Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo

Substantial evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have potential as chemopreventative/therapeutic agents. However, these agents cannot be universally recommended for prevention purposes due to their potential side-effect profiles. Here, we compared the growth inhibitory and mechanistic activity of aspirin to two novel analogues, diaspirin (DiA) and fumaryl diaspirin (F-DiA). We found that the aspirin analogues inhibited cell proliferation and induced apoptosis of colorectal cancer cells at significantly lower doses than aspirin. Similar to aspirin, we found that an early response to the analogues was a reduction in levels of cyclin D1 and stimulation of the NF-κB pathway. This stimulation was associated with a significant reduction in basal levels of NF-κB transcriptional activity, in keeping with previous data for aspirin. However, in contrast to aspirin, DiA and F-DiA activity was not associated with nucleolar accumulation of RelA. For all assays, F-DiA had a more rapid and significant effect than DiA, identifying this agent as particularly active against colorectal cancer. Using a syngeneic colorectal tumour model in mice, we found that, while both agents significantly inhibited tumour growth in vivo, this effect was particularly pronounced for F-DiA. These data identify two compounds that are active against colorectal cancer in vitro and in vivo. They also identify a potential mechanism of action of these agents and shed light on the chemical structures that may be important for the antitumour effects of aspirin.

Influence of Egr-1 in cardiac tissue-derived mesenchymal stem cells in response to glucose variations

Mesenchymal stem cells (MSCs) represent a promising cell population for cell therapy and regenerative medicine applications. However, how variations in glucose are perceived by MSC pool is still unclear. Since, glucose metabolism is cell type and tissue dependent, this must be considered when MSCs are derived from alternative sources such as the heart. The zinc finger transcription factor Egr-1 is an important early response gene, likely to play a key role in the glucose-induced response. Our aim was to investigate how short-term changes in in vitro glucose concentrations affect multipotent cardiac tissue-derived MSCs (cMSCs) in a mouse model of Egr-1 KO (Egr-1-/-). Results showed that loss of Egr-1 does not significantly influence cMSC proliferation. In contrast, responses to glucose variations were observed in wt but not in Egr-1 -/- cMSCs by clonogenic assay. Phenotype analysis by RT-PCR showed that cMSCs Egr-1-/- lost the ability to regulate the glucose transporters GLUT-1 and GLUT-4 and, as expected, the Egr-1 target genes VEGF, TGFβ-1, and p300. Acetylated protein levels of H3 histone were impaired in Egr-1-/- compared to wt cMSCs. We propose that Egr-1 acts as immediate glucose biological sensor in cMSCs after a short period of stimuli, likely inducing epigenetic modifications. © 2014 Daniela Bastianelli et al.

Retinal arteriolar diameter response to flicker light provocation - A useful marker for risk stratification in cardiovascular disease?

Purpose: To to evaluate the benefit of bilinear and linear fitting to characterize the retinal vessel dilation to flicker light stimulation for the purpose of risk stratification in cardiovascular disease. Methods: Forty-five patients (15 with coronary artery disease (CAD), 15 with Diabetes Mellitus (DM) and 15 with CAD and DM) all underwent contact tonometry, digital blood pressure measurement, fundus photography, retinal vessel oximetry, static retinal vessel analysis and continous retinal diameter assessment using the retinal vessel analyser (and flicker light provocation). In addition we measured blood glucose (HbA1c) and keratinin levels in DM patients. Results: With increased severity of cardiovascular disease a more linear reaction profile of retinal arteriolar diameter to flicker light provocation can be observed. Conclusion: Absolute values of vessel dilation provide only limited information on the state of retinal arteriolar dilatory response to flicker light. The approach of bilinear fitting takes into account the immediate response to flicker light provocation as well as the maintained dilatory capacity during prolonged stimulation. Individuals with cardiovascular disease however show a largely linear reaction profile indicating an impairment of the initial rapid dilatory response as usually observed in healty individuals

Molecular and cellular effects of ultraviolet light-induced genotoxicity

Exposure to the solar ultraviolet spectrum that penetrates the Earth's stratosphere (UVA and UVB) causes cellular DNA damage within skin cells. This damage is elicited directly through absorption of energy (UVB), and indirectly through intermediates such as sensitizer radicals and reactive oxygen species (UVA). DNA damage is detected as strand breaks or as base lesions, the most common lesions being 8-hydroxydeoxyguanosine (8OHdG) from UVA exposure and cyclobutane pyrimidine dimers from UVB exposure. The presence of these products in the genome may cause misreading and misreplication. Cells are protected by free radical scavengers that remove potentially mutagenic radical intermediates. In addition, the glutathione-S-transferase family can catalyze the removal of epoxides and peroxides. An extensive repair capacity exists for removing (1) strand breaks, (2) small base modifications (8OHdG), and (3) bulky lesions (cyclobutane pyrimidine dimers). UV also stimulates the cell to produce early response genes that activate a cascade of signaling molecules (e.g., protein kinases) and protective enzymes (e.g., haem oxygenase). The cell cycle is restricted via p53-dependent and -independent pathways to facilitate repair processes prior to replication and division. Failure to rescue the cell from replication block will ultimately lead to cell death, and apoptosis may be induced. The implications for UV-induced genotoxicity in disease are considered.

A specific and rapid neural signature for parental instinct

Darwin originally pointed out that there is something about infants which prompts adults to respond to and care for them, in order to increase individual fitness, i.e. reproductive success, via increased survivorship of one's own offspring. Lorenz proposed that it is the specific structure of the infant face that serves to elicit these parental responses, but the biological basis for this remains elusive. Here, we investigated whether adults show specific brain responses to unfamiliar infant faces compared to adult faces, where the infant and adult faces had been carefully matched across the two groups for emotional valence and arousal, as well as size and luminosity. The faces also matched closely in terms of attractiveness. Using magnetoencephalography (MEG) in adults, we found that highly specific brain activity occurred within a seventh of a second in response to unfamiliar infant faces but not to adult faces. This activity occurred in the medial orbitofrontal cortex (mOFC), an area implicated in reward behaviour, suggesting for the first time a neural basis for this vital evolutionary process. We found a peak in activity first in mOFC and then in the right fusiform face area (FFA). In mOFC the first significant peak (p<0.001) in differences in power between infant and adult faces was found at around 130 ms in the 10-15 Hz band. These early differences were not found in the FFA. In contrast, differences in power were found later, at around 165 ms, in a different band (20-25 Hz) in the right FFA, suggesting a feedback effect from mOFC. These findings provide evidence in humans of a potential brain basis for the "innate releasing mechanisms" described by Lorenz for affection and nurturing of young infants. This has potentially important clinical applications in relation to postnatal depression, and could provide opportunities for early identification of families at risk.

Neuronal convergence in early contrast vision: binocular summation is followed by response nonlinearity and area summation

We assessed summation of contrast across eyes and area at detection threshold ( C t). Stimuli were sine-wave gratings (2.5 c/deg) spatially modulated by cosine- and anticosine-phase raised plaids (0.5 c/deg components oriented at ±45°). When presented dichoptically the signal regions were interdigitated across eyes but produced a smooth continuous grating following their linear binocular sum. The average summation ratio ( C t1/([ C t1+2]) for this stimulus pair was 1.64 (4.3 dB). This was only slightly less than the binocular summation found for the same patch type presented to both eyes, and the area summation found for the two different patch types presented to the same eye. We considered 192 model architectures containing each of the following four elements in all possible orders: (i) linear summation or a MAX operator across eyes, (ii) linear summation or a MAX operator across area, (iii) linear or accelerating contrast transduction, and (iv) additive Gaussian, stochastic noise. Formal equivalences reduced this to 62 different models. The most successful four-element model was: linear summation across eyes followed by nonlinear contrast transduction, linear summation across area, and late noise. Model performance was enhanced when additional nonlinearities were placed before binocular summation and after area summation. The implications for models of probability summation and uncertainty are discussed.

Speech and non-speech stimuli in the prediction of early reading skills:the influence of processing demands and response-type

Purpose: Both phonological (speech) and auditory (non-speech) stimuli have been shown to predict early reading skills. However, previous studies have failed to control for the level of processing required by tasks administered across the two levels of stimuli. For example, phonological tasks typically tap explicit awareness e.g., phoneme deletion, while auditory tasks usually measure implicit awareness e.g., frequency discrimination. Therefore, the stronger predictive power of speech tasks may be due to their higher processing demands, rather than the nature of the stimuli. Method: The present study uses novel tasks that control for level of processing (isolation, repetition and deletion) across speech (phonemes and nonwords) and non-speech (tones) stimuli. 800 beginning readers at the onset of literacy tuition (mean age 4 years and 7 months) were assessed on the above tasks as well as word reading and letter-knowledge in the first part of a three time-point longitudinal study. Results: Time 1 results reveal a significantly higher association between letter-sound knowledge and all of the speech compared to non-speech tasks. Performance was better for phoneme than tone stimuli, and worse for deletion than isolation and repetition across all stimuli. Conclusions: Results are consistent with phonological accounts of reading and suggest that level of processing required by the task is less important than stimuli type in predicting the earliest stage of reading.

What drives the prediction of early reading? An analysis of stimulus and response-type

Purpose: Phonological accounts of reading implicate three aspects of phonological awareness tasks that underlie the relationship with reading; a) the language-based nature of the stimuli (words or nonwords), b) the verbal nature of the response, and c) the complexity of the stimuli (words can be segmented into units of speech). Yet, it is uncertain which task characteristics are most important as they are typically confounded. By systematically varying response-type and stimulus complexity across speech and non-speech stimuli, the current study seeks to isolate the characteristics of phonological awareness tasks that drive the prediction of early reading. Method: Four sets of tasks were created; tone stimuli (simple non-speech) requiring a non-verbal response, phonemes (simple speech) requiring a non-verbal response, phonemes requiring a verbal response, and nonwords (complex speech) requiring a verbal response. Tasks were administered to 570 2nd grade children along with standardized tests of reading and non-verbal IQ. Results: Three structural equation models comparing matched sets of tasks were built. Each model consisted of two 'task' factors with a direct link to a reading factor. The following factors predicted unique variance in reading: a) simple speech and non-speech stimuli, b) simple speech requiring a verbal response but not simple speech requiring a non-verbal-response, and c) complex and simple speech stimuli. Conclusions: Results suggest that the prediction of reading by phonological tasks is driven by the verbal nature of the response and not the complexity or 'speechness' of the stimuli. Findings highlight the importance of phonological output processes to early reading.

Deconstructing phonological tasks:the contribution of stimulus and response type to the prediction of early decoding skills

Abstract Phonological tasks are highly predictive of reading development but their complexity obscures the underlying mechanisms driving this association. There are three key components hypothesised to drive the relationship between phonological tasks and reading; (a) the linguistic nature of the stimuli, (b) the phonological complexity of the stimuli, and (c) the production of a verbal response. We isolated the contribution of the stimulus and response components separately through the creation of latent variables to represent specially designed tasks that were matched for procedure. These tasks were administered to 570 6 to 7-year-old children along with standardised tests of regular word and non-word reading. A structural equation model, where tasks were grouped according to stimulus, revealed that the linguistic nature and the phonological complexity of the stimulus predicted unique variance in decoding, over and above matched comparison tasks without these components. An alternative model, grouped according to response mode, showed that the production of a verbal response was a unique predictor of decoding beyond matched tasks without a verbal response. In summary, we found that multiple factors contributed to reading development, supporting multivariate models over those that prioritize single factors. More broadly, we demonstrate the value of combining matched task designs with latent variable modelling to deconstruct the components of complex tasks.