Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C >T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression

GSuite HyperBrowser: integrative analysis of dataset collections across the genome and epigenome

Background: Recent large-scale undertakings such as ENCODE and Roadmap Epigenomics have generated experimental data mapped to the human reference genome (as genomic tracks) representing a variety of functional elements across a large number of cell types. Despite the high potential value of these publicly available data for a broad variety of investigations, little attention has been given to the analytical methodology necessary for their widespread utilisation. Findings: We here present a first principled treatment of the analysis of collections of genomic tracks. We have developed novel computational and statistical methodology to permit comparative and confirmatory analyses across multiple and disparate data sources. We delineate a set of generic questions that are useful across a broad range of investigations and discuss the implications of choosing different statistical measures and null models. Examples include contrasting analyses across different tissues or diseases. The methodology has been implemented in a comprehensive open-source software system, the GSuite HyperBrowser. To make the functionality accessible to biologists, and to facilitate reproducible analysis, we have also developed a web-based interface providing an expertly guided and customizable way of utilizing the methodology. With this system, many novel biological questions can flexibly be posed and rapidly answered. Conclusions: Through a combination of streamlined data acquisition, interoperable representation of dataset collections, and customizable statistical analysis with guided setup and interpretation, the GSuite HyperBrowser represents a first comprehensive solution for integrative analysis of track collections across the genome and epigenome. The software is available at: https://hyperbrowser.uio.no.This work was supported by the Research Council of Norway (under grant agreements 221580, 218241, and 231217/F20), by the Norwegian Cancer Society (under grant agreements 71220’PR-2006-0433 and 3485238-2013), and by the South-Eastern Norway Regional Health Authority (under grant agreement 2014041).Peer Reviewe

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.We thank the DKFZ Genomics and Proteomics Core Facility and the OICR Genome Technologies Platform for provision of sequencing services. Financial support was provided by the consortium projects READNA under grant agreement FP7 Health-F4-2008-201418, ESGI under grant agreement 262055, GEUVADIS under grant agreement 261123 of the European Commission Framework Programme 7, ICGC-CLL through the Spanish Ministry of Science and Innovation (MICINN), the Instituto de Salud Carlos III (ISCIII) and the Generalitat de Catalunya. Additional financial support was provided by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883; the Ontario Institute for Cancer Research to PCB and JDM through funding provided by the Government of Ontario, Ministry of Research and Innovation; Genome Canada; the Canada Foundation for Innovation and Prostate Cancer Canada with funding from the Movember Foundation (PCB). PCB was also supported by a Terry Fox Research Institute New Investigator Award, a CIHR New Investigator Award and a Genome Canada Large-Scale Applied Project Contract. The Synergie Lyon Cancer platform has received support from the French National Institute of Cancer (INCa) and from the ABS4NGS ANR project (ANR-11-BINF-0001-06). The ICGC RIKEN study was supported partially by RIKEN President’s Fund 2011, and the supercomputing resource for the RIKEN study was provided by the Human Genome Center, University of Tokyo. MDE, LB, AGL and CLA were supported by Cancer Research UK, the University of Cambridge and Hutchison-Whampoa Limited. SD is supported by the Torres Quevedo subprogram (MI CINN) under grant agreement PTQ-12-05391. EH is supported by the Research Council of Norway under grant agreements 221580 and 218241 and by the Norwegian Cancer Society under grant agreement 71220-PR-2006-0433. Very special thanks go to Jennifer Jennings for administrating the activity of the ICGC Verification Working Group and Anna Borrell for administrative support.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1000

Converting data from a laser distance meter to PC through RS-422

Import 22/07/2015Bakalářská práce byla zpracována na téma ,,Převod dat z laserového měřiče vzdálenosti do PC pomocí RS-422“. Práce je rozdělena do dvou částí. Teoretická část se zabývá popisem laseru a možnostmi průmyslové komunikace. V praktické části bylo provedeno několik měření laserovým senzorem optoNCDT1302 vyrobeným firmou Micro-Epsilon. Data jsem zpracovával v programu ILD1302 Tool. Následně bylo vytvořeno programové prostředí pro zpracování dat a realizaci grafu.This thesis was prepared on the topic,, Converting data from a laser distance meter to a PC through RS-422. "The work is divided into two parts. The theoretical part describes the laser and industrial communications options. In the practical part was conducted several measurements of the laser sensor optoNCDT1302 manufactured by Micro-Epsilon. Data I worked in the program ILD1302 Tool. It was subsequently established software environment for data processing and realization of the chart.638 - Katedra automatizace a počítačové techniky v metalurgiidobř

Design of database and web application for elevator switchboards records

Tématem diplomové práce je návrh databáze a webové aplikace pro evidenci výtahových rozváděčů. Práce je rozdělena na část teoretickou a praktickou. Teoretická část je zaměřena na teorii, která je nezbytná k úspěšnému splnění cílů práce. Jsou v ní uvedeny potřebné informace týkající se návrhu databáze a webové aplikace. V praktické části je stručně popsána analýza současného stavu výtahové databáze společnosti Amsoft s.r.o. Jádrem práce je vlastní návrh nového datového modelu a aplikační logiky. Závěr práce je věnován srovnání navržené koncepce se současným stavem a možnosti dalšího rozšíření.The theme of this thesis is the design of a database and a web application for the recording of elevator cabinets. The thesis is divided into the theoretical and practical part. The theoretical part focuses on the theory that is necessary for the successful fulfilment of the goals of the work. It provides the necessary information regarding the design of the database and the web application. In the practical part is briefly described the analysis of the current state of the elevator database of Amsoft s.r.o. The core of the thesis is the design of a new data model and application logic. The conclusion of the thesis is devoted to the comparison of the proposed concept with the current state and possibilities of further expansion.638 - Katedra automatizace a počítačové techniky v metalurgiivýborn

Porovnání českého účetnictví s americkými zásadami US GAAP

Import 20/04/2006Prezenční výpůjčkaVŠB - Technická univerzita Ostrava. Fakulta metalurgie a materiálového inženýrství. Katedra (634) ekonomiky a managementu v metalurgi

Recyklace autovraků v České republice

Import 11/11/2010Recyklace autovraků má své opodstatnění nejen z hlediska současného pohledu na životní prostředí, ale i jako možný, potencionální zdroj druhotných surovin. Materiálová výtěžnost ekonomiky bude stále více jedním z faktorů, jak snižovat tlak na získávání potřebných surovin, jejichž cena nadále poroste. Likvidace autovraků v procesu jejich sběru, zpracování a využití v České republice probíhá, ale systém je nekoncepční a to jak z hlediska tvorby prostředků na dotační politiku státu, tak z hlediska stimulace účastníků likvidace a v neposlední řadě i nepropracovanou legislativou. Disertační práce si klade za cíl výše uvedené problémy detailněji popsat, analyzovat příčiny jejich přetrvávání a vypracovat ucelený návrh řešení v takovém stupni podrobnosti, aby mohl sloužit jako důvodová zpráva k přijetí zákonných opatření a zároveň jako zásady a limity pro činnost nově navrhované státní účelové instituce.Recycling of car wrecks is well founded not only in terms of the current perspective of environment, but also as a potential source of secondary raw materials. The material recovery factor of the economics will be an increasing factor of how to decrease the pressure of necessary raw materials acquiring while their prices will continue to increase. Disposal of car wrecks in its process of collection, manipulation and utilization in the Czech Republic is being currently proceeded, however the system is not conceptual, both in terms of endowment funds of the state policy creation and disposal’s participants stimulation and last but not least, an unelaborated legislation. This thesis objective is to describe the above mentioned problems in detail, to analyze the reason of their persistence and to develop a comprehensive proposal of resolution in such details to make it an explanatory memorandum of legal measures‘ acceptance as well as the principles and limits for the newly proposed state special-purpose institution.Prezenční634 - Katedra ekonomiky a managementu v metalurgiivyhově