Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

Tailoring the resonance of bilayer graphene sheets by interlayer sp3 bonds

Graphene-based resonators are envisioned to build the ultimate limit of two-dimensional nanoelectromechanical system due to their ultrasensitive detection of mass, force, pressure and charge. However, such application has been greatly impeded by their extremely low quality factor. In the present work, we explore, using the large-scale molecular dynamics simulation, the possibility of tailoring the resonance properties of a bilayer graphene sheet (GS) with interlayer sp3 bonds. For the bilayer GS resonator with interlayer sp3 bonds, we discovered that the sp3 bonds can either degrade or enhance the resonance properties of the resonator depending on their density and location. It is found that the distribution of sp3 bonds only along the edges of either pristine or hydrogenated bilayer GS, leads to a greatly enhanced quality factor. A quality factor of ~1.18×105 is observed for a 3.07×15.31 nm2 bilayer GS resonator with sp3 bonds, which is more than 30 times larger comparing with that of a pristine bilayer GS. The present study demonstrates that the resonance properties of a bilayer GS resonator can be tuned by introducing sp3 bonds. This finding provides a useful guideline for the synthesis of the bilayer GS for its application as a resonator component.

Predicting the fatigue life of internal fracture fixation plates

Failures of fracture fixation plates, often related to fatigue fractures of the implants, have been reported (Banovetz et al, 1996). While metallurgical defects can usually be excluded, many of these fractures can be explained with the biomechanical situation. This study investigated the biomechanics of two clinical cases, both of which used a 14-hole locking compression plate. In the first case, a titanium plate was used in a rigid configuration with 12 screws resulting in plate breakage after 7 weeks (Sommer et al, 2003). In the second case, a stainless steel plate, which endured the entire healing process, was used in a flexible application with only 6 screws.

Vascular remodeling in the internal mammary artery graft and association with in situ endothelin-1 and receptor expression

BACKGROUND: The vasoconstricting peptide endothelin-1 (ET-1) has been associated with atherosclerotic cardiovascular disease, vascular smooth muscle cell (VSMC) growth stimulation, and intimal thickening. ET-1 binds 2 receptor subtypes, endothelin A and B, and the ETA receptor mediates vasoconstriction and VSMC growth. This study aims to quantitatively assess arterial remodeling variables and compare them with changes in ET-1, ETA, and ETB expression in the internal mammary artery (IMA). METHODS AND RESULTS: Specimens from 55 coronary artery disease (CAD) patients (45 men, 10 women; mean age 65 years) and 14 control IMA specimens (from 7 men and 7 women; mean age 45 years) were collected. IMA cross sections were assessed by histochemical and immunohistochemical staining methods to quantify the levels of medionecrosis, fibrosis, VSMC growth, ET-1, ETA, ETB, and macrophage infiltration. The percentage area of medionecrosis in the patients was almost double that in the controls (31.85+/-14.52% versus 17.10+/-9.96%, P=0.0006). Total and type 1 collagen was significantly increased compared with controls (65.8+/-18.3% versus 33.7+/-13.7%, P=0.07, and 14.2+/-10.0% versus 4.8+/-2.8%, P=0.01, respectively). Despite ACE and/or statin therapy, ET-1 expression and cell cycling were significantly elevated in the patient IMAs relative to the controls (46.27+/-18.46 versus 8.56+/-8.42, P=0.0001, and 37.29+/-12.88 versus 11.06+/-8.18, P=0.0001, respectively). ETA and ETB staining was elevated in the patient vessels (46.88+/-11.52% versus 18.58+/-7.65%, P=0.0001, and 42.98+/-7.08% versus 34.73+/-5.20%, P=0.0067, respectively). A mild presence of macrophages was noted in all sections. CONCLUSIONS: Elevated distribution of collagen indicative of fibrosis coupled with increased cell cycling and high levels of ET-1 and ETA expression in the absence of chronic inflammation suggests altered IMA VSMC regulation is fundamental to the remodeling process.

Thinking about internal states, a qualitative investigation into metacognitions in women with eating disorders

Background There is a need for qualitative research to help develop case conceptualisations to guide the development of Metacognitive Therapy interventions for Eating Disorders. Method A qualitative study informed by grounded theory methodology was conducted involving open-ended interviews with 27 women aged 18–55 years, who were seeking or receiving treatment for a diagnosed ED. Results The categories identified in this study appeared to be consistent with a metacognitive model including constructs of a Cognitive Attentional Syndrome and metacognitive beliefs. These categories appear to be transdiagnostic, and the interaction between the categories is proposed to explain the maintenance of EDs. Conclusions The transdiagnostic model proposed may be useful to guide the development of future metacognitive therapy interventions for EDs with the hope that this will lead to improved outcomes for individuals with EDs.

Internal audit involvement in enterprise risk management

Purpose The paper examines the impact of internal auditors’ involvement in Enterprise Risk Management (ERM) on perceptions of their willingness to report a breakdown in risk procedures and whether a strong relationship with the audit committee affects such willingness to report. The study also investigates the use of ERM and the role of internal audit in ERM in Australian private and public sector entities. Design/methodology/approach The study uses an experimental design, manipulating (i) the internal auditor’s involvement in ERM and (ii) the strength of the relationship between internal audit and the audit committee. Participants are 117 certified internal auditors. The study also gathers descriptive data on the use of ERM. Findings The study indicates that a high involvement in ERM impacts the perceptions of internal auditors’ willingness to report a breakdown in risk procedures to the audit committee. However, a strong relationship with the audit committee does not appear to affect their perceived willingness to report. The study also finds that the majority of organisations have recently adopted ERM. Internal auditors are involved in ERM assurance activities but some also engage in activities that could compromise objectivity.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. Because fMRI records, through the monitoring of blood flow activity, the location of localised brain activity within the brain, the possibility of combining fMRI measurements with EEG, as a joint inversion activity, was discussed and examined in detail. (3) A major goal for the BRI is to improve understanding about ``when'' (at what time) an epileptic seizure actually commenced before it is identified on an eeg recording, ``where'' the source of this initiation is located in the brain, and ``what'' is the initiator. Because of the general agreement in the literature that, in one way or another, epileptic events and seizures represent abnormal synchronisations of localised and/or global brain activity the modelling of synchronisations was examined in some detail. References C. M. Michel, G. Thut, S. Morand, A. Khateb, A. J. Pegna, R. Grave de Peralta, S. Gonzalez, M. Seeck and T. Landis, Electric source imaging of human brain functions, Brain Res. 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Electron capture of tetracyanoethylene oxide in the gas phase. Rearrangement of the parent radical anion to form [(NC)(3)C](-). A joint experimental and ab initio study

Capture of an electron by tetracyanoethylene oxide can initiate a number of decomposition pathways. One of these decompositions yields [(NC)3C]− as the ionic product. Ab initio calculations (at the B3LYP/6-31+G∗ level of theory) indicate that the formation of [(NC)3C]− is initiated by capture of an electron into the LUMO of tetracyanoethylene oxide to yield the anion radical [(NC)2C–O–C(CN)2]−· that undergoes internal nucleophilic substitution to form intermediate [(NC)3C–OCCN]−·. This intermediate dissociates to form [(NC)3C]− (m/z 90) as the ionic product. The radical (NC)3C· has an electron affinity of 4.0 eV (385 kJ mol−1). Ab initio calculations show that [(NC)3C]− is trigonal planar with the negative charge mainly on the nitrogens. A pictorial representation of this structure is the resonance structure formed from three degenerate contributing structures (NC)2–CCN−. The other product of the reaction is nominally (NCCO)·, but there is no definitive experimental evidence to indicate whether this radical survives intact, or decomposes to NC· and CO. The overall process [(NC)2C–O–C(CN)2]−· → [(NC)3C]− + (NCCO)· is calculated to be endothermic by 21 kJ mol−1 with an overall barrier of 268 kJ mol−1.

Nonlinear container ship model for the study of parametric roll resonance

Parametric roll is a critical phenomenon for ships, whose onset may cause roll oscillations up to +-40 degrees, leading to very dangerous situations and possibly capsizing. Container ships have been shown to be particularly prone to parametric roll resonance when they are sailing in moderate to heavy head seas. A Matlab/Simulink parametric roll benchmark model for a large container ship has been implemented and validated against a wide set of experimental data. The model is a part of a Matlab/Simulink Toolbox (MSS, 2007). The benchmark implements a 3rd-order nonlinear model where the dynamics of roll is strongly coupled with the heave and pitch dynamics. The implemented model has shown good accuracy in predicting the container ship motions, both in the vertical plane and in the transversal one. Parametric roll has been reproduced for all the data sets in which it happened, and the model provides realistic results which are in good agreement with the model tank experiments.

Optimising employee engagement with internal communication : a social exchange perspective

Drawing on principles of social exchange this thesis employs mediated regression to investigate the relationship between internal communication and employee engagement in the Australian workforce. Findings suggest organisations and supervisors should focus internal communication efforts toward building greater perceptions of support and stronger identification among employees in order to foster optimal engagement. This research contributes to public relations and management scholarship through understanding how perceived support and identification act as mediating mechanisms in the relationship between internal communication and employee engagement at the organisational and supervisory level.

Simultaneous magnetic resonance imaging and consolidation measurement of articular cartilage

Magnetic resonance imaging (MRI) offers the opportunity to study biological tissues and processes in a non-disruptive manner. The technique shows promise for the study of the load-bearing performance (consolidation) of articular cartilage and changes in articular cartilage accompanying osteoarthritis. Consolidation of articular cartilage involves the recording of two transient characteristics: the change over time of strain and the hydrostatic excess pore pressure (HEPP). MRI study of cartilage consolidation under mechanical load is limited by difficulties in measuring the HEPP in the presence of the strong magnetic fields associated with the MRI technique. Here we describe the use of MRI to image and characterize bovine articular cartilage deforming under load in an MRI compatible consolidometer while monitoring pressure with a Fabry-Perot interferometer-based fiber-optic pressure transducer.

Stabilization of parametric roll resonance with active u-tanks via Lyapunov control design

Parametric ship roll resonance is a phenomenon where a ship can rapidly develop high roll motion while sailing in longitudinal waves. This effect can be described mathematically by periodic changes of the parameters of the equations of motion, which lead to a bifurcation. In this paper, the control design of an active u-tank stabilizer is carried out using Lyapunov theory. A nonlinear backstepping controller is developed to provide global exponential stability of roll. An extension of commonly used u-tank models is presented to account for large roll angles, and the control design is tested via simulation on a high-fidelity model of a vessel under parametric roll resonance.

Resonance of graphene nanoribbons doped with nitrogen and boron : a molecular dynamics study

Based on its enticing properties, graphene has been envisioned with applications in the area of electronics, photonics, sensors, bioapplications and others. To facilitate various applications, doping has been frequently used to manipulate the properties of graphene. Despite a number of studies conducted on doped graphene regarding its electrical and chemical properties, the impact of doping on the mechanical properties of graphene has been rarely discussed. A systematic study of the vibrational properties of graphene doped with nitrogen and boron is performed by means of a molecular dynamics simulation. The influence from different density or species of dopants has been assessed. It is found that the impacts on the quality factor, Q, resulting from different densities of dopants vary greatly, while the influence on the resonance frequency is insignificant. The reduction of the resonance frequency caused by doping with boron only is larger than the reduction caused by doping with both boron and nitrogen. This study gives a fundamental understanding of the resonance of graphene with different dopants, which may benefit their application as resonators.

Tuneable resonance properties of graphene by nitrogen-dopant

Doping as one of the popular methods to manipulate the properties of nanomaterials has received extensive application in deriving different types of graphene derivates, while the understanding of the resonance properties of dopant graphene is still lacking in literature. Based on the large-scale molecular dynamics simulation, reactive empirical bond order potential, as well as the tersoff potential, the resonance properties of N-doped graphene were studied. The studied samples were established according to previous experiments with the N atom’s percentage ranging from 0.43%-2.98%, including three types of N dopant locations, i.e., graphitic N, pyrrolic N and pyridinic N. It is found that different percentages of N-dopant exert different influence to the resonance properties of the graphene, while the amount of N-dopant is not the only factor that determines its impact. For all the considered cases, a relative large percentage of N-dopant (2.98% graphitic N-dopant) is observed to introduce significant influence to the profile of the external energy, and thus lead to an extremely low Q-factor comparing with that of the pristine graphene. The most striking finding is that, the natural frequency of the defective graphene with N-dopant appears uniformly larger than that of the pristine defective graphene. While for the perfect graphene, the N-dopant shows less influence to its natural frequency. This study will enrich the current understanding of the influence of dopants on graphene, which will eventually shed lights on the design of different molecules-doped graphene sheet.