4DNvestigator: time series genomic data analysis toolbox.

Data on genome organization and output over time, or the 4D Nucleome (4DN), require synthesis for meaningful interpretation. Development of tools for the efficient integration of these data is needed, especially for the time dimension. We present the '4DNvestigator', a user-friendly network-based toolbox for the analysis of time series genome-wide genome structure (Hi-C) and gene expression (RNA-seq) data.

Correlating in Vitro Solubilization and Supersaturation Profiles with in Vivo Exposure for Lipid Based Formulations of the CETP Inhibitor CP-532,623.

Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids.

Pharmaceutical solid-state kinetic stability investigation by using moisture-modified Arrhenius equation and JMP statistical software.

An accelerated stress approach utilizing the moisture-modified Arrhenius equation and JMP statistical software was utilized to quantitatively assess the solid state stability of an investigational oncology drug MLNA under the influence of temperature (1/T) and humidity (%RH). Physical stability of MLNA under stress conditions was evaluated by using XRPD, DSC, TGA, and DVS, while chemical stability was evaluated by using HPLC. The major chemical degradation product was identified as a hydrolysis product of MLNA drug substance, and was subsequently subjected to an investigation of kinetics based on the isoconversion concept.

In vitro-in vivo evaluation of lipid based formulations of the CETP inhibitors CP-529,414 (torcetrapib) and CP-532,623.

The present study investigated the use of lipid based drug delivery systems to enhance the oral bioavailability of the CETP inhibitors CP-532,623 and torcetrapib. A series of self-emulsifying lipid based drug delivery systems (SEDDS) were assembled and examined using an in vitro lipid digestion model to evaluate patterns of drug precipitation under simulated intestinal conditions. Drug exposure after oral administration of the same formulations was subsequently assessed in beagle dogs.

Multivariate detection of gene-gene interactions.

Unraveling the nature of genetic interactions is crucial to obtaining a more complete picture of complex diseases. It is thought that gene-gene interactions play an important role in the etiology of cancer, cardiovascular, and immune-mediated disease. Interactions among genes are defined as phenotypic effects that differ from those observed for independent contributions of each gene, usually detected by univariate logistic regression methods.

Squaring the Circle and Cubing the Sphere: Circular and Spherical Copulas.

Do there exist circular and spherical copulas in [Formula: see text]? That is, do there exist circularly symmetric distributions on the unit disk in [Formula: see text] and spherically symmetric distributions on the unit ball in [Formula: see text], d ≥ 3, whose one-dimensional marginal distributions are uniform? The answer is yes for d = 2 and 3, where the circular and spherical copulas are unique and can be determined explicitly, but no for d ≥ 4. A one-parameter family of elliptical bivariate copulas is obtained from the unique circular copula in [Formula: see text] by oblique coordinate transformations. Copulas obtained by a non-linear transformation of a uniform distribution on the unit ball in [Formula: see text] are also described, and determined explicitly for d = 2.

The emergence of lineage-specific chromosomal topologies from coordinate gene regulation.

Although the importance of chromosome organization during mitosis is clear, it remains to be determined whether the nucleus assumes other functionally relevant chromosomal topologies. We have previously shown that homologous chromosomes have a tendency to associate during hematopoiesis according to their distribution of coregulated genes, suggesting cell-specific nuclear organization. Here, using the mathematical approaches of distance matrices and coupled oscillators, we model the dynamic relationship between gene expression and chromosomal associations during the differentiation of a multipotential hematopoietic progenitor.

A note on one-sided tests with multiple endpoints.

Testing problems with multivariate one-sided alternative hypotheses are common in clinical trials with multiple endpoints. In the case of comparing two treatments, treatment 1 is often preferred if it is superior for at least one of the endpoints and not biologically inferior for the remaining endpoints. Bloch et al.

Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib.

Objective: The ability of the potent cholesteryl ester transfer protein (CETP) inhibitor torcetrapib (CP-529,414) to raise high-density lipoprotein cholesterol (HDL-C) levels in healthy young subjects was tested in this initial phase 1 multidose study.

Methods And Results: Five groups of 8 subjects each were randomized to placebo (n=2) or torcetrapib (n=6) at 10, 30, 60, and 120 mg daily and 120 mg twice daily for 14 days. Torcetrapib was well tolerated, with all treated subjects completing the study.