Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma

We have recently described the enzymatic subunit of telomerase (hTERT) as an important prognostic marker for paediatric ependymoma. Because of the lack of good, representative pre-clinical models for ependymoma, we took advantage of our large cohort of ependymoma patients, some with multiple recurrences, to investigate telomere biology in these tumours. Our cohort consisted of 133 ependymomas from 83 paediatric patients and included 31 patients with recurrences. Clinical outcome was measured as overall survival, progression-free survival and response to therapy. In all 133 tumours, hTERT expression correlated with proliferative markers, including MIB-1 index (P<0.0001) and mitotic index (P=0.005), as well as overall tumour grade (P=0.001), but not with other markers of anaplasia. There was no correlation between telomere length and hTERT expression or survival. Surprisingly, prior radiation or chemotherapy neither induced sustained DNA damage nor affected telomere maintenance in recurrent tumours. There was an inverse correlation between hTERT expression and telomere dysfunction as measured by γH2AX expression (P=0.016). Combining γH2AX and hTERT expressions could segregate tumours into three different survival groups (log rank, P<0.0001) such that those patients whose tumours expressed hTERT and showed no evidence of DNA damage had the worst outcome. This study emphasises the importance of telomere biology as a prognostic tool and telomerase inhibition as a therapeutic target for paediatric ependymoma. Furthermore, we have demonstrated that analysing tumours as they progress in vivo is a viable approach to studying tumour biology in humans

Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel

EFFECTIVENESS ASSESSMENT METHODOLOGY OF INFORMATION SECURITY MANAGEMENT SYSTEM THROUGH THE SYSTEM RESPONSE TIME TO INFORMATION SECURITY INCIDENTS

Quality assessment of information security management system is an important step for obtaining baseline data for analysis of the security system control effectiveness, and evaluating implementation of the specified information security requirements of the organization. Proceeding from current analysis practice of information security management systems effectiveness assessment, it can be concluded that, in most cases, independent measurement of security control is carried out without regard to their interaction. The uncertainty of the stochastic nature of the measured security controls is not taken into account. There is a list of related measures for control and management; however, structural elements for measuring of these interactions are absent. Thus, there is an important and urgent task of improving the effectiveness assessing methodology for information security management system that can be solved by introducing a new integral effectiveness indicator of the system, which would give the possibility to take into account the above-mentioned shortcomings. The author proposes the usage of a new integral efficiency indicator - system response time to information security incidents. This efficiency indicator will make it possible to pass from the binary effectiveness assessment of the system "approve or disapprove" to a quantitative one. New performance indicator gives the possibility to take into account the uncertainty of the stochastic nature of the attributes and measures of management and control, provides a quantitative assessment of the information security state and has a clear physical interpretation for the organization management and information security officers. Dynamics of the indicator change from test to test will assess the information security management system state in general and effectiveness of taken control and management measures. The method for calculating of the new information security management system performance indicator is based on the experimental design theory. Its advantages are: information security service staff has an opportunity to control the attributes measurement, the same accuracy of estimates for attribute parameters during the measurement is provided, interaction degree between attributes and their importance in the computation of the effectiveness of information security managemen

TECHNIQUE OF OPTIMAL AUDIT PLANNING FOR INFORMATION SECURITY MANAGEMENT SYSTEM

Complication of information security management systems leads to the necessity of improving the scientific and methodological apparatus for these systems auditing. Planning is an important and determining part of information security management systems auditing. Efficiency of audit will be defined by the relation of the reached quality indicators to the spent resources. Thus, there is an important and urgent task of developing methods and techniques for optimization of the audit planning, making it possible to increase its effectiveness. The proposed technique gives the possibility to implement optimal distribution for planning time and material resources on audit stages on the basis of dynamics model for the ISMS quality. Special feature of the proposed approach is the usage of a priori data as well as a posteriori data for the initial audit planning, and also the plan adjustment after each audit event. This gives the possibility to optimize the usage of audit resources in accordance with the selected criteria. Application examples of the technique are given while planning audit information security management system of the organization. The result of computational experiment based on the proposed technique showed that the time (cost) audit costs can be reduced by 10-15% and, consequently, quality assessments obtained through audit resources allocation can be improved with respect to well-known methods of audit planning

A Common Molecular Mechanism Underlies Two Phenotypically Distinct 17p13.1 Microdeletion Syndromes

DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature

Metal–Metal Interaction in Fischer Carbene Complexes: A Study of Ferrocenyl and Biferrocenyl Tungsten Alkylidene Complexes

A series of ferrocenyl (Fc = ferrocenyl; fc = ferrocen-1,1'-diyl) and biferrocenyl (Bfc = 1',1''-biferrocenyl; bfc = 1',1''-biferrocen-1,1'''-diyl) mono- and biscarbene tungsten(0) complexes of the type [(CO)5W=C(OMe)R] (1, R = Fc; 3, R = Bfc) and [(CO)5W=C(OMe)-R'-(OMe)C=W(CO)5] (2, R' = fc; 4, R' = bfc) were synthesized according to the classical synthetic methodology by reacting W(CO)6 with LiR (R = Fc, fc, bfc), followed by a subsequent alkylation using methyl trifluoromethanesulfonate. Electrochemical investigations were carried out on these complexes to get a closer insight into the electronic properties of 1 - 4. The ferrocenyl and biferrocenyl moieties in 1 – 4 show reversible one electron redox events. It was further found that the Fischer carbene unit is reducible in an electrochemical one electron transfer process. For the tungsten carbonyl moieties, irreversible oxidation processes were found. In addition, charge transfer studies were performed on 1 - 4 by the use of in situ UV-Vis-NIR and infrared spectroelectrochemical techniques. During the UV-Vis-NIR investigations typical low energy transitions for the mixed-valent biferrocenyl unit were found. A further observed high energy NIR absorption is attributed to a metal-metal charge transfer transition between the tungsten carbonyl fragment and the ferrocenyl/biferrocenyl group in the corresponding oxidized states, which can be described as class II systems according to Robin and Day. This assignment was verified by infrared spectroelectrochemical studies. The electrochemical investigations are supported by DFT calculations. The structural properties of 1 - 4 in the solid state were investigated by single-crystal Xray diffraction studies showing no substituent effects on bond lengths and angles. The biferrocenyl derivatives exhibit synconformation of the ferrocenyl and carbene building blocks.D.I.B. and B.v.d.W. acknowledge the National Research Foundation, South Africa for financial support (Grant number 76226). We are grateful to the Fonds der Chemischen Industrie for financial support. J.M.S. and M.K. thank the FCI for Chemiefonds Fellowships.http://pubs.acs.org/journal/inocajhb201

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies