Deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events that occur during the development of aggressive neuroblastoma. Clinically, 11q deletion is associated with higher disease stage and decreased survival probability. During the last 25 years, extensive efforts have been invested to identify the precise frequency of 11q aberrations in neuroblastoma, the recurrently involved genes, and to understand the molecular mechanisms of 11q deletion, but definitive answers are still unclear. In this review, it is our intent to compile and review the evidence acquired to date on 11q deletion in neuroblastoma.
Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1
Lipoteichoic and wall teichoic acids (TA) are highly anionic cell envelope-associated polymers containing repeating polyglycerol/ribitol phosphate moieties. Substitution of TA with D-alanine is important for modulation of many cell envelope-dependent processes, such as activity of autolytic enzymes, binding of divalent cations, and susceptibility to innate host defenses. D-Alanylation of TA is diminished when bacteria are grown in medium containing increased NaCl concentrations, but the effects of increased salt concentration on expression of the dlt operon encoding proteins mediating D-alanylation of TA are unknown. We demonstrate that Staphylococcus aureus transcriptionally represses dlt expression in response to high concentrations of Na The cell envelope provides a protective barrier and regulates communication between the inside and outside of the cell. In nonencapsulated gram-positive bacteria, the cell envelope consists of the cytoplasmic membrane and cell wall peptidoglycan layers, to which proteins and teichoic acids (TA) are covalently linked. The covalently linked wall teichoic acid (WTA) and cell membrane-anchored lipoteichoic acid (LTA) contain repeating units of ribitol or glycerol-phosphate (29). Together, TA represent the most abundant polyanions of the gram-positive bacterial cell envelope (8). The charge properties of these polymers can be modified by substitution for the ribitol or glycerol-phosphate units by glycosyl substituents or D-alanine esters (29). As judged by comparison of wild-type and mutant strains, esterification of D-alanine to TA has pleiotropic effects, including effects on regulation of the activity of autolytic enzymes (33, 42), binding of cations (e.g., Na ϩ , Mg 2ϩ , and Ca 2ϩ ) to the cell envelope (16,26,35), resistance to many antimicrobial cationic peptides/proteins (23, 32), and virulence (4). D-Alanylation of TA also promotes coaggregation, biofilm formation, and adhesion of bacteria on artificial surfaces (3, 13). In addition, D-alanylation increases the proinflammatory activity of LTA (5).An operon, including dltABCD, is necessary for D-alanylation of both LTA and WTA in Staphylococcus aureus. DAlanyl carrier protein ligase (Dcl; dltA) activates D-alanine using ATP. With assistance of DltD (dltD), this activated complex is delivered to the D-alanine carrier protein (Dcp) encoded by dltC. DltB (dltB) is predicted to be a transmembrane protein and is thought to be involved in passage of the Dalanyl-Dcp complex across the cytoplasmic membrane, where D-alanine is transferred to the glycerol phosphate backbone of LTA (29). D-Alanine esterified to LTA is the precursor for D-alanylation of WTA (15).Relatively little is known about the regulation of D-alanylation of TA in S. aureus. It is known that the degree of Dalanylation of TA varies depending on several different environmental factors such as pH, temperature, and salt (e.g., NaCl) concentration (16,19,28). An increase in pH, temperature, or NaCl concentration lowers the degree of D-alanylation of TA. For example, the...
BackgroundDespite identification of the major genes and pathways involved in the development of colorectal cancer (CRC), it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC. Therefore we wanted to improve our understanding of the genetic mechanisms of CRC development.MethodsWe used microarrays to identify novel genes involved in the development of CRC. Real time PCR was used for mRNA expression as well as to search for chromosomal abnormalities within candidate genes. The correlation between the expression obtained by real time PCR and the presence of the KRAS mutation was investigated.ResultsWe detected significant previously undescribed underexpression in CRC for genes SLC26A3, TPM1 and DCN, with a suggested tumour suppressor role. We also describe the correlation between TPM1 and DCN expression and the presence of KRAS mutations in CRC. When searching for chromosomal abnormalities, we found deletion of the TPM1 gene in one case of CRC, but no deletions of DCN and SLC26A3 were found.ConclusionOur study provides further evidence of decreased mRNA expression of three important tumour suppressor genes in cases of CRC, thus implicating them in the development of this type of cancer. Moreover, we found underexpression of the TPM1 gene in a case of CRCs without KRAS mutations, showing that TPM1 might serve as an alternative path of development of CRC. This downregulation could in some cases be mediated by deletion of the TPM1 gene. On the other hand, the correlation of DCN underexpression with the presence of KRAS mutations suggests that DCN expression is affected by the presence of activating KRAS mutations, lowering the amount of the important tumour suppressor protein decorin.
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