Cancer studies
From Biomatics.org
Contents |
DNA Microarray Data
Eight Clusters
In the Alizadeh dataset, data were available on n = 96 samples for whom gene expression values on p = 4026 different genes were measured. Application of the Ben-Hur et al. [8] methodology to the average-linkage solution suggested the presence of eight true clusters in the data.
http://www.biomedcentral.com/1471-2105/4/36
They also identified eight independent gene clusters that seemed to reflect contributions of specific cell types present within tumors such as endothelial cells or B lymphocytes.
http://www.jco.org/cgi/content/full/20/7/1932
Clustering analysis demonstrated that cancerous and non-cancerous specimens could be readily distinguished…These genes could be divided into eight clusters with distinct expression kinetics following p53 induction, and into several distinct functional groups, such as genes involved in
- Cell regulation (P21, GADD45 and GOS8),
- Apoptosis (FAS, KILLER),
- Oxidative stress (PIG3,
- Genes for neutrophil NADPH oxidase and superoxide dismutase 3),
- Cell structure (genes for collagen and NRP/B nuclear matrix protein),
- Signal transduction (ECK, P2XM, EPR1, ACK, HSR1, ARL2, C/EBPα, TGF-α)
- Oncogenes (genes for endothelin 2 and thrombospondin).
http://breast-cancer-research.com/content/3/3/158
Fractals
"Fractal analysis shows its greatest promise as an objective measure of seemingly random structures and as a tool for examining the mechanistic origins of pathological form."
Fractals and Cancer
Breast tumor dimensions, as with all tissue dimensions in biology, can be calculated by fractals. A less cell-dense tissue usually has a lower fractal dimension than a tissue with more cells (i.e., a higher cell density is usually due to a higher fractal dimension). Density is the number of cells divided by the tissue volume. When allowed to grow, the density of a tissue with a lower fractal dimension drops quickly. However, a tumor, since it has a higher fractal mass dimension, maintains a high density as it grows bigger, resulting in a more rapid growth rate and a larger final size. Fractal dimensions of infiltrating ductal adenocarcinomas of the breast are high (i.e., 2.98), which results in a very dense tissue compared with normal breast tissue (with a fractal dimension of about 2.25). As expected, the higher fractal dimension results in a high rate of growth.
http://theoncologist.alphamedpress.org/cgi/content/abstract/10/6/370
"We conclude that the tumor vasculature, and perhaps healthy tissue vascular architecture as well, does not exhibit clearly defined fractal properties suitable for box-counting fractal analysis. Although it is true that fractal objects demonstrate a linear log-log behavior with noninteger slopes when the "ruler size" for a measurement is changed, being able to obtain a noninteger slope in a log-log plot, however, does not prove that the object under investigation is fractal. Consequently, we suggest that fractal analysis methods be applied in biomedical studies only with a thorough understanding of its physical meanings, in order for the new methodology to be useful"
http://cancerres.aacrjournals.org/cgi/content/full/61/22/8347
Groups
The Histone Code
Computational Oncology
I'm Paul Macklin, and welcome to my website. I'm an assistant professor of health informatics here at the School of Health Information Sciences at the University of Texas Health Science Center - Houston. I work at the intersection between biology, medicine, mathematics, and computer science to develop and validate sophisticated computer models of cancer. I work under Vittorio Cristini and several collaborators on several research projects in the field of computational and predictive oncology.
To learn more about computational oncology, please visit my research section. I've written a cancer primer for the layman, as well as an introduction to computational and predictive oncology. Also, take a look at my cancer simulation animations and publications.
http://biomathematics.shis.uth.tmc.edu/
The Indiana University Biocomplexity Institute (http://biocomplexity.indiana.edu/) has a research program that uses the cellular Potts model http://en.wikipedia.org/wiki/Cellular_potts_model to conduct in silico biological experiments. We have ongoing projects studying avascular tumor growth and age related macular degeneration, which results from out-of-place vascularization. We are currently building a collaboration with a clinical group to combine our tumor and vascularization models into a virtual model of their in vivo neuroblastoma model. To facilitate our work, we are developing (in collaboration with a group at University of Notre Dame), a cellular Potts model environment called CompuCell3D http://en.wikipedia.org/wiki/Compucell.
This is an open source, user friendly modeling environment that allows the user to specify cell based models through an XML based markup language and optional python scripts. Simulations are run and configures through a GUI interface we call the "Player."
The human breast cancer resistance protein (BCRP/ABCG2) shows conformational changes with mitoxantrone.
Source
Manchester Interdisciplinary Biocentre, 131 Princess Street, University of Manchester, Manchester, M1 7DN, UK. mark.rosenberg@manchester.ac.uk
Erratum in
- Structure. 2010 Dec 8;18(12):1688-9.
Abstract
BCRP/ABCG2 mediates efflux of drugs and xenobiotics. BCRP was expressed in Pichia pastoris, purified to > 90% homogeneity, and subjected to two-dimensional (2D) crystallization. The 2D crystals showed a p12(1) symmetry and projection maps were determined at 5 A resolution by cryo-electron microscopy. Two crystal forms with and without mitoxantrone were observed with unit cell dimensions of a = 55.4 A, b = 81.4 A, gamma = 89.8 degrees , and a = 57.3 A, b = 88.0 A, gamma = 89.7 degrees , respectively. The projection map without mitoxantrone revealed an asymmetric structure with ring-shaped density features probably corresponding to a bundle of transmembrane alpha helices, and appeared more open and less symmetric than the map with mitroxantrone. The open and closed inward-facing forms of BCRP were generated by homology modeling, representing the substrate-free and substrate-bound conformations in the absence of nucleotide, respectively. These models are consistent with the experimentally observed conformational change upon substrate binding.
Copyright 2010 Elsevier Ltd. All rights reserved.
- PMID:
- 20399185
- [PubMed - indexed for MEDLINE]
- PMCID: PMC2858361
Restoring p53 active conformation by zinc increases the response of mutant p53 tumor cells to anticancer drugs.
Source
National Cancer Institute Regina Elena, Rome, Italy.
Abstract
Absence of p53 expression or expression of mutant p53 (mtp53) are common in human cancers and are associated with increased cancer resistance to chemo- and radiotherapy. Therefore, significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway. We previously reported that, in HIPK2 knockdown background, p53 undergoes misfolding with inhibition of DNA binding and transcriptional activities that correlate with increased chemoresistance, and that zinc rescues wild-type p53 activity. Zinc has a crucial role in the biology of p53, in that p53 binds to DNA through a structurally complex domain stabilized by zinc atom. In this study, we explored the role of zinc in p53 reactivation in mutant p53-expressing cancer cells. We found that zinc re-established chemosensitivity in breast cancer SKBR3 (expressing R175H mutation) and glioblastoma U373MG (expressing R273H mutation) cell lines. Biochemical studies showed that zinc partly induced the transition of mutant p53 protein (reactive to conformation-sensitive PAb240 antibody for mutant conformation) into a functional conformation (reactive to conformation-sensitive PAb1620 antibody for wild-type conformation). Zinc-mediated p53 reactivation also reduced the mtp53/p73 interaction restoring both wtp53 and p73 binding to target gene promoters by ChIP assay with in vivo induction of wtp53 target gene expression, which rendered mutant p53 cells more prone to drug killing in vitro. Finally, zinc administration in U373MG tumor xenografts increased drug-induced tumor regression in vivo, which correlated with increased wild-type p53 protein conformation. These results show that the use of zinc might restore drug sensitivity and inhibit tumor growth by reactivating mutant p53.
Comment in
- PMID:
- 21508668
- [PubMed - indexed for MEDLINE]
