Prognostic value of TP53, KRAS and EGFR mutations in nonsmall cell lung cancer : the EUELC cohort

Nonsmall cell lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in the TP53, KRAS and EGFR genes. The series included 11 never-smokers, 86 former smokers, 152 current smokers and one patient without informed smoking status. There were 110 squamous cell carcinomas (SCCs), 133 adenocarcinomas (ADCs) and seven large cell carcinomas or mixed histologies. Expression of p53 was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues. TP53 mutations were detected in 48.8% of cases and were more frequent among SCCs than ADCs (p<0.0001). TP53 mutation status was not associated with prognosis. G to T transversions, known to be associated with smoking, were marginally more common among patients who developed a second primary lung cancer or recurrence/metastasis (progressive disease). EGFR mutations were almost exclusively found in never-smoking females (p=0.0067). KRAS mutations were detected in 18.5% of cases, mainly ADC (p<0.0001), and showed a tendency toward association with progressive disease status. These results suggest that mutations are good markers of different aetiologies and histopathological forms of lung cancers but have little prognostic value, with the exception of KRAS mutation, which may have a prognostic value in ADC. Copyright©ERS 2012.

Phospho-Akt expression is associated with a favorable outcome in non-small cell lung cancer

Akt, a Serine/Threonine protein kinase, mediates growth factor-associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non-small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables. Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037). These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC. © 2005 American Association for Cancer Research.

Expression of thrombospondin-1 in resected colorectal liver metastases predicts poor prognosis

Purpose The aim of this study was to examine the expression and prognostic relevance of thrombospondin-1 (TSP-1) in tumor biopsies taken from a consecutive series of liver resections done at the University Hospitals of Leicester and the Royal Liverpool Hospital. Experimental Design Patients having undergone a liver resection for colorectal liver metastases at our institutions between 1993 and 1999 inclusive were eligible. Inclusion criteria were curative intent, sufficient tumor biopsy, and patient follow-up data. One hundred eighty-two patients were considered in this study. Standard immunohistochemical techniques were used to study the expression of TSP-1 in 5-μm tumor sections from paraffin-embedded tissue blocks. TSP-1 was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. Results One hundred eighty-two patients (male, n = 122 and female, n = 60) ages between 25 and 81 years (mean, 61 years) were included. TSP-1 was expressed around blood vessels (n = 45, 25%) or in the stroma (n = 59, 33%). No expression was detected in the remaining tumors. TSP-1 significantly correlated with poor survival on univariate (P = 0.01 for perivascular expression and P = 0.03 for stromal expression) and multivariate analysis (P = 0.01 for perivascular expression). Conclusion TSP-1 is a negatively prognostic factor for survival in resected colorectal liver metastases. © 2005 American Association for Cancer Research.

How transit route passenger load and distance can together influence quality of service

This paper investigates quality of service and resource productivity implications of transit route passenger loading and travel distance. Weekday Automatic Fare Collection data for a premium radial bus route in Brisbane, Australia, is used to investigate correlation between load factor and distance factor. Relationships between boardings and transit work indicate that distance factor generally increases with load factor. Time series analysis is then presented by examining each direction on an hour by hour basis. Inbound correlation is medium to strong across the entire span of service and strong for daytime services up to 19:30, while outbound correlation is strong across the entire span. Passengers tend to be making longer distance, peak direction commuter trips under the least comfortable conditions under stretched peak schedules than off-peak. Therefore productivity gains may be possible by adjusting fleet utilization during off-peak times. Weekday profiles by direction are established for a composite load-distance factor. A threshold corresponding to standing passengers on the Maximum Load Segment reveals that on-board loading and travel distance combined are more severe during the morning inbound peak than evening outbound peak, although the sharpness of the former suggests that encouraging shoulder peak travel during the morning would be more effective than evening peak. Further research suggested includes: consideration of travel duration factor, relating noise within hour to Peak Hour Factor, profiling load-distance factor across a range of case studies, and relating load-distance factor threshold to line length.

Serum HE4 as a prognostic marker in endometrial cancer : a population based study

Objective HE4 has emerged as a promising biomarker in gynaecological oncology. The purpose of this study was to evaluate serum HE4 as a biomarker for high-risk phenotypes in a population-based endometrial cancer cohort. Methods Peri-operative serum HE4 and CA125 were measured in 373 patients identified from the prospective Australian National Endometrial Cancer Study (ANECS). HE4 and CA125 were quantified on the ARCHITECT instrument in a clinically accredited laboratory. Receiver operator curves (ROC), Spearman rank correlation coefficient, and chi-squared and Mann–Whitney tests were used for statistical analysis. Survival analysis was performed using Kaplan–Meier and Cox multivariate regression analyses. Results Median CA125 and HE4 levels were higher in stage III and IV tumours (p < 0.001) and in tumours with outer-half myometrial invasion (p < 0.001). ROC analysis demonstrated that HE4 (area under the curve (AUC) = 0.76) was a better predictor of outer-half myometrial invasion than CA125 (AUC = 0.65), particularly in patients with low-grade endometrioid tumours (AUC 0.77 vs 0.64 for CA125). Cox multivariate analysis demonstrated that elevated HE4 was an independent predictor of recurrence-free survival (HR = 2.40, 95% CI 1.19–4.83, p = 0.014) after adjusting for stage and grade of disease, particularly in the endometrioid subtype (HR = 2.86, 95% CI 1.25–6.51, p = 0.012). Conclusion These findings demonstrate the utility of serum HE4 as a prognostic biomarker in endometrial cancer in a large, population-based study. In particular they highlight the utility of HE4 for pre-operative risk stratification to identify high-risk patients within low-grade endometrioid endometrial cancer patients who might benefit from lymphadenectomy.

Corporate reputation and financial performance : underlying dimensions of corporate reputation and their relation to sustained financial performance

This thesis examined the relationship between firms' corporate reputation and their future financial performance. Corporate reputation was represented by measuring the level of senior executives' attention to a number of intangible firm' resources (e.g. financial reputation, service culture) within firms' annual reports over a 17 year period. Initial findings suggested there was only a small relationship between reputation and future performance which lead to a reformulation of the problem. Reputation was posited to be a source of corporate resilience that helped firms with stronger reputations to sustain superior financial performance in times of difficulty, as well as allowing them to rebound more quickly from performance decline. Results suggest this interpretation of corporate reputation as well as indicating that industry sectors operate in different reputational 'domains' in which the relative importance of financial versus stakeholder aspects of corporate reputation varies.

Australian baby boomers switched to more environment friendly modes of transport during the global financial crisis

The global financial crisis (GFC) in 2008 rocked local, regional, and state economies throughout the world. Several intermediate outcomes of the GFC have been well documented in the literature including loss of jobs and reduced income. Relatively little research has, however, examined the impacts of the GFC on individual level travel behaviour change. To address this shortcoming, HABITAT panel data were employed to estimate a multinomial logit model to examine mode switching behaviour between 2007 (pre-GFC) and 2009 (post-GFC) of a baby boomers cohort in Brisbane, Australia—a city within a developed country that has been on many metrics the least affected by the GFC. In addition, a Poisson regression model was estimated to model the number of trips made by individuals in 2007, 2008, and 2009. The South East Queensland Travel Survey datasets were used to develop this model. Four linear regression models were estimated to assess the effects of the GFC on time allocated to travel during a day: one for each of the three travel modes including public transport, active transport, less environmentally friendly transport; and an overall travel time model irrespective of mode. The results reveal that individuals were more likely to switch to public transport who lost their job or whose income reduced between 2007 and 2009. Individuals also made significantly fewer trips in 2008 and 2009 compared to 2007. Individuals spent significantly less time using less environmentally friendly transport but more time using public transport in 2009. Baby boomers switched to more environmentally friendly travel modes during the GFC.

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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Motor controller simulation and embedded implementation for a blood pump

This study was a step forward in modeling, simulation and microcontroller implementation of a high performance control algorithm for the motor of a blood pump. The rotor angle is sensed using three Hall effect sensors and an algorithm is developed to obtain better angular resolution from the three signals for better discrete-time updates of the controller. The performance of the system was evaluated in terms of actual and reference speeds, stator currents and power consumption over a range of reference speeds up to 4000 revolutions per minute. The use of fewer low cost Hall effect sensors compared to expensive high resolution sensors could reduce the cost of blood pumps for total artificial hearts.

An Introduction to Constrained Control

An ubiquitous problem in control system design is that the system must operate subject to various constraints. Although the topic of constrained control has a long history in practice, there have been recent significant advances in the supporting theory. In this chapter, we give an introduction to constrained control. In particular, we describe contemporary work which shows that the constrained optimal control problem for discrete-time systems has an interesting geometric structure and a simple local solution. We also discuss issues associated with the output feedback solution to this class of problems, and the implication of these results in the closely related problem of anti-windup. As an application, we address the problem of rudder roll stabilization for ships.

On optimal control of constrained linear systems with imperfect state information and stochastic disturbances

We address the problem of finite horizon optimal control of discrete-time linear systems with input constraints and uncertainty. The uncertainty for the problem analysed is related to incomplete state information (output feedback) and stochastic disturbances. We analyse the complexities associated with finding optimal solutions. We also consider two suboptimal strategies that could be employed for larger optimization horizons.

Transfection of MDA-MB-231 human breast carcinoma cells with bone sialoprotein (BSP) stimulates migration and invasion in vitro and growth of primary and secondary tumors in nude mice

We have investigated the role of bone sialoprotein (BSP), a secreted glycoprotein normally found in bone, in breast cancer progression. To explore functions for BSP in human breast cancer invasion and metastasis, the full-length BSP cDNA was transfected into the MDA-MB-231-BAG human breast cancer cell line under the control of the CMV promoter. Clones expressing BSP and vector control clones were isolated. BSP producing clones showed increased monolayer wound healing, a faster rate of stellate outgrowth in Matrigel and increased rate of invasion into a collagen matrix when compared to control clones. Clones were also examined in models of breast cancer growth and metastasis in vivo. BSP transfected clones showed an increased rate of primary tumor growth following mammary fat pad injection of nude mice. BSP transfected clones and vector control clones metastasized to soft organs and bone at a similar rate after intra-cardiac injection as determined by real-time PCR and X-ray analysis. Although these organs were targets for both BSP transfected and non-transfected cells, the size of the metastatic lesion was shown to be significantly larger for BSP expressing clones. This was determined by real-time PCR analysis for soft organs and by X-ray analysis of bone lesions. For bone this was confirmed by intra-tibial injections of cells in nude mice. We conclude that BSP acts to drive primary and secondary tumor growth of breast cancers in vivo.

Metachronous carcinomas in colorectum and its clinicopathological significance

PURPOSE The study was designed to examine the significance of colorectal metachronous carcinoma in a large cohort of patients. METHODS Over a mean follow-up period of 10 years, the clinicopathological features, microsatellite instability (MSI) and clinical follow-up of 56 patients with metachronous colorectal carcinoma were analysed. RESULTS The prevalence of metachronous colorectal carcinoma was 2.1 %. The metachronous colorectal carcinomas appeared between 7 and 246 months (mean = 66 months) after surgical resection of the index colorectal carcinomas. Thirty-six per cent (n = 20) of the metachronous carcinoma occurred more than 5 years after the operation of the index carcinoma. Of the 56 patients, 20 % (n = 11) of the metachronous colorectal carcinomas were mucinous adenocarcinoma. Cancers detected in the secondary operations (metachronous colorectal carcinomas), when compared with the primary index cancers, were smaller, showed higher proportions of mucinous adenocarcinoma and more often located in the proximal colon. Patients with metachronous colorectal cancers had higher prevalence of mucinous adenocarcinoma, loss of staining for MSI markers and better survival rates than other patients with colorectal cancers. CONCLUSIONS Patients with metachronous colorectal carcinomas have characteristic features, and attention to these features is important for better management of this group of cancer.

Interacting motile agents : taking a mean-field approach beyond monomers and nearest-neighbor steps

We consider a discrete agent-based model on a one-dimensional lattice, where each agent occupies L sites and attempts movements over a distance of d lattice sites. Agents obey a strict simple exclusion rule. A discrete-time master equation is derived using a mean-field approximation and careful probability arguments. In the continuum limit, nonlinear diffusion equations that describe the average agent occupancy are obtained. Averaged discrete simulation data are generated and shown to compare very well with the solution to the derived nonlinear diffusion equations. This framework allows us to approach a lattice-free result using all the advantages of lattice methods. Since different cell types have different shapes and speeds of movement, this work offers insight into population-level behavior of collective cellular motion.

Collective motion of dimers

We consider a discrete agent-based model on a one-dimensional lattice and a two-dimensional square lattice, where each agent is a dimer occupying two sites. Agents move by vacating one occupied site in favor of a nearest-neighbor site and obey either a strict simple exclusion rule or a weaker constraint that permits partial overlaps between dimers. Using indicator variables and careful probability arguments, a discrete-time master equation for these processes is derived systematically within a mean-field approximation. In the continuum limit, nonlinear diffusion equations that describe the average agent occupancy of the dimer population are obtained. In addition, we show that multiple species of interacting subpopulations give rise to advection-diffusion equations. Averaged discrete simulation data compares very well with the solution to the continuum partial differential equation models. Since many cell types are elongated rather than circular, this work offers insight into population-level behavior of collective cellular motion.