazowiecka St. 6/8, 92-215, Lodz, Poland.

Purpose: Mutated KRAS oncogene in exhaled breath condensate (EBC) can be a genetic marker of non-small cell lung cancer (NSCLC). However, a possibility of inhomogeneous distribution in cancer tissue and intratumor heterogeneity of KRAS mutation may decrease its significance. We investigated a status of KRAS point mutation and its sequence at codon 12 in 51 NSCLC patients after tumor resection. The comparison of KRAS mutation status between EBC-DNA and cancer tissue was performed in 19 cases.

Methods: Five cancer tissue samples from disparate tumor regions and one from normal lung were harvested at surgery. EBC was collected for DNA analysis the previous day. KRAS point mutations at codon 12 were detected using mutant-enriched PCR technique and pyrosequenced.

Results: Forty-six cancers revealed concordance of KRAS mutation status: 27 contained mutated KRAS and 19 had only wild KRAS. Five NSCLCs revealed inhomogeneous distribution of KRAS mutation. Two different mutations were found in 14 NSCLCs and the most frequent one was G12D and G12V (n = 8). No mutated KRAS was found in normal lung. The concordance ratios of KRAS sequence in codon 12 between EBC-DNA and cancer were 18/19 for NSCLC patients and 11/12 for KRAS mutation positive NSCLC.

Conclusions: Intratumor heterogeneity and inhomogeneous distribution of KRAS point mutation in codon 12 in cancer tissue can occur in NSCLCs. There was a high accordance between KRAS mutation status in EBC-DNA and cancer tissue in NSCLC patients what suggests usefulness of monitoring KRAS mutation in EBC-DNA as a biomarker of NSCLC.
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http://dx.doi.org/10.1007/s00432-018-2779-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325989PMC
January 2019

CD151 regulates expression of FGFR2 in breast cancer cells via PKC-dependent pathways.

J Cell Sci 2018 10 29;131(21). Epub 2018 Oct 29.

Institute of Cancer and Genomic Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Expression of the tetraspanin CD151 is frequently upregulated in epithelial malignancies and correlates with poor prognosis. Here, we report that CD151 is involved in regulation of the expression of fibroblast growth factor receptor 2 (FGFR2). Depletion of CD151 in breast cancer cells resulted in an increased level of FGFR2. Accordingly, an inverse correlation between CD151 and FGFR2 was observed in breast cancer tissues. CD151-dependent regulation of the FGFR2 expression relies on post-transcriptional mechanisms involving HuR (also known as ELAVL1), a multifunctional RNA-binding protein, and the assembly of processing bodies (P-bodies). Depletion of CD151 correlated with inhibition of PKC, a well-established downstream target of CD151. Accordingly, the levels of dialcylglycerol species were decreased in CD151-negative cells, and inhibition of PKC resulted in the increased expression of FGFR2. Whereas expression of FGFR2 itself did not correlate with any of the clinicopathological data, we found that FGFR2/CD151 patients were more likely to have developed lymph node metastasis. Conversely, FGFR2/CD151 patients demonstrated better overall survival. These results illustrate functional interdependency between CD151 complexes and FGFR2, and suggest a previously unsuspected role of CD151 in breast tumorigenesis.
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http://dx.doi.org/10.1242/jcs.220640DOI Listing
October 2018

Recurrent Pineocytomalike Papillary Tumor of The Pineal Region: A Case Report and Literature Review.

World Neurosurg 2018 Dec 27;120:1-14. Epub 2018 Aug 27.

Department of Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland.

Background: Papillary tumors of the pineal region (PTPRs) are malignant World Health Organization grade II/III tumors; however, they may perfectly mimic benign tumors (e.g., pineocytomas [World Health Organization grade I]).

Case Description: We present a case of a 28-year-old man with a 35-mm tumor of the pineal region. Considering the typical radiological and pathologic presentation, the tumor was first diagnosed as pineocytoma. However, despite first total resection, the tumor recurred after 7 years. The recurrent neoplasm was composed mainly of papillary structures with low-grade atypical cells positive for CKAE1/AE3 and CK18. This categorization led to the final diagnosis of PTPR. The patient underwent adjuvant radiotherapy, which vastly improved his neurologic condition and resulted in significant tumor regression.

Conclusions: This case exemplifies that PTPRs can perfectly mimic pineocytomas and simple staining for cytokeratins may warrant correct diagnosis and better treatment.
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http://dx.doi.org/10.1016/j.wneu.2018.08.125DOI Listing
December 2018

MicroRNAs in regulation of triple-negative breast cancer progression.

J Cancer Res Clin Oncol 2018 Aug 19;144(8):1401-1411. Epub 2018 Jun 19.

Department of Pathology, Medical University of Lodz, Lodz, Poland.

Purpose: Dysregulation of miRNA profile has been associated with a broad spectrum of cellular processes underlying progression of various human malignancies. Increasing evidence suggests that specific microRNA clusters might be of clinical utility, especially in triple-negative breast carcinoma (TNBC), devoid of both predictive markers and potential therapeutic targets. Here we provide a comprehensive review of the existing data on microRNAs in TNBC, their molecular targets, a putative role in invasive progression with a particular emphasis on the epithelial-to-mesenchymal transition (EMT) and acquisition of stem-cell properties (CSC), regarded both as prerequisites for metastasis, and significance for therapy.

Methods: PubMed and Medline databases were systematically searched for the relevant literature. 121 articles have been selected and thoroughly analysed.

Results: Several miRNAs associated with EMT/CSC and invasion were identified as significantly (1) upregulated: miR-10b, miR-21, miR-29, miR-9, miR-221/222, miR-373 or (2) downregulated: miR-145, miR-199a-5p, miR-200 family, miR-203, miR-205 in TNBC. Dysregulation of miR-10b, miR-21, miR-29, miR-145, miR-200 family, miR-203, miR-221/222 was reported of prognostic value in TNBC patients.

Conclusion: Available data suggest that specific microRNA clusters might play an important role in biology of TNBC, understanding of which should assist disease prognostication and therapy.
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http://dx.doi.org/10.1007/s00432-018-2689-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061037PMC
August 2018

SMAC protein expression as a potent favorable prognostic factor in locally advanced breast cancer.

Pol J Pathol 2018;69(1):33-41

Preoperative systemic therapy including neoadjuvant chemotherapy (NCT) is standard treatment in locally advanced breast cancer (LABC), the aim of which is to enable a radical surgery and to reduce the risk of local and distant recurrence. It has been established that NCT in LABC may effectively induce apoptosis. The study objective was to assess the role of a proapoptotic second mitochondria-derived activator of apoptosis (SMAC) in LABC. The study group comprised 56 patients with advanced non-metastatic breast cancer (stage IIB -node positive and III), who received NCT followed by surgery and adjuvant treatment. Expression of SMAC protein was analysed using the immunohistochemistry technique in core biopsies sampled from the patients' breasts before NCT and in surgical specimens collected after completion of NCT. Expression of SMAC was significantly higher in the breast cancer specimens after NCT (p < 0.01). High expression of SMAC in the core biopsy before NCT correlated with a pathological complete remission (pCR, p < 0.01). The patients with a high expression of SMAC in the surgical specimens after NCT had longer DFS. Our study proves a potential role of SMAC expression in LABC as a novel favourable prognostic factor in LABC for pCR and disease-free survival (DFS).
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http://dx.doi.org/10.5114/pjp.2018.75334DOI Listing
July 2018

Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF-Phe-Asp]NH.

J Enzyme Inhib Med Chem 2018 Dec;33(1):560-566

a Department of Biomolecular Chemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland.

Opioid peptides and opiate drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor. However, delta- and kappa-opioid receptors can also contribute to the analgesic effects of opioids. Recent findings showed that simultaneous activation of multiple opioid receptors may result in additional analgesia with fewer side effects. Here, we evaluated the pharmacological profile of our formerly developed mixed mu/kappa-opioid receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH (C-36) and Dmt-c[D-Lys-Phe-p-CF-Phe-Asp]NH (F-81). The ability of these peptides to cross the blood-brain barrier was tested in the parallel artificial membrane permeability (PAMPA) assay. On the basis of the hot-plate test in mice after central and peripheral administration, analog F-81 was selected for the anti-nociceptive and anti-inflammatory activity assessment after peripheral administration.
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http://dx.doi.org/10.1080/14756366.2018.1441839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010070PMC
December 2018

Pure hepatocellular carcinoma originates from an ectopic liver nodule located in the pancreas.

Contemp Oncol (Pozn) 2017 30;21(4):311-314. Epub 2017 Dec 30.

Department of Pathology, Chair of Oncology, Medical University of Lodz, Poland.

Ectopic liver (EL) is a rare congenital abnormality, which is localised most commonly in the wall of the gallbladder. Histoarchitectural abnormalities, which lead to impaired transfer of blood and bile, as well as well demarcation, are characteristic features of ectopic liver nodules. Both features may explain the discrepancies between hepatocellular carcinoma (HCC) cases originating from ectopic liver in comparison to HCC cases originating from orthotopic liver: the strong propensity of ectopic liver to the development of HCC. The latter feature may be linked to the better treatment prognosis in patients with HCC originating from ectopic liver tissue in comparison to those with HCC within orthotopic liver. In this paper, we discuss these differences based on a unique case of pure HCC, which developed in a small ectopic liver nodule in the pancreas.
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http://dx.doi.org/10.5114/wo.2017.72403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799705PMC
December 2017