Publications by authors named "Mariam Gachechiladze"

17 Publications

  • Page 1 of 1

Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech Republic.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.
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http://dx.doi.org/10.3390/ijms22062844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000894PMC
March 2021

Comparative Analysis of Immunohistochemical Staining Intensity Determined by Light Microscopy, ImageJ and QuPath in Placental Hofbauer Cells.

Acta Histochem Cytochem 2021 Feb 20;54(1):21-29. Epub 2021 Feb 20.

Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, 779 00, Olomouc, Czech Republic.

Software based analyses of immunohistochemical staining are designed for obtaining quantitative, reproducible, and objective data. However, often times only a certain type of positive cells or structures need to be quantified thus whole image analysis cannot be performed. Such an example is Hofbauer placental cells, which show positivity of some antigens together with trophoblast, but only Hofbauer cells represent the regions of interest (ROIs). Two independent observers evaluated the immunohistochemical staining intensity of Hofbauer cells in placenta samples stained for cytoplasmic antigens by ImageJ, QuPath and light microscopy. Thus, the precise manual determination of ROIs, i.e. Hofbauer cells, was necessary. We detected low inter-observer variability in staining intensity. Almost perfect agreement between observers was reached for ImageJ and QuPath whilst substantial agreement was reached for light microscopy evaluation. As for the comparison of ImageJ, QuPath and light microscopy, the agreement of all three methods (identical immunohistochemical intensity) was achieved for 38.1% samples. The almost perfect agreement of staining intensities was reached between ImageJ and QuPath, and moderate agreement for comparison of the light microscopy to both software. Software analyses are much more time-consuming, thus their utilization is at least questionable to evaluate ROIs with selection.
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http://dx.doi.org/10.1267/ahc.20-00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947637PMC
February 2021

Predictive and Prognostic Value of DNA Damage Response Associated Kinases in Solid Tumors.

Front Oncol 2020 3;10:581217. Epub 2020 Nov 3.

Department of Medical Oncology and Haematology, Cantonal Hospital, St. Gallen, Switzerland.

Dysfunctional DNA repair with subsequent genome instability and high mutational burden represents a major hallmark of cancer. In established malignant tumors, increased DNA repair capacity mediates resistance to DNA-damaging therapeutics, including cytotoxic drugs, radiotherapy, and selected small molecules including inhibitors of poly (ADP-ribose) polymerase (PARP), Ataxia Telangiectasia Mutated (ATM), ataxia telangiectasia and Rad3-related protein (ATR), and Wee1 kinase (Wee1). In addition, DNA repair deficiency is not only associated with sensitivity to selected anticancer drugs, but also with increased mutagenicity and increased neoantigen load on tumor cells, resulting in increased immunogenicity and improved response to CTLA4- or PD-(L)1 targeting monoclonal antibodies. DNA damage response (DDR) is composed of complex signalling pathways, including the sensing of the DNA damage, signal transduction, cellular response pathways to DNA damage, and activation of DNA repair. DNA double strand breaks (DSBs) are the most dangerous form of DNA damage. Tumor cells are characterised by frequent accumulation of DSBs caused by either endogenous replication stress or the impact of cancer treatment, most prominently chemotherapy and radiotherapy. Therefore, response of cancer cells to DSBs represents a crucial mechanism for how tumors respond to systemic treatment or radiotherapy, and how resistance develops. Ample clinical evidence supports the importance of DDR associated kinases as predictive and prognostic biomarkers in cancer patients. The ATM-CHK2 and ATR-CHK1-WEE1 pathways initiate DNA DSB repair. In the current review, we focus on major DDR associated kinases including ATM, ATR, CHK1, CHK2, and WEE1, and discuss their potential prognostic and predictive value in solid malignancies.
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http://dx.doi.org/10.3389/fonc.2020.581217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670868PMC
November 2020

Prognostic value of tumor-infiltrating lymphocytes (TILs) and their association with PD-L1 expression and DNA repair protein RAD51 in patients with resected non-small cell lung carcinoma.

Lung Cancer 2020 09 23;147:30-38. Epub 2020 Jun 23.

Department of Medical Oncology and Hematology, Cantonal Hospital, CH-9007, St. Gallen, Switzerland.

Objectives: DNA repair proteins have emerged as potential predictors for immunotherapy response alongside PD-L1 expression, tumor-infiltrating lymphocytes (TILs) and tumor mutational burden. We analyzed expression of PD-L1, TILs count and expression of the homologous recombination (HR) protein RAD51, as potential prognostic factors in patients with resected non-small-cell lung carcinoma (NSCLC).

Materials And Methods: Discovery set included 96 NSCLC patients from the University Hospital Olomouc (Czech Republic) and a replication set included 1109 NSCLC patients from University Hospital Zurich (Switzerland). Tissue microarrays (TMAs) were stained using the automated staining platform Ventana Benchmark Ultra with antibodies against RAD51,CD3, CD8, CD68 and PD-L1.

Results: Loss of nuclear RAD51 protein was associated with high TILs (r=-0.25, p = 0.01) and PD-L1 status (10.6 vs. 2.4 %, p = 0.012) in patients receiving neoadjuvant chemo-/radiotherapy (CT/RT). In silico analysis from the TCGA data set showed a negative relationship between RAD51 mRNA expression and CD45 (r = ‒0.422, p < 0.0001), CD68 (r = ‒0.326, p < 0.001), CD3 (r = ‒0.266, p < 0.001) and CD8 (r = ‒0.102, p < 0.001). RAD51 low/PD-L1 high patients were clustered as separate entity in the replication set and in TCGA dataset. High TILs status was significantly associated with improved OS in the replication set (unadjusted HR = 0.57, 95 % CI 0.42-0.76, p < 0.001). Similar results have been seen for CD3, CD8 and CD68.

Conclusions: In conclusion, RAD51 nuclear loss is weakly associated with increased TILs and high PD-L1 at the time of surgery in curatively resected NSCLC and after prior exposure to neoadjuvant chemo- or radiotherapy. Both high TILs and RAD51 nuclear loss were confirmed as independent prognostic factors in curatively resected NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.025DOI Listing
September 2020

RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether.

Cell 2019 Sep;179(1):147-164.e20

NINDS, NIH, Bethesda, MD, USA. Electronic address:

Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for RNA transport in which RNA granules "hitchhike" on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as a molecular tether between RNA granules and lysosomes. ANXA11 possesses an N-terminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. RNA granule transport requires ANXA11, and amyotrophic lateral sclerosis (ALS)-associated mutations in ANXA11 impair RNA granule transport by disrupting their interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in ALS.
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http://dx.doi.org/10.1016/j.cell.2019.08.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890474PMC
September 2019

Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

Oncol Lett 2019 Aug 7;18(2):1259-1266. Epub 2019 Jun 7.

Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, 77515 Olomouc, Czech Republic.

Sphingosine 1-phosphate (S1P) is a bioactive lipid metabolite associated with cancer cell proliferation, survival, migration and regulation of tumor angiogenesis in various cellular and animal models. Sphingosine kinase-1 (SphK1) and S1P lyase are the main enzymes that respectively control the synthesis and degradation of S1P. The present study analyzed the prognostic and predictive value of SphK1 and S1P lyase expression in patients with non-small cell lung cancer (NSCLC), treated with either surgery alone or in combination with adjuvant carboplatin and navelbine. Formalin-fixed, paraffin-embedded tissue samples from 176 patients with NSCLC were stained immunohistochemically using antibodies against SphK1 and S1P lyase, and their expression was correlated with all available clinicopathological factors. Increased expression of SphK1 was significantly associated with shorter overall and disease free survival in patients treated with adjuvant platinum-based chemotherapy. No prognostic relevance for S1P lyase expression was observed. Collectively, the results suggest that the immunohistochemical detection of SphK1 may be a promising predictive marker in NSCLC patients treated with adjuvant platinum-based chemotherapy.
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http://dx.doi.org/10.3892/ol.2019.10447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607215PMC
August 2019

CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons.

Neuron 2019 10 15;104(2):239-255.e12. Epub 2019 Aug 15.

Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:

CRISPR/Cas9-based functional genomics have transformed our ability to elucidate mammalian cell biology. However, most previous CRISPR-based screens were conducted in cancer cell lines rather than healthy, differentiated cells. Here, we describe a CRISPR interference (CRISPRi)-based platform for genetic screens in human neurons derived from induced pluripotent stem cells (iPSCs). We demonstrate robust and durable knockdown of endogenous genes in such neurons and present results from three complementary genetic screens. First, a survival-based screen revealed neuron-specific essential genes and genes that improved neuronal survival upon knockdown. Second, a screen with a single-cell transcriptomic readout uncovered several examples of genes whose knockdown had strikingly cell-type-specific consequences. Third, a longitudinal imaging screen detected distinct consequences of gene knockdown on neuronal morphology. Our results highlight the power of unbiased genetic screens in iPSC-derived differentiated cell types and provide a platform for systematic interrogation of normal and disease states of neurons. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2019.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813890PMC
October 2019

Tumor autophagy is associated with survival outcomes in patients with resected non-small cell lung cancer.

Lung Cancer 2019 03 8;129:85-91. Epub 2019 Jan 8.

Laboratory of Molecular Pathology, Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentristy, Palacký University, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentristy, Palacký University, Olomouc, Czech Republic. Electronic address:

Objectives: LC3A protein is associated with autophagosomes, and LC3A immunohistochemistry (IHC) is used for the detection of autophagy activity. The aim of this study was to assess the prognostic value of LC3A expression in patients with resected non-small cell lung cancer (NSCLC).

Materials And Methods: We used tissue microarrays (TMAs) constructed from 116 resected stage IB-III NSCLC patients. Standard immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue sections using antibody against LC3A autophagic potein. Stained slides were scanned by Olympus dotSlide Digital Virtual Microscopy System (Japan) and the LC3A staining was evaluated digitally. Groups were compared using the Mann Whitney U test, and correlations were assessed using Spearman's rank test. Survival was calculated using Kaplan-Meier analysis. Primary study endpoint was overall survival (OS), secondardy study endpoint disease-free survival (DFS). Cut-off optimization for LC3A prognostic value was performed using the "cut-off finder' 'software (Charite, Berlin, Germany). In addition, the Kaplan Meier plotter (KmPlot) was used to assess the relationship between LC3A mRNA expression and clinical outcome (OS and DFS) in patients with NSCLC.

Results: From 116 patients, 88 tissue samples were available for final examination. No significant association was found between LC3A staining and other clinicopathological variables, including tumor grade, stage and histological subtype. A higher number of LC3A stone-like structures (SLSs) (>20), was significanly associated with poor OS (HR = 2.27, p = 0.011) and DFS (HR = 2.27, p = 0.003). A significant association between high LC3A mRNA and both a worse OS and worse DFS was found by KMPlot analysis in patients with stage I-III NSCLC.

Conslusion: This retrospective study suggests that SLSs as assessed by LC3A IHC as well as LC3A mRNA expression has a clinically relevant negative prognostic value in patients with resected NSCLC, and should be further investigated.
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http://dx.doi.org/10.1016/j.lungcan.2019.01.001DOI Listing
March 2019

Heterochromatin anomalies and double-stranded RNA accumulation underlie poly(PR) toxicity.

Science 2019 02;363(6428)

Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA, USA.

How hexanucleotide GGGGCC (GC) repeat expansions in cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded GC repeats. The expression of green fluorescent protein-conjugated (PR) (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of -associated FTD and ALS.
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http://dx.doi.org/10.1126/science.aav2606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524780PMC
February 2019

Targeting genotoxic and proteotoxic stress-response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram.

Prostate 2019 03 29;79(4):352-362. Epub 2018 Nov 29.

Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.

Background: Castration-resistant prostate cancer (PCa) represents a serious health challenge. Based on mechanistically-supported rationale we explored new therapeutic options based on clinically available drugs with anticancer effects, including inhibitors of PARP1 enzyme (PARPi), and histone deacetylases (vorinostat), respectively, and disulfiram (DSF, known as alcohol-abuse drug Antabuse) and its copper-chelating metabolite CuET that inhibit protein turnover.

Methods: Drugs and their combination with ionizing radiation (IR) were tested in various cytotoxicity assays in three human PCa cell lines including radio-resistant stem-cell like derived cells. Mechanistically, DNA damage repair, heat shock and unfolded protein response (UPR) pathways were assessed by immunofluorescence and immunoblotting.

Results: We observed enhanced sensitivity to PARPi/IR in PC3 cells consistent with lower homologous recombination (HR) repair. Vorinostat sensitized DU145 cells to PARPi/IR and decreased mutant p53. Vorinostat also impaired HR-mediated DNA repair, as determined by Rad51 foci formation and downregulation of TOPBP1 protein, and overcame radio-resistance of stem-cell like DU145-derived cells. All PCa models responded well to CuET or DSF combined with copper. We demonstrated that DSF interacts with copper in the culture media and forms adequate levels of CuET indicating that DSF/copper and CuET may be considered as comparable treatments. Both DSF/copper and CuET evoked hallmarks of UPR in PCa cells, documented by upregulation of ATF4, CHOP and phospho-eIF2α, with ensuing heat shock response encompassing activation of HSF1 and HSP70. Further enhancing the cytotoxicity of CuET, combination with an inhibitor of the anti-apoptotic protein survivin (YM155, currently undergoing clinical trials) promoted the UPR-induced toxicity, yielding synergistic effects of CuET and YM155.

Conclusions: We propose that targeting genotoxic and proteotoxic stress responses by combinations of available drugs could inspire innovative strategies to treat castration-resistant PCa.
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http://dx.doi.org/10.1002/pros.23741DOI Listing
March 2019

RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies.

Int J Cancer 2017 10 19;141(7):1286-1294. Epub 2017 May 19.

Department of Medical Oncology and Hematology, Cantonal Hospital, St.Gallen, Switzerland.

Targeting deficient mechanisms of cellular DNA repair still represents the basis for the treatment of the majority of solid tumors, and increased DNA repair capacity is a hallmark mechanism of resistance not only to DNA-damaging treatments such as cytotoxic drugs and radiotherapy, but also to small molecule targeted drugs such as inhibitors of poly-ADP ribose polymerase (PARP). Hence, there is substantial medical need for potent and convenient biomarkers of individual response to DNA-targeted treatment in personalized cancer care. RAD51 is a highly conserved protein that catalyzes DNA repair via homologous recombination, a major DNA repair pathway which directly modulates cellular sensitivity to DNA-damaging treatments. The clinical and biological significance of RAD51 protein expression is still under investigation. Pre-clinical studies consistently show the important role of nuclear RAD51 immunoreactivity in chemo- and radioresistance. Validating data from clinical trials however is limited at present, and some clinical studies show controversial results. This review gives a comprehensive overview on the current knowledge about the prognostic and predictive value of RAD51 protein expression and genetic variability in patients with solid malignancies.
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http://dx.doi.org/10.1002/ijc.30764DOI Listing
October 2017

Prognostic and predictive value of loss of nuclear RAD51 immunoreactivity in resected non-small cell lung cancer patients.

Lung Cancer 2017 03 18;105:31-38. Epub 2017 Jan 18.

Department of Medical Oncology and Hematology, Cantonal Hospital, CH-9007 St. Gallen, Switzerland. Electronic address:

Objectives: In response to DNA damage, recombination proteins are relocalized into sub-nuclear complexes that are microscopically detected as RAD51-containing nuclear foci. We aimed for assessing the prognostic and predictive value of loss of nuclear RAD51 immunoreactivity ('RAD51 loss') in 2 independent stage I to III non-small cell lung cancer (NSCLC) patient cohorts undergoing surgical resection and eventual perioperative chemo-/radiotherapy (CT/RT).

Materials And Methods: The discovery set included 69 evaluable patients (19 adenocarcinomas, ADC, 50 squamous cell carcinomas, SCC) from Palacky University Hospital, 45/69 (65.2%) with additional platinum-based CT. The replication set entailed 845 evaluable patients (446 ADC, 399 SCC) from University Hospital Zurich, 308/845 (36.5%) with platinum based CT or RT. RAD51 loss was defined as ≤20% of tumor cell nuclei having any nuclear RAD51 expression. We assessed the prognostic value of RAD51 loss in all patients and its predictive value in patients receiving CT/RT.

Results: RAD51 loss was observed in 40/69 (58.0%) and 439/845 (51.9%) evaluable tumors in the discovery and replication set, respectively (p=0.34). It was more frequent in ADC compared to SCC (57.2% vs 47.4%, p=0.003). RAD51 loss was significantly associated with worse OS in both the discovery (adjusted HR=2.39, p=0.039) and replication set (adjusted HR=1.31, p=0.008). The unfavourable prognostic effect of RAD51 loss seen in the overall population was not observed in patients receiving perioperative CT (adjusted HR=1.07, p=0.73) or perioperative RT (adjusted HR=1.05, p=0.82).

Conclusion: RAD51 loss has an unfavourable prognostic impact in NSCLC patients undergoing curative surgical resection, but it may have a favourable predictive value in the subgroup of patients receiving perioperative platinum-based CT or RT, most likely as a consequence of deficient DNA repair.
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http://dx.doi.org/10.1016/j.lungcan.2017.01.009DOI Listing
March 2017

Apolipoprotein E Genotype Affects Size of ApoE Complexes in Cerebrospinal Fluid.

J Neuropathol Exp Neurol 2016 Oct 11;75(10):918-924. Epub 2016 Aug 11.

From the Department of Biology (NMH, MAG); and Department of Neuroscience, Georgetown University (GWR), Washington, District of Columbia

Apolipoprotein E (apoE) is associated with lipoproteins in the cerebrospinal fluid (CSF). APOE4 increases and APOE2 decreases the risk for Alzheimer disease (AD) compared to the risk associated with APOE3 Because apoE4 is less efficient at cholesterol efflux than apoE2 or apoE3 in vitro, we hypothesized that APOE genotype may affect apoE particle size in vivo and that these size differences may be related to AD risk. We used nondenaturing gel electrophoresis to test for differences in the size of apoE complexes in human CSF samples of various APOE genotypes and created profiles of each sample to compare the patterns of apoE distribution. For middle-aged adults with no dementia, APOE 2.3 individuals had significantly larger apoE complexes than APOE 3.3 subjects, who had significantly larger apoE complexes than APOE 3.4 and APOE 4.4 individuals. Similarly, in an independent cohort of older adults, CSF apoE complexes of APOE4-positive individuals were smaller than those of the APOE4-negative individuals. Compared to individuals with no dementia, those with the mildest stages of dementia had similar sized CSF apoE complexes. These results identify a novel phenotypic difference in the size of CSF apoE complexes in middle age that correlate with the risk of AD later in life.
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http://dx.doi.org/10.1093/jnen/nlw067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996536PMC
October 2016

Primitive neuroectodermal tumor (PNET) of the lung in an adult woman.

World J Surg Oncol 2014 Dec 5;12:374. Epub 2014 Dec 5.

Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine (IMTM), Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 3, 775 15 Olomouc, Czech Republic.

Primary primitive neuroectodermal tumors (PNETs) are extremely rare in the lung and especially in adult women. We describe a case of PNET of the lung with aggressive behavior in 31-year-old woman. Diagnosis was based on histopathological and immunohistochemical studies, and confirmed by molecular genetic analysis of chromosome rearrangements in the EWSR1 gene region. Clinical follow-up, post-mortem findings, and differential diagnosis are also discussed.
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http://dx.doi.org/10.1186/1477-7819-12-374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289161PMC
December 2014

The role of cancer-associated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance.

Cancer Cell Int 2014 16;14:41. Epub 2014 May 16.

Laboratory of Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.

Tumors are not merely masses of neoplastic cells but complex tissues composed of cellular and noncellular elements. This review provides recent data on the main components of a dynamic system, such as carcinoma associated fibroblasts that change the extracellular matrix (ECM) topology, induce stemness and promote metastasis-initiating cells. Altered production and characteristics of collagen, hyaluronan and other ECM proteins induce increased matrix stiffness. Stiffness along with tumor growth-induced solid stress and increased interstitial fluid pressure contribute to tumor progression and therapy resistance. Second, the role of immune cells, cytokines and chemokines is outlined. We discuss other noncellular characteristics of the tumor microenvironment such as hypoxia and extracellular pH in relation to neoangiogenesis. Overall, full understanding of the events driving the interactions between tumor cells and their environment is of crucial importance in overcoming treatment resistance and improving patient outcome.
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http://dx.doi.org/10.1186/1475-2867-14-41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038849PMC
June 2014

Correlation between BRCA1 expression and clinicopathological factors including brain metastases in patients with non-small-cell lung cancer.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013 Sep 1;157(3):227-32. Epub 2012 Nov 1.

Laboratory of Molecular Pathology, Department of Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.

Background: Previously identified as a breast and ovarian cancer susceptibility gene, BRCA1 has gained major scientific interest as a potential prognostic and/or predictive marker for various tumors, including non-small-cell lung cancer (NSCLC), the leading cause of cancer related mortality worldwide. BRCA1 plays a central role in DNA damage response (DDR. It undergoes phosphorylation by various DDR kinases at different serine residues, of which ser1524 is known to be specifically phosphorylated by ATM in response to genotoxic stress.

Methods: We performed BRCA1 immunohistochemistry on several tissue microarrays (TMAs) of 113 early (I, II stage) and advanced (III, IV stage) NSCLCs, using MS110 antibody against the BRCA1 N-terminal and S1524 antibody against the phosphorylated form of BRCA1 protein at ser1524 (Abcam). Patients with III and IV stage disease were treated by adjuvant cisplatin-based chemotherapy. Staining results were correlated with overall survival (OS), disease free survival (DFS) and with the occurrence of brain metastases.

Results: BRCA1 S1524 nuclear positivity was significantly correlated with longer OS and DFS in stage I and II patients (P<0.05), while OS and DFS were shorter in S1524 positive stage III and IV patients (P<0.05). No significant correlation was found with brain metastases.

Conclusion: The results show that BRCA1 phosphorylaton, at least in ser1524, differentiates the fate of early and advanced NSCLC as well as response to chemotherapy, but the underlying mechanisms are not completely understood. Detection of phosphorylated forms of BRCA1 might serve as a useful prognostic and predictive marker for patients with NSCLC.
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http://dx.doi.org/10.5507/bp.2012.099DOI Listing
September 2013

The role of BRCA1 in non-small cell lung cancer.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2012 Sep 1;156(3):200-3. Epub 2012 Jun 1.

Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.

Background: BRCA1 (Breast cancer 1) was previously identified as a breast and ovarian cancer susceptibility gene, but recently gained a major scientific interest as a prognostic and/or predictive marker for various tumors, including non-small cell lung cancer (NSCLC), which is the leading cause of cancer related mortality in the world. We aimed to review the role of BRCA1 in NSCLC based on currently available literature.

Methods: We performed the literature search in Pubmed database, using key words: BRCA1, non small cell lung cancer, chemotherapy, drug resistance. Articles published in English were selected for review.

Results: Research papers are mainly focused on BRCA1 mRNA expression studies in response to DNA damaging chemotherapy. Several articles about genetic and epigenetic changes of BRCA1 in NSCLC were also available.

Conclusions: BRCA1 is a multifunctional tumor supressor protein, which plays a key role in essential cellular processes and modulates the cellular response to cytotoxic chemotherapy. With the difference from breast and ovarian cancer, BRCA1 has no role in NSCLC cancerogenesis and mainly discussed as a promising genomic marker for customized chemotherapy in NSCLC patients.
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http://dx.doi.org/10.5507/bp.2012.049DOI Listing
September 2012
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