• Targeting HSP90 for cancer therapy

      Mahalingam, D; Swords, R; Carew, Jennifer S; Nawrocki, S T; Bhalla, Kapil N.; Giles, F J; GHSU Cancer Center (2009-04-28)
      Heat-shock proteins (HSPs) are molecular chaperones that regulate protein folding to ensure correct conformation and translocation and to avoid protein aggregation. Heat-shock proteins are increased in many solid tumours and haematological malignancies. Many oncogenic proteins responsible for the transformation of cells to cancerous forms are client proteins of HSP90. Targeting HSP90 with chemical inhibitors would degrade these oncogenic proteins, and thus serve as useful anticancer agents. This review provides an overview of the HSP chaperone machinery and the structure and function of HSP90. We also highlight the key oncogenic proteins that are regulated by HSP90 and describe how inhibition of HSP90 could alter the activity of multiple signalling proteins, receptors and transcriptional factors implicated in carcinogenesis.
    • Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays.

      Gardina, Paul J; Lo, Ken C; Lee, Walter; Cowell, John K.; Turpaz, Yaron; GHSU Cancer Center (2008-10-30)
      BACKGROUND: Genomic hybridization platforms, including BAC-CGH and genotyping arrays, have been used to estimate chromosome copy number (CN) in tumor samples by detecting the relative strength of genomic signal. The methods rely on the assumption that the predominant chromosomal background of the samples is diploid, an assumption that is frequently incorrect for tumor samples. In addition to generally greater resolution, an advantage of genotyping arrays over CGH arrays is the ability to detect signals from individual alleles, allowing estimation of loss-of-heterozygosity (LOH) and allelic ratios to enhance the interpretation of copy number alterations. Copy number events associated with LOH potentially have the same genetic consequences as deletions. RESULTS: We have utilized allelic ratios to detect patterns that are indicative of higher ploidy levels. An integrated analysis using allelic ratios, total signal and LOH indicates that many or most of the chromosomes from 24 glioblastoma tumors are in fact aneuploid. Some putative whole-chromosome losses actually represent trisomy, and many apparent sub-chromosomal losses are in fact relative losses against a triploid or tetraploid background. CONCLUSION: These results suggest a re-interpretation of previous findings based only on total signal ratios. One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns. The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation.
    • T Cell Immune Response in Persistent Infection of Lymphocytic Choriomeningitis Virus (LCMV)

      Ou, Rong; Georgia Cancer Center (2004-07)
      The m urine LCMV system provides a ciassic model to study the mechanism of immunological tolerance, an efficient strategy used by virus to establish a persistent infection by selective down-regulation of virus-specific T lymphocytes. High viral burden in the onset o f infection drives responding cells into functional unresposiveness (anergy) that can, be followed by their physical elimination. In this study, the downregulation o f the virus-specific CD8^-T-ceil response was studied during a persistent infection o f adult mice, with particular emphasis on the contribution of the interferon response in promoting host defense, or perforin-, Fas/FasL-, or TN FR l-m ediated cytolysis in regulating T-cell homeostasis. Since LCMV infects a broad range o f host tissues, the functional properties o f virus-specific CD8'^ T cells in different tissues during LCMV infection were also evaluated. Infection of mice deficient in receptor for type I (IFN-a/p), type II (IFN-y), or both type I and II IFNs with LCMV isolates that vary in their capacity to induce T-celi exhaustion, revealed a critical role for IFN -a/p in restricting LCMV spread at the onset o f infection while IFN-y has impact on effector cells. The production o f IF N -a/p and/or IFN-y critically regulates the virus-host balance during the acute phase o f infection, such that a high viral burden drives responding cells into different programs o f exhaustion. Infection o f mice deficient in perferin, FasL or TNFRl with the Docile or Aggressive strains of LCMV revealed comparable kinetics of expansion and functional inactivation o f virusspecific C D ^ T cells in the early phase o f Infection in C57BL/6 controls. However, the data underscore a critical role for these molecules in the persistence o f the virus-specific CD8"‘-T-ceil population once it has become anergic. Study o f the functional properties of virus-specific CD8'^ T cells in different tissues during LCMV infections showed that a centra! role for the viral load in lymphoid tissue in the induction and maintenance of clonal exhaustion. The data strongly suggest that CD8^ T ceils may be differentially regulated in the environments o f lymphoid versus nonlymphoid tissues, and the pattern of T cell exhaustion observed with mice is likely a common feature o f the immune response during chronic infections in humans.
    • Molecular Biology of Amino Acid and Peptide Transport Systems

      Li, Huiwu; Georgia Cancer Center (1999)
      (First Paragraph) Amino acids are essential components in cellular metabolism. Some of these amino acids can be synthesized within the cells from other biological molecules and these amino acids are termed ‘nonessential’. These ‘nonessential’ amino acids are alanine, aspartate, cysteine, glutamate, glycine, pro line, serine, tyrosine, glutamine and asparagine. In contrast, some amino acids cannot be synthesized endogenously and have to be supplied in the diet (1). These amino acids are termed ‘essential’. These ‘essential’ amino acids are histidine, arginine, leucine, isoleucine, lysine, methionine, threonine, phenylalanine, tryptophan, and valine. Mammalian cells require ‘essential’ as well as ‘nonessential’ amino acids for their metabolic activity. Even though the cells can synthesize the ‘nonessential’ amino acids to some extent, most of the amino acids have to be supplied to the cells via specific membrane transport mechanisms.
    • Georgia Cancer Center Integrated Genomics Resource & HPC Server

      Chang, Chang-Shen (Sam); Georgia Cancer Center
      Georgia Cancer Center at Augusta University is home to a High Performance Computing (HPC) Server. One goal of the HPC server is to host the new Biorepository software, LabVantage. This software is a web-based laboratory information management system, which tracks samples throughout their lifespan. All specimens that the Georgia Cancer Center Biorepository receives is entered into LabVantage, which generates a unique barcode number for each sample. Chain of custody is recorded throughout the sample’s lifespan, from inception to eventual withdrawal. LabVantage organizes data such as patient demographics, diagnosis, organ site, and linked pathology reports. 
LabVantage is compliant with all regulations relevant to patient privacy and satisfies all regulations set forth by The College of American Pathologists (CAP). All Biorepository personnel are trained to maintain confidentiality of patient information according to HIPAA regulations. The HPC Server is also used for the analysis of complex data including Next-Generation Sequencing data (NGS). It is currently used to perform data analysis on datasets such as those obtained from The Cancer Genome Atlas (TCGA). The analyses that used to take several weeks can now be performed in a matter of days. Georgia Cancer Center HPC Server is composed of 544 total compute cores and an aggregated memory of 2.9TB. The system is composed of (15) PowerEdge R430 1U systems (128 GB RAM each), (1) PowerEdge R830 (1024 GB RAM) and a high-speed 10GbE interconnect for intra-node communication. The HPCC also houses 633 TB RAW storage capacity. We will also be integrating existing Cancer Center servers including our Illumina Compute system that collects data directly from the Sequencer housed in the Georgia Cancer Center Integrated Genomics Shared Resource and the existing Bioinformatics HPC (see configuration diagram below). Access to the server is available to all Augusta University employees. There is a nominal fee associated with usage and users are required to undergo training.