Development of reverse phase protein microarrays for clinical applications and patient-tailored therapy

While genomics provide important information about the somatic genetic changes, and RNA transcript profiling can reveal important expression changes that correlate with outcome and response to therapy, it is the proteins that do the work in the cell. At a functional level, derangements within the proteome, driven by post-translational and epigenetic modifications, such as phosphorylation, is the cause of a vast majority of human diseases. Cancer, for instance, is a manifestation of deranged cellular protein molecular networks and cell signaling pathways that are based on genetic changes at the DNA level. Importantly, the protein pathways contain the drug targets in signaling networks that govern overall cellular survival, proliferation, invasion and cell death. Consequently, the promise of proteomics resides in the ability to extend analysis beyond correlation to causality. A critical gap in the information knowledge base of molecular profiling is an understanding of the ongoing activity of protein signaling in human tissue: what is activated and “in use” within the human body at any given point in time. To address this gap, we have invented a new technology, called reverse phase protein microarrays, that can generate a functional read-out of cell signaling networks or pathways for an individual patient obtained directly from a biopsy specimen. This “wiring diagram” can serve as the basis for both, selection of a therapy and patient stratification.

Effect of soil properties on the response of pile to underground explosion

This paper develops and presents a fully coupled non-linear finite element procedure to treat the response of piles to ground shocks induced by underground explosions. The Arbitrary Lagrange Euler coupling formulation with proper state material parameters and equations are used in the study. Pile responses in four different soil types, viz, saturated soil, partially saturated soil and loose and dense dry soils are investigated and the results compared. Numerical results are validated by comparing with those from a standard design manual. Blast wave propagation in soils, horizontal pile deformations and damages in the pile are presented. The pile damage presented through plastic strain diagrams will enable the vulnerability assessment of the piles under the blast scenarios considered. The numerical results indicate that the blast performance of the piles embedded in saturated soil and loose dry soil are more severe than those in piles embedded in partially saturated soil and dense dry soil. Present findings should serve as a benchmark reference for future analysis and design.

Biodiesel production from non-edible beauty leaf (Calophyllum Inophyllum) oil : process optimization using response surface methodology (RSM)

In recent years, the beauty leaf plant (Calophyllum Inophyllum) is being considered as a potential 2nd generation biodiesel source due to high seed oil content, high fruit production rate, simple cultivation and ability to grow in a wide range of climate conditions. However, however, due to the high free fatty acid (FFA) content in this oil, the potential of this biodiesel feedstock is still unrealized, and little research has been undertaken on it. In this study, transesterification of beauty leaf oil to produce biodiesel has been investigated. A two-step biodiesel conversion method consisting of acid catalysed pre-esterification and alkali catalysed transesterification has been utilized. The three main factors that drive the biodiesel (fatty acid methyl ester (FAME)) conversion from vegetable oil (triglycerides) were studied using response surface methodology (RSM) based on a Box-Behnken experimental design. The factors considered in this study were catalyst concentration, methanol to oil molar ratio and reaction temperature. Linear and full quadratic regression models were developed to predict FFA and FAME concentration and to optimize the reaction conditions. The significance of these factors and their interaction in both stages was determined using analysis of variance (ANOVA). The reaction conditions for the largest reduction in FFA concentration for acid catalysed pre-esterification was 30:1 methanol to oil molar ratio, 10% (w/w) sulfuric acid catalyst loading and 75 °C reaction temperature. In the alkali catalysed transesterification process 7.5:1 methanol to oil molar ratio, 1% (w/w) sodium methoxide catalyst loading and 55 °C reaction temperature were found to result in the highest FAME conversion. The good agreement between model outputs and experimental results demonstrated that this methodology may be useful for industrial process optimization for biodiesel production from beauty leaf oil and possibly other industrial processes as well.

Making smart decisions : key steps towards a typology for emergency communication during natural hazards

Governments, authorities, and organisations dedicate significant resources to encourage communities to prepare for and respond to natural hazards such as cyclones, earthquakes, floods, and bushfires. However, recent events, media attention, and ongoing academic research continue to highlight cases of non-compliance including swift water rescues. Individuals who fail to comply with instructions issued during natural hazards significantly impede the emergency response because they divert resources to compliance-enforcement and risk the lives of emergency service workers who may be required to assist them. An initial investigation of the field suggests several assumptions or practices that influence emergency management policy, communication strategy, and community behaviours during natural hazards: 1) that community members will comply with instructions issued by governments and agencies that represent the most authoritative voice, 2) that communication campaigns are shaped by intuition rather than evidence-based approaches (Wood et al., 2012), and 3) that emergency communication is linear and directional. This extended abstract represents the first stage of a collaborative research project that integrates industry and cross-disciplinary perspectives to provide evidence-based approaches for emergency and risk communication during the response and recovery phases of a natural hazard. Specifically, this abstract focuses on the approach taken and key elements that will form the development of a typology of compliance-gaining messages during the response phase of natural hazards, which will be the focus of the conference presentation.

Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults

CONTEXT AND OBJECTIVE: Suboptimal vitamin D status can be corrected by vitamin D supplementation, but individual responses to supplementation vary. We aimed to examine genetic and nongenetic determinants of change in serum 25-hydroxyvitamin D (25(OH)D) after supplementation. DESIGN AND PARTICIPANTS: We used data from a pilot randomized controlled trial in which 644 adults aged 60 to 84 years were randomly assigned to monthly doses of placebo, 30 000 IU, or 60 000 IU vitamin D3 for 12 months. Baseline characteristics were obtained from a self-administered questionnaire. Eighty-eight single-nucleotide polymorphisms (SNPs) in 41 candidate genes were genotyped using Sequenom MassArray technology. Serum 25(OH)D levels before and after the intervention were measured using the Diasorin Liaison platform immunoassay. We used linear regression models to examine associations between genetic and nongenetic factors and change in serum 25(OH)D levels. RESULTS: Supplement dose and baseline 25(OH)D level explained 24% of the variability in response to supplementation. Body mass index, self-reported health status, and ambient UV radiation made a small additional contribution. SNPs in CYP2R1, IRF4, MC1R, CYP27B1, VDR, TYRP1, MCM6, and HERC2 were associated with change in 25(OH)D level, although only CYP2R1 was significant after adjustment for multiple testing. Models including SNPs explained a similar proportion of variability in response to supplementation as models that included personal and environmental factors. CONCLUSION: Stepwise regression analyses suggest that genetic variability may be associated with response to supplementation, perhaps suggesting that some people might need higher doses to reach optimal 25(OH)D levels or that there is variability in the physiologically normal level of 25(OH)D.

Assessing rod, cone and melanopsin contributions to human pupil flicker responses

Purpose: To determine the relative contributions of rods, cones and melanopsin to pupil responses in humans using temporal sinusoidal stimulation for light levels spanning the low mesopic to photopic range. Methods: A four-primary Ganzfeld photostimulator controlled flicker stimulations at seven light levels (-2.7 to 2 log cd/m2) and five frequencies (0.5 to 8Hz). Pupil diameter was measured using a high-resolution eyetracker. Three kinds of sinusoidal photoreceptor modulations were generated using silent substitution: 1) rod modulation, 2) cone modulation, and 3) combined rod and cone modulation in phase (Experiment 1) or phase shifted (Experiment 2) from a fixed rod phase. The melanopsin excitation was computed for each condition. A vector sum model was used to estimate the relative contribution of rods, cones and melanopsin to the pupil response. Results: From Experiment 1, the pupil frequency response peaked at 1Hz at two mesopic light levels for the three modulation conditions. Analyzing the rod-cone phase difference for the combined modulations (Experiment 2) identified a V-shaped response amplitude with a minimum between 135° and 180°. The pupil response phases increased as cone modulation phase increased. The pupil amplitude increased with increasing light level for cone and combined in-phase rod and cone modulation, but not for the rod modulation. Conclusions: These results demonstrate that cone- and rod-pathway contributions are more predominant than melanopsin contribution to the phasic pupil response. The combined rod, cone and melanopsin inputs to the phasic state of the pupil light reflex follow linear summation.

The entrepreneurial break-up : disengaging from the start-up phase

Research on firm exit has grown considerably in volume and sophistication in recent years, leading to new insights and strengthened research-based evidence. However, no framework explicitly explains nascent disengagement, i.e., termination of start-up efforts before the firm has reached an operational stage. Further, prior research has had limited success at explaining nascent entrepreneurial behaviour using theories based on logics of resource availability and economic rationality. In response, this chapter approaches nascent stage disengagement unconventionally by proposing to analogously apply Sternberg’s (1986) Triangular Theory of Love, arguing that founders are less likely to give up the start-up effort if they create strong, almost loving relations to their businesses. Nascent entrepreneurs who terminate the start-up process are proposed to lack one or more of the components – intimacy, passion, and commitment – which are essential according to Sternberg’s theory.

Novel non-linear elastic structural analysis with generalised transverse element loads using a refined finite element

In the finite element modelling of structural frames, external loads such as wind loads, dead loads and imposed loads usually act along the elements rather than at the nodes only. Conventionally, when an element is subjected to these general transverse element loads, they are usually converted to nodal forces acting at the ends of the elements by either lumping or consistent load approaches. In addition, it is especially important for an element subjected to the first- and second-order elastic behaviour, to which the steel structure is critically prone to; in particular the thin-walled steel structures, when the stocky element section may be generally critical to the inelastic behaviour. In this sense, the accurate first- and second-order elastic displacement solutions of element load effect along an element is vitally crucial, but cannot be simulated using neither numerical nodal nor consistent load methods alone, as long as no equilibrium condition is enforced in the finite element formulation, which can inevitably impair the structural safety of the steel structure particularly. It can be therefore regarded as a unique element load method to account for the element load nonlinearly. If accurate displacement solution is targeted for simulating the first- and second-order elastic behaviour on an element on the basis of sophisticated non-linear element stiffness formulation, the numerous prescribed stiffness matrices must indispensably be used for the plethora of specific transverse element loading patterns encountered. In order to circumvent this shortcoming, the present paper proposes a numerical technique to include the transverse element loading in the non-linear stiffness formulation without numerous prescribed stiffness matrices, and which is able to predict structural responses involving the effect of first-order element loads as well as the second-order coupling effect between the transverse load and axial force in the element. This paper shows that the principle of superposition can be applied to derive the generalized stiffness formulation for element load effect, so that the form of the stiffness matrix remains unchanged with respect to the specific loading patterns, but with only the magnitude of the loading (element load coefficients) being needed to be adjusted in the stiffness formulation, and subsequently the non-linear effect on element loadings can be commensurate by updating the magnitude of element load coefficients through the non-linear solution procedures. In principle, the element loading distribution is converted into a single loading magnitude at mid-span in order to provide the initial perturbation for triggering the member bowing effect due to its transverse element loads. This approach in turn sacrifices the effect of element loading distribution except at mid-span. Therefore, it can be foreseen that the load-deflection behaviour may not be as accurate as those at mid-span, but its discrepancy is still trivial as proved. This novelty allows for a very useful generalised stiffness formulation for a single higher-order element with arbitrary transverse loading patterns to be formulated. Moreover, another significance of this paper is placed on shifting the nodal response (system analysis) to both nodal and element response (sophisticated element formulation). For the conventional finite element method, such as the cubic element, all accurate solutions can be only found at node. It means no accurate and reliable structural safety can be ensured within an element, and as a result, it hinders the engineering applications. The results of the paper are verified using analytical stability function studies, as well as with numerical results reported by independent researchers on several simple frames.

A phase II trial of brivanib in recurrent or persistent endometrial cancer: An NRG oncology/gynecologic oncology group study

PURPOSE Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed. RESULTS Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1-24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6%-31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9%-43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS. CONCLUSION Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.

Antioxidant responses to an acute ultra-endurance exercise: Impact on DNA stability and indications for an increased need for nutritive antioxidants in the early recovery phase

Antioxidant requirements have neither been defined for endurance nor been defined for ultra-endurance athletes. To verify whether an acute bout of ultra-endurance exercise modifies the need for nutritive antioxidants, we aimed (1) to investigate the changes of endogenous and exogenous antioxidants in response to an Ironman triathlon; (2) to particularise the relevance of antioxidant responses to the indices of oxidatively damaged blood lipids, blood cell compounds and lymphocyte DNA and (3) to examine whether potential time-points of increased susceptibility to oxidative damage are associated with alterations in the antioxidant status. Blood that was collected from forty-two well-trained male athletes 2 d pre-race, immediately post-race, and 1, 5 and 19 d later was sampled. The key findings of the present study are as follows: (1) Immediately post-race, vitamin C, alpha-tocopherol, and levels of the Trolox equivalent antioxidant capacity, the ferric reducing ability of plasma and the oxygen radical absorbance capacity (ORAC) assays increased significantly. Exercise-induced changes in the plasma antioxidant capacity were associated with changes in uric acid, bilirubin and vitamin C. (2) Significant inverse correlations between ORAC levels and indices of oxidatively damaged DNA immediately and 1 d post-race suggest a protective role of the acute antioxidant responses in DNA stability. (3) Significant decreases in carotenoids and gamma-tocopherol 1 d post-race indicate that the antioxidant intake during the first 24 h of recovery following an acute ultra-endurance exercise requires specific attention. Furthermore, the present study illustrates the importance of a diversified and well-balanced diet to maintain a physiological antioxidant status in ultra-endurance athletes in reference to recommendations.

Factors influencing vulnerability and positive post-disaster response following the Mackay 2008 and Brisbane 2011 floods

This project investigated which aspects of being flooded most affected mental health outcomes. It found that stress in the aftermath of the flood, during the clean-up and rebuilding phase, including stress due to difficulties with insurance companies, was a previously overlooked risk factor, and social support and sense of belonging were the strongest protective factors. Implications for community recovery following disasters include providing effective targeting of support services throughout the lengthy rebuilding phase; the need to co-ordinate tradespeople; and training for insurance company staff aimed at minimising the incidence of insurance company staff inadvertently adding to disaster victims' stress.

Motor response suppression and the prepotent tendency to respond: A parametric fMRI study

In the present study we utilised functional magnetic resonance imaging (fMRI) to examine cerebral activation during performance of a classic motor task in which response suppression load was parametrically varied. Linear increases in activity were observed in a distributed network of regions across both cerebral hemispheres, although with more extensive involvement of the right prefrontal cortex. Activated regions included prefrontal, parietal and occipitotemporal cortices. Decreasing activation was similarly observed in a distributed network of regions. These response forms are discussed in terms of an increasing requirement for visual cue discrimination and suppression/selection of motor responses, and a decreasing probability of the occurrence of non-target stimuli and attenuation of a prepotent tendency to respond. The results support recent proposals for a dominant role for the right-hemisphere in performance of motor response suppression tasks that emphasise the importance of the right prefrontal cortex.

EVERSUN: A phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

Background We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). Patients and methods A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. Results We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5–10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12–undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. Conclusions The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.

A new single-phase frequency adaptive Phase-Locked Loop (PLL) for harmonic measurement

The paper presents an improved Phase-Locked Loop (PLL) for measuring the fundamental frequency and selective harmonic content of a distorted signal. This information can be used by grid interfaced devices and harmonic compensators. The single-phase structure is based on the Synchronous Reference Frame (SRF) PLL. The proposed PLL needs only a limited number of harmonic stages by incorporating Moving Average Filters (MAF) for eliminating the undesired harmonic content at each stage. The frequency dependency of MAF in effective filtering of undesired harmonics is also dealt with by a proposed method for adaptation to frequency variations of input signal. The method is suitable for high sampling rates and a wide frequency measurement range. Furthermore, an extended model of this structure is proposed which includes the response to both the frequency and phase angle variations. The proposed algorithm is simulated and verified using Hardware-in-the-Loop (HIL) testing.

The root locus method: application to linear stability analysis and design of cooperative car-following models

A global framework for linear stability analyses of traffic models, based on the dispersion relation root locus method, is presented and is applied taking the example of a broad class of car-following (CF) models. This approach is able to analyse all aspects of the dynamics: long waves and short wave behaviours, phase velocities and stability features. The methodology is applied to investigate the potential benefits of connected vehicles, i.e. V2V communication enabling a vehicle to send and receive information to and from surrounding vehicles. We choose to focus on the design of the coefficients of cooperation which weights the information from downstream vehicles. The coefficients tuning is performed and different ways of implementing an efficient cooperative strategy are discussed. Hence, this paper brings design methods in order to obtain robust stability of traffic models, with application on cooperative CF models