Molecular cytogenetic evaluation of uveal melanoma cell lines and archival tissue

Uveal melanoma is the most common intraocular tumor in adults and often results in unilateral blindness and/or death. Previous cytogenetic characterizations of this tumor have consistently revealed chromosomal abnormalities involving chromosomes 3, 6, and 8; reports of other abnormalities vary in frequency. We further defined cytogenetic abnormalities of this tumor using molecular cytogenetic techniques on 10 uveal malignant melanoma cell lines and 100 formalin-fixed paraffin-embedded (FFPE) tumors.;The synthesis of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) results revealed that chromosomal rearrangement plays a significant role in the generation of DNA sequence copy number abnormalities throughout the genome, but none of the cell lines demonstrated monosomy 3. Centromeric fluorescence in situ hybridization (FISH) for chromosome 3 revealed approximately one signal per cell, but further evaluation with telomeric probes demonstrated multiple signals per cell, suggesting chromosomal rearrangement without the loss of an entire chromosome 3. Based on combined CGH, SKY and FISH data, we propose that chromosome 3 is more frequently involved in chromosomal rearrangements rather than whole-chromosome loss in uveal melanoma.;CGH was similarly employed to elucidate characteristic DNA-sequence copy number abnormalities of FFPE archival cases of uveal melanoma, and correlate genomic imbalance abnormalities with a prognosis. We set out to study 100 archival uveal melanoma cases, each with comprehensive patient follow-up, by correlation of copy number imbalances with survival. Fifty-one patients survived more than 9 years without evident metastasis, and the remaining 49 patients died with metastatic disease. Viable probe was generated from 82 of the 100 cases, allowing correlation of CGH findings with patient histories for all but 18 of the cases. Significant copy number imbalances were tested for univariate prognostic significance. The most powerful predictor of prognosis was gain of 18q11.2, which was subsequently compared with other significant chromosomal regions, as well as histological and clinical factors in a multivariate analysis. Multivariate analyses revealed that the gain of 18q11.2 and concomitant loss of 1p33 was the strongest indicator of a poor prognosis.;Our large-scale molecular cytogenetic analysis of cell lines and archival material contributes significantly to the characterization of uveal melanoma. This research is intended to direct further gene-specific study of malignancy in uveal melanoma

Multifactor Dimensionality Reduction Analysis Identifies Specific Nucleotide Patterns Promoting Genetic Polymorphisms

The fidelity of DNA replication serves as the nidus for both genetic evolution and genomic instability fostering disease. Single nucleotide polymorphisms (SNPs) constitute greater than 80% of the genetic variation between individuals. A new theory regarding DNA replication fidelity has emerged in which selectivity is governed by base-pair geometry through interactions between the selected nucleotide, the complementary strand, and the polymerase active site. We hypothesize that specific nucleotide combinations in the flanking regions of SNP fragments are associated with mutation

Accumulation of zinc, copper, or cerium in carrot (Daucus carota) exposed to metal oxide nanoparticles and metal ions

The release of engineered nanoparticles (ENPs) into the environment has raised concerns about the potential risks to food safety and human health. There is a particular need to determine the extent of ENP uptake into plant foods. Belowground vegetables growing in direct contact with the growth substrate are likely accumulate the highest concentration of ENPs. Carrot (Daucus carota) was grown in sand amended with ZnO, CuO, or CeO2 NPs or the same concentrations of Zn2+, Cu2+, or Ce4+. Treatment with ZnO or Zn2+ produced a concentration-dependent decrease in root and total biomass. Ionic Cu2+ and Ce4+ caused a greater reduction in shoot biomass as compared to the corresponding ENP treatments. Accumulation of Zn, Cu, or Ce in the taproot was restricted to the taproot periderm. Metal concentrations in the taproot periderm were higher for the ionic treatments than for the ENP treatments. Radial penetration of the metals into the taproot and subsequent translocation to shoots was also generally greater for plants receiving the ionic treatment than the ENP treatment. The distribution of the metals from the ENP treatments across the periderm, taproot, and shoots differed from that observed for the ionic treatments. Overall, the ENPs were no more toxic than the ionic treatments and showed reduced accumulation in the edible tissues of carrot. The results demonstrate that the understanding of ionic metal transport in plants may not accurately predict ENP transport and that additional comparative study is needed for this and other crop plants

Averting HIV Infections in New York City: A Modeling Approach Estimating the Future Impact of Additional Behavioral and Biomedical HIV Prevention Strategies

Background:New York City (NYC) remains an epicenter of the HIV epidemic in the United States. Given the variety of evidence-based HIV prevention strategies available and the significant resources required to implement each of them, comparative studies are needed to identify how to maximize the number of HIV cases prevented most economically.Methods:A new model of HIV disease transmission was developed integrating information from a previously validated micro-simulation HIV disease progression model. Specification and parameterization of the model and its inputs, including the intervention portfolio, intervention effects and costs were conducted through a collaborative process between the academic modeling team and the NYC Department of Health and Mental Hygiene. The model projects the impact of different prevention strategies, or portfolios of prevention strategies, on the HIV epidemic in NYC.Results:Ten unique interventions were able to provide a prevention benefit at an annual program cost of less than $360,000, the threshold for consideration as a cost-saving intervention (because of offsets by future HIV treatment costs averted). An optimized portfolio of these specific interventions could result in up to a 34$106,378; the total cost was in excess of $2 billion (over the 20 year period, or approximately$100 million per year, on average). The cost-savings of prevented infections was estimated at more than $5 billion (or approximately$250 million per year, on average).Conclusions:Optimal implementation of a portfolio of evidence-based interventions can have a substantial, favorable impact on the ongoing HIV epidemic in NYC and provide future cost-saving despite significant initial costs. © 2013 Kessler et al

The Multiscale Backbone of the Human Phenotype Network Based on Biological Pathways

Background: Networks are commonly used to represent and analyze large and complex systems of interacting elements. In systems biology, human disease networks show interactions between disorders sharing common genetic background. We built pathway-based human phenotype network (PHPN) of over 800 physical attributes, diseases, and behavioral traits; based on about 2,300 genes and 1,200 biological pathways. Using GWAS phenotype-to-genes associations, and pathway data from Reactome, we connect human traits based on the common patterns of human biological pathways, detecting more pleiotropic effects, and expanding previous studies from a gene-centric approach to that of shared cell-processes. Results: The resulting network has a heavily right-skewed degree distribution, placing it in the scale-free region of the network topologies spectrum. We extract the multi-scale information backbone of the PHPN based on the local densities of the network and discarding weak connection. Using a standard community detection algorithm, we construct phenotype modules of similar traits without applying expert biological knowledge. These modules can be assimilated to the disease classes. However, we are able to classify phenotypes according to shared biology, and not arbitrary disease classes. We present examples of expected clinical connections identified by PHPN as proof of principle. Conclusions: We unveil a previously uncharacterized connection between phenotype modules and discuss potential mechanistic connections that are obvious only in retrospect. The PHPN shows tremendous potential to become a useful tool both in the unveiling of the diseases’ common biology, and in the elaboration of diagnosis and treatments

Sacrificial templates for manufacturing multidimensional vasculature

Biological systems employ complex, composite architectures that are intimately related to homeostatic functionality. A common necessity underlying many of these systems is the transport of fluids that distribute nutrients, remove waste, and provide thermal regulation. Parallels exist in engineered materials; however, the architectures are comparatively less complex. No single fabrication technique has emerged with the flexibility to create architectures of various size-scale and dimensionality. Esser-Kahn et al. introduced a technique referred to as vaporization of sacrificial components (VaSC) [1]. Poly(lactic acid) PLA fibers are first treated with a catalyst, tin oxalate (SnOx), to lower their depolymerization temperature. The fibers are embedded in a thermoset matrix and then vaporized to leave behind straight channels (1D dimensionality). In this study, we extend the application of sacrificial PLA and VaSC to all levels of spatial dimensionality (0D–3D). Sacrificial PLA templates of each level of dimensionality: 0D-spheres, 1D-fibers, 2D-sheets, and 3D-printed structures are fabricated. Two different tin catalysts (tin oxalate, SnOx, and tin octoate, SnOc) are incorporated into PLA to promote depolymerization at modest temperatures (~200°C). Spheres with diameters averaging 23 μm are fabricated using an emulsion/solvent evaporation technique. Fibers spanning two orders of magnitude in diameter are fabricated using electrospinning (~5 μm) and melt-spinning (~300 μm) techniques. Sheets (~550 μm thick) are hot-pressed and laser cut to form branched planar networks. Fused deposition modeling is used to create a 3D branching tree-like structure. Each template is embedded in epoxy and removed using VaSC (200°C in a vacuum oven, 24–48 h) to reveal the inverse of the template architecture. The effectiveness of VaSC is evaluated using isothermal thermogravimetric analysis (iTGA) at 200°C (ex situ), and by tracking weight of the embedded °C in a vacuum oven (in situ). The templates in epoxy subjected to 200°C choice of catalyst influences the vaporization time with SnOc promoting more rapid removal. Comparison of in situ and ex situ tests reveals a delay in VaSC completion in the embedded state. The structures created using template materials from each level of dimensionality (0D–3D) are evaluated by flow rate testing. Experiments were performed under laminar flow conditions and compared to appropriate predictive models. Structures tested include porous sheets, 1D channels, a 2D-bifurcating network, and a 3D-branched tree-like structure. Flow in porous sheets is compared to Darcy’s law using a porosity-permeability correlation, whereas flow in one-dimensional channels is compared to the Hagen–Poiseuille equation. Computational fluid dynamics simulations of flow in both the 2D and 3D structure are performed in ANSYS FLUENT. Experimental data agreed well with modeling/simulation for every level of dimensionality. Sacrificial templates provide a technique to form multiscale, multidimensional, and interconnected vascular and porous networks in thermosetting polymers. Further work in this area will focus on extending the concept to more types of polymers and improving precision and resolution in complex 2D and 3D structures. REFERENCE [1] Esser-Kahn et al.. Adv. Mater. 2011, 23, 3654

Projected Dietary Intake of Zinc, Copper, and Cerium from Consumption of Carrot (Daucus carota) Exposed to Metal Oxide Nanoparticles or Metal Ions

The expanding production and use of engineered nanomaterials have raised concerns about the potential risk of those materials to food safety and human health. In a prior study, the accumulation of Zn and Cu from ZnO, CuO, or CeO2, respectively, was examined in carrot (Daucus carota L.) grown in sand culture in comparison to accumulation from exposure to equivalent concentrations of ionic Zn2+, Cu2+, or Ce4+. The fresh weight concentration data for peeled and unpeeled carrots were used to project dietary intake of each metal by seven age-mass classes from child to adult based on consumption of a single serving of carrot. Dietary intake was compared to the oral reference dose (oral Rfd) for chronic toxicity for Zn or Cu and estimated mean and median oral RfD values for Ce based on nine other rare earth elements. Reverse dietary intake calculations were also conducted to estimate the number of servings of carrot, the mass of carrot consumed, or the tissue concentration of Zn or Cu that would cause the oral RfD to be exceeded upon consumption. The projections indicated for Zn and Cu, the oral RfD would be exceeded in only a few highly unrealistic scenarios of exceedingly high Zn or Cu concentrations in the substrate from ZnO or CuO or consumption of excessive amounts of unpeeled carrot. The implications associated with the presence of Ce in the carrot tissues depended upon whether the mean or median oral RfD value from the rare earth elements was used as a basis for comparison. The calculations further indicated that peeling carrots reduced the projected dietary intake by one to two orders of magnitude for both ENM- and ionic-treated carrots. Overall in terms of total metal concentration, the results suggested no specific impact of the ENM form on dietary intake. The effort here provided a conservative view of the potential dietary intake of these three metals that might result from consumption of carrots exposed to nanomaterials and how peeling mitigated that dietary intake. The results also demonstrate the utility of dietary intake projections for examining potential risks of nanomaterial exposure from agricultural foods

Гарри Поттер как современный миф

Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB) (p = 1.09 x 10(-7)). We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3). Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL)