Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

Colon tumors from four independent mouse models and 100 human colorectal cancers all exhibited striking recapitulation of embryonic colon gene expression from embryonic days 13.5-18.5

Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

Abstract Background The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5. Results We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear β-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF). Conclusion Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models

Multichannel equalization using linear matrix inequality optimization

In digital communication receiver systems equalization is either a linear or nonlinear process. The primary task of the equalizer is to remove or at least reduce intersymbol interference (ISI) between transmitted symbols. ISI arises from time dispersion whereby a transmitted symbol is smeared across several symbol time intervals, hence interfering with other transmitted symbols. Time dispersion stems from the characteristics of the channel medium. Some examples of time dispersion would be the band-limited nature of the channel medium and multi-path interference. Not compensating for ISI typically results in an unacceptable probability of error at the receiver. This research focuses on designing multi-channel equalizing filters for digital communication systems. The design methodologies developed in this research relies on numerical convex optimization based on Linear Matrix Inequalities (LMIs). Digital communication systems are modeled as having an additive noise source to account noise distortions. ISI and the additive noise source are primary performance impairments in most digital communication systems. Thus it is prudent to account for both of these factors in designing an equalizing filter. Under certain conditions it is well known that ISI reduction and output noise power are competing entities. The design techniques developed in this research exploit the trade-off between ISI and equalizer output noise power, by utilizing an equalizer design methodology based on LMI optimization. Additionally, concepts such as spatial diversity, i.e., multiple channels, and sample-spaced equalization (to be defined later), are used to solve problems associated with multi-path channels which exhibit severe fading. Performance gains are shown in terms the post-equalizer constellation mean-square error (MSE) and the bit-error-rate (BER) of the receiver

Determination of threshold adverse effect doses of percutaneous VX exposure in African green monkeys

Percutaneous exposure to the chemical warfare nerve agent VX was evaluated in African green monkeys (n = 9). Doses of VX (7.5–100 μg/kg) were applied to the skin for 60 min and residual agent was quantified (before decontamination) to estimate the absorbed dose. Monkeys were evaluated for the presence or absence of clinical signs of toxicity and blood was sampled periodically (30 min–12 weeks) following exposure to measure the degree of circulating acetylcholinesterase (AChE) inhibition. Monkeys were also evaluated for behavioral changes fromVXexposure using a serial probe recognition (SPR) task. The lowest observable adverse effect level (LOAEL) for the production of major clinical signs was determined to be 42.22 μg/kg (absorbed dose estimate = 17.36 μg/kg) and the LOAEL for AChE inhibition was 13.33 μg/kg (absorbed dose estimate = 6.53 μg/kg). Behavioral performance was unaffected at doses that, while producing substantial AChE inhibition, did not produce clinical signs. VX represents a substantial threat as a contact hazard and these results complement previous studies using the percutaneous route of exposure with VX and extend the findings to a non-human primate species

Improving irrigated rice production in the Senegal River Valley through experiential learning and innovation

Research facilitating farmer–researcher collaboration and experiential learning may provide the missing element to tailor crop management recommendations to meet farmers’ needs. We tested different crop management systems for irrigated rice in three seasons of adaptive research trials in three locations in the middle Senegal River Valley. Our objectives were to assess the agronomic and socio-economic viability of Recommended Management Practices (RMPs) compared to the System of Rice Intensification (SRI) and Farmers’ Practices (FPs). During the 2008 dry season, RMP and SRI significantly increased yields over FP by 2.3 and 2.6 t ha−1 across sites. Farmers analyzed their experiences in post-experiment meetings. They appreciated SRI’s yield and water-saving potential, but found it labor demanding, especially for weed management requirements that coincided with horticultural activities. Conversely, farmers described RMP’s elevated herbicide rate as costly, and indicated that because of poorly functioning agro-chemical markets, herbicide volumes larger than typically used in FP might be difficult to reliably source. To modify management systems to fit farmers’ needs and assets, we collaboratively developed a fourth, ‘Farmer Adapted Practice’ (FAP) that blended RMP and SRI. FAP used intermittent irrigation during the late vegetative stage, recommended crop density, intermediate seedling age, and a single round of mechanical weeding followed by localized herbicide application. Farmers compared FAP against the initial management systems in the subsequent seasons. Though no yield differences were found between RMP, SRI and FAP, each yielded significantly more (+1.0, +1.1 and +1.5 t ha−1) than FP. FAP also reduced labor requirements without increasing weed biomass compared to RMP or SRI, and used 40% and 10% less herbicide than RMP and FP, respectively. Cumulative distribution functions showed that FAP increased net profit potential and decreased economic risk. Prior to the 2009 dry season trials, the Senegalese state eliminated herbicide subsidies, doubling their cost. RMP, SRI and FAP yielded 2.9, 3.0 and 3.1 t ha−1 more than FP. FAP again reduced weeding labor and herbicide requirements while lowering production risk across sites. This study demonstrates the value-added outcomes that result from research that facilitates farmer–researcher collaboration to learn from, innovate and tailor management systems to fit local circumstances