A framework for Operational Security Metrics Development for industrial control environment

Security metrics are very crucial towards providing insights when measuring security states and susceptibilities in industrial operational environments. Obtaining practical security metrics depend on effective security metrics development approaches. To be effective, a security metrics development framework should be scope-definitive, objective-oriented, reliable, simple, adaptable, and repeatable (SORSAR). A framework for Operational Security Metrics Development (OSMD) for industry control environments is presented, which combines concepts and characteristics from existing approaches. It also adds the new characteristic of adaptability. The OSMD framework is broken down into three phases of: target definition, objective definition, and metrics synthesis. A case study scenario is used to demonstrate an instance of how to implement and apply the proposed framework to demonstrate its usability and workability. Expert elicitation has also be used to consolidate the validity of the proposed framework. Both validation approaches have helped to show that the proposed framework can help create effective and efficient ICS-centric security metrics taxonomy that can be used to evaluate capabilities or vulnerabilities. The understanding from this can help enhance security assurance within industrial operational environments

High-Throughput Molecular Cancer Cell Line Characterization Using Digital Multiplex Ligation-Dependent Probe Amplification for Improved Standardization of in Vitro Research.

Tumor cell lines are widely used for cancer research, but challenges regarding quality control of cell line identity, cross contamination, and tumor somatic molecular stability remain, demanding novel approaches beyond conventional short tandem repeat profiling. A total of 21 commonly used multiple myeloma cell lines obtained from public repositories were analyzed by digital multiplex ligation-dependent probe amplification (digitalMLPA) to characterize germline single-nucleotide polymorphisms, insertions/deletions, and somatic copy number aberrations (CNAs). Using generated profiles and an in-house developed analytical pipeline, blinded experiments were performed to determine capability of digitalMLPA to predict cell line identity and potential spike-in DNA contamination in 41 anonymized cell line samples. The dominant cell line was correctly identified in all cases, and cross contamination was correctly detected in 33 of 37 samples with spike-in DNA; there were no false-positive predictions. The four samples in which spike in was not detected all carried low levels of contamination (1%), whereas levels of contamination ≥5% were correctly identified in all cases. Unsupervised clustering of CNA profiles identified shared commonalities that correlated with initiating Ig heavy locus translocation events. Longitudinal CNA assessment of nine cell lines revealed changes under standard culturing conditions not detected by insertion/deletion profiling alone. Results suggest that digitalMLPA can be utilized as a high-throughput tool for advanced quality assurance for in vitro cancer research

Using mutual information to investigate non-linear correlation between AE index, ULF Pc5 wave activity and electron precipitation

In this study, we use mutual information from information theory to investigate non-linear correlation between geomagnetic activity indicated by auroral electrojet (AE) index with both the global ultra low frequency (ULF) Pc5 wave power and medium energy (>= 30 keV) electron precipitation at the central outer radiation belt. To investigate the energy and magnetic local time (MLT) dependence of the non-linearity, we calculate the mutual information and Pearson correlation coefficient separately for three different energy ranges (30-100 keV, 100-300 keV and >= 300 keV) and four different MLT sectors (0-6, 6-12, 12-18, 18-24). We compare results from 2 years 2004 and 2007 representing geomagnetically more active and less active years, respectively. The correlation analysis between the AE index and electron precipitation shows a clear MLT and energy dependence in both active and quiet conditions. In the two lowest energy ranges of the medium energy electrons (30-100 keV and 100-300 keV) both non-linear correlation and Pearson correlation indicate strong dependence with the AE index in the dawn sector. The linear dependence indicated by the Pearson correlation coefficient decreases from dawn to dusk while the change in the non-linear correlation is smaller indicating an increase in the non-linearity from dawn to dusk. The non-linearity between the AE index and electron precipitation is larger at all MLT sectors except MLTs 6-12 during geomagnetically more active year when larger amount of the activity is driven by interplanetary coronal mass ejections (ICMEs) compared to lower activity year with high speed stream (HSS) and stream interaction region (SIR) driven activity. These results indicate that the processes leading to electron precipitation become more non-linear in the dusk and during geomagnetically more active times when the activity is driven by ICMEs. The non-linearity between the AE index and global ULF Pc5 activity is relatively low and seems not to be affected by the difference in the geomagnetic activity during the 2 years studied.Peer reviewe

A robust pipeline with high replication rate for detection of somatic variants in the adaptive immune system as a source of common genetic variation in autoimmune disease

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of > 55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.Peer reviewe

Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis

The introduction of new therapies against particular genetic mutations in non-small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-toinosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis.This work was supported by the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 268626—EPINORC project, the Grant agreement number HEALTH-F2-2010-258677—CURELUNG project, the Spanish Ministry of Economy and Competitiveness (MINECO Projects no. SAF2011-22803, PI13-01339 and SAF2014-55000- R), the Institute of Health Carlos III (ISCIII)—PI10/02992, Ministerio de Educación, Ciencia e Innovación Grant SAF2010-14935, the Cellex Foundation, the National Cancer Center Research and Development Fund (NCC Biobank: 23 A-1) and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya) AGAUR—project no. 2009SGR1315 and 2014SGR633.Peer Reviewe

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1,905 trial patients

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10−7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10−14) and 1.68 (P=2.18 × 10−14), respectively. Patients with ‘double-hit’ defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10−27) for all patients and 3.19 (P=1.23 × 10−18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10−15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10 -7 ), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10 -14 ) and 1.68 (P=2.18 × 10 -14 ), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10 -27 ) for all patients and 3.19 (P=1.23 × 10 -18 ) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10 -15 ), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment