Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells.

Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought.

Towards a Resilience Metric Framework for Cyber-Physical Systems

Resilience is widely accepted as a desirable system property for cyber-physical systems. However, there are no metrics that can be used to measure the resilience of cyber-physical systems (CPS) while the multi-dimensional nature of performance in these systems is considered. In this work, we present first results towards a resilience metric framework. The key contributions of this framework are threefold: First, it allows to evaluate resilience with respect to different performance indicators that are of interest. Second, complexities that are relevant to the performance indicators of interest, can be intentionally abstracted. Third and final, it supports the identification of reasons for good or bad resilience to improve system design.