Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM

Ataxia telangiectasia mutated (ATM) is an important signaling molecule in the DNA damage response (DDR). ATM loss of function can produce a synthetic lethal phenotype in combination with tumor-associated mutations in FA/BRCA pathway components. In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of reactive oxygen species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTEN-deficient cells, suggesting a requirement for oxidative DNA damage in the mechanism of cell death. Lastly, the ATM inhibitor KU-60019 was specifically toxic to PTEN mutant cancer cells in tumor xenografts and reversible by reintroduction of wild-type PTEN. Together, our results offer a mechanistic rationale for clinical evaluation of ATM inhibitors in PTEN-deficient tumors.

Predicting low velocity impact damage and Compression-After-Impact (CAI) behaviour of composite laminates

Low-velocity impact damage can drastically reduce the residual strength of a composite structure even when the damage is barely visible. The ability to computationally predict the extent of damage and compression-after-impact (CAI) strength of a composite structure can potentially lead to the exploration of a larger design space without incurring significant time and cost penalties. A high-fidelity three-dimensional composite damage model, to predict both low-velocity impact damage and CAI strength of composite laminates, has been developed and implemented as a user material subroutine in the commercial finite element package, ABAQUS/Explicit. The intralaminar damage model component accounts for physically-based tensile and compressive failure mechanisms, of the fibres and matrix, when subjected to a three-dimensional stress state. Cohesive behaviour was employed to model the interlaminar failure between plies with a bi-linear traction–separation law for capturing damage onset and subsequent damage evolution. The virtual tests, set up in ABAQUS/Explicit, were executed in three steps, one to capture the impact damage, the second to stabilize the specimen by imposing new boundary conditions required for compression testing, and the third to predict the CAI strength. The observed intralaminar damage features, delamination damage area as well as residual strength are discussed. It is shown that the predicted results for impact damage and CAI strength correlated well with experimental testing without the need of model calibration which is often required with other damage models.

Modelling Damage in Thin-Walled Structures [Keynote speaker]

A high-fidelity composite damage model is presented and applied to predict low-velocity impact damage, compression after impact (CAI) strength and crushing of thin-walled composite structures. The simulated results correlated well with experimental testing in terms of overall force-displacement response, damage morphologies and energy dissipation. The predictive power of this model makes it suitable for use as part of a virtual testing methodology, reducing the reliance on physical testing.  

Numerical prediction of the low-velocity impact damage and compression after impact strength of composite laminates

Low-velocity impact damage can drastically reduce the residual mechanical properties of the composite structure even when there is barely visible impact damage. The ability to computationally predict the extent of damage and compression after impact (CAI) strength of a composite structure can potentially lead to the exploration of a larger design space without incurring significant development time and cost penalties. A three-dimensional damage model, to predict both low-velocity impact damage and compression after impact CAI strength of composite laminates, has been developed and implemented as a user material subroutine in the commercial finite element package, ABAQUS/Explicit. The virtual tests were executed in two steps, one to capture the impact damage and the other to predict the CAI strength. The observed intra-laminar damage features, delamination damage area as well as residual strength are discussed. It is shown that the predicted results for impact damage and CAI strength correlated well with experimental testing.

Ultrasound entropy may be a new non-invasive measure of pre-clinical vascular damage in young hypertensive patients

Background: The identification of pre-clinical microvascular damage in hypertension by non-invasive techniques has proved frustrating for clinicians. This proof of concept study investigated whether entropy, a novel summary measure for characterizing blood velocity waveforms, is altered in participants with hypertension and may therefore be useful in risk stratification.

Methods: Doppler ultrasound waveforms were obtained from the carotid and retrobulbar circulation in 42 participants with uncomplicated grade 1 hypertension (mean systolic/diastolic blood pressure (BP) 142/92 mmHg), and 26 healthy controls (mean systolic/diastolic BP 116/69 mmHg). Mean wavelet entropy was derived from flow-velocity data and compared with traditional haemodynamic measures of microvascular function, namely the resistive and pulsatility indices.

Results: Entropy, was significantly higher in control participants in the central retinal artery (CRA) (differential mean 0.11 (standard error 0.05 cms(-1)), CI 0.009 to 0.219, p 0.017) and ophthalmic artery (0.12 (0.05), CI 0.004 to 0.215, p 0.04). In comparison, the resistive index (0.12 (0.05), CI 0.005 to 0.226, p 0.029) and pulsatility index (0.96 (0.38), CI 0.19 to 1.72, p 0.015) showed significant differences between groups in the CRA alone. Regression analysis indicated that entropy was significantly influenced by age and systolic blood pressure (r values 0.4-0.6). None of the measures were significantly altered in the larger conduit vessel.

Conclusion: This is the first application of entropy to human blood velocity waveform analysis and shows that this new technique has the ability to discriminate health from early hypertensive disease, thereby promoting the early identification of cardiovascular disease in a young hypertensive population.

Seismic damage detection for a steel braced frame structure

A new approach for global detection of seismic damage in a single-storey steel concentrically braced frame (CBF) structure is presented. The filtered lateral in-plane acceleration response of the CBF structure is integrated twice to provide the lateral in-plane displacement which is used to infer buckling and yielding damage. The level of interstorey drift of the CBF during a seismic excitation allows the yield and buckling of the bracing members to be identified and indirectly detects damage based on exceedance of calculated lateral in-plane displacement limits. A band-pass filter removes noise from the acceleration signal followed by baseline correction being used to reduce the drift in velocity and displacement during numerical integration. This pre-processing results in reliable numerical integration of the frame acceleration that predicts the displacement response accurately when compared to the measured lateral displacement of the CBF structure. Importantly, the structural damage is not assumed through removal of bracing members, rather damage is induced through actual seismic loading. The buckling and yielding displacement threshold limits used to identify damage are demonstrated to accurately identify the initiation of buckling and yielding.

Brca1 and brca2:Role in the DNA damage response, cancer formation and treatment

BRCA1 and BRCA2 are highly penetrant breast and ovarian cancer susceptibility genes that are mutated in a significant proportion of familial breast and ovarian cancer syndromes. Both of these genes are tumour suppressors, the products of which play vital roles in the cellular response to DNA damage. These proteins function in a number of cellular pathways in order to maintain genomic stability including DNA damage signaling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodeling, transcriptional regulation and apoptosis. This chapter will discuss the functions of these proteins and how they relate to tumour development, and therapy. © 2009 Springer Science+Business Media B.V.

Impact of average household income and damage exposure on post-earthquake distress and functioning: A community study following the February 2011 Christchurch earthquake.

Post-traumatic stress, depression and anxiety symptoms are common outcomes following earthquakes, and may persist for months and years. This study systematically examined the impact of neighbourhood damage exposure and average household income on psychological distress and functioning in 600 residents of Christchurch, New Zealand, 4–6 months after the fatal February, 2011 earthquake. Participants were from highly affected and relatively unaffected suburbs in low, medium and high average household income areas. The assessment battery included the Acute Stress Disorder Scale, the depression module of the Patient Health Questionnaire (PHQ-9), and the Generalized Anxiety Disorder Scale (GAD-7), along with single item measures of substance use, earthquake damage and impact, and disruptions in daily life and relationship functioning. Controlling for age, gender and social isolation, participants from low income areas were more likely to meet diagnostic cut-offs for depression and anxiety, and have more severe anxiety symptoms. Higher probabilities of acute stress, depression and anxiety diagnoses were evident in affected versus unaffected areas, and those in affected areas had more severe acute stress, depression and anxiety symptoms. An interaction between income and earthquake effect was found for depression, with those from the low and medium income affected suburbs more depressed. Those from low income areas were more likely, post-earthquake, to start psychiatric medication and increase smoking. There was a uniform increase in alcohol use across participants. Those from the low income affected suburb had greater general and relationship disruption post-quake. Average household income and damage exposure made unique contributions to earthquake-related distress and dysfunction.

Plasmid DNA damage following exposure to atmospheric pressure non-thermal plasma: kinetics and influence of oxygen admixture

The nature and kinetics of plasmid DNA damage after DNA exposure to a kHz-driven atmospheric pressure nonthermal plasma jet has been investigated. Both single-strand break (SSB) and double-strand break (DSB) processes are reported here. While SSB had a higher rate constant, DSB is recognized to be more significant in living systems, often resulting in loss of viability. In a helium-operated plasma jet, adding oxygen to the feed gas resulted in higher rates of DNA DSB, which increased linearly with increasing oxygen content, up to an optimum level of 0.75% oxygen, after which the DSB rate decreased slightly, indicating an essential role for reactive oxygen species in the rapid degradation of DNA.

Concrete damage plasticity model for modeling FRP-to-concrete bond behavior

The technique of externally bonding fiber-reinforced polymer (FRP) composites has become very popular worldwide for retrofitting existing reinforced concrete (RC) structures. Debonding of FRP from the concrete substrate is a typical failure mode in such strengthened structures. The bond behavior between FRP and concrete thus plays a crucial role in these structures. The FRP-to-concrete bond behavior has been extensively investigated experimentally, commonly using a single or double shear test of the FRP-to-concrete bonded joint. Comparatively, much less research has been concerned with numerical simulation, chiefly due to difficulties in the accurate modeling of the complex behavior of concrete. This paper presents a simple but robust finite-element (FE) model for simulating the bond behavior in the entire debonding process for the single shear test. A concrete damage plasticity model is proposed to capture the concrete-to-FRP bond behavior. Numerical results are in close agreement with test data, validating the model. In addition to accuracy, the model has two further advantages: it only requires the basic material parameters (i.e., no arbitrary user-defined parameter such as the shear retention factor is required) and it can be directly implemented in the FE software ABAQUS.

Finite element modelling of FRP-to-concrete bond behaviour using the concrete damage plasticity theory combined with a plastic degradation model

The technique of externally bonding fibre reinforced polymer (FRP) composites has been becoming popular worldwide for retrofitting existing reinforced concrete (RC) structures. A major failure mode in such strengthened structures is the debonding of FRP from the concrete substrate. The bond behaviour between FRP and concrete thus plays a crucial role in these structures. The FRP-to-concrete bond behaviour has been extensively investigated experimentally, commonly using the pull-off test of FRP-to-concrete bonded joint. Comparatively, much less research has been concerned with the numerical simulation of this bond behaviour, chiefly due to difficulties in accurately modelling the complex behaviour of concrete. This paper proposes a robust finite element (FE) model for simulating the bond behaviour in the entire loading process in the pull-off test. A concrete damage plasticity model based on the plastic degradation theory is proposed to overcome the weakness of the elastic degradation theory which has been commonly adopted in previous studies. The model produces results in very close agreement with test data. © Tsinghua University Press, Beijing and Springer-Verlag Berlin Heidelberg 2011.