Cancer Hallmarks Analytics Tool (CHAT): A text mining approach to organise and evaluate scientific literature on cancer

Motivation: To understand the molecular mechanisms involved in cancer development, significant efforts are being invested in cancer research. This has resulted in millions of scientific articles. An efficient and thorough review of the existing literature is crucially important to drive new research. This time-demanding task can be supported by emerging computational approaches based on text mining which offer a great opportunity to organise and retrieve the desired information efficiently from sizable databases. One way to organise existing knowledge on cancer is to utilise the widely accepted framework of the Hallmarks of Cancer. These hallmarks refer to the alterations in cell behaviour that characterise the cancer cell. Results: We created an extensive Hallmarks of Cancer taxonomy and developed automatic text mining methodology and a tool (CHAT) capable of retrieving and organising millions of cancer-related references from PubMed into the taxonomy. The efficiency and accuracy of the tool was evaluated intrinsically as well as extrinsically by case studies. The correlations identified by the tool show that it offers a great potential to organise and correctly classify cancer-related literature. Furthermore, the tool can be useful, for example, in identifying hallmarks associated with extrinsic factors, biomarkers and therapeutics targets

Physical interpretation of stochastic Schroedinger equations in cavity QED

We propose physical interpretations for stochastic methods which have been developed recently to describe the evolution of a quantum system interacting with a reservoir. As opposed to the usual reduced density operator approach, which refers to ensemble averages, these methods deal with the dynamics of single realizations, and involve the solution of stochastic Schr\"odinger equations. These procedures have been shown to be completely equivalent to the master equation approach when ensemble averages are taken over many realizations. We show that these techniques are not only convenient mathematical tools for dissipative systems, but may actually correspond to concrete physical processes, for any temperature of the reservoir. We consider a mode of the electromagnetic field in a cavity interacting with a beam of two- or three-level atoms, the field mode playing the role of a small system and the atomic beam standing for a reservoir at finite temperature, the interaction between them being given by the Jaynes-Cummings model. We show that the evolution of the field states, under continuous monitoring of the state of the atoms which leave the cavity, can be described in terms of either the Monte Carlo Wave-Function (quantum jump) method or a stochastic Schr\"odinger equation, depending on the system configuration. We also show that the Monte Carlo Wave-Function approach leads, for finite temperatures, to localization into jumping Fock states, while the diffusion equation method leads to localization into states with a diffusing average photon number, which for sufficiently small temperatures are close approximations to mildly squeezed states.Comment: 12 pages RevTeX 3.0 + 6 figures (GIF format; for higher-resolution postscript images or hardcopies contact the authors.) Submitted to Phys. Rev.

Text mining for improved exposure assessment

Chemical exposure assessments are based on information collected via different methods, such as biomonitoring, personal monitoring, environmental monitoring and questionnaires. The vast amount of chemical-specific exposure information available from web-based databases, such as PubMed, is undoubtedly a great asset to the scientific community. However, manual retrieval of relevant published information is an extremely time consuming task and overviewing the data is nearly impossible. Here, we present the development of an automatic classifier for chemical exposure information. First, nearly 3700 abstracts were manually annotated by an expert in exposure sciences according to a taxonomy exclusively created for exposure information. Natural Language Processing (NLP) techniques were used to extract semantic and syntactic features relevant to chemical exposure text. Using these features, we trained a supervised machine learning algorithm to automatically classify PubMed abstracts according to the exposure taxonomy. The resulting classifier demonstrates good performance in the intrinsic evaluation. We also show that the classifier improves information retrieval of chemical exposure data compared to keyword-based PubMed searches. Case studies demonstrate that the classifier can be used to assist researchers by facilitating information retrieval and classification, enabling data gap recognition and overviewing available scientific literature using chemical-specific publication profiles. Finally, we identify challenges to be addressed in future development of the system.S.B. received funding from Commonwealth Scholarship Commission (http://cscuk.dfid.gov.uk/), Cambridge Trust (https://www.cambridgetrust.org/). A.K. received funding from Medical Research Council UK grant MR/M013049/1

Estrogen-Like Effects of Cadmium in Vivo Do Not Appear to be Mediated via the Classical Estrogen Receptor Transcriptional Pathway

Cadmium is a toxic metal classified as human carcinogen and ubiquitously found in our environment mainly from anthropogenic activities. Exposure to cadmium has been associated with increased risk of certain hormone-dependent cancers in humans, and the metal has been proposed to possess endocrine disruptive properties by mimicking the physiological actions of estrogens. However, the mechanisms behind these effects are unclear. The overall aim of this thesis was to provide mechanistic insights into the estrogenicity of cadmium that may have implications for the human health. To achieve this aim, investigations on the estrogen-like effects of cadmium as well as possible involvement of classical/non-classical estrogen receptor signaling was studied in mice, and these mechanisms were further scrutinized in cell-based models. Furthermore, associations of biomarker of cadmium exposure with endogenous circulating sex hormones were evaluated in a population-based study of women. Results presented here indicate that exposure to cadmium does not affect the genomic estrogen response in vivo in mice, suggesting that classical estrogen signaling is not targeted by cadmium. However, some estrogen-like effects were observed in cadmium exposed mice, i.e. significant thickening of uterine epithelia, in the absence of uterine weight increase, and activation of ERK1/2 MAPKs in the liver. This suggests the existence of alternative signaling pathways modulated by cadmium. In addition, exposure to a wide dose range of cadmium, dose-dependently increased the expression of the endogenous genes Mt1, Mt2, p53, c-fos, and Mdm2 in mouse liver, with p53 being the most sensitive gene. However, phosphorylation of ERK1/2 was already induced at the lowest exposure level (0.5µg/kg body weight), rendering ERK1/2 a more sensitive marker of exposure than any change in gene expression. Furthermore, in vivo findings suggest that cadmium-induced effects are markedly concentration dependent: low-level exposure activates protein-kinases whereas high-level exposure turns on cellular stress responses. The data from in vitro studies indicate that cadmium at regular human exposure levels activates protein-kinase signaling through Raf-MEK-ERK/MAPKs, and we identified EGFR and GPR30 as the mediating receptors. This cadmium-induced activation of protein-kinases further leads to a disturbance in Mdm2/p53 balance, with a significant increase in the Mdm2/p53 ratio in the presence of genotoxic compounds, which in turn suggest that cadmium may disrupt stress response to genotoxins. In 438 postmenopausal women, a positive association was observed between the concentrations of cadmium in blood and testosterone in serum, while an inverse association was observed with estradiol. This may suggest that cadmium affects steroidogenesis. In conclusion, data presented in this thesis collectively suggests that cadmium-induced estrogen-like effects do not involve classical estrogen receptor signaling but rather appear to be mediated via membrane-associated signaling. The activation/ transactivation of GPR30/EGFR-Raf-MEK-ERK/MAPKs and Mdm2 represent a general mechanism by which cadmium may exert its effects. Since EGFR, ERK and Mdm2 are all known key players in cancer promotion, cadmium-induced activation of these and disturbance in the estradiol/testosterone balance in women may have implications for the promotion/development of hormone-related cancers

Theory of Pseudomodes in Quantum Optical Processes

This paper deals with non-Markovian behaviour in atomic systems coupled to a structured reservoir of quantum EM field modes, with particular relevance to atoms interacting with the field in high Q cavities or photonic band gap materials. In cases such as the former, we show that the pseudo mode theory for single quantum reservoir excitations can be obtained by applying the Fano diagonalisation method to a system in which the atomic transitions are coupled to a discrete set of (cavity) quasimodes, which in turn are coupled to a continuum set of (external) quasimodes with slowly varying coupling constants and continuum mode density. Each pseudomode can be identified with a discrete quasimode, which gives structure to the actual reservoir of true modes via the expressions for the equivalent atom-true mode coupling constants. The quasimode theory enables cases of multiple excitation of the reservoir to now be treated via Markovian master equations for the atom-discrete quasimode system. Applications of the theory to one, two and many discrete quasimodes are made. For a simple photonic band gap model, where the reservoir structure is associated with the true mode density rather than the coupling constants, the single quantum excitation case appears to be equivalent to a case with two discrete quasimodes

Treating asthma with omega-3 fatty acids: where is the evidence? A systematic review

BACKGROUND: Considerable interest exists in the potential therapeutic value of dietary supplementation with the omega-3 fatty acids. Given the interplay between pro-inflammatory omega-6 fatty acids, and the less pro-inflammatory omega-3 fatty acids, it has been thought that the latter could play a key role in treating or preventing asthma. The purpose was to systematically review the scientific-medical literature in order to identify, appraise, and synthesize the evidence for possible treatment effects of omega-3 fatty acids in asthma. METHODS: Medline, Premedline, Embase, Cochrane Central Register of Controlled Trials, CAB Health, and, Dissertation Abstracts were searched to April 2003. We included randomized controlled trials (RCT's) of subjects of any age that used any foods or extracts containing omega-3 fatty acids as treatment or prevention for asthma. Data included all asthma related outcomes, potential covariates, characteristics of the study, design, population, intervention/exposure, comparators, and co interventions. RESULTS: Ten RCT's were found pertinent to the present report. CONCLUSION: Given the largely inconsistent picture within and across respiratory outcomes, it is impossible to determine whether or not omega-3 fatty acids are an efficacious adjuvant or monotherapy for children or adults. Based on this systematic review we recommend a large randomized controlled study of the effects of high-dose encapsulated omega-3 fatty acids on ventilatory and inflammatory measures of asthma controlling diet and other asthma risk factors. This review was limited because Meta-analysis was considered inappropriate due to missing data; poorly or heterogeneously defined populations, interventions, intervention-comparator combinations, and outcomes. In addition, small sample sizes made it impossible to meaningfully assess the impact on clinical outcomes of co-variables. Last, few significant effects were found

Optimisation of Over-Expression in E. coli and Biophysical Characterisation of Human Membrane Protein Synaptogyrin 1

Progress in functional and structural studies of integral membrane proteins (IMPs) is lacking behind their soluble counterparts due to the great challenge in producing stable and homogeneous IMPs. Low natural abundance, toxicity when over-expressed and potential lipid requirements of IMPs are only a few reasons for the limited progress. Here, we describe an optimised workflow for the recombinant over-expression of the human tetraspan vesicle protein (TVP) synaptogyrin in Escherichia coli and its biophysical characterisation. TVPs are ubiquitous and abundant components of vesicles. They are believed to be involved in various aspects of the synaptic vesicle cycle, including vesicle biogenesis, exocytosis and endocytotic recycling. Even though TVPs are found in most cell types, high-resolution structural information for this class of membrane proteins is still missing. The optimisation of the N-terminal sequence of the gene together with the usage of the recently developed Lemo21(DE3) strain which allows the balancing of the translation with the membrane insertion rate led to a 50-fold increased expression rate compared to the classical BL21(DE3) strain. The protein was soluble and stable in a variety of mild detergents and multiple biophysical methods confirmed the folded state of the protein. Crosslinking experiments suggest an oligomeric architecture of at least four subunits. The protein stability is significantly improved in the presence of cholesteryl hemisuccinate as judged by differential light scattering. The approach described here can easily be adapted to other eukaryotic IMPs

Introducing the Complexity of Educational Diversification

Peer reviewe

Altered mRNA expression of genes related to nerve cell activity in the fracture callus of older rats: A randomized, controlled, microarray study

BACKGROUND: The time required for radiographic union following femoral fracture increases with age in both humans and rats for unknown reasons. Since abnormalities in fracture innervation will slow skeletal healing, we explored whether abnormal mRNA expression of genes related to nerve cell activity in the older rats was associated with the slowing of skeletal repair. METHODS: Simple, transverse, mid-shaft, femoral fractures with intramedullary rod fixation were induced in anaesthetized female Sprague-Dawley rats at 6, 26, and 52 weeks of age. At 0, 0.4, 1, 2, 4, and 6 weeks after fracture, a bony segment, one-third the length of the femur, centered on the fracture site, including the external callus, cortical bone, and marrow elements, was harvested. cRNA was prepared and hybridized to 54 Affymetrix U34A microarrays (3/age/time point). RESULTS: The mRNA levels of 62 genes related to neural function were affected by fracture. Of the total, 38 genes were altered by fracture to a similar extent at the three ages. In contrast, eight neural genes showed prolonged down-regulation in the older rats compared to the more rapid return to pre-fracture levels in younger rats. Seven genes were up-regulated by fracture more in the younger rats than in the older rats, while nine genes were up-regulated more in the older rats than in the younger. CONCLUSIONS: mRNA of 24 nerve-related genes responded differently to fracture in older rats compared to young rats. This differential expression may reflect altered cell function at the fracture site that may be causally related to the slowing of fracture healing with age or may be an effect of the delayed healing