SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population

The Effect of Modularity Representation and Presentation Medium on the Understandability of Business Process Models in BPMN

Many factors influence the creation of understandable business process models for an appropriate audience. Understandability of process models becomes critical particularly when a process is complex and its model is large in structure. Using modularization to represent such models hierarchically (e.g. using sub-processes) is considered to contribute to the understandability of these models. To investigate this assumption, we conducted an experiment that involved 2 large-scale real-life business process models that were modeled using BPMN v2.0 (Business Process Model and Notation). Each process was modeled in 3 modularity forms: fully-flattened, flattened where activities are clustered using BPMN groups, and modularized using separately viewed BPMN sub-processes. The objective is to investigate if and how different forms of modularity representation in BPMN collaboration diagrams influence the understandability of process models. In addition to the forms of modularity representation, we also looked into the presentation medium (paper vs. computer) as a factor that potentially influences model comprehension. Sixty business practitioners from a large organization participated in the experiment. The results of our experiment indicate that for business practitioners, to optimally understand a BPMN model in the form of a collaboration diagram, it is best to present the model in a ‘fully-flattened’ fashion (without using collapsed sub-processes in BPMN) in the ‘paper’ format

Theories in Business and Information Systems Engineering

Even though the idea of science enjoys an impressive reputation, there seems to be no precise conception of science. On the one hand, there is no unified definition of the extension of activities subsumed under the notion of science. According to the narrow conception that is common in Anglo-Saxon countries, science is restricted to those disciplines that investigate nature and aim at explanation and prediction of natural phenomena. A wider conception that can be found in various European countries includes social sciences, the humanities and engineering. On the other hand and related to the first aspect, there is still no general consensus on the specific characteristics of scientific discoveries and scientific knowledge

Process management in hospitals: an empirically grounded maturity model

In order to improve transparency and stabilise health care costs, several countries have decided to reform their healthcare system on the basis of diagnosis-related groups (DRG). DRGs are not only used for classifying medical treatments, but also for case-based reimbursement, hence induce active competition among hospitals, forcing them to become more efficient and effective. In consequence, hospitals are investing considerably in process orientation and management. However, to date there is neither a consensus on what capabilities hospitals need to acquire for becoming process-oriented, nor a general agreement on the sequence of development stages they have to traverse. To this end, this study proposes an empirically grounded conceptualisation of process management capabilities and presents a staged capability maturity model algorithmically derived on the basis of empirical data from 129 acute somatic hospitals in Switzerland. The five capability maturity levels start with 'encouragement of process orientation' (level 1), 'case-by-case handling' (level 2), and 'defined processes' (level 3). Ultimately, hospitals can reach the levels 'occasional corrective action' (level 4) and 'closed loop improvement' (level 5). The empirically derived model reveals why existing, generic capability maturity models for process management are not applicable in the hospitals context: their comparatively high complexity on the one hand and their strong focus on topics like an adequate IT integration and process automation on the other make them inadequate for solving the problems felt in the hospital sector, which are primarily of cultural and structural nature. We deem the proposed capability maturity model capable to overcome these shortcomings

Influence of soil heterogeneity on load redistribution and settlement of a hyperstatic three-support frame

Spatial and geometrical variability of mechanical soil properties can induce differential settlements and load redistribution in hyperstatic structures. Therefore damage prevention requires specific attention to be paid to the global mechanisms of soil–structure interaction. A reduced-scale model of a hyperstatic three-support frame (scale 1:100) is installed on the CEA-CESTA centrifuge, up to 100g. Various configurations are studied, with different loadings, different structural stiffnesses, and different geometries of the soil layer. Strain gauges are fixed at various points so as to enable the retro-analysis of all components of forces at free ends. Displacements are recorded at several points on the structure and on the free surface. A numerical model of the frame (based on beam theory with elastic supports) is calibrated, first to determine an equivalent support stiffness, and second to quantify the effect of variations of the structural stiffness/soil modulus ratio on the structural response. A probabilistic approach based on Monte Carlo simulation is thus developed. It mixes the soil description, based on random field theory and enabling the description of spatial correlation of properties and the frame model identified above. The influence of (a) scattering in soil properties and (b) spatial correlation of soil properties—through correlation length or scale of fluctuation—is quantified in terms of displacements and bending moments in the frame. The approach reveals the important weight/influence of soil variability on differential settlement and load redistribution, particularly when the scale of fluctuation of soil and length of span have the same magnitude. The analysis makes it possible to evaluate the risk that the bending moment in any critical section may be larger than predicted by the usual engineer's model. Some conclusions are drawn to better estimate ‘characteristic bending moments’ in the frame, accounting for both the soil variability and the soil–frame interaction. </jats:p

Reciprocal and Cooperative Teaching in Adult Education Programs to Foster Improved Human Connections— An Annotated Bibliography

Unrestricted sharingAdult education programs are often understaffed and lack financial resources. Implementing reciprocal and cooperative teaching strategies take advantage of the knowledge and abilities already in the classroom. When resources are scarce, reciprocal and cooperative teaching are methods that have the additional benefits of developing shared responsibility in each student’s success. The Body of Knowledge utilized by Family and Consumer Sciences offers a framework through which to view and understand the importance of reciprocal teaching in adult learning settings. This annotated bibliography aims to be a resource for articles that evidence and support the use of reciprocal and cooperative teaching strategies to improve comprehension and instruction in adult education programs

A generic approach to soil–structure interaction considering the effects of soil heterogeneity

The longitudinal variation of soil properties has a major influence for many types of structure, including pavements, buried pipes, raft foundations and railways, as it induces stresses and/or displacements that cannot be predicted when assuming soil homogeneity. A set of simple numerical models has been developed to describe how soil–structure interaction can be influenced by soil variability. These models include: (a) a description of the soil spatial variability, within the frame of geostatistics, where the correlation length of soil properties is the main parameter; and (b) a mechanical description of the soil–structure interaction, which depends on the structure resting on the ground. There are some differences between a (more or less) rigid raft on piles, a set of buried pipes with (more or less) flexible connections and a hyperstatic beam, but the basic principles of mechanics are similar in all these cases. Several very general conclusion are drawn. (a) Soil heterogeneity induces effects (differential settlements, bending moments, stresses and possible cracking) that cannot be predicted if homogeneity is assumed. (b) The magnitude of the induced stresses depends on three factors: the magnitude of the soil variability (i.e. its coefficient of variation); a soil–structure stiffness ratio (in some cases, where the mechanics are more complex, one can consider two stiffness ratios, as in buried pipes for example, when one has to account for the flexibility both of the pipes and of the connections); a soil–structure length ratio, which combines the soil fluctuation scale and a structural characteristic length (distance between supports, buried pipe length, etc). In all cases, a worst value, corresponding to the value leading (from a statistical point of view) to the (statistically) largest effects in the structure, can be found. The principal benefit of such an approach is to provide some new approaches for better considering phenomena such as the geometrical irregularities in the longitudinal profile of pavements or during the control of soil compaction of sewer trench filling. This kind of approach can also give experts new tools for better calibration of safety in soil–structure interaction problems, when the soil variability is an influential parameter. Some practical conclusions are drawn in this direction. </jats:p