Mechanistic insights into the role of microRNAs in cancer: influence of nutrient crosstalk

A plethora of studies have described the disruption of key cellular regulatory mechanisms involving non-coding RNAs, specifically microRNAs (miRNA) from the let-7 family, the miR-17 family, miR-21, miR-143, and the miR-200 family, which contribute to aberrant signaling and tumor formation. Certain environmental factors, such as bioactive dietary agents, e.g., folate, curcumin, polyunsaturated fatty acids, are also thought to impact the progression and severity of cancer. In terms of the chemoprotective mechanisms of action, these bioactive dietary agents appear to act, in part, by modulating tissue levels of miR-16, miR-17 family, miR-26b, miR-106b, and miR-200 family miRNAs and their target genes. However, the mechanisms of nutrient action are not yet fully understood. Therefore, additional characterization of the putative underlying mechanisms is needed to further our understanding of the biology, early diagnosis, prevention, and the treatment of cancer. For the purpose of elucidating the epigenetic landscape of cancer, this review will summarize the key findings from recent studies detailing the effect of bioactive dietary agents on miRNA regulation in cancer

Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment

AbstractInterleukin-2 receptor α chain (IL-2Rα) expression occurs at specific stages of early T and B lymphocyte development and is induced upon activation of mature lymphocytes. Young mice that lack IL-2Rα have phenotypically normal development of T and B cells. However, as adults, these mice develop massive enlargement of peripheral lymphoid organs associated with polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo. Older IL-2Rα-deficient mice also develop autoimmune disorders, including hemolytic anemia and inflammatory bowel disease. Thus, IL-2Rα is essential for regulation of both the size and content of the peripheral lymphoid compartment, probably by influencing the balance between clonal expansion and cell death following lymphocyte activation

Evaluation of fecal mRNA reproducibility via a marginal transformed mixture modeling approach

<p>Abstract</p> <p>Background</p> <p>Developing and evaluating new technology that enables researchers to recover gene-expression levels of colonic cells from fecal samples could be key to a non-invasive screening tool for early detection of colon cancer. The current study, to the best of our knowledge, is the first to investigate and report the reproducibility of fecal microarray data. Using the intraclass correlation coefficient (ICC) as a measure of reproducibility and the preliminary analysis of fecal and mucosal data, we assessed the reliability of mixture density estimation and the reproducibility of fecal microarray data. Using Monte Carlo-based methods, we explored whether ICC values should be modeled as a beta-mixture or transformed first and fitted with a normal-mixture. We used outcomes from bootstrapped goodness-of-fit tests to determine which approach is less sensitive toward potential violation of distributional assumptions.</p> <p>Results</p> <p>The graphical examination of both the distributions of ICC and probit-transformed ICC (PT-ICC) clearly shows that there are two components in the distributions. For ICC measurements, which are between 0 and 1, the practice in literature has been to assume that the data points are from a beta-mixture distribution. Nevertheless, in our study we show that the use of a normal-mixture modeling approach on PT-ICC could provide superior performance.</p> <p>Conclusions</p> <p>When modeling ICC values of gene expression levels, using mixture of normals in the probit-transformed (PT) scale is less sensitive toward model mis-specification than using mixture of betas. We show that a biased conclusion could be made if we follow the traditional approach and model the two sets of ICC values using the mixture of betas directly. The problematic estimation arises from the sensitivity of beta-mixtures toward model mis-specification, particularly when there are observations in the neighborhood of the the boundary points, 0 or 1. Since beta-mixture modeling is commonly used in approximating the distribution of measurements between 0 and 1, our findings have important implications beyond the findings of the current study. By using the normal-mixture approach on PT-ICC, we observed the quality of reproducible genes in fecal array data to be comparable to those in mucosal arrays.</p

Overexpression of Protein Kinase C βII Induces Colonic Hyperproliferation and Increased Sensitivity to Colon Carcinogenesis

Protein kinase C βII (PKC βII) has been implicated in proliferation of the intestinal epithelium. To investigate PKC βII function in vivo, we generated transgenic mice that overexpress PKC βII in the intestinal epithelium. Transgenic PKC βII mice exhibit hyperproliferation of the colonic epithelium and an increased susceptibility to azoxymethane-induced aberrant crypt foci, preneoplastic lesions in the colon. Furthermore, transgenic PKC βII mice exhibit elevated colonic β-catenin levels and decreased glycogen synthase kinase 3β activity, indicating that PKC βII stimulates the Wnt/adenomatous polyposis coli (APC)/β-catenin proliferative signaling pathway in vivo. These data demonstrate a direct role for PKC βII in colonic epithelial cell proliferation and colon carcinogenesis, possibly through activation of the APC/β-catenin signaling pathway

Non-invasive analysis of intestinal development in preterm and term infants using RNA-Sequencing

The state and development of the intestinal epithelium is vital for infant health, and increased understanding in this area has been limited by an inability to directly assess epithelial cell biology in the healthy newborn intestine. To that end, we have developed a novel, noninvasive, molecular approach that utilizes next generation RNA sequencing on stool samples containing intact epithelial cells for the purpose of quantifying intestinal gene expression. We then applied this technique to compare host gene expression in healthy term and extremely preterm infants. Bioinformatic analyses demonstrate repeatable detection of human mRNA expression, and network analysis shows immune cell function and inflammation pathways to be up-regulated in preterm infants. This study provides incontrovertible evidence that whole-genome sequencing of stool-derived RNA can be used to examine the neonatal host epithelial transcriptome in infants, which opens up opportunities for sequential monitoring of gut gene expression in response to dietary or therapeutic interventions

A metagenomic study of diet-dependent interaction between gut microbiota and host in infants reveals differences in immune response

BACKGROUND: Gut microbiota and the host exist in a mutualistic relationship, with the functional composition of the microbiota strongly affecting the health and well-being of the host. Thus, it is important to develop a synthetic approach to study the host transcriptome and the microbiome simultaneously. Early microbial colonization in infants is critically important for directing neonatal intestinal and immune development, and is especially attractive for studying the development of human-commensal interactions. Here we report the results from a simultaneous study of the gut microbiome and host epithelial transcriptome of three-month-old exclusively breast- and formula-fed infants. RESULTS: Variation in both host mRNA expression and the microbiome phylogenetic and functional profiles was observed between breast- and formula-fed infants. To examine the interdependent relationship between host epithelial cell gene expression and bacterial metagenomic-based profiles, the host transcriptome and functionally profiled microbiome data were subjected to novel multivariate statistical analyses. Gut microbiota metagenome virulence characteristics concurrently varied with immunity-related gene expression in epithelial cells between the formula-fed and the breast-fed infants. CONCLUSIONS: Our data provide insight into the integrated responses of the host transcriptome and microbiome to dietary substrates in the early neonatal period. We demonstrate that differences in diet can affect, via gut colonization, host expression of genes associated with the innate immune system. Furthermore, the methodology presented in this study can be adapted to assess other host-commensal and host-pathogen interactions using genomic and transcriptomic data, providing a synthetic genomics-based picture of host-commensal relationships

Carbon Sequestration in Synechococcus Sp.: From Molecular Machines to Hierarchical Modeling

The U.S. Department of Energy recently announced the first five grants for the Genomes to Life (GTL) Program. The goal of this program is to "achieve the most far-reaching of all biological goals: a fundamental, comprehensive, and systematic understanding of life." While more information about the program can be found at the GTL website (www.doegenomestolife.org), this paper provides an overview of one of the five GTL projects funded, "Carbon Sequestration in Synechococcus Sp.: From Molecular Machines to Hierarchical Modeling." This project is a combined experimental and computational effort emphasizing developing, prototyping, and applying new computational tools and methods to ellucidate the biochemical mechanisms of the carbon sequestration of Synechococcus Sp., an abundant marine cyanobacteria known to play an important role in the global carbon cycle. Understanding, predicting, and perhaps manipulating carbon fixation in the oceans has long been a major focus of biological oceanography and has more recently been of interest to a broader audience of scientists and policy makers. It is clear that the oceanic sinks and sources of CO2 are important terms in the global environmental response to anthropogenic atmospheric inputs of CO2 and that oceanic microorganisms play a key role in this response. However, the relationship between this global phenomenon and the biochemical mechanisms of carbon fixation in these microorganisms is poorly understood. The project includes five subprojects: an experimental investigation, three computational biology efforts, and a fifth which deals with addressing computational infrastructure challenges of relevance to this project and the Genomes to Life program as a whole. Our experimental effort is designed to provide biology and data to drive the computational efforts and includes significant investment in developing new experimental methods for uncovering protein partners, characterizing protein complexes, identifying new binding domains. We will also develop and apply new data measurement and statistical methods for analyzing microarray experiments. Our computational efforts include coupling molecular simulation methods with knowledge discovery from diverse biological data sets for high-throughput discovery and characterization of protein-protein complexes and developing a set of novel capabilities for inference of regulatory pathways in microbial genomes across multiple sources of information through the integration of computational and experimental technologies. These capabilities will be applied to Synechococcus regulatory pathways to characterize their interaction map and identify component proteins in these pathways. We will also investigate methods for combining experimental and computational results with visualization and natural language tools to accelerate discovery of regulatory pathways. Furthermore, given that the ultimate goal of this effort is to develop a systems-level of understanding of how the Synechococcus genome affects carbon fixation at the global scale, we will develop and apply a set of tools for capturing the carbon fixation behavior of complex of Synechococcus at different levels of resolution. Finally, because the explosion of data being produced by high-throughput experiments requires data analysis and models which are more computationally complex, more heterogeneous, and require coupling to ever increasing amounts of experimentally obtained data in varying formats, we have also established a companion computational infrastructure to support this effort as well as the Genomes to Life program as a whole.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63164/1/153623102321112746.pd

Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer

The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing

Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes