Publications by authors named "Krzysztof Okon"

138 Publications

Reticular Basement Membrane Thickness Is Associated with Growth- and Fibrosis-Promoting Airway Transcriptome Profile-Study in Asthma Patients.

Int J Mol Sci 2021 Jan 20;22(3). Epub 2021 Jan 20.

College of Natural Sciences, Institute of Computer Science, University of Rzeszów, Pigonia 1, 35-310 Rzeszów, Poland.

Airway remodeling in asthma is characterized by reticular basement membrane (RBM) thickening, likely related to epithelial structural and functional changes. Gene expression profiling of the airway epithelium might identify genes involved in bronchial structural alterations. We analyzed bronchial wall geometry (computed tomography (CT)), RBM thickness (histology), and the bronchial epithelium transcriptome profile (gene expression array) in moderate to severe persistent ( = 21) vs. no persistent ( = 19) airflow limitation asthmatics. RBM thickness was similar in the two studied subgroups. Among the genes associated with increased RBM thickness, the most essential were those engaged in cell activation, proliferation, and growth (e.g., , , , and ) and inhibiting apoptosis (e.g., higher mRNA expression of , , , and lower of , , ). Additionally, RBM thickness correlated with the expression of genes encoding extracellular matrix (ECM) components (, ), involved in ECM remodeling (), neovascularization (, ), nerve functioning (, ), oxidative stress adaptation (, ), epigenetic modifications (, ), and the innate immune response (, ). Cluster analysis revealed that genes linked with RBM thickness were also related to thicker bronchial walls in CT. Our study suggests that the pro-fibrotic profile in the airway epithelial cell transcriptome is associated with a thicker RBM, and thus, may contribute to asthma airway remodeling.
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http://dx.doi.org/10.3390/ijms22030998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863966PMC
January 2021

In Vitro Spectroscopy-Based Profiling of Urothelial Carcinoma: A Fourier Transform Infrared and Raman Imaging Study.

Cancers (Basel) 2021 Jan 2;13(1). Epub 2021 Jan 2.

Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30-387 Krakow, Poland.

Markers of bladder cancer cells remain elusive, which is a major cause of the low recognition of this malignant neoplasm and its recurrence. This implies an urgent need for additional diagnostic tools which are based on the identification of the chemism of bladder cancer. In this study, we employed label-free techniques of molecular imaging-Fourier Transform Infrared and Raman spectroscopic imaging-to investigate bladder cancer cell lines of various invasiveness (T24a, T24p, HT-1376, and J82). The urothelial HCV-29 cell line was the healthy control. Specific biomolecules discriminated spatial distribution of the nucleus and cytoplasm and indicated the presence of lipid bodies and graininess in some cell lines. The most prominent discriminators are the total content of lipids and sugar moieties as well as the presence of glycogen and other carbohydrates, un/saturated lipids, cytochromes, and a level of S-S bridges in proteins. The combination of the obtained hyperspectral database and chemometric methods showed a clear differentiation of each cell line at the level of the nuclei and cytoplasm and pointed out spectral signals which differentiated bladder cancer cells. Registered spectral markers correlated with biochemical composition changes can be associated with pathogenesis and potentially used for the diagnosis of bladder cancer and response to experimental therapies.
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http://dx.doi.org/10.3390/cancers13010123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796146PMC
January 2021

Prognostic effect of renal collecting system invasion on survival of patients with renal cell carcinoma and tumor thrombus.

Cent European J Urol 2020 8;73(3):280-286. Epub 2020 Sep 8.

Department of Urology, Jagiellonian University Medical College, Cracow, Poland.

Introduction: Urinary collecting system invasion (UCSI) has been found to have significant prognostic value for patients with renal cell carcinoma (RCC). However, for RCC patients with venous tumor thrombus (VTT), only contradictory data exist regarding the prognostic efficacy of UCSI. Therefore, the aim of this study is to assess the prognostic relevance of UCSI in survival of patients with RCC and VTT.

Material And Methods: Medical records in a prospectively maintained institutional database were analyzed for RCC-VTT patients who had undergone nephrectomy with thrombectomy. Then, the effect of UCSI on overall survival was analyzed.

Results: The study examined data for 114 patients, including patients with VTT present in the renal vein (35 patients, 31%), infrahepatic inferior vena cava (28 patients, 24%), and suprahepatic inferior vena cava (51 patients, 45%). Nineteen percent of patients had UCSI. The median overall survival of patients with UCSI was 9 months, whereas median overall survival was 10 months for patients without collecting system invasion. Survival and regression analyses rejected UCSI as a prognostic marker for overall survival.

Conclusions: UCSI has no effect on survival in our cohort of RCC-VTT patients. Therefore, it should not be considered in risk stratification models or in treatment decision-making for this patient group.
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http://dx.doi.org/10.5173/ceju.2020.0172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587485PMC
September 2020

Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature.

Am J Surg Pathol 2020 09;44(9):1224-1234

Laboratory of Pathology, National Cancer Institute, Bethesda, MD.

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001512DOI Listing
September 2020

Prevalence of APC and PTEN Alterations in Urachal Cancer.

Pathol Oncol Res 2020 Oct 4;26(4):2773-2781. Epub 2020 Aug 4.

Department of Urology, Semmelweis University, Budapest, 1082, Hungary.

Urachal carcinoma (UrC) is a rare tumor with remarkable histological and molecular similarities to colorectal cancer (CRC). Adenomatous polyposis coli (APC) is the most frequently affected gene in CRC, but the prevalence and significance of its alterations in UrC is poorly understood. In addition, loss of phosphatase and tensin homologue (PTEN) was shown to be associated with therapy resistance in CRC. Our primary aim was to assess specific genetic alterations including APC and PTEN in a large series of UrC samples in order to identify clinically significant genomic alterations. We analyzed a total of 40 UrC cases. Targeted 5-gene (APC, PTEN, DICER1, PRKAR1A, TSHR, WRN) panel sequencing was performed on the Illumina MiSeq platform (n = 34). In addition, ß-catenin (n = 38) and PTEN (n = 30) expressions were assessed by immunohistochemistry. APC and PTEN genes were affected in 15% (5/34) and 6% (2/34) of cases. Two of five APC alterations (p.Y1075*, p.K1199*) were truncating pathogenic mutations. One of the two PTEN variants was a pathogenic frameshift insertion (p.C211fs). In 29% (11/38) of samples, at least some weak nuclear ß-catenin immunostaining was detected and PTEN loss was observed in 20% (6/30) of samples. The low prevalence of APC mutations in UrC represents a characteristic difference to CRC. Based on APC and ß-catenin results, the Wnt pathway seems to be rarely affected in UrC. Considering the formerly described involvement of PTEN protein loss in anti-EGFR therapy-resistance its immunohistochemical testing may have therapeutic relevance.
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http://dx.doi.org/10.1007/s12253-020-00872-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471184PMC
October 2020

Gastric neuroendocrine tumor as a rare type of neoplasm in a kidney transplant recipient.

Pol Arch Intern Med 2020 09 3;130(9):801-802. Epub 2020 Jun 3.

Department of Nephrology, Jagiellonian University Medical College, Kraków, Poland.

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http://dx.doi.org/10.20452/pamw.15413DOI Listing
September 2020

Image analysis discloses differences in nuclear parameters between ERG+ and ERG- prostatic carcinomas.

Pol J Pathol 2020 ;71(1):20-29

Department of Urology, Jagiellonian University Medical College, Krakow, Poland.

Prostatic carcinoma (PC) is the most frequent urologic cancer and one of the most frequent cancers in males; it is a heterogeneous disease, in terms of molecular features, morphology and prognosis. About half of cases depends on TMPRSS2-ETS translocation which leads to a production of ERG transcription factor. ERG+ and ERG- cancers seem to differ in a number of features, which could lead to an altered nuclear structure; the aim of the study was to test this hypothesis. The material consisted of total 39 PC cases, representing ERG+ and ERG-, as well as Gleason pattern 3 and 4. Filtering by color deconvolution and automatic segmentation were used, and the properly detected nuclei were manually selected. From each case fifty nuclei were obtained; then geometric features and texture parameters were assessed. The analysis of the collected data showed differences both between ERG+/ERG- and Gleason pattern 3 and 4 cases in most of the features analyzed. Our results suggest that indeed the ERG status, thus likely TMPRSS2-ETS translocation, has an impact on morphology of nuclei in PC, and their differences are evident enough to be detectable by image analysis.
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http://dx.doi.org/10.5114/pjp.2020.95412DOI Listing
September 2020

Effect of Maternal Diet and Medium Chain Fatty Acids Supplementation for Piglets on Their Digestive Tract Development, Structure, and Chyme Acidity as Well as Performance and Health Status.

Animals (Basel) 2020 May 11;10(5). Epub 2020 May 11.

Institute of Animal Nutrition and Bromatology, Faculty of Animal Sciences and Bioeconomy, University of Life Sciences in Lublin, Akademicka 12, 20-950 Lublin, Poland.

The objective of the present study was to evaluate the effect of oils for sows during late pregnancy and lactation on offspring performance. In addition, the effect of caprylic acid (C8) or medium-chain triglyceride oil (MCT) in piglets' feed on their gut development, performance, and health status was determined. The experiment was conducted on 24 sows allocated to two treatments: diet with rapeseed oil or with coconut oil. Newborn piglets were randomly allocated to three treatments: feed with no supplement or supplemented with 0.3% MCT or with 0.3% C8. The results showed that both oils had no effect on sow reproductive rates; however, fatty acid patterns of milk differed significantly and the number of lost piglets was lower in sow fed with coconut oil. Both caprylic and MCT oil significantly improved piglet performance and villus height. These additives did not change triacylglycerol content in blood, but C8 lowered total cholesterol and MCT increased IgG content. It can be concluded that coconut oil fed to pregnant and lactating sows can markedly reduce the mortality of piglets and that caprylic acid and medium-chain fatty acid oil can be a good supplement in weaned piglet feed.
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http://dx.doi.org/10.3390/ani10050834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278414PMC
May 2020

Evaluation of Proinflammatory, NF-kappaB Dependent Cytokines: IL-1α, IL-6, IL-8, and TNF-α in Tissue Specimens and Saliva of Patients with Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders.

J Clin Med 2020 Mar 21;9(3). Epub 2020 Mar 21.

Jagiellonian University Medical College, Faculty of Medicine, Institute of Dentistry, Chair and Department of Periodontology and Clinical Oral Pathology, Montelupich 4, 31-155 Krakow, Poland.

Background: Oral squamous cell carcinoma (OSCC) is a life-threatening disease. It could be preceded by oral potentially malignant disorders (OPMDs). It was confirmed that chronic inflammation can promote carcinogenesis. Cytokines play a crucial role in this process. The aim of the study was to evaluate interleukin-1alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α) in tissue specimens and saliva of patients with OSCC and OPMDs.

Methods: Cytokines were evaluated in 60 tissue specimens of pathological lesions (OSCCs or OPMDs) and in 7 controls (normal oral mucosa, NOM) by immunohistochemistry and in saliva of 45 patients with OSCC or OPMDs and 9 controls (healthy volunteers) by enzyme-linked immunosorbent assays.

Results: Immunohistochemical analysis revealed significantly higher expression of IL-8 in OSCC specimens and TNF-α in OSCCs and OPMDs with dysplasia as compared to NOM. Moreover, expression of TNF-α was significantly higher in oral leukoplakia and oral lichen planus without dysplasia, whereas expression of IL-8 only in oral leukoplakia without dysplasia in comparison with NOM. Salivary concentrations of all evaluated cytokines were significantly higher in patients with OSCC than in controls. Moreover, levels of IL-8 were significantly higher in saliva of patients with OPMDs with dysplasia as compared to controls and in OSCC patients as compared to patients with dysplastic lesions. There was also significant increase in salivary concentrations of IL-6, IL-8 and TNF-α in patients with OSCC as compared to patients with OPMDs without dysplasia.

Conclusion: The study confirmed that proinflammatory, NF-kappaB dependent cytokines are involved in pathogenesis of OPMDs and OSCC. The most important biomarker of malignant transformation process within oral mucosa among all assessed cytokines seems to be IL-8. Further studies on a larger sample size are needed to corroborate these results.
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http://dx.doi.org/10.3390/jcm9030867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141524PMC
March 2020

Metastatic and non-metastatic sentinel inguinofemoral lymph nodes in vulvar cancer show an increased lymphangiogenesis.

Ann Agric Environ Med 2020 Mar 26;27(1):123-128. Epub 2019 Mar 26.

Department of Gynecology and Oncology, Jagiellonian University Medical College, Krakow, Poland.

Introduction And Objective: Lymph node involvement is a strong predictor of disease recurrence and patient survival in vulvar cancer. The aim of the study was to evaluate the feasibility of sentinel lymph node (SLN) screening, the incidence of skip metastases, and lymph node lymphangiogenesis.

Material And Methods: Fifty-five patients participated in this prospective, single centre study. A double SLN screening method was employed using radiocolloid (technetium-99 sulfur colloid) and 1.0% Isosulfan Blue. Immunohistochemistry, using a mouse monoclonal antibody against D2-40, was used to evaluate lymphatic vessel density (LVD). All calculations were performed using STATISTICA software v. 10 (StatSoft, USA, 2011); p < 0.05 was considered significant.

Results: Using both methods of SLN detection, 100% accuracy was achieved, and skip metastases were diagnosed in only one woman (1.82%). Peri-tumour median LVD was significantly increased compared with matched intra-tumour samples (p < 0.001), while median LVD was significantly lower in negative, compared with positive SLN, regardless of whether matched non-SLN were negative (p < 0.001) or positive (p = 0.005). Metastatic SLN exhibited significantly higher median LVD compared with matched negative non-SLN (p = 0.015), while no significant difference in median LVD was detected between positive SLN and matched positive non-SLN. However, negative SLN had a significantly higher median LVD compared with matched negative non-SLN (p = 0.012).

Conclusions: SLN detection is a safe and feasible procedure in vulvar cancer. In patients without nodular involvement, SLN, compared with non-SLN, exhibited significantly higher median LVD, which may be an indication of its preparation to host metastases, and thus requires further investigation.
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http://dx.doi.org/10.26444/aaem/105925DOI Listing
March 2020

Could the kinetin riboside be used to inhibit human prostate cell epithelial-mesenchymal transition?

Med Oncol 2020 Feb 6;37(3):17. Epub 2020 Feb 6.

Chair of Pathomorphology, Jagiellonian University Medical College, Kraków, Poland.

The epithelial-mesenchymal transition (EMT) is a molecular process connected to higher expression of vimentin and increased activity of transcription factors (Snail, Twist) which restrains E-cadherin. EMT has been linked to prostate cancer metastatic potential, therapy resistance, and poor outcomes. Kinetin riboside (9-(b-dribofuranosyl)-6-furfurylaminopurine, KR) is a naturally occurring cytokinin, which induces apoptosis and shows strong antiproliferative activity against various human cancer cell lines. To establish the effect of KR on human prostate cell lines, expression of, e.g. AR, E-, N-cadherins, Vimentin, Snail, Twist, and MMPs, was analysed at mRNA and protein levels using Western Blot and RT-PCR and/or RQ-PCR techniques. KR inhibited the growth of human prostate cancer cells, but also, to a small extent, of normal cells. This effect depended on the type of the cells and their androgen sensitivity. KR also decreased the level of p-Akt, which takes part in androgen signalling modulation. The antiapoptotic Bcl-2 protein was down-regulated in cancer cell lines, while that of Bax is up-regulated upon KR exposure. KR contributed to re-expression of the E-cadherin as well as to significant changes in cell migration. Taken together, our results indicate for the first time that KR can be proposed as a factor for signalling pathways regulation that participates in the inhibition of development of aggressive forms of prostate cancer, and may alter the approach to therapeutic interventions. We propose KR as a potent inhibitor of EMT in human prostate cells.
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http://dx.doi.org/10.1007/s12032-020-1338-1DOI Listing
February 2020

Metachronous skin cancers as an indicator of a posttransplant solid tumor in a kidney recipient.

Pol Arch Intern Med 2020 01 4;130(1):70-71. Epub 2019 Nov 4.

Department of Nephrology, Jagiellonian University Medical College, Kraków, Poland.

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http://dx.doi.org/10.20452/pamw.15047DOI Listing
January 2020

ALK-rearranged renal cell carcinomas in Polish population.

Pathol Res Pract 2019 Dec 25;215(12):152669. Epub 2019 Sep 25.

Department of Pathomorphology, Medical University of Gdansk, Mariana Smoluchowskiego 17, 80-214 Gdansk, Poland. Electronic address:

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, the activation of which is considered an important event in the pathogenesis of several neoplasms and a predictive factor for the targeted therapy with ALK inhibitors. Thus far, ALK rearrangements have been identified in 22 renal cell carcinomas in both pediatric and adult patients. We evaluated the incidence of ALK rearrangement-associated RCC in adult Central European population. An immunohistochemical evaluation of 1019 kidney tumors was performed with use of three different clones of anti-ALK antibodies. None of the tested samples showed positive staining, which suggests that the incidence of ALK rearrangement-associated renal cell carcinomas is significantly lower in the Polish population, and indicates a potential association between ethnicity and occurrence of these rare neoplasms.
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http://dx.doi.org/10.1016/j.prp.2019.152669DOI Listing
December 2019

CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness.

J Pathol 2020 02 3;250(2):205-216. Epub 2019 Dec 3.

Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan.

Diffuse malignant mesothelioma of the pleura (MPM) is a highly aggressive tumour that typically is associated with short survival. CD70 and CD27 belong to the tumour necrosis factor (TNF) and the TNF receptor (TNFR) superfamily, respectively. Under physiological conditions, the tightly regulated interaction between CD70 and CD27 plays a co-stimulatory role in promoting T-cell expansion and differentiation through the NFκB pathway. Aberrantly high CD70 expression has been documented in haematological and solid malignancies in association with immune evasion in malignant cells. In this study, 172 well-characterised primary diffuse MPM tumours including epithelioid (n = 145), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, CD27, CD3, CD4, CD8, CD56, PDCD1 (PD-1), and FOXP3 expression. Twenty per cent (34/172) of the mesothelioma cells expressed CD70 on the cell membrane. Overall survival was significantly decreased in the cohort of patients with CD70-expressing tumour cells (p < 0.01). Patients with MPM containing a higher number of CD3 (p < 0.01), CD4 (p < 0.01), CD8 (p < 0.01), or FOXP3 (p < 0.01) tumour-infiltrating lymphoid cells (TILs) showed significantly worse clinical outcomes. As potential independent risk factors for MPM patients, multivariate Cox proportional hazards regression analysis revealed CD70 expression on mesothelioma cells [hazard ratio (HR) 2.25; p = 0.010], higher FOXP3 TILs (HR 2.81; p = 0.004), and higher CD3 TIL accumulation (HR 6.12; p < 0.001). In contrast, as a potential independent favourable factor, higher CD27 TIL accumulation (HR 0.48; p = 0.037) was identified. In vitro experiments and an immunodeficient mouse model revealed that CD70 enhances the invasiveness of MPM cells through MET-ERK axis activation. Further analyses in syngeneic mouse models demonstrated possible roles for CD70 in immune evasion. Collectively, these findings suggest that the CD70-CD27 pathway enhances the malignant phenotypes of MPM and diminishes anti-tumor immune response in patients with these neoplasms. These markers might be useful in MPM for prognostic evaluations as well as targeted therapeutics. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5361DOI Listing
February 2020

The Prognostic Value of Tumor Regression Grades Combined With TNM Classification in Patients With Muscle-Invasive Bladder Cancer Who Underwent Neoadjuvant Chemotherapy Followed by Radical Cystectomy.

Clin Genitourin Cancer 2019 12 12;17(6):e1203-e1211. Epub 2019 Sep 12.

Department of Intensive Care and Perioperative Medicine, Jagiellonian University Medical College, Cracow, Poland.

Introduction: Tumor regression grades (TRGs) quantify the pathologic response to neoadjuvant chemotherapy (NAC). The aim of the study was to investigate the prognostic value of TRGs in combination with the TNM classification in an independent cohort of patients with muscle-invasive bladder cancer (MIBC) treated with NAC followed by radical cystectomy (RC) in a retrospective setting.

Patients And Methods: Patients treated with a complete course of NAC followed by RC for MIBC between December 2012 and December 2017 were enrolled in the study. TRGs were determined in RC specimens. Data were collected preoperatively, and the follow-up was continued up to August 2018. Kaplan-Meier curves and the Cox proportional hazards model were used to compare survival probabilities between major responders (no MIBC, < ypT2 and ypN0), partial responders (≥ ypT2 or ypN+ and TRG2), and non-responders (≥ ypT2 or ypN+ and TRG3).

Results: A group of 70 patients with a median age of 64 years (interquartile range, 58-67 years) was analyzed. There were 36 major responders, 21 partial responders, and 13 non-responders. In comparison with a major response, a partial response was associated with a hazard ratio of 9.44 (95% confidence interval, 1.10-80.89; P = .04) and non- responders showed a hazard ratio of 17.85 (95% confidence interval, 2.18-145.85; P = .007) for death.

Conclusions: The study confirms the prognostic value of the pathologic response to NAC. Determination of TRGs is straightforward, provides valuable information, and could be easily included in the standard pathologic examination of RC surgical specimen. Prospective studies are needed to establish the role of TRG in routine clinical practice.
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http://dx.doi.org/10.1016/j.clgc.2019.09.003DOI Listing
December 2019

Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature.

Am J Surg Pathol 2020 02;44(2):162-173

Laboratory of Pathology, National Cancer Institute, Bethesda, MD.

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.
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http://dx.doi.org/10.1097/PAS.0000000000001377DOI Listing
February 2020

The relationship of airway structural changes to blood and bronchoalveolar lavage biomarkers, and lung function abnormalities in asthma.

Clin Exp Allergy 2020 01 6;50(1):15-28. Epub 2019 Oct 6.

Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.

Background: Airway structural changes are important in asthma pathology and require further investigations.

Objective: We sought to evaluate which computed tomography (CT) indices, bronchial histological traits, or blood and bronchoalveolar lavage (BAL) biomarkers correlate best with lung function abnormalities in asthma.

Methods: In 105 white adult asthmatics (53 with a component of fixed airflow obstruction), we determined airway cross-sectional geometry of two proximal (the right upper lobe apical segmental and the left apicoposterior) and two distal (the right and the left basal posterior) bronchi, quantified the low-attenuation lung area (LAA%), and analysed clusters based on airway CT-metrics. We also performed bronchofiberoscopy with BAL and endobronchial biopsy, assessed blood and BAL biomarkers, including interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12p70, IL-17A, IL-23, interferon (INF)γ and periostin, together with circulating a disintegrin and metalloproteinase domain-containing protein (ADAM)33, and investigated interplays between analysed variables.

Results: Patients with fixed airflow limitation were characterized by lower lumen area and increased wall area and wall thickness ratios in distal airways, accompanied by raised LAA%. They had also higher blood neutrophilia, blood and BAL eosinophilia, increased circulating fibrinogen, periostin, and ADAM33. Blood neutrophilia, serum high density lipoproteins, thyroid-stimulating hormone, and shortened activated partial thromboplastin time were determinants of thicker reticular basement membrane (RBM). BAL eosinophilia was the only positive predictor of collagen I accumulation. Surprisingly, we observed a negative correlation between RBM thickening and collagen I deposit. Cluster analysis based on CT-metrics of the right lower lobe basal posterior bronchus revealed three well-separated clusters similar in age, asthma duration, and BMI, but different in RBM thickness, collagen I accumulation, and inflammatory markers.

Conclusions And Clinical Relevance: Airway remodelling traits are mainly related to the Th profile, higher circulating ADAM33, and blood neutrophilia. Lung function abnormalities and RBM thickening correlate better with CT-metrics of distal than proximal airways.
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http://dx.doi.org/10.1111/cea.13501DOI Listing
January 2020

Patterns of gene expression characterize T1 and T3 clear cell renal cell carcinoma subtypes.

PLoS One 2019 31;14(5):e0216793. Epub 2019 May 31.

Center for Medical Genomics OMICRON, Medical Faculty, Jagiellonian University Medical College, Krakow, Poland.

Renal carcinoma is the 20th most common cancer worldwide. Clear cell renal cell carcinoma is the most frequent type of renal cancer. Even in patients diagnosed at an early stage, characteristics of disease progression remain heterogeneous. Up-to-date molecular classifications stratify the ccRCC samples into two clusters. We analyzed gene expression in 23 T1 or T3 ccRCC samples. Unsupervised clustering divided this group into three clusters, two of them contained pure T1 or T3 samples while one contained a mixed group. We defined a group of 36 genes that discriminate the mixed cluster. This gene set could be associated with tumor classification into a higher stage and it contained significant number of genes coding for molecular transporters, channel and transmembrane proteins. External data from TCGA used to test our findings confirmed that the expression levels of those 36 genes varied significantly between T1 and T3 tumors. In conclusion, we found a clustering pattern of gene expression, informative for heterogeneity among T1 and T3 tumors of clear cell renal cell carcinoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216793PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544217PMC
January 2020

The composition of T cell infiltrates varies in primary invasive breast cancer of different molecular subtypes as well as according to tumor size and nodal status.

Virchows Arch 2019 Jul 17;475(1):13-23. Epub 2019 Apr 17.

Department of Pathomorphology, Jagiellonian University Medical College, ul. Grzegórzecka 16, 31-531, Kraków, Poland.

T lymphocytes are the most numerous immune cells in tumor-associated infiltrates and include several subpopulations of either anticancer or pro-tumorigenic functions. However, the associations between levels of different T cell subsets and breast cancer molecular subtypes as well as other prognostic factors have not been fully established yet. We performed immunohistochemistry for CD8 (cytotoxic T cells (CTL)), FOXP3 (regulatory T cells (Tregs)), and GATA3 (Th2 cells) in 106 formalin-fixed paraffin-embedded invasive breast cancer tissue samples and analyzed both the numbers and percentages of investigated cells in tumor-associated infiltrates. We observed that triple-negative breast cancer (TNBC) and HER2+ non-luminal breast tumors were associated with more numerous CTLs and Tregs and a higher Treg/Th2 cell ratio as compared with luminal A subtype. A higher Treg percentage was related to a decreased hormone receptor expression, an increase in the Ki67 level, a greater tumor size of luminal tumors, and the presence of lymph node metastases. Moreover, differences in the composition of T cell infiltrates were associated with HER2 status and histologic grade and type, and a distinct immune pattern was observed in tumors of different phenotypes regarding pT stage and nodal status. The results of our work show the diversity of T cell infiltrates in primary invasive breast cancers of different phenotypes and suggest that progression of luminal or non-luminal tumors is related to distinct tumor-associated T cell composition.
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http://dx.doi.org/10.1007/s00428-019-02568-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611750PMC
July 2019

Omalizumab may decrease the thickness of the reticular basement membrane and fibronectin deposit in the bronchial mucosa of severe allergic asthmatics.

J Asthma 2020 05 23;57(5):468-477. Epub 2019 Mar 23.

Department of Pulmonology, University Hospital, Krakow, Poland.

: Immunoglobulin E is an important modulator of the inflammatory reaction in allergic asthma. It also contributes to airway remodeling in the course of the disease. The authors evaluated airway structural changes in severe allergic asthma during the omalizumab therapy. : The study included 13 patients with severe allergic asthma treated with omalizumab for at least one year. In each patient clinical, laboratory, and spirometry parameters were evaluated before and after the treatment. In addition, bronchoscopy with bronchial mucosa biopsy and bronchoalveolar lavage was performed. The basal lamina thickness, inflammatory cell infiltration, fibronectin, as well as type I and III collagen accumulation were assessed in bronchial mucosa specimens, together with the assessment of bronchoalveolar lavage cellularity. : The omalizumab therapy led to a decrease in the basal lamina thickness ( = 0.002), and to a reduction in fibronectin ( = 0.02), but not collagen deposits in the bronchial mucosa. The decrease in fibronectin accumulation was associated with an improvement in asthma control and quality of life ( = 0.01, both), and a diminished dose of systemic corticosteroids ( = 0.001). It was also associated with a tendency towards reduction of the eosinophil count in the peripheral blood, bronchoalveolar lavage fluid, and bronchial mucosa specimens. : Our study has shown that omalizumab, effective in the treatment of severe allergic asthma, may also decrease unfavorable structural airway changes in allergic asthmatics, at least with respect to the fibronectin deposit and an increased thickness of the basal lamina. However, more extensive observational studies are needed to verify the above hypothesis.
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http://dx.doi.org/10.1080/02770903.2019.1585872DOI Listing
May 2020

3D laparoscopy as a tertiary cytoreductive (TCR) surgery in infiltrating ureter recurrent epithelial ovarian cancer - case report and a mini-review of the literature.

Prz Menopauzalny 2018 Dec 31;17(4):185-188. Epub 2018 Dec 31.

Mazovia Hospital, Warsaw, Poland.

The paper describes a case of a 61-year-old woman with recurrent epithelial ovarian cancer infiltrating the ureter treated with 3D laparoscopy as a tertiary cytoreductive surgery (TCR). In addition, a mini-review of the literature concerning TCR is presented.
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http://dx.doi.org/10.5114/pm.2018.81745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372846PMC
December 2018

Immunoexpression of DNA fragmentation factor 40, DNA fragmentation factor 45, and B-cell lymphoma 2 protein in normal human endometrium and uterine myometrium depends on menstrual cycle phase and menopausal status.

Arch Med Sci 2018 Oct 31;14(6):1254-1262. Epub 2017 Jul 31.

Department of Gynecology and Oncology, Jagiellonian University Medical College, Krakow, Poland.

Introduction: DNA fragmentation factors 40 and 45 (DFF40 and DFF45) are final executors of apoptosis, and B-cell lymphoma 2 (Bcl-2) is a well-recognized apoptosis inhibitor. We aimed to evaluate DFF40, DFF45 and Bcl-2 immunoexpression in the normal human endometrium with respect to the glandular and stromal layer and in uterine myometrium.

Material And Methods: DFF40, DFF45, and Bcl-2 expression was assessed via immunohistochemistry in the endometrium and myometrium collected postmenopausally and premenopausally during the proliferative and secretory phases of the menstrual cycle.

Results: Compared to the myometrium and stroma, endometrial glands showed the highest DFF40 and DFF45 expression in pre- and postmenopausal specimens. DFF45, but not DFF40, glandular expression dependent on menstrual cycle phase and DFF40 and DFF45 scoring was significantly lower in postmenopausal specimens. Significantly higher Bcl-2 expression was observed in proliferative glandular endometrium compared to secretory and postmenopausal specimens. No cycle- or menopause-dependent changes were reported for stromal or myometrial DFF40, DFF45 or Bcl-2 expression. DFF40, DFF45 and Bcl-2 expression was independent of age, age at menarche and menopause, BMI, menstrual cycle and menses lengths, parity and gravidity.

Conclusions: The study provides important evidence regarding menstrual cycle-dependent changes in the expression of DFF40, DFF45 and Bcl-2 in the normal human endometrium, especially in the glandular layer, and shows that their levels are stable in the normal uterine myometrium.
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http://dx.doi.org/10.5114/aoms.2017.69383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209718PMC
October 2018

Lymphoid environment in molecular subtypes of breast cancer.

Pol J Pathol 2018;69(2):169-181

Recently, a large body of evidence has shown that the microenvironment of invasive breast carcinoma affects its development and the patient's outcome, and vice versa - cancer cells express factors that modulate tumour milieu in terms of its composition and function. We performed an immunohistochemical (IHC) staining of 108 formalin-fixed, paraffin-embedded (FFPE) tissue samples to investigate the relationships between T-cell, B-cell, and NK-cell infiltrate, invasive breast carcinomas molecular subtypes, and other prognostic indicators. The main findings of our study were as follows: the significantly higher infiltrate of the analysed immune cell subsets in triple-negative (TNBC), HER2-positive, non-luminal and luminal B/HER2+ breast carcinomas than in luminal A cancers; their higher densities in poorly differentiated lesions; correlations between lymphoid cells and the expression of hormonal receptors, HER2 receptor status, and marker of cancer proliferation. Furthermore, we observed T-cell numbers to be associated with greater tumour diameter. In summary, the results of our study indicate associations between tumoural lymphoid infiltration and the unfavourable intrinsic subtypes as well as other detrimental prognostic factors in invasive breast carcinomas.
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http://dx.doi.org/10.5114/pjp.2018.76700DOI Listing
May 2019

Lactobacilli with superoxide dismutase-like or catalase activity are more effective in alleviating inflammation in an inflammatory bowel disease mouse model.

Drug Des Devel Ther 2018 28;12:3221-3233. Epub 2018 Sep 28.

Department of Microbiology, Jagiellonian University Medical College, Poland,

Purpose: Some lactobacilli, which possess superoxide dismutase-like activity and catalase activity naturally, have strong antioxidative properties. The aim of this study was to identify such strains and check which of them play a crucial role in alleviating intestinal inflammation.

Methods: We selected two strains for use in animal studies: 30B (which has the highest catalase activity) and 900 (which has the highest dismutase-like activity). Forty mice (C57B1/6J) were divided into four experimental groups with ten mice in each group. Group I (control group) was not supplemented with , group II (catalase group) was orally supplemented with 30B, group III (dismutase-like group) was supplemented with 900, and group IV (mixed group) was supplemented with both strains. For 23 days, the temperature and body mass of each mouse were recorded and fecal samples for microbiological examination were collected. On day 23, the animals were sacrificed, and their intestines were removed for microbiological and histopathological studies.

Results: Compared to the control group, the highest drop in the body temperature was observed in groups II (<0.05) and IV (<0.05). Similarly, groups II (<0.05) and IV (<0.05) had the highest drop in body mass. Moreover, histopathological evaluation of colon fragments showed intracryptic abscesses in these groups. Group III mice showed most limited degree of inflammation.

Conclusion: strains with dismutase-like activity are more effective in alleviating intestinal inflammation than strains producing catalase, suggesting that superoxide anion radical decomposition is crucial in this process.
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http://dx.doi.org/10.2147/DDDT.S164559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167993PMC
February 2019

AFM-based nanomechanical characterization of bronchoscopic samples in asthma patients.

J Mol Recognit 2018 12 18;31(12):e2752. Epub 2018 Jul 18.

Institute of Nuclear Physics, Polish Academy of Sciences, PL-31342, Kraków, Poland.

Asthma is not a single disease, but recently, it is considered as a syndrome characterized through various clinical presentations and different etiopathologies. Large degree of the disease heterogeneity manifests in distinct characteristics that translate into variability of properties at single cell and molecular levels. Here, we conducted measurements of mechanical properties of bronchial tissue samples collected from patients suffering from asthma. The results obtained from different applied protocols for sample preparation may indicate that deep freezing and storage in liquid nitrogen, followed by consecutive unfreezing of tissue samples, preserve tissue mechanical properties as indicated by a parameter referred here as a tissue relative stiffness index. Tissue relative stiffness index quantifies both the degree of heterogeneity and deformability of tissue samples regarding healthy one. These studies demonstrate that the freezing protocol, optimized towards asthma tissue, can facilitate atomic force microscopy use what, together with recent findings on standardization of elasticity measurements, enables the measurements of large group of samples with minimized influence of errors stemming from the applied methodology of tissue stiffness determination.
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http://dx.doi.org/10.1002/jmr.2752DOI Listing
December 2018

Frequent expression of somatostatin receptor 2a in olfactory neuroblastomas: a new and distinctive feature.

Hum Pathol 2018 09 25;79:144-150. Epub 2018 May 25.

Department of Pathology, Technische Universität München, München, Germany.

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogs and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of 40 ONBs. In addition, tissue microarrays containing 40 high-grade sinonasal carcinomas as well as 6 sinonasal lymphomas, 3 rhabdomyosarcomas, and 3 Ewing sarcomas were evaluated. Volante system was applied for staining evaluation. Thirty cases (75%) were immunopositive for SSTR2A and 3 (7.5%) for SSTR5. Among the 30 SSTR2A-positive ONBs, 19 tumors (63.3%) scored 2+ and 11 (36.7%) scored 3+. All SSTR5-positive ONBs scored 2+. Neither sinonasal carcinomas nor sinonasal small round blue cell neoplasms expressed SSTR2A or SSTR5. The frequent expression of SSTR2A provides a rationale for radioreceptor diagnosis and therapy with SST analogs in ONBs. SSTR2A expression in ONBs is a helpful adjunct in the differential diagnosis of ONBs.
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http://dx.doi.org/10.1016/j.humpath.2018.05.013DOI Listing
September 2018

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas.

Int J Cancer 2018 10 10;143(7):1764-1773. Epub 2018 May 10.

Department of Urology, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, Essen, Germany.

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.
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http://dx.doi.org/10.1002/ijc.31547DOI Listing
October 2018

Non-endometrioid and high-grade endometrioid endometrial cancers show DNA fragmentation factor 40 (DFF40) and B-cell lymphoma 2 protein (BCL2) underexpression, which predicts disease-free and overall survival, but not DNA fragmentation factor 45 (DFF45) underexpression.

BMC Cancer 2018 04 13;18(1):418. Epub 2018 Apr 13.

Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.

Background: The expression of DNA fragmentation factor 45 (DFF45) and B-cell lymphoma 2 (BCL2) in glands of the normal human endometrium is related to phases of the menstrual cycle and decreases after menopause, whereas the expression of DNA fragmentation factor 40 (DFF40) is stable. Moreover, DF45, BCL2 and DFF40 underexpression has been reported in numerous malignancies, including uterine leiomyosarcomas. In this study, we aimed to investigate DFF45, BCL2 and DFF40 expression in endometrioid and non-endometrioid types of endometrial cancers (ECs). We also evaluated the correlations between DFF45, BCL2 and DFF40 expression levels and clinicopathological parameters and determined the value of these three proteins as prognostic markers of disease-free survival (DFS) and overall survival (OS).

Methods: Immunohistochemistry was performed to evaluate DFF45, BCL2 and DFF40 expression in 342 cases of ECs. Student's t-test, the Mann-Whitney U-test, and the chi-squared test were used for the statistical analyses as appropriate. The Cox-Mantel test, Cox's proportional hazard model, and relative risk analyses were used to evaluate associations between DFF40, DFF45, and BCL2 expression and clinicopathological characteristics.

Results: DFF40 and BCL2, but not DFF45, were significantly underexpressed in non-endometrioid and high-grade endometrioid ECs compared with low- and moderate-grade endometrioid ECs. Women with DFF40- and BCL2-negative tumors had higher risks of disease recurrence, lymph node involvement, lympho-vascular space infiltration, and deep myometrial invasion compared with women with DFF40- and BCL2-positive tumors. Additionally, women with DFF40- and BCL2-negative tumors had significantly lower OS and DFS than women with DFF40- and BCL2-positive tumors. A multivariable analysis of the model, including the clinicopathological characteristics and immunohistochemical results, showed that negative BCL2 expression, lymph node involvement, and high-stage and high-grade disease were independent predictors of OS, whereas negative BCL2 expression, lymph node involvement, and high-stage disease were independent predictors of DFS.

Conclusions: Compared with low- and moderate-grade endometrioid ECs, non-endometrioid and high-grade endometrioid ECs showed significant DFF40 and BCL2 underexpression. The absence of DFF40 and BCL2 expression negatively affects DFS and OS. Further prospective studies are warranted to assess the potential utility of DFF40 and BCL2 as targets in the diagnosis or treatment of ECs.
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http://dx.doi.org/10.1186/s12885-018-4333-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899339PMC
April 2018

Interaction between iodine and glucosinolates in rutabaga sprouts and selected biomarkers of thyroid function in male rats.

J Trace Elem Med Biol 2018 Mar 15;46:110-116. Epub 2017 Dec 15.

Department of Food Chemistry and Nutrition, Medical College, Jagiellonian University, Kraków, Poland. Electronic address:

Rutabaga sprouts belong to the Brassicaceae family and may exert a negative influence on thyroid function, because they are a rich in glucosinolates. These sprouts are also valuable source of iodine (6.5 ± 0.6 μg/100 g of fresh weight). Sprouts were tested in a long-term experiment with young male rats as an element of their diet, combined with two models of hypothyroidism, the first - deficit of iodine and the second - sulfadimethoxine ingestion as a pharmacological agent caused inhibition of thyroid peroxidase. Evaluations were performed for the serum TSH and thyroid hormones together with analyzes of thyroid histopathology, cytosolic glutathione peroxidase (GPX1), thioredoxin reductase in the thyroid, plasma GPX3 and CAT, erythrocyte GPX1. Rutabaga sprouts' intake by healthy rats did not cause any harmful effect on their health, including thyroid function. For animals with hypothyroidism, rutabaga sprouts enhanced the adverse effect of iodine deficiency or ingestion of sulfadimethoxine on the organism. According to the results obtained for young male rats thyroid function, the interpretation of data for human exposure to rutabaga sprouts has to be avoided. Furthermore, unless new scientific data confirms a lack of the negative effect of brassica sprouts on thyroid function in human, they should not be excluded from the group of goitrogenic products.
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http://dx.doi.org/10.1016/j.jtemb.2017.12.002DOI Listing
March 2018

DNA fragmentation factors 40 and 45 (DFF40/DFF45) and B-cell lymphoma 2 (Bcl-2) protein are underexpressed in uterine leiomyosarcomas and may predict survival.

Onco Targets Ther 2017 14;10:4579-4589. Epub 2017 Sep 14.

Department of Public Health, Faculty of Health Science, Medical University of Warsaw.

Objectives: DNA fragmentation factors 40 and 45 (DFF40 and DFF45) are responsible for final DNA-laddering during apoptosis, whereas Bcl-2 (B-cell lymphoma 2) is an apoptosis inhibitor. Our aim was to investigate the expression of DFF40, DFF45, and Bcl-2 in uterine leiomyosarcomas (uLMS), leiomyomas (uLM), and the normal myometrium. Furthermore, the correlation between DFF40, DFF45, and Bcl-2 expression and clinicopathological parameters in leiomyosarcomas was assessed. Their prognostic value in disease-free survival (DFS) and overall survival (OS) was also calculated.

Materials And Methods: This study included 53 cases of uLMS from patients matched for age and menopausal status with 53 cases of uLM and 53 controls of normal myometrium (uM). Case samples of uterine myometrium from leiomyosarcomas (uLMS-M) and leiomyomas (uLM-M) were also studied. Immunohistochemical scoring was undertaken for DFF40, DFF45, and Bcl-2.

Results: DFF40, DFF45, and Bcl-2 were significantly underexpressed in uLMS compared with uLMS-M and uM. In uLMS samples, no correlation between the analyzed proteins was observed. Negative DFF40 and Bcl-2, but not DFF45, staining was a predictor of poorer DFS and OS in women with uLMS. uLM showed DFF40 and Bcl-2 overexpression compared with uM and uLM-M, with a significant positive correlation between DFF40 and DFF45. No differences in DFF40, DFF45, and Bcl-2 expression were observed between the uLMS-M, uLM-M, and uM samples, with a significant positive correlation between DFF40 and DFF45 expression.

Conclusion: DFF40, DFF45, and Bcl-2 are significantly underexpressed in uLMS, but only a lack of DFF40 and Bcl-2 negatively influences DFS and OS. Disruption of DFF40 and DFF45 expression was observed in uLMS, but not in uLM or control and case myometrium; this may play a role in tumor pathogenesis.
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http://dx.doi.org/10.2147/OTT.S142979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609795PMC
September 2017