Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis.

BACKGROUND People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. METHODS We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. RESULTS We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. CONCLUSIONS In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches

Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model’s structure and in silico “experimental” data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation

Expression of Ksp-cadherin during kidney development and in renal cell carcinoma

Cadherins are a large family of cell–cell adhesion molecules acting in a homotypic, homophilic manner that play an important role in the maintenance of tissue integrity. In the human kidney, several members of the cadherin family (including E- and N-cadherin, cadherin-6, -8 and -11) are expressed in a controlled spatiotemporal pattern. Cadherin-16, also called kidney-specific (Ksp-) cadherin, is exclusively expressed in epithelial cells of the adult kidney. In renal cell carcinomas (RCCs), which are considered to originate from epithelial kidney tubular cells, a complex pattern of cadherin expression can be observed, but Ksp-cadherin expression has not been analysed so far. In the present study, we show that the expression of Ksp-cadherin is completely abrogated in RCCs. Whereas Ksp-cadherin can be detected at later stages of tubulogenesis during human renal development and in the distal tubules of adult kidneys, no expression was found by immunohistochemistry or Western blot analysis in RCC tumour tissues and several RCC cell lines. However, despite the lack of protein expression, mRNA synthesis of Ksp-cadherin could be detected by reverse transcriptase–polymerase chain reaction analysis in all RCC tissues and most of the RCC cell lines studied, although at a reduced level. The loss of Ksp-cadherin protein was only observed in the malignant part of the tumour kidneys, whereas in the normal part of the affected kidneys Ksp-cadherin expression was clearly detected. These results indicate a downregulation of Ksp-cadherin in RCC and suggest a role for this cell adhesion molecule in tumour suppression

Разработка дизайна оболочки велотренажера для людей с ограниченными физическими возможностями

Объектом исследования является велотренажер для людей с ограниченными физическими возможностями. Цель работы – проектирование оболочки велотренажера для людей с ограниченными физическими возможностями. В процессе проектирования проводилась разработка вариантов дизайнерских решений оболочки корпуса. В результате проектирования была разработана велотренажера для людей с ограниченными физическими возможностями.The object of the study is an exercise bike for people with disabilities. The aim of the work is to design the shell of an exercise bike for people with disabilities. In the design process, the development of variants of the design solutions of the hull shell was carried out. As a result of the design, an exercise bike was developed for people with disabilities

Degradation of haloaromatic compounds

An ever increasing number of halogenated organic compounds has been produced by industry in the last few decades. These compounds are employed as biocides, for synthetic polymers, as solvents, and as synthetic intermediates. Production figures are often incomplete, and total production has frequently to be extrapolated from estimates for individual countries. Compounds of this type as a rule are highly persistent against biodegradation and belong, as "recalcitrant" chemicals, to the class of so-called xenobiotics. This term is used to characterise chemical substances which have no or limited structural analogy to natural compounds for which degradation pathways have evolved over billions of years. Xenobiotics frequently have some common features. e.g. high octanol/water partitioning coefficients and low water solubility which makes for a high accumulation ratio in the biosphere (bioaccumulation potential). Recalcitrant compounds therefore are found accumulated in mammals, especially in fat tissue, animal milk supplies and also in human milk. Highly sophisticated analytical techniques have been developed for the detection of organochlorines at the trace and ultratrace level