Use of germline genetic variability for prediction of chemoresistance and prognosis of breast cancer patients

The aim of our study was to set up a panel for targeted sequencing of chemoresistance genes and the main transcription factors driving their expression and to evaluate their predictive and prognostic value in breast cancer patients. Coding and regulatory regions of 509 genes, selected from PharmGKB and Phenopedia, were sequenced using massive parallel sequencing in blood DNA from 105 breast cancer patients in the testing phase. In total, 18,245 variants were identified of which 2565 were novel variants (without rs number in dbSNP build 150) in the testing phase. Variants with major allele frequency over 0.05 were further prioritized for validation phase based on a newly developed decision tree. Using emerging in silico tools and pharmacogenomic databases for functional predictions and associations with response to cytotoxic therapy or disease-free survival of patients, 55 putative variants were identified and used for validation in 805 patients with clinical follow up using KASP™ technology. In conclusion, associations of rs2227291, rs2293194, and rs4376673 (located in ATP7A, KCNAB1, and DFFB genes, respectively) with response to neoadjuvant cytotoxic therapy and rs1801160 in DPYD with disease-free survival of patients treated with cytotoxic drugs were validated and should be further functionally characterized. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.Czech Medical Council [15-25618A]; Charles University [GAUK 1776218

Role of genetic variation in ABC transporters in breast cancer prognosis and therapy response

Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants in coding and regulatory sequences of all human ABC genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 43 prioritized variants associating with response or survival in the above testing phase were then analyzed by allelic discrimination in the large validation set (n = 802). Variants in ABCA4, ABCA9, ABCA12, ABCB5, ABCC5, ABCC8, ABCC11, and ABCD4 associated with response and variants in ABCA7, ABCA13, ABCC4, and ABCG8 with survival of the patients. No association passed a false discovery rate test, however, the rs17822931 (Gly180Arg) in ABCC11, associating with response, and the synonymous rs17548783 in ABCA13 (survival) have a strong support in the literature and are, thus, interesting for further research. Although replicated associations have not reached robust statistical significance, the role of ABC transporters in breast cancer should not be ruled out. Future research and careful validation of findings will be essential for assessment of genetic variation which was not in the focus of this study, e.g., non-coding sequences, copy numbers, and structural variations together with somatic mutations. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.Czech Medical Council [17-28470A]; Czech Ministry of Education, Youth and SportsMinistry of Education, Youth & Sports - Czech Republic [CZ.02.1.01/0.0/0.0/16_013/0001634]; Grant Agency of Charles University [UNCE/MED/006]; Grant Agency of the Czech RepublicGrant Agency of the Czech Republic [19-03063S

Author's book on the theme of Memories

Jako svoji bakalářskou práci jsem se rozhodla vytvořit autorskou knihu na téma vzpomínky. Kniha je o vzpomínkách mé babičky a její sestry. Jejich vzpomínky jsem doplnila vlastními ilustracemi vytvořenými grafickou technikou, linorytu. Většina linorytů je černobílá, některé jsou doplněné o modrou nebo červenou barvu. Kniha je určená dětem i dospělým, zejména mé babičce a mým blízkým. Zachycuje vzpomínky na dobu, kterou jsem nezažila.ObhájenoFor my bachelor's thesis, I created an artist's book on the topic of memories. The book is about the memories of my grandmother and her sister. I supplemented their memories with my own illustrations created using the printmaking technique of linocut. Most linocuts are black and white, some are complemented by blue or red. The book is intended for both children and adults, especially for my grandmother and my loved ones. The book depicts the memories of a time that I did not experience

BIBLIOPHILIA

Tématem mé diplomové práce je bibliofilie. Vybrala jsem si knihu Malý Alenáš od Ivana Vyskočila. Tato kniha je o Malém Alenáši, který je správcem snů. Jelikož je kniha o snech, které se nám po probuzení rychle vytrácejí z paměti, vytvořila jsem ilustrace pomocí lihových fix rozpitých lihem. Tím jsem docílila toho, že obrázky nejsou zcela zřetelné, tak jako sny. Kromě knih jsou součástí mé diplomové práce také dva soubory grafických listů. Při jejich tvorbě jsem vycházela z ilustrací použitých v knize. Dělala jsem je formou monotypu v kombinaci s malými razítky.ObhájenoThe topic of my diploma thesis is Bibliophilia. I chose a book called Malý Alenáš written by Ivan Vyskočil. This book is about Malý Alenáš, who is the manager of dreams. Since the book is about dreams, which quickly fade from our memory when we wake up, I created the illustrations using a black permanent marker pen blurred with alcohol. In doing so, I have achieved that the images are not quite clear, just as the dreams are. In addition to books, my diploma thesis also includes two sets of graphic sheets. They are based on the illustrations used in the book. I made them in the form of a monotype in combination with small stamps

BIBLIOPHILIA

Tématem mé diplomové práce je bibliofilie. Vybrala jsem si knihu Malý Alenáš od Ivana Vyskočila. Tato kniha je o Malém Alenáši, který je správcem snů. Jelikož je kniha o snech, které se nám po probuzení rychle vytrácejí z paměti, vytvořila jsem ilustrace pomocí lihových fix rozpitých lihem. Tím jsem docílila toho, že obrázky nejsou zcela zřetelné, tak jako sny. Kromě knih jsou součástí mé diplomové práce také dva soubory grafických listů. Při jejich tvorbě jsem vycházela z ilustrací použitých v knize. Dělala jsem je formou monotypu v kombinaci s malými razítky.ObhájenoThe topic of my diploma thesis is Bibliophilia. I chose a book called Malý Alenáš written by Ivan Vyskočil. This book is about Malý Alenáš, who is the manager of dreams. Since the book is about dreams, which quickly fade from our memory when we wake up, I created the illustrations using a black permanent marker pen blurred with alcohol. In doing so, I have achieved that the images are not quite clear, just as the dreams are. In addition to books, my diploma thesis also includes two sets of graphic sheets. They are based on the illustrations used in the book. I made them in the form of a monotype in combination with small stamps

The impact of computer criminality on the society

Import 04/07/2011Počítačová kriminalita je mladý, dynamicky se rozvíjející obor. Významnou charakteristikou pro počítačovou kriminalitu jsou v jejím důsledku značné ztráty, ať již přímo v podobě finančních částek nebo v podobě zneužitých údajů. Hlavním cílem mé diplomové práce je poukázat na společenskou nebezpečnost počítačové kriminality, na její aktuální a nejzajímavější aspekty a její ekonomický a právní dopad. Úvodní kapitola se zabývá teoretickým výkladem obecné terminologie počítačové kriminality. Je zde uveden vznik počítačové kriminality, spolu s návazností na historický vývoj výpočetní techniky. Významná část je zde věnována také prevenci a represi z pohledu počítačové kriminality. Nedílnou součástí teoretického vymezení je charakteristika pachatele tohoto druhu kriminality. Ve stěžejní a zároveň nejrozsáhlejší části mé diplomové práce jsou rozčleněny hlavní dopady počítačové kriminality na společnost a to jak z právního tak ekonomického hlediska. Je zde nastíněna situace v České republice ve srovnání se zahraničím, spolu s výkladem příslušných právních norem. V této části je také prostor pro kriminalitu na internetu a kyberterorismus, jehož součástí je i kyberšikana. Závěrečná část práce je věnována ochraně dat. Jedná se o velmi důležitou součást preventivních opatření vztahujících se k počítačové kriminalitě. Hlavním aspektem je zde především problematika porušování autorských práv a její trestněprávní úprava. Součástí kapitoly o ochraně dat je také problematika zabývající se porušováním předpisů o ochraně osobních údajů.Computer crime is a young, rapidly growing field. An important characteristic of computer crimes are the result of significant losses, either directly in the form of financial amounts or in the form of misused data. The main goal of my thesis is to highlight the social hazards of cyber crime, its current and interesting aspects and their economic and legal impact. The opening chapter deals with the theoretical interpretation of the general terminology of computer crime. Here there is the emergence of cyber crime, along with links to the historical development of computer technology. A significant portion is also devoted to the prevention and repression from the perspective of cyber crime. An integral part of this theoretical characteristics of the perpetrators of crime. In the core, while the largest part of my thesis is divided main effects of computer crime on society and from both a legal and economic terms. It describes the situation in the Czech Republic in comparison with other countries, together with the interpretation of relevant laws. This section also has space for online crime and cyberterrorism, which also includes cyberbullying. The final part is devoted to data protection. This is a very important part of preventive measures related to cyber crime. The main aspect here is mainly the issue of copyright infringement and its criminal laws. A critical component in the chapter on data protection issues is also dealing with violations of legislation on protection of personal data.121 - Katedra ekonomické žurnalistikyvýborn

Economic Criminality in the Czech Republic

Import 01/09/2009Prezenční121 - Katedra ekonomické žurnalistikyvýborn

SLC46A1 haplotype with predicted functional impact has prognostic value in breast carcinoma

Background and Objective: Membrane solute carrier transporters play an important role in the transport of a wide spectrum of substrates including anticancer drugs and cancer-related physiological substrates. This study aimed to assess the prognostic relevance of gene expression and genetic variability of selected solute carrier transporters in breast cancer. Methods: Gene expression was determined by quantitative real-time polymerase chain reaction. All SLC46A1 and SLCO1A2 exons and surrounding non-coding sequences in DNA extracted from the blood of patients with breast cancer (exploratory phase) were analyzed by next-generation sequencing technology. Common variants (minor allele frequency ≥ 5%) with in silico-predicted functional relevance were further analyzed in a large cohort of patients with breast cancer (n = 815) and their prognostic and predictive potential was estimated (validation phase). Results: A gene expression and bioinformatics analysis suggested SLC46A1 and SLCO1A2 to play a putative role in the prognosis of patients with breast cancer. In total, 135 genetic variants (20 novel) were identified in both genes in the exploratory phase. Of these variants, 130 were non-coding, three missense, and two synonymous. One common variant in SLCO1A2 and four variants in SLC46A1 were predicted to be pathogenic by in silico programs and subsequently validated. A SLC46A1 haplotype block composed of rs2239911-rs2239910-rs8079943 was significantly associated with ERBB2/HER2 status and disease-free survival of hormonally treated patients. Conclusions: This study revealed the prognostic value of a SLC46A1 haplotype block for breast cancer that should be further studied. © 2020, The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.Ministry of Health of the Czech RepublicMinistry of Health, Czech Republic [17-28470A]; National Center of Medical Genomics [CZ.02.1.01/0.0/0.0/16_ 013/0001634]; Czech Ministry of Education, Youth and Sports INTERCOST [LTC19020]; Charles University project "Center of clinical and experimental liver surgery" [UNCE/MED/006]CZ.02.1.01/0.0/0.0/16_013/0001634; Univerzita Karlova v Praze, UK: UNCE/MED/006; Grantová Agentura, Univerzita Karlova, GA, UK; Ministerstvo Školství, Mládeže a Tělovýchovy, MŠMT: LTC19020; Ministerstvo Zdravotnictví Ceské Republiky, MZCR: 17-28470

Integrative analysis of mRNA and miRNA expression profiles and somatic variants in oxysterol signaling in early‐stage luminal breast cancer

Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N = 162 in total) with early‐stage estrogen‐receptor‐positive luminal BC—high‐coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro‐RNA (miRNA) transcriptome microarrays—we describe complex oxysterol‐related interaction (correlation) networks, with validation in public datasets (n = 538) and 11 databases. The ESR1‐CH25H‐INSIG1‐ABCA9 axis was the most prominent, interconnected through miR‐125b‐5p, miR‐99a‐5p, miR‐100‐5p, miR‐143‐3p, miR‐199b‐5p, miR‐376a‐3p, and miR‐376c‐3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol‐related genes. STARD5 was upregulated in patients with positive lymph node status. High expression of hsa‐miR‐19b‐3p was weakly associated with poor survival. This is the first study of oxysterol‐related genes in BC that combines DNA, mRNA, and miRNA multiomics with detailed clinical data. Future studies should provide links between intratumoral oxysterol signaling depicted here, circulating oxysterol levels, and therapy outcomes, enabling eventual clinical exploitation of present findings