Publications by authors named "Jaromir Gumulec"

71 Publications

Sensitivity to Cisplatin in Head and Neck Cancer Cells Is Significantly Affected by Patient-Derived Cancer-Associated Fibroblasts.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic.

Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different "sensitizing ratio". Increased expression of , , , , and in cancer cells was characteristic for the increase of resistance. On the other hand, expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells.
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http://dx.doi.org/10.3390/ijms22041912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918851PMC
February 2021

DNA repair in head and neck tumor cells and possibilities of its monitoring to estimate individual tumor radioresistance and selection of optimal primary treatment.

Cas Lek Cesk 2020 ;159(7-8):268-274

In order to maximize post-therapeutic quality of life, radio(chemo)therapy becomes preferred over surgery in head-and-neck tumor (HNT) treatment. However, the therapy selection is only based on the clinical experience and patient's preferences as the radiosensitivity markers remain unknown. New possibilities of deciding on the best primary therapy, moving us towards personalized medicine based on quantifiable biomarkers, have been opened by studies on DNA radiation damage and repair in individual patients tumors. Together with the importance of radiotherapy in HNT oncology, we discuss here our preliminary results revealing the existence of several HNT groups with respect to genome stability and repair ability of tumor cells after irradiation. Monitoring of the formation and disappearance of γH2AX/53BP1 foci in tumor cell primo-cultures derived from individual patients suggests that DNA repair capacity of the identified groups correlates with the tumor cell radiosensitivity. Our findings thus improve understanding of HNT biology; nevertheless, the relationship between the repair groups and in vivo response of tumors to radiotherapy must be further studied. Since most HNTs do not suffer from repair defects, although their viability varies after irradiation, pre-therapeutic tests covering the full spectrum of HNT radiosensitivity causes will require the use of a combination of multiple, still undiscovered biomarkers.
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January 2021

Quantitative Morphology of Cerebral Thrombi Related to Intravital Contraction and Clinical Features of Ischemic Stroke.

Stroke 2020 12 12;51(12):3640-3650. Epub 2020 Oct 12.

Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia (R.R.K., C.N., R.I.L., J.W.W.).

Background And Purpose: The purpose was to assess quantitatively and qualitatively the composition and structure of cerebral thrombi and correlate them with the signs of intravital clot contraction (retraction), as well as with etiology, severity, duration, and outcomes of acute ischemic stroke.

Methods: We quantified high-resolution scanning electron micrographs of 41 cerebral thrombi for their detailed cellular and noncellular composition and analyzed histological images for the overall structure with the emphasis on red blood cell compression, fibrin age, and the signs of inflammation.

Results: Cerebral thrombi were quite compact and had extremely low porosity. The prevailing cell type was polyhedral compressed erythrocytes (polyhedrocytes) in the core, and fibrin-platelet aggregates were concentrated at the periphery; both findings are indicative of intravital contraction of the thrombi. The content of polyhedrocytes directly correlated with the stroke severity. The prevalence of fibrin bundles was typical for more severe cases, while the content of fibrin sponge prevailed in cases with a more favorable course. The overall platelet content in cerebral thrombi was surprisingly small, while the higher content of platelet aggregates was a marker of stroke severity. Fibrillar types of fibrin prevailed in atherothrombogenic thrombi. Older fibrin prevailed in thrombi from the patients who received thrombolytics, and younger fibrin dominated in cardioembolic thrombi. Alternating layers of erythrocytes and fibrin mixed with platelets were common for thrombi from the patients with more favorable outcomes. Thrombi with a higher number of leukocytes were associated with fatal cases.

Conclusions: Most cerebral thrombi undergo intravital clot contraction (retraction) that may be of underestimated clinical importance. Despite the high variability of the composition and structure of cerebral thrombi, the content of certain types of blood cells and fibrin structures combined with the morphological signs of intravital contraction correlate with the clinical course and outcomes of acute ischemic stroke.
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http://dx.doi.org/10.1161/STROKEAHA.120.031559DOI Listing
December 2020

Caveolin-1 in oncogenic metabolic symbiosis.

Int J Cancer 2020 10 21;147(7):1793-1807. Epub 2020 Apr 21.

Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Metabolic phenotypes of cancer cells are heterogeneous and flexible as a tumor mass is a hurriedly evolving system capable of constant adaptation to oxygen and nutrient availability. The exact type of cancer metabolism arises from the combined effects of factors intrinsic to the cancer cells and factors proposed by the tumor microenvironment. As a result, a condition termed oncogenic metabolic symbiosis in which components of the tumor microenvironment (TME) promote tumor growth often occurs. Understanding how oncogenic metabolic symbiosis emerges and evolves is crucial for perceiving tumorigenesis. The process by which tumor cells reprogram their TME involves many mechanisms, including changes in intercellular communication, alterations in metabolic phenotypes of TME cells, and rearrangement of the extracellular matrix. It is possible that one molecule with a pleiotropic effect such as Caveolin-1 may affect many of these pathways. Here, we discuss the significance of Caveolin-1 in establishing metabolic symbiosis in TME.
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http://dx.doi.org/10.1002/ijc.32987DOI Listing
October 2020

The Importance of Cancer-Associated Fibroblasts in the Pathogenesis of Head and Neck Cancers.

Klin Onkol 2020 ;33(1):39-48

Background: Despite progress in anticancer therapies, head and neck squamous cell carcinoma (HNSCC) has still a low survival rate. Recent studies have shown that tumour stroma may play an important role in the pathogenesis of this malignant disease. Fibroblasts are a major component of the tumour microenvironment and may significantly influence HNSCC progression as indicated by the contribution they make to important hallmarks of cancer, such as inflammation, non-restricted growth, angiogenesis, invasion, metastasis, and therapy resistance. It is well known that tumour cells can confer a cancer-associated fibroblast (CAF) phenotype that supports the growth and dissemination of cancer cells. CAFs can stimulate cancer progression through cell-cell contacts and communication, remodelling of extracellular matrix, and production of many signal molecules and matrix metalloproteinases. Consequently, genetic changes in epithelial cells are probably not the only factor that drives HNSCC carcinogenesis. Non-genetic changes in the tumour stroma can also be significantly involved. Stress-induced signals can induce a multicellular program, creating a field of tissue that is predisposed to malignant transformation. The “field cancerization” concept represents a process of active evolution of intercellular interactions and feedback loops between tumour and stromal cells. This model paves the way to study cancer from a new perspective and identify new therapeutic targets.

Purpose: In this review, we discuss current knowledge about CAFs, such as their cellular origin, phenotypical plasticity and functional heterogeneity, and stress their contribution to HNSCC progression. This article was supported by the project AZV 16-29835A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 18. 6. 2019 Accepted: 9. 9. 2019.
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http://dx.doi.org/10.14735/amko202039DOI Listing
November 2020

Metabolic and Amino Acid Alterations of the Tumor Microenvironment.

Curr Med Chem 2021 ;28(7):1270-1289

Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-61600 Brno, Czech Republic.

Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and the effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely, alterations in the metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show the effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in a healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from the metabolism of other tissues. Findings from different tissues are, therefore, not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.
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http://dx.doi.org/10.2174/0929867327666200207114658DOI Listing
May 2021

The Quantitative-Phase Dynamics of Apoptosis and Lytic Cell Death.

Sci Rep 2020 01 31;10(1):1566. Epub 2020 Jan 31.

Department of Pathological Physiology, Faculty of Medicine, Masaryk University/Kamenice 5, CZ-625 00, Brno, Czech Republic.

Cell viability and cytotoxicity assays are highly important for drug screening and cytotoxicity tests of antineoplastic or other therapeutic drugs. Even though biochemical-based tests are very helpful to obtain preliminary preview, their results should be confirmed by methods based on direct cell death assessment. In this study, time-dependent changes in quantitative phase-based parameters during cell death were determined and methodology useable for rapid and label-free assessment of direct cell death was introduced. The goal of our study was distinction between apoptosis and primary lytic cell death based on morphologic features. We have distinguished the lytic and non-lytic type of cell death according to their end-point features (Dance of Death typical for apoptosis versus swelling and membrane rupture typical for all kinds of necrosis common for necroptosis, pyroptosis, ferroptosis and accidental cell death). Our method utilizes Quantitative Phase Imaging (QPI) which enables the time-lapse observation of subtle changes in cell mass distribution. According to our results, morphological and dynamical features extracted from QPI micrographs are suitable for cell death detection (76% accuracy in comparison with manual annotation). Furthermore, based on QPI data alone and machine learning, we were able to classify typical dynamical changes of cell morphology during both caspase 3,7-dependent and -independent cell death subroutines. The main parameters used for label-free detection of these cell death modalities were cell density (pg/pixel) and average intensity change of cell pixels further designated as Cell Dynamic Score (CDS). To the best of our knowledge, this is the first study introducing CDS and cell density as a parameter typical for individual cell death subroutines with prediction accuracy 75.4% for caspase 3,7-dependent and -independent cell death.
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http://dx.doi.org/10.1038/s41598-020-58474-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994697PMC
January 2020

Cell segmentation methods for label-free contrast microscopy: review and comprehensive comparison.

BMC Bioinformatics 2019 Jun 28;20(1):360. Epub 2019 Jun 28.

Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-62500, Czech Republic.

Background: Because of its non-destructive nature, label-free imaging is an important strategy for studying biological processes. However, routine microscopic techniques like phase contrast or DIC suffer from shadow-cast artifacts making automatic segmentation challenging. The aim of this study was to compare the segmentation efficacy of published steps of segmentation work-flow (image reconstruction, foreground segmentation, cell detection (seed-point extraction) and cell (instance) segmentation) on a dataset of the same cells from multiple contrast microscopic modalities.

Results: We built a collection of routines aimed at image segmentation of viable adherent cells grown on the culture dish acquired by phase contrast, differential interference contrast, Hoffman modulation contrast and quantitative phase imaging, and we performed a comprehensive comparison of available segmentation methods applicable for label-free data. We demonstrated that it is crucial to perform the image reconstruction step, enabling the use of segmentation methods originally not applicable on label-free images. Further we compared foreground segmentation methods (thresholding, feature-extraction, level-set, graph-cut, learning-based), seed-point extraction methods (Laplacian of Gaussians, radial symmetry and distance transform, iterative radial voting, maximally stable extremal region and learning-based) and single cell segmentation methods. We validated suitable set of methods for each microscopy modality and published them online.

Conclusions: We demonstrate that image reconstruction step allows the use of segmentation methods not originally intended for label-free imaging. In addition to the comprehensive comparison of methods, raw and reconstructed annotated data and Matlab codes are provided.
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http://dx.doi.org/10.1186/s12859-019-2880-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599268PMC
June 2019

HPV, protein p16 and squamous cell carcinoma of the oral cavity.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2020 Sep 17;164(3):292-299. Epub 2019 Jun 17.

Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Masaryk University, Brno and University Hospital Brno, Brno, Czech Republic.

Background: Squamous cell carcinoma of the oral cavity is generally caused by the long-term impact of known risk factors, e.g. tobacco and alcohol, along with chronic traumatisation. A number of studies now implicate HPV infection in head and neck tumour carcinogenesis but the exact role of HPV infection in the oral cavity remains unclear.

Methods: In this study, we evaluated 78 patients with oral squamous cell carcinoma (OSCC) for the expression of protein p16 in the context of HPV positivity and its influence on the overall survival rate, disease location, staging and grading.

Results: Regarding the tumour location, no significant difference was found between HPV-positive and HPV-negative patients, nor between p16-positive and p16-negative patients. There was also no trend in terms of HPV status and stage, and differentiation of carcinoma. There was no effect on HPV-positive patients relative to the time to progression (P=0.84) and overall survival rate (P=0.78). P16 positivity was not found to have an effect on the overall survival rate of patients (P=0.41) and there was no correlation between p16 positivity relative to the time to progression (P=0.66).

Conclusions: In summary, the data suggest that there is no effect of HPV status on the prognosis of OSCC patients compared to other HNSCC locations.
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http://dx.doi.org/10.5507/bp.2019.026DOI Listing
September 2020

Unexpected therapeutic effects of cisplatin.

Metallomics 2019 07;11(7):1182-1199

Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic. and Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic and BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, CZ-252 50 Vestec, Czech Republic.

Cisplatin is a widely used chemotherapeutic agent that is clinically approved to fight both carcinomas and sarcomas. It has relatively high efficiency in treating ovarian cancers and metastatic testicular cancers. It is generally accepted that the major mechanism of cisplatin anti-cancer action is DNA damage. However, cisplatin is also effective in metastatic cancers and should, therefore, affect slow-cycling cancer stem cells in some way. In this review, we focused on the alternative effects of cisplatin that can support a good therapeutic response. First, attention was paid to the effects of cisplatin at the cellular level such as changes in intracellular pH and cellular mechanical properties. Alternative cellular targets of cisplatin, and the effects of cisplatin on cancer cell metabolism and ER stress were also discussed. Furthermore, the impacts of cisplatin on the tumor microenvironment and in the whole organism context were reviewed. In this review, we try to reveal possible causes of the unexpected effectiveness of this anti-cancer drug.
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http://dx.doi.org/10.1039/c9mt00049fDOI Listing
July 2019

Prognostic Significance of Serum Free Amino Acids in Head and Neck Cancers.

Cells 2019 05 9;8(5). Epub 2019 May 9.

Department of Physiology, Faculty of Medicine, Masaryk University/Kamenice 5, CZ-625 00 Brno, Czech Republic.

Despite distinctive advances in the field of head and neck squamous cell cancer (HNSCC) biomarker discovery, the spectrum of clinically useful prognostic serum biomarkers is limited. As metabolic activities in highly proliferative transformed cells are fundamentally different from those in non-transformed cells, specific shifts in concentration of different metabolites may serve as diagnostic or prognostic markers. Blood amino acids have been identified as promising biomarkers in different cancers before, but little is known about this field in HNSCC. Blood amino acid profiles of 140 HNSCC patients were examined using high-performance liquid chromatography. Cox proportional hazards regression model was used to assess the prognostic value of amino acid concentrations in serum. Colony forming assay was used to identify the effect of amino acids that were significant in Cox proportional hazards regression models on colony forming ability of FaDu and Detroit 562 cell lines. In the multivariable Cox regression model for overall survival (OS), palliative treatment was associated with an unfavourable prognosis while high serum levels of methionine have had a positive prognostic impact. In the relapse-free survival (RFS) multivariable model, methionine was similarly identified as a positive prognostic factor, along with tumor localization in the oropharynx. Oral cavity localization and primary radio(chemo)therapy treatment strategy have been linked to poorer RFS. 1mM serine was shown to support the forming of colonies in both tested HNSCC cell lines. Effect of methionine was exactly the opposite.
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http://dx.doi.org/10.3390/cells8050428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562773PMC
May 2019

Cisplatin enhances cell stiffness and decreases invasiveness rate in prostate cancer cells by actin accumulation.

Sci Rep 2019 02 7;9(1):1660. Epub 2019 Feb 7.

Department of Physiology, Faculty of Medicine, Masaryk University/Kamenice 5, CZ-625 00, Brno, Czech Republic.

We focused on the biomechanical and morphological characteristics of prostate cancer cells and their changes resulting from the effect of docetaxel, cisplatin, and long-term zinc supplementation. Cell population surviving the treatment was characterized as follows: cell stiffness was assessed by atomic force microscopy, cell motility and invasion capacity were determined by colony forming assay, wound healing assay, coherence-controlled holographic microscopy, and real-time cell analysis. Cells of metastatic origin exhibited lower height than cells derived from the primary tumour. Cell dry mass and CAV1 gene expression followed similar trends as cell stiffness. Docetaxel- and cisplatin-surviving cells had higher stiffness, and decreased motility and invasive potential as compared to non-treated cells. This effect was not observed in zinc(II)-treated cells. We presume that cell stiffness changes may represent an important overlooked effect of cisplatin-based anti-cancer drugs. Atomic force microscopy and confocal microscopy data images used in our study are available for download in the Zenodo repository ( https://zenodo.org/ , Digital Object Identifiers:10.5281/zenodo.1494935).
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http://dx.doi.org/10.1038/s41598-018-38199-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367361PMC
February 2019

Post-treatment urinary sarcosine as a predictor of recurrent relapses in patients with prostate cancer.

Cancer Med 2018 11 12;7(11):5411-5419. Epub 2018 Sep 12.

Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic.

To date, there has been no evidence regarding the association between urinary sarcosine content and prostate cancer survival. Our main objective was to investigate whether levels of post-treatment urinary sarcosine are associated with relapse. The inclusion criteria were (in accordance with EAU 2017) as follows: histopathologically verified adenocarcinoma in prostate biopsy cores or specimens from transurethral resection of the prostate (TURP) or prostatectomy for benign prostatic enlargement (BPE) with retained ability to urinate. The median follow-up was 53 months. In the study, we retrospectively evaluated a cohort of 511 patients with prostate cancer with various risk factors and treatment strategies. Post-treatment sarcosine levels were elevated in 266 (52%) patients and highly elevated (≥200 nmol/L) in 71 (13%) patients. Urinary sarcosine content was significantly associated with number of relapses that patients experienced, P = 0.002 for sarcosine ≥200 vs ≤30 nmol/L. Multivariate analysis revealed that sarcosine was an independent predictor of recurrent relapses (≥2 relapses with an intermediate period of remission), HR = 3.89 (95% CI 1.29-11.7) for sarcosine >200 vs <30 nmol/L. This trend was even more pronounced in a subgroup of patients who underwent radical prostatectomy, HR = 3.29 (95% CI 1.06-10.18), where (single) relapse-free survival could also be predicted by sarcosine levels, HR = 1.96 (1.05-3.66). Urinary sarcosine may become a possible predictor for patients' outcomes, because patients with elevated post-treatment sarcosine could be predicted to have recurrent relapses of the disease.
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http://dx.doi.org/10.1002/cam4.1767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246947PMC
November 2018

C-terminal RUNX1 mutation in familial platelet disorder with predisposition to myeloid malignancies.

Int J Hematol 2018 Dec 6;108(6):652-657. Epub 2018 Aug 6.

Central European Institute of Technology (CEITEC), University Hospital, Masaryk University, Brno, Czech Republic.

Here we report a C-terminal RUNX1 mutation in a family with platelet disorder and predisposition to myeloid malignancies. We identified the mutation c.866delG:p.Gly289Aspfs*22 (NM_001754) (RUNX1 b-isoform NM_001001890; c.785delG:p.Gly262Aspfs*22) using exome sequencing of samples obtained from eight members of a single family. The mutation found in our pedigree is within exon eight and the transactivation domain of RUNX1. One of the affected individuals developed myelodysplastic syndrome (MDS), which progressed to acute myelogenous leukemia (AML). A search for the second hit which led to the development of MDS and later AML in this individual revealed the PHF6 gene variant (exon9:c.872G > A:p.G291E; NM_001015877), BCORL1 (exon3:c.1111A > C:p.T371P; NM_001184772) and BCOR gene variant (exon4:c.2076dupT:p.P693fs; NM_001123383), which appear to be very likely second hits participating in the progression to myeloid malignancy.
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http://dx.doi.org/10.1007/s12185-018-2514-3DOI Listing
December 2018

Prognostic role of c-Met in head and neck squamous cell cancer tissues: a meta-analysis.

Sci Rep 2018 07 10;8(1):10370. Epub 2018 Jul 10.

Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.

This meta-analysis aims to evaluate the effects of high c-Met levels in head and neck squamous cell carcinomas (HNSCC) on survival and clinicopathological features. Publications concerned with the clinical significance of c-Met protein expression in HNSCC were identified from the Scopus and Web of Science database searches. To elucidate the relationship between c-Met expression and clinical outcomes, a meta-analysis of the selected articles was conducted. Seventeen publications involving a total of 1724 patients met the inclusion criteria. c-Met overexpression was significantly correlated with poor overall survival (hazard ratio (HR) = 2.19, 95% confidence interval (CI) = 1.55-3.10). c-Met immunohistochemical staining positivity was also associated with worse relapse-free survival (HR = 1.64, 95% CI = 1.24-2.17) and presence of regional lymph node metastases (odds ratio (OR) = 1.76, 95% CI = 1.26-2.45). High levels of c-Met expression in HNSCC predict unfavorable prognosis associated with common clinicopathological features.
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http://dx.doi.org/10.1038/s41598-018-28672-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039483PMC
July 2018

The Role of von Willebrand Factor, ADAMTS13, and Cerebral Artery Thrombus Composition in Patient Outcome Following Mechanical Thrombectomy for Acute Ischemic Stroke.

Med Sci Monit 2018 Jun 11;24:3929-3945. Epub 2018 Jun 11.

Department of Cell and Developmental Biology, University of Pensylvania School of Medicine, Philadelphia, PA, USA.

BACKGROUND The aim of the study was to investigate the role of von Willebrand factor (vWF), the vWF-cleaving protease, ADAMTS13, the composition of thrombus, and patient outcome following mechanical cerebral artery thrombectomy in patients with acute ischemic stroke. MATERIAL AND METHODS A prospective cohort study included 131 patients with ischemic stroke (<6 hours) with or without intravenous thrombolysis. Interventional procedure parameters, hemocoagulation markers, vWF, ADAMTS13, and histological examination of the extracted thrombi were performed. The National Institutes of Health Stroke Scale (NIHSS) score was used on hospital admission, after 24 hours, at day 7; the three-month modified Rankin Scale score was used. RESULTS Mechanical thrombectomy resulted in a Treatment in Cerebral Ischemia (TICI) score of 2-3, with recanalization in 89% of patients. Intravenous thrombolysis was used in 101 (78%). Patients with and without intravenous thrombolysis therapy had a good clinical outcome (score 0-2) in 47% of cases (P=0.459) using the three-month modified Rankin Scale. Patients with a National Institutes of Health Stroke Scale (NIHSS) score ≥15 had significantly increased vWF levels (P=0.003), and a significantly increased vWF: ADAMTS13 ratio (P=0.038) on hospital admission. Significant correlation coefficients were found for plasma vWF and thrombo-embolus vWF (r=0.32), platelet (r=0.24), and fibrin (r=0.26) levels. In the removed thrombus, vWF levels were significantly correlated with platelet count (r=0.53), CD31-positive cells (r=0.38), and fibrin (r=0.48). CONCLUSIONS In patients with acute ischemic stroke, mechanical cerebral artery thrombectomy resulted in a good clinical outcome in 47% of cases, with and without intravenous thrombolysis therapy.
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http://dx.doi.org/10.12659/MSM.908441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029516PMC
June 2018

Establishment of oral squamous cell carcinoma cell line and magnetic bead-based isolation and characterization of its CD90/CD44 subpopulations.

Oncotarget 2017 Sep 3;8(39):66254-66269. Epub 2017 Aug 3.

Department of Physiology, Faculty of Medicine, Masaryk University, CZ-62500 Brno, Czech Republic.

In this study, we describe the establishment of the human papillomavirus 18-positive, stage II, grade 1, T2N0M0 head and neck tumor primary cell line derived from oral squamous cell carcinoma of a non-smoking patient by using two different protocols. Furthermore, a preparation of subpopulations derived from this primary cell line according to the cluster of differentiation molecules CD44/CD90 status using magnetic bead-based separation and their characterization was performed. Impedance-based real-time cell analysis, enzyme-linked immunsorbant assay (ELISA), wound-healing assay, flow-cytometry, gene expression analysis, and MTT assay were used to characterize these four subpopulations (CD44/CD90, CD44/CD90, CD44/CD90, CD44/CD90). We optimised methodics for establishement of primary cell lines derived from oral squamous cell carcinoma tissue samples and subsequent separation of mesenchymal (CD90) and epithelial (CD90) types of tumorous cells. Primary cell line prepared by using trypsin proteolysis was more viable than the one prepared by using collagenase. According to our results, CD90 separation is a necessary step in preparation of permanent tumor-tissue derived cell lines. Based on the wound-healing assay, CD44 cells exhibited stronger migratory capacity than CD44 subpopulations. CD44 subpopulations had also significantly higher expression of and , lower expression of and , and higher levels of basal autophagy compared to CD44 subpopulations. Furthermore, co-cultivation experiments revealed that CD44/CD90 cells supported growth of epithelial tumor cells (CD44/CD90). On the contrary, factors released by CD44/CD90 type of cells seem to have rather inhibiting effect. The most cisplatin-resistant subpopulation with the shortest doubling time was CD44/CD90, but this subpopulation had a low migratory capacity.
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http://dx.doi.org/10.18632/oncotarget.19914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630409PMC
September 2017

The effect of Benzothiazolone-2 on the expression of Metallothionein-3 in modulating Alzheimer's disease.

Brain Behav 2017 09 15;7(9):e00799. Epub 2017 Aug 15.

Central European Institute of Technology Brno University of Technology Brno Czech Republic.

Introduction: Metallothioneins (MTs) are a class of ubiquitously occurring low-molecular-weight cysteine- and metal-rich proteins containing sulfur-based metal clusters. MT-3 exhibits neuro-inhibitory activity. The possibility to enhance the expression of MT-3 or protect it from degradation is an attractive therapeutic target, because low levels of MT-3 were found in brains of Alzheimer's disease (AD) patients.

Objectives: The primary objective of this study was to test an enhancement of MT-3 cellular concentration after MT-3 binding treatment, which could prevent MT-3 degradation.

Methods: MTT assay, flow-cytometry, fluorescence microscopy, quantitative real-time polymerase chain reaction, and immunodetection of MT3 were used for analysis of effect of STOCK1N-26544, STOCK1N-26929, and STOCK1N-72593 on immortalized human microglia-SV40 cell line.

Results: All three tested compounds enhanced concentration of MT-3 protein in cells and surprisingly also mRNA concentration. IC50 values of tested molecules exceeded about ten times the concentration that was needed for induction of MT-3 expression. The tested compound Benzothiazolone-2 enhanced apoptosis and necrosis, but it was not of severe effect. About 80% of cells were still viable. There was no serious ROS-generation and no severe decrease in mitochondria numbers or stress induced endoplasmic reticulum changes after test treatments. The selected compound showed stable hydrophobic and electrostatic interaction during MT-3 ligand interaction.

Conclusion: Benzothiazolone-2 compounds significantly enhanced MT-3 protein and mRNA levels. The compounds can be looked upon as one of the probable lead compounds for future drug designing experiments in the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1002/brb3.799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607561PMC
September 2017

VPA does not enhance platinum binding to DNA in cisplatin-resistant neuroblastoma cancer cells.

Tumour Biol 2017 Sep;39(9):1010428317711656

1 Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Neuroblastoma represents a malignancy of the sympathetic nervous system characteristic by biological heterogeneity. Thus, chemotherapy exhibits only low effectivity in curing high-risk forms. Previous studies revealed the cytotoxic potential of valproate on neuroblastoma cells. Nevertheless, these studies omitted effects of hypoxia, despite its undeniable tumorigenic role. In this study, we addressed the question whether valproate promotes binding of platinum-based anti-cancer drugs (cisplatin, carboplatin and oxaliplatin) to DNA and role of hypoxia, cellular antioxidant capacity and cisplatin resistance in this process. Following parameters differed significantly when cells were exposed to treatment with platinum-based drugs: elevation of platinum content bound to DNA, elevation of total thiol content, GSH/GSSG ratio, glutathione reductase and peroxidase, superoxide dismutase and elevation of antioxidant capacity. Hypoxia caused a decrease in cytosine/adenine peak, and no changes in platinum-DNA binding properties were observed. After valproate co-treatment, oxidative stress-related parameters and cytosine/adenine peak were only elevated. The amount of platinum bound to DNA was not changed significantly. Valproate is not able to enhance platinum binding to DNA in neuroblastoma cells, neither in case of intrinsic resistance (UKF-NB-4) nor in case of acquired resistance (UKF-NB-4). Therefore, another mechanism different from increase in platinum binding to DNA should be considered as a synergistic effect of valproate by cisplatin treatment.
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http://dx.doi.org/10.1177/1010428317711656DOI Listing
September 2017

Platinum nanoparticles induce damage to DNA and inhibit DNA replication.

PLoS One 2017 12;12(7):e0180798. Epub 2017 Jul 12.

Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic.

Sparsely tested group of platinum nanoparticles (PtNPs) may have a comparable effect as complex platinum compounds. The aim of this study was to observe the effect of PtNPs in in vitro amplification of DNA fragment of phage λ, on the bacterial cultures (Staphylococcus aureus), human foreskin fibroblasts and erythrocytes. In vitro synthesized PtNPs were characterized by dynamic light scattering (PtNPs size range 4.8-11.7 nm), zeta potential measurements (-15 mV at pH 7.4), X-ray fluorescence, UV/vis spectrophotometry and atomic absorption spectrometry. The PtNPs inhibited the DNA replication and affected the secondary structure of DNA at higher concentrations, which was confirmed by polymerase chain reaction, DNA sequencing and DNA denaturation experiments. Further, cisplatin (CisPt), as traditional chemotherapy agent, was used in all parallel experiments. Moreover, the encapsulation of PtNPs in liposomes (LipoPtNPs) caused an approximately 2.4x higher of DNA damage in comparison with CisPt, LipoCisPt and PtNPs. The encapsulation of PtNPs in liposomes also increased their antibacterial, cytostatic and cytotoxic effect, which was determined by the method of growth curves on S. aureus and HFF cells. In addition, both the bare and encapsulated PtNPs caused lower oxidative stress (determined by GSH/GSSG ratio) in the human erythrocytes compared to the bare and encapsulated CisPt. CisPt was used in all parallel experiments as traditional chemotherapy agent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180798PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507526PMC
October 2017

Amino Acid Profiling of Zinc Resistant Prostate Cancer Cell Lines: Associations With Cancer Progression.

Prostate 2017 May 19;77(6):604-616. Epub 2017 Jan 19.

Faculty of Medicine, Department of Physiology, Masaryk University, Brno, Czech Republic.

Background: Failure in intracellular zinc accumulation is a key process in prostate carcinogenesis. Nevertheless, epidemiological studies of zinc administration have provided contradicting results. In order to examine the impact of the artificial intracellular increase of zinc(II) ions on prostate cancer metabolism, PNT1A, 22Rv1, and PC-3 prostatic cell lines-depicting different stages of cancer progression-and their zinc-resistant counterparts were used. To determine "benign" and "malignant" metabolic profiles, amino acid patterns, gene expression, and antioxidant capacity of these cell lines were assessed.

Methods: Amino acid profiles were examined using an ion-exchange liquid chromatography. Intracellular zinc content was measured by atomic absorption spectrometry. Metallothionein was quantified using differential pulse voltammetry. The content of reduced glutathione was determined using high performance liquid chromatography coupled with an electrochemical detector. Cellular antioxidant capacity was determined by the ABTS test and gene expression analysis was performed by qRT-PCR.

Results And Conclusions: Long-term zinc treatment was shown to reroute cell metabolism from benign to more malignant type. Long-term application of high concentration of zinc(II) significantly enhanced cisplatin resistance, invasiveness, cellular antioxidant capacity, synthesis of glutathione, and expression of treatment resistance- and stemness-associated genes (SOX2, POU5F1, BIRC5). Tumorous cell lines universally displayed high accumulation of aspartate and sarcosine and depletion of essential amino acids. Increased aspartate/threonine, aspartate/methionine, and sarcosine/serine ratios were associated with cancer phenotype with high levels of sensitivity and specificity. Prostate 77: 604-616, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pros.23304DOI Listing
May 2017

Levels of heavy metals and their binding protein metallothionein in type 2 diabetics with kidney disease.

J Biochem Mol Toxicol 2017 Jun 6;31(6). Epub 2017 Jan 6.

Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Hyperglycemia, a major metabolic disturbance present in diabetes, promotes oxidative stress. Activation of antioxidant defense is an important mechanism to prevent cell damage. Levels of heavy metals and their binding proteins can contribute to oxidative stress. Antiradical capacity and levels of metallothionein (MT), metals (zinc and copper), and selected antioxidants (bilirubin, cysteine, and glutathione) were determined in 70 type 2 diabetes mellitus (T2DM) subjects and 80 healthy subjects of Caucasian origin. Single nucleotide polymorphism (rs28366003) in MT gene was detected. Antiradical capacity, conjugated bilirubin, and copper were significantly increased in diabetics, whereas MT and glutathione were decreased. Genotype AA of rs28366003 was associated with higher zinc levels in the diabetic group. The studied parameters were not influenced by renal function. This is the first study comprehensively investigating differences in MT and metals relevant to oxidative stress in T2DM. Ascertained differences indicate increased oxidative stress in T2DM accompanied by abnormalities in non-enzymatic antioxidant defense systems.
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http://dx.doi.org/10.1002/jbt.21891DOI Listing
June 2017

Reduction of Doxorubicin-Induced Cardiotoxicity Using Nanocarriers: A Review.

Curr Drug Metab 2017 ;18(3):237-263

Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno. Czech Republic.

Background: Anthracycline antibiotic doxorubicin (DOX) is a very potent and extensively prescribed chemotherapeutic drug. It is widely utilized in the therapy of variety of haematological and solid tumours, although its administration is commonly accompanied with several severe side effects. The most serious one is a development of dose-dependent and cumulative cardiotoxicity. In the course of time, many strategies have been investigated in order to avoid or at least to diminish DOX-induced cardiac dysfunction; these include reduction of toxic effect by coadministration with iron chelators (dexrazoxane), trastuzumab, taxanes, statins, and ACE-inhibitors. However, the attenuation of cardiotoxic effect is still not satisfactory yet.

Objective: This review represents an overall appraisal of studies concerning with the utilization of various doxorubicinloaded nanoparticles in the cancer treatment with specific emphasis on those studies evaluating their influence on the reduction of heart tissue damage.

Conclusion: Introduction of nanoscale drug delivery systems undoubtedly represents nowadays one of the most promising tools for lowering systemic toxicity. Nanoparticles enable to target the therapeutic payload directly towards the tumor tissue, thus leading to the increased accumulation of the drug in the desired tissue and simultaneously protecting surrounding healthy tissues.
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http://dx.doi.org/10.2174/1389200218666170105165444DOI Listing
May 2018

Expression profiles of miR-29c, miR-200b and miR-375 in tumour and tumour-adjacent tissues of head and neck cancers.

Tumour Biol 2016 Sep 20;37(9):12627-12633. Epub 2016 Jul 20.

Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic.

Altered expression of microRNAs (miRNAs) has been shown in many types of malignancies including the head and neck squamous cell carcinoma (HNSCC). Although there are many new and innovative approaches in the treatment of HNSCC, a clear marker of this disease is still missing. Three candidate miRNAs (miR-29c-3p, miR-200b-5p and miR-375-3p) were studied in connection with HNSCC using quantitative real-time PCR expression levels in 42 tissue samples of HNSCC patients and histologically normal tumour-adjacent tissue samples of these patients. Primary HNSCC carcinoma tissues can be distinguished from histologically normal-matched noncancerous tumour-adjacent tissues based on hsa-miR-375-3p expression (sensitivity 87.5 %, specificity 65 %). Additionally, a significant decrease of hsa-miR-200b-5p expression was revealed in tumour-adjacent tissue samples of patients with node positivity. Lower expression of hsa-miR-200b-5p and hsa-miR-29c-3p in HNSCC tumour tissue was associated with higher tumour grade. Consequently, survival analysis was performed. Lower expression of hsa-miR-29c-3p in tumour-adjacent tissue was associated with worse overall and disease-specific survivals. Lower expression of miR-29c-3p in tumourous tissue was associated with worse relapse-free survival. hsa-miR-375-3p seems to be a relatively promising diagnostic marker in HNSCC but is not suitable for prognosis of patients. Furthermore, this study highlighted the importance of histologically normal tumour-adjacent tissue in HNSCC progress (significant decrease of hsa-miR-200b-5p expression in tumour-adjacent tissue of patients with node positivity and low expression of hsa-miR-29c-3p in HNSCC tumour-adjacent tissue associated with worse prognosis).
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http://dx.doi.org/10.1007/s13277-016-5147-2DOI Listing
September 2016

Evaluation of EGFR as a prognostic and diagnostic marker for head and neck squamous cell carcinoma patients.

Oncol Lett 2016 Sep 21;12(3):2127-2132. Epub 2016 Jul 21.

Central European Institute of Technology, Brno University of Technology, CZ-616 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, CZ-625 00 Brno, Czech Republic.

Approximately 90% of all head and neck tumors are squamous cell carcinomas. The overall survival of patients with head and neck squamous cell carcinoma (HNSCC) is low (≤50%). A non-invasive marker of disease progression is sorely required. The present study focused on the plasmatic levels of epidermal growth factor receptor (EGFR) in HNSCC patients (N=92) compared with healthy (N=29) and diabetic [type 2 diabetes mellitus (T2DM); N=26] controls. Enzyme-linked immunosorbent assay using antibodies against the extracellular region of EGFR (L25-S645) was performed. No significant changes were observed between diabetic and healthy controls. However, there were significantly higher EGFR plasma levels in HNSCC patients compared with both control groups (P=0.001 and 0.005, respectively). Receiver operating characteristic curve analysis identified a sensitivity of 76.09%, a specificity of 67.27% and an area under curve of 0.727 for this comparison. No significant association was observed between EGFR plasma levels and tumor stage, tumor grade, lymph node or distant metastasis occurrence, smoking habit or hypertension. However, the presence of human papillomavirus infection and T2DM in HNSCC patients had borderline effect on the plasma EGFR levels. Survival analysis revealed no significant influence of plasmatic EGFR levels on the overall and disease-specific survival of HNSCC patients. In conclusion, EGFR plasma levels appear to be a relatively promising diagnostic, but poor prognostic, HNSCC marker.
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http://dx.doi.org/10.3892/ol.2016.4896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998659PMC
September 2016

Zinc and Copper Homeostasis in Head and Neck Cancer: Review and Meta-Analysis.

Curr Med Chem 2016 ;23(13):1304-30

Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic.

Metals are known for playing essential roles in human physiology. Copper and zinc are trace elements closely dependent on one another and are involved in cell proliferation, growth, gene expression, apoptosis and other processes. Their homeostasis is crucial and tightly controlled by a resourceful system of transporters and transport proteins which deliver copper and zinc ions to their target sites. Abnormal zinc and copper homeostasis can be seen in a number of malignancies and also in head and neck cancer. Imbalance in this homeostasis is observed as an elevation or decrease of copper and zinc ions in serum or tissue levels in patients with cancer. In head and neck cancer these altered levels stand out from those of other malignancies which makes them an object of interest and therefore zinc and copper ions might be a good target for further research of head and neck cancer development and progression. This review aims to summarize the physiological roles of copper and zinc, its binding and transport mechanisms, and based on those, its role in head and neck cancer. To provide stronger evidence, dysregulation of levels is analysed by a meta-analytical approach.
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http://dx.doi.org/10.2174/0929867323666160405111543DOI Listing
February 2017

Influence of Long-Distance Bicycle Riding on Serum/Urinary Biomarkers of Prostate Cancer.

Int J Mol Sci 2016 Mar 17;17(3):377. Epub 2016 Mar 17.

Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic.

Herein, we present a study focused on the determination of the influence of long-distance (53 km) bicycle riding on levels of chosen biochemical urinary and serum prostate cancer (PCa) biomarkers total prostate-specific antigen (tPSA), free PSA (fPSA) and sarcosine. Fourteen healthy participants with no evidence of prostate diseases, in the age range from 49-57 years with a median of 52 years, underwent physical exercise (mean race time of 150 ± 20 min, elevation increase of 472 m) and pre- and post-ride blood/urine sampling. It was found that bicycle riding resulted in elevated serum uric acid (p = 0.001, median 271.76 vs. 308.44 µmol/L pre- and post-ride, respectively), lactate (p = 0.01, median 2.98 vs. 4.8 mmol/L) and C-reactive protein (p = 0.01, 0.0-0.01 mg/L). It is noteworthy that our work supports the studies demonstrating an increased PSA after mechanical manipulation of the prostate. The subjects exhibited either significantly higher post-ride tPSA (p = 0.002, median 0.69 vs. 1.1 ng/mL pre- and post-ride, respectively) and fPSA (p = 0.028, median 0.25 vs. 0.35 ng/mL). Contrary to that, sarcosine levels were not significantly affected by physical exercise (p = 0.20, median 1.64 vs. 1.92 µmol/mL for serum sarcosine, and p = 0.15, median 0.02 µmol/mmol of creatinine vs. 0.01 µmol/mmol of creatinine for urinary sarcosine). Taken together, our pilot study provides the first evidence that the potential biomarker of PCa-sarcosine does not have a drawback by means of a bicycle riding-induced false positivity, as was shown in the case of PSA.
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http://dx.doi.org/10.3390/ijms17030377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813236PMC
March 2016

Relation of exposure to amino acids involved in sarcosine metabolic pathway on behavior of non-tumor and malignant prostatic cell lines.

Prostate 2016 May 5;76(7):679-90. Epub 2016 Feb 5.

Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic, European Union.

Background: Sarcosine (N-methylglycine) was previously delineated as a substantial oncometabolite of prostate cancer (PCa) and its metabolism seems to be significantly involved in PCa development and behavior.

Methods: We focused on investigation whether the exposure of prostate cells (PNT1A, 22Rv1, and PC-3) to sarcosine-related amino acids (glycine, dimethylglycine, and sarcosine) affects their aggressiveness (cell mobility and division rates, using real-time cell based assay). The effect of supplementation on expression of glycine-N-methyltransferase (GNMT) mRNA was examined using qRT-PCR. Finally, post-treatment amino acids patterns were determined with consequent statistical processing using the Ward's method, factorial ANOVA and principal component analysis (P < 0.05).

Results: The highest migration induced sarcosine and glycine in metastatic PC-3 cells (a decrease in relative free area about 53% and 73%). The highest cell division was achieved after treatment of 22Rv1 and PC-3 cells with sarcosine (time required for division decreased by 65% or 45%, when compared to untreated cells). qRT-PCR revealed also significant effects on expression of GNMT. Finally, amino acid profiling shown specific amino acid patterns for each cell line. In both, treated and untreated PC-3 cells significantly higher levels of serine, glutamic acid, and aspartate, linked with prostate cancer progression were found.

Conclusions: Sarcosine-related amino acids can exceptionally affect the behavior of benign and malignant prostate cells.
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http://dx.doi.org/10.1002/pros.23159DOI Listing
May 2016

Laboratory-Based Markers as Predictors of Brain Infarction During Carotid Stenting: a Prospective Study.

J Atheroscler Thromb 2016 Jul 19;23(7):839-47. Epub 2016 Jan 19.

Department of Neurology, Comprehensive Stroke Center, University Hospital Ostrava.

Aim: New ischemic lesions in the brain can be detected in approximately 50% of patients undergoing carotid artery stenting (CAS). We wished to discover the laboratory-based predictors of new infarctions in the brain after CAS.

Methods: All consecutive patients with internal carotid artery stenosis of ≥70% with indication for CAS were enrolled in a prospective study for 16 months. All patients used dual antiplatelet therapy for ≥7 days before CAS. Neurologic examination and magnetic resonance imaging (MRI) of the brain were undertaken before and at 24 h after CAS. Samples of venous blood were collected at <24 h before CAS for the evaluation of hematology, reticulocytes, coagulation markers (PT, APTT, Fbg, Clauss), vWF antigen, PAI-1 activity, PAI-1 polymorphism 4G/5G, and the multiplate (aspirin and clopidogrel) resistance test. Blood samples for the assessment of anti-Xa activity were collected during CAS. Differences in the values of laboratory markers between patients with and without new ischemic lesions of the brain on control MRI were evaluated.

Results: The cohort comprised 81 patients (53 males; mean age, 67.3±7.2 years). New ischemic infarctions in the brain on control MRI were found in 46 (56.8%) patients. Three of seven patients with resistance to aspirin or clopidogrel had a new ischemic infarction in the brain. No significant differences for particular markers were found between patients with and without an ischemic lesion in the brain.

Conclusion: A high risk of a new ischemic infarction in the brain was detected in patients undergoing CAS, but a laboratory-based predictor of such an infarction could not be identified.
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http://dx.doi.org/10.5551/jat.31799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399266PMC
July 2016