A multiscale road map of cancer spheroids : incorporating experimental and mathematical modelling to understand cancer progression

Computational models represent a highly suitable framework, not only for testing biological hypotheses and generating new ones but also for optimising experimental strategies. As one surveys the literature devoted to cancer modelling, it is obvious that immense progress has been made in applying simulation techniques to the study of cancer biology, although the full impact has yet to be realised. For example, there are excellent models to describe cancer incidence rates or factors for early disease detection, but these predictions are unable to explain the functional and molecular changes that are associated with tumour progression. In addition, it is crucial that interactions between mechanical effects, and intracellular and intercellular signalling are incorporated in order to understand cancer growth, its interaction with the extracellular microenvironment and invasion of secondary sites. There is a compelling need to tailor new, physiologically relevant in silico models that are specialised for particular types of cancer, such as ovarian cancer owing to its unique route of metastasis, which are capable of investigating anti-cancer therapies, and generating both qualitative and quantitative predictions. This Commentary will focus on how computational simulation approaches can advance our understanding of ovarian cancer progression and treatment, in particular, with the help of multicellular cancer spheroids, and thus, can inform biological hypothesis and experimental design.

A pilot randomised trial of Medilixir cream shows some promising results, but control treatment may have been inappropriate

Aim To test the efficacy of Medilixir [cream] against the standard treatment of aqueous cream in the provision of relief from the symptoms of postburn itch. Design RCT with two parallel arms. Setting Professor Stuart Pegg Adult Burns Centre, Royal Brisbane and Women's Hospital, Brisbane, Australia. Participants Fifty-two patients aged between 18 and 80 years, admitted directly to the burns centre between 10 March and 22 July 2008, were able to provide informed consent, and had shown no allergic reaction to a patch test with the study medication, were randomised. Patients admitted from intensive care or high dependency were excluded. Main results Effect estimates and confidence intervals were not reported for any of the outcomes; only group means/proportions and P-values from hypothesis testing were provided. More patients in the intervention group reported itch reduction compared to comparison treatment (91 vs. 82%, P=0.001). Itch recurrence after cream application occurred later in the intervention group compared to the control group (P<0.001). Use of antipruritic medication was significantly greater in the control group (P=0.023). There was no difference in sleep disturbance between groups (not quantified). On average, Medilixir took longer to apply than aqueous cream (157s for Medilixir vs. 139s for aqueous cream; mean difference 17s), but authors noted that the groups did not differ significantly (CI for mean difference and P-values were not reported).

Polymorphisms in inflammation pathway genes and endometrial cancer risk

BACKGROUND Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. METHODS To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. RESULTS Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. CONCLUSIONS These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.

Agility in consumer retail: sense-response alignment through the eyes of customers

In hyper competition, firms that are agile: sensing and responding better to customer requirements tend to be more successful and achieve supernormal profits. In spite of the widely accepted importance of customer agility, research is limited on this construct. The limited research also has predominantly focussed on the firm’s perspective of agility. However, we propose that the customers are better positioned to determine how well a firm is responding to their requirements (aka a firm’s customer agility). Taking the customers’ stand point, we address the issue of sense and respond alignment in two perspectives-matching and mediating. Based on data collected from customers in a field study, we tested hypothesis pertaining to the two methods of alignment using polynomial regression and response surface methodology. The results provide a good explanation for the role of both forms of alignment on customer satisfaction. Implication for research and practice are discussed.

Measuring the effects of small group deliberation on public attitudes towards sentencing : benefits and challenges

This article reports on the outcomes of small group deliberations on levels of punitiveness and public confidence in the sentencing functions of Australian criminal courts, conducted as part of a larger project investigating public attitudes to sentencing. One hypothesis of the project as a whole was that a more informed and involved public is likely to be less punitive in their views on the sentencing of offenders, and to express less cynical views about the role of sentencing courts. The aim of the small group deliberations as part of the broader project was to engender a more thoughtful and considered approach by participants to issues around sentencing. It was hypothesised that the opportunity to discuss, deliberate and consider would lead to a measurable reduction in punitiveness and an increase in people’s confidence in the courts. While the results do indeed indicate such changes in attitudes, the current study also shed light on some of the conceptual, methodological and practical challenges inherent in this type of research.

Literature review: Student centred schools make the difference

Student-centred schools focus on designing learning experiences that recognise and respond to the individual needs of each of their students. They encourage all members of their school community to be active learners, working to enhance the educational opportunities available at their school. This literature review seeks to address and explore the hypothesis that studentcentred schools make the difference. The review commences by defining the concept of student-centred schooling and the various learning and educational theories that underpin related research. The authors present a model comprising six core elements of learning environments that student-centred schools demonstrate, with a focus on leadership. They also link their findings to the five professional practices in AITSL’s Australian Professional Standard for Principals to illustrate how these leadership practices drive and sustain studentcentred schools. Drawing from Viviane Robinson’s work on the dimensions of student-centred school leadership, together with several further dimensions identified through an environmental scan of literature, the authors consider how and in what ways student-centred schools make the difference.

Literature review : A culture of trust enhances performance

In this environmental scan of research and policy literature, the authors consider various definitions of trust as they seek to address and inform the hypothesis that ‘a culture of trust enhances performance’ in schools. The discussion draws on the work of the Australian Institute for Teaching and School Leadership in school leadership and research by Caldwell and Harris (2008) to consider ways in which trust is linked to performance in schools and organisations. It explores the concept of trust as a form of capital available to schools, and highlights how successful school leaders work to align trust, strategy and passion in implementing effective change. At the heart of the review is the relationship between trust and school improvement. An adapted model of the elements of a culture of trust developed by Bryk and Schneider in their influential study of trust in school reform in Chicago is used to frame this aspect of the review. The authors identify four essential categories of relationships that enable schools to be described as having a culture of trust. The review concludes with a discussion of the relationship between trust and school governance.

Document ranking with quantum probabilities

In this thesis we investigate the use of quantum probability theory for ranking documents. Quantum probability theory is used to estimate the probability of relevance of a document given a user's query. We posit that quantum probability theory can lead to a better estimation of the probability of a document being relevant to a user's query than the common approach, i. e. the Probability Ranking Principle (PRP), which is based upon Kolmogorovian probability theory. Following our hypothesis, we formulate an analogy between the document retrieval scenario and a physical scenario, that of the double slit experiment. Through the analogy, we propose a novel ranking approach, the quantum probability ranking principle (qPRP). Key to our proposal is the presence of quantum interference. Mathematically, this is the statistical deviation between empirical observations and expected values predicted by the Kolmogorovian rule of additivity of probabilities of disjoint events in configurations such that of the double slit experiment. We propose an interpretation of quantum interference in the document ranking scenario, and examine how quantum interference can be effectively estimated for document retrieval. To validate our proposal and to gain more insights about approaches for document ranking, we (1) analyse PRP, qPRP and other ranking approaches, exposing the assumptions underlying their ranking criteria and formulating the conditions for the optimality of the two ranking principles, (2) empirically compare three ranking principles (i. e. PRP, interactive PRP, and qPRP) and two state-of-the-art ranking strategies in two retrieval scenarios, those of ad-hoc retrieval and diversity retrieval, (3) analytically contrast the ranking criteria of the examined approaches, exposing similarities and differences, (4) study the ranking behaviours of approaches alternative to PRP in terms of the kinematics they impose on relevant documents, i. e. by considering the extent and direction of the movements of relevant documents across the ranking recorded when comparing PRP against its alternatives. Our findings show that the effectiveness of the examined ranking approaches strongly depends upon the evaluation context. In the traditional evaluation context of ad-hoc retrieval, PRP is empirically shown to be better or comparable to alternative ranking approaches. However, when we turn to examine evaluation contexts that account for interdependent document relevance (i. e. when the relevance of a document is assessed also with respect to other retrieved documents, as it is the case in the diversity retrieval scenario) then the use of quantum probability theory and thus of qPRP is shown to improve retrieval and ranking effectiveness over the traditional PRP and alternative ranking strategies, such as Maximal Marginal Relevance, Portfolio theory, and Interactive PRP. This work represents a significant step forward regarding the use of quantum theory in information retrieval. It demonstrates in fact that the application of quantum theory to problems within information retrieval can lead to improvements both in modelling power and retrieval effectiveness, allowing the constructions of models that capture the complexity of information retrieval situations. Furthermore, the thesis opens up a number of lines for future research. These include: (1) investigating estimations and approximations of quantum interference in qPRP; (2) exploiting complex numbers for the representation of documents and queries, and; (3) applying the concepts underlying qPRP to tasks other than document ranking.

Mechanical tension as a driver of connective tissue growth in vitro

We propose the progressive mechanical expansion of cell-derived tissue analogues as a novel, growth-based approach to in vitro tissue engineering. The prevailing approach to producing tissue in vitro is to culture cells in an exogenous “scaffold” that provides a basic structure and mechanical support. This necessarily pre-defines the final size of the implantable material, and specific signals must be provided to stimulate appropriate cell growth, differentiation and matrix formation. In contrast, surgical skin expansion, driven by increments of stretch, produces increasing quantities of tissue without trauma or inflammation. This suggests that connective tissue cells have the innate ability to produce growth in response to elevated tension. We posit that this capacity is maintained in vitro, and that order-of-magnitude growth may be similarly attained in self-assembling cultures of cells and their own extracellular matrix. The hypothesis that growth of connective tissue analogues can be induced by mechanical expansion in vitro may be divided into three components: (1) tension stimulates cell proliferation and extracellular matrix synthesis; (2) the corresponding volume increase will relax the tension imparted by a fixed displacement; (3) the repeated application of static stretch will produce sustained growth and a tissue structure adapted to the tensile loading. Connective tissues exist in a state of residual tension, which is actively maintained by resident cells such as fibroblasts. Studies in vitro and in vivo have demonstrated that cellular survival, reproduction, and matrix synthesis and degradation are regulated by the mechanical environment. Order-of-magnitude increases in both bone and skin volume have been achieved clinically through staged expansion protocols, demonstrating that tension-driven growth can be sustained over prolonged periods. Furthermore, cell-derived tissue analogues have demonstrated mechanically advantageous structural adaptation in response to applied loading. Together, these data suggest that a program of incremental stretch constitutes an appealing way to replicate tissue growth in cell culture, by harnessing the constituent cells’ innate mechanical responsiveness. In addition to offering a platform to study the growth and structural adaptation of connective tissues, tension-driven growth presents a novel approach to in vitro tissue engineering. Because the supporting structure is secreted and organised by the cells themselves, growth is not restricted by a “scaffold” of fixed size. This also minimises potential adverse reactions to exogenous materials upon implantation. Most importantly, we posit that the growth induced by progressive stretch will allow substantial volumes of connective tissue to be produced from relatively small initial cell numbers.

Fatty acid uptake and incorporation into phospholipids in the rat lens

PURPOSE. Phospholipids are a major component of lens fiber cells and influence the activity of membrane proteins. Previous investigations of fatty acid uptake by the lens are limited. The purpose of the present study was thus to determine whether exogenous fatty acids could be taken up by the rat lens and incorporated into molecular phospholipids. METHODS. Lenses were incubated with fluorescently labeled palmitic acid and then analyzed by confocal microscopy. Concurrently, lenses incubated with either fluorescently labeled palmitic acid or the more physiologically relevant (13)C(18)-oleic acid were sectioned into nuclear and cortical regions and analyzed by highly sensitive and structurally selective electrospray ionization tandem mass spectrometry techniques. RESULTS. The detection of fluorescently labeled palmitic acid, even after 16 hours of incubation, was limited to approximately the outer 25% to 30% of the rat lens. Mass spectrometry also revealed the presence of free (13)C(18)-oleic acid in the cortex but not the nucleus. No evidence could be found for incorporation of fluorescently labeled palmitic acid into phospholipids; however, a low level of (13)C(18)-oleic acid incorporation into phosphatidylethanolamine (PE), specifically PE (PE 16:0/(13)C(18) 18:1) was detected in the lens cortex after 16 hours. CONCLUSIONS. These data demonstrate that uptake of exogenous (e.g., dietary fatty acids) by the lens and their incorporation into phospholipids is minimal, most likely occurring only during de novo synthesis in the outermost region of the lens. This finding adds support to the hypothesis that once synthesized there is no active remodeling or turnover of fiber cell phospholipids.

Exploring the boundary between the siphon and barometer in a hypobaric chamber

Siphons have been used since ancient times, but exactly how they work is still a matter of debate. In order to elucidate the modus operandi of a siphon, a 1.5 m high siphon was set up in a hypobaric chamber to explore siphon behaviour in a low-pressure environment. When the pressure in the chamber was reduced to about 0.18 atmospheres, a curious waterfall-like feature appeared downstream from the apex of the siphon. A hypothesis is presented to explain the waterfall phenomenon. When the pressure was reduced further the siphon broke into two columns - in effect becoming two back-to-back barometers. This experiment demonstrates the role of atmospheric pressure in explaining the hydrostatic characteristics of a siphon and the role of molecular cohesion in explaining the hydrodynamic aspects.

Essays on momentum investing strategies

The momentum investment strategy, which buys recent winner stocks and sells recent loser stocks, earns returns that are simply too good to be explained by traditional finance theories. This thesis extends our understanding of the sources of momentum profits. The research shows that part of the seemingly anomalous returns can be explained by the market's reaction to public news, is affected by how delisting returns are calculated, and is biased by ignoring the time-varying risk of the trading strategy.

The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells

Glioblastoma multiforme (GBM) is a malignant astrocytoma of the central nervous system associated with a median survival time of 15 months, even with aggressive therapy. This rapid progression is due in part to diffuse infiltration of single tumor cells into the brain parenchyma, which is thought to involve aberrant interactions between tumor cells and the extracellular matrix (ECM). Here, we test the hypothesis that mechanical cues from the ECM contribute to key tumor cell properties relevant to invasion. We cultured a series of glioma cell lines (U373-MG, U87-MG, U251-MG, SNB19, C6) on fibronectin-coated polymeric ECM substrates of defined mechanical rigidity and investigated the role of ECM rigidity in regulating tumor cell structure, migration, and proliferation. On highly rigid ECMs, tumor cells spread extensively, form prominent stress fibers and mature focal adhesions, and migrate rapidly. As ECM rigidity is lowered to values comparable with normal brain tissue, tumor cells appear rounded and fail to productively migrate. Remarkably, cell proliferation is also strongly regulated by ECM rigidity, with cells dividing much more rapidly on rigid than on compliant ECMs. Pharmacologic inhibition of nonmuscle myosin II–based contractility blunts this rigidity-sensitivity and rescues cell motility on highly compliant substrates. Collectively, our results provide support for a novel model in which ECM rigidity provides a transformative, microenvironmental cue that acts through actomyosin contractility to regulate the invasive properties of GBM tumor cells.

Electrical imaging and fluid modeling of convective fingering in a shallow water-table aquifer

Unstable density-driven flow can lead to enhanced solute transport in groundwater. Only recently has the complex fingering pattern associated with free convection been documented in field settings. Electrical resistivity (ER) tomography has been used to capture a snapshot of convective instabilities at a single point in time, but a thorough transient analysis is still lacking in the literature. We present the results of a 2 year experimental study at a shallow aquifer in the United Arab Emirates that was designed to specifically explore the transient nature of free convection. ER tomography data documented the presence of convective fingers following a significant rainfall event. We demonstrate that the complex fingering pattern had completely disappeared a year after the rainfall event. The observation is supported by an analysis of the aquifer halite budget and hydrodynamic modeling of the transient character of the fingering instabilities. Modeling results show that the transient dynamics of the gravitational instabilities (their initial development, infiltration into the underlying lower-density groundwater, and subsequent decay) are in agreement with the timing observed in the time-lapse ER measurements. All experimental observations and modeling results are consistent with the hypothesis that a dense brine that infiltrated into the aquifer from a surficial source was the cause of free convection at this site, and that the finite nature of the dense brine source and dispersive mixing led to the decay of instabilities with time. This study highlights the importance of the transience of free convection phenomena and suggests that these processes are more rapid than was previously understood.

Randomised controlled trial of amoxycillin clavulanate in children with chronic wet cough

Background Despite guideline recommendations, there are no published randomised controlled trial data on the efficacy of antibiotics for chronic wet cough in children. The majority of children with chronic wet cough have protracted bacterial bronchitis (PBB), a recognised condition in multiple national guidelines. The authors conducted a parallel 1:1 placebo randomised controlled trial to test the hypothesis that a 2-week course of amoxycillin clavulanate is efficacious in the treatment of children with chronic wet cough. Methods 50 children (median age 1.9 years, IQR 0.9–5.1) with chronic (>3 weeks) wet cough were randomised to 2 weeks of twice daily oral amoxycillin clavulanate (22.5 mg/kg/dose) or placebo. The primary outcome was ‘cough resolution’ defined as a >75% reduction in the validated verbal category descriptive cough score within 14 days of treatment compared with baseline scores, or cessation of cough for >3 days. In selected children, flexible bronchoscopy and bronchoalveolar lavage (BAL) were undertaken at baseline. Results Cough resolution rates (48%) were significantly higher in children who received amoxycillin clavulanate compared with those who received placebo (16%), p=0.016. The observed difference between proportions was 0.32 (95% CI 0.08 to 0.56). Post treatment, median verbal category descriptive score in the amoxycillin clavulanate group of 0.5 (IQR 0.0–2.0) was significantly lower than in the placebo group, 2.25 (IQR 1.15–2.9) (p=0.02). Pre-treatment BAL data were consistent with PBB in the majority of children, with no significant difference between groups. Conclusion A 2-week course of amoxycillin clavulanate will achieve cough resolution in a significant number of children with chronic wet cough. BAL data support the diagnosis of PBB in the majority of these children.