Identifying cancer sub-types from genomic scale data sets using confidence based integration (CBI).

Precision medicine is a method involving refined diagnosis of patients and searching for causes that are unseen in their patient cohorts who otherwise have largely similar health conditions. As the technology evolved to extract features from a wide variety of sources including genetics, a large quantum of data is available to the researchers for conducting micro studies in the field of disease and cures. In cancer research, integrative methods using genomic data sets has become a major area of interest. The petabytes of data that is available at The Cancer Genome Atlas (TCGA), a program jointly under NCI and National Human Genome Research Institute, has made possible more nuanced research in cancer genomics. Our method, Confidence Based Integration (CBI) is an integration method to extract similar as well as complementing information from the genomic data sets. This information will provide insight into the status of patients and their prospects. We used the expression data sets of gene, miRNA and DNA methylation in our fusion experiments on five different cancer types. These data sets, after fusion, are clustered using 'Spectral Clustering' algorithm, which derives clusters that form the disease sub types. Survival properties of each sub type demonstrates the reasons to consider the samples inside them highly similar. The performance of CBI, we report, is better, in terms of P-value in log-rank test, than other methods like similarity network fusion or SNF in forming clusters of significance. Individual features clustered extremely poor compared to CBI in most of the experiments.

Allelic frequency database of 15 polymorphic autosomal STRs in the Malayalam-speaking population of Kerala, India.

In this study, we assessed and established an allelic frequency database of Malayalam-speaking population of south western Indian state Kerala, using 15 polymorphic short tandem repeats (STRs) genetic markers. For this study, 464 unrelated healthy individuals were randomly selected following the ethical standards. The most polymorphic and most discriminating locus was D2S1338, with a value of 0.860 and 0.968, respectively. The range of heterozygosity extended from a minimum of 0.668 (TH01) to a maximum of 0.847 (D2S1338). The combined discrimination power (CPD) and combined exclusion power (CPE) were 1 and 0.999997861, respectively, for all 15 autosomal STR loci under study. The combined probability of match (CPM) and combined paternity index (CPI) for all 15 autosomal STR loci were found to be 9.85 × 10-19 and 4.18 × 105, respectively.

FOXO3 expression during colorectal cancer progression: biomarker potential reflects a tumour suppressor role.

BACKGROUND: In previous studies, the Forkhead/winged-helix-box-class-O3 (FOXO3) transcription factor has displayed both tumour suppressive and metastasis-promoting properties.To clarify its role in human colorectal cancer (CRC) progression, we examined in vivo FOXO3 expression at key points of the metastatic cascade. METHODS: Formalin-fixed paraffin-embedded resection specimens from normal colon, adenomas, primary CRC specimens of different pathological stage and CRC specimens with matched liver metastases were used to generate three separate custom-designed tissue microarray (TMA) representations of metastatic progression. Triplicate cores, immunostained for FOXO3 were scored semiquantitatively by two investigators. RESULTS: The FOXO3 expression is significantly reduced in CRC specimens compared with normal tissue, and progressive FOXO3 downregulation is associated with advancing pathological stage. In addition, recurrent stage I/II primary tumours show a significantly lower FOXO3 expression compared with stage-matched non-recurrent tumours. When stratified according to high and low FOXO3 expression, mean disease-free survival in the low-expressing group was 28 months (95% CI 15.8-50.6) compared with 64 months (95% CI 52.9-75.4) in the high-expressing group. CONCLUSION: We have demonstrated an association between low FOXO3 expression and CRC progression in vivo using purpose-designed TMAs. Forkhead/winged-helix-box-class-O3 may represent a novel biomarker of nodal and distant disease spread with clinical utility in CRC.

Regulation of p73 activity by post-translational modifications.

The transcription factor p73 is a member of the p53 family that can be expressed as at least 24 different isoforms with pro- or anti-apoptotic attributes. The TAp73 isoforms are expressed from an upstream promoter and are regarded as bona fide tumor suppressors; they can induce cell cycle arrest/apoptosis and protect against genomic instability. On the other hand, ΔNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TAp73 or p53 to block their transcriptional activities. Therefore, the ratio of TAp73 isoforms to ΔNp73 isoforms is critical for the quality of the response to a genomic insult and needs to be delicately regulated at both transcriptional and post-translational level. In this review, we will summarize the current knowledge on the post-translational regulatory pathways involved to keep p73 protein under control. A comprehensive understanding of p73 post-translational modifications will be extremely useful for the development of new strategies for treating and preventing cancer.

Lattice Monte Carlo simulation of semiconductor nanocrystal synthesis in microemulsion droplets.

A lattice Monte Carlo model has been developed to describe the formation of a single semiconductor nanocrystal (quantum dot) inside a droplet of a microemulsion. The motivation stems from the need to understand the kinetics of quantum dot formation in microemulsion templates with minimal droplet-droplet coalescence. In these systems, a fixed amount of a reactant is dissolved in each droplet, and another reactant is supplied by diffusion through the interface. Nucleation is facilitated by a spontaneous reaction between the precursors at the droplet interface, and the coalescence of nuclei and clusters ultimately leads to the formation of a single particle. The size of the final particle is controlled by the concentration of the first reactant. A hard-sphere potential is used to describe cluster-cluster interactions. The overall particle formation time initially increases with final particle size, quickly passes through a maximum, and subsequently decreases due to the formation of large intermediate clusters apparently acting as effective collision partners to smaller ones. Studies of the evolution of intermediate cluster sizes provided mechanistic details of the final particle formation through cluster-cluster coalescence. A generalized dimensionless equation is obtained that relates the formation time of the final particle to its size for various droplet sizes and diffusivities of the first reactant and clusters. A parametric study reveals that the final particle formation time is more sensitive to changes in the cluster-cluster coalescence probability than in the probability of nucleation.

Maternal high-fat diet: effects on offspring bone structure.

UNLABELLED: Peak bone mass is believed to partly be programmed in utero. Mouse dams and offspring were given a high-fat diet and offspring studied as adults. Female offspring from high-fat dams exhibited altered trabecular structure indicative of in utero programming. In utero nutrition has consequences in later life. INTRODUCTION: Epidemiological studies suggest that skeletal growth is programmed during intrauterine and early postnatal life. We hypothesise that development of optimal peak bone mass has, in part, a foetal origin and investigated this using a mouse model of maternal dietary fat excess. METHODS: Offspring from mouse dams fed either standard chow (C) or lifetime high-fat diet (HF) were maintained on a HF diet to adulthood. Femur samples were taken at 30 weeks of age and bone structure, adiposity and strength analysed. Sample sizes were four to six for each sex and each diet group. RESULTS: Offspring from HF-fed dams showed increased adiposity in the femur in comparison to offspring from C-fed dams. Female offspring from HF dams exhibited altered trabecular structure indicative of in utero programming. CONCLUSIONS: A maternal HF diet during pregnancy increases bone marrow adiposity and alters bone structure in their offspring.

Patellar button dissociation in a mobile-bearing LCS patellofemoral joint arthroplasty.

Patellofemoral arthroplasty is an effective treatment for isolated patellofemoral arthritis. Midterm results reveal a success rate of approximately 80% to 90% with modern designs. The reported failure mechanisms associated with patellofemoral arthroplasty include progressive tibiofemoral arthritis, patellar pain, catching or subluxation caused by soft-tissue imbalance, component malposition, and problematic designs. We present a previously unreported new complication of patellar button dissociation in a mobile-bearing LCS Patellofemoral Joint Replacement Prosthesis.

Volatile sulfur compounds produced by probiotic bacteria in the presence of cysteine or methionine.

AIMS: To investigate the abilities of various probiotic bacteria to produce volatile sulfur compounds (VSCs) relevant to food flavour and aroma. METHODS AND RESULTS: Probiotic strains (Lactobacillus acidophilus NCFM, Lactobacillus plantarum 299v, Lactobacillus rhamnosus GG, Lactobacillus reuteri ATCC55730 and L. reuteri BR11), Lactobacillus delbrueckii ATCC4797, L. plantarum ATCC14917 and Lactococcus lactis MG1363 were incubated with either cysteine or methionine. Volatile compounds were captured, identified and quantified using a sensitive solid-phase microextraction (SPME) technique combined with gas chromatography coupled to a pulsed flame photometric detector (SPME/GC/PFPD). Several VSCs were identified including H(2)S, methanethiol, dimethyldisulfide and dimethyltrisulfide. The VSC profiles varied substantially for different strains of L. plantarum and L. reuteri and it was found that L. reuteri ATCC55730 and L. lactis MG1363 produced the lowest levels of VSCs (P < 0.05). Levels of VSCs generated by bacteria were found to be equivalent to, or higher than, that found in commercial cheeses. CONCLUSIONS: Several probiotic strains are able to generate considerable levels of VSCs and substantial variations in VSC generating potential exists between different strains from the same species. SIGNIFICANCE AND IMPORTANCE OF THE STUDY: This study demonstrates that probiotic bacteria are able to efficiently generate important flavour and aroma compounds and therefore has implications for the development of probiotic containing foods.

IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22.

Interleukin (IL) 22 is a type II cytokine that is produced by immune cells and acts on nonimmune cells to regulate local tissue inflammation. As a product of the recently identified T helper 17 lineage of CD4(+) effector lymphocytes, IL-22 plays a critical role in mucosal immunity as well as in dysregulated inflammation observed in autoimmune diseases. We used comprehensive mutagenesis combined with mammalian cell expression, ELISA cell-based, and structural methods to evaluate how IL-22 interacts with its cell surface receptor, IL-22R/IL-10R2, and with secreted IL-22 binding protein. This study identifies those amino acid side chains of IL-22 that are individually important for optimal binding to IL-22R, considerably expands the definition of IL-22 surface required for binding to IL-10R2, and demonstrates how IL-22 binding protein prevents IL-22R from binding to IL-22. The IL-22R and IL-10R2 binding sites are juxtaposed on adjacent IL-22 surfaces contributed mostly by helices A, D, and F and loop AB. Our results also provide a model for how IL-19, IL-20, IL-24, and IL-26 which are other IL-10-like cytokines, interact with their respective cell surface receptors.

Identification of critical amino acid residues for human iNOS functional activity.

Nitric oxide (NO) is a short-lived signaling molecule that mediates a variety of biological functions, including vascular homeostasis, neurotransmission, antimicrobial defense and antitumor activities. Three known NOS isoforms (eNOS, nNOS and iNOS) have been cloned and sequenced. Here, we show that upon expression in Escherichia coli using a novel expression vector, an iNOS sequence containing three mutations (A805D, F831S and L832P) within the iNOS reductase domain produced very little functionally active iNOS protein compared to the wild type (wt) iNOS. Each of these point mutations also was individually constructed into the wt iNOS sequence. The activity of the iNOS protein containing the A805D mutation was comparable to wt, while a drastic reduction in iNOS activity was observed for the F831S and L832P mutants. A comparison of the molecular models of the reductase domain of the wt and mutant iNOS revealed a reduced core packing density for the F831S and L832P mutations compared to wt. In addition, the modeling also suggests altered hydrogen bonding, van der Waals and hydrophobic interactions of these mutants.