Methylation discriminators in NSCLC identified by a microarray based approach

Aberrant DNA methylation is a frequent phenomenon in non-small cell lung cancers. We have used a microarray approach to assess the methylation status of 245 CpG positions in 59 candidate genes in 26 squamous cell carcinomas, and 22 adenocarcinomas as well as 26 normal adjacent lung tissue samples from smokers to identify genes that show a distinct methylation status difference between the two different tumour type tissues and normal adjacent tissue. Tumour tissue samples were grouped together and compared to the normal tissue sample group. A multivariate test was performed, taking into account all CpG positions that were analyzed for a particular gene, to calculate p-values for each gene based on the observed methylation difference between the two groups, p-values obtained were corrected for multiple testing. The highest degree of differential DNA methylation in squamous cell carcinoma compared to normal was observed in ARHI, MGMT, GP1bbeta, RARbeta and TMEFF2 genes, while TMEFF2, MGMT and CDKNIC genes differentiated between adenocarcinomas and normal tissue. It is of note that some of the genes for which differential methylation status was observed, have not been previously described in lung cancer. Our results provide compelling evidence that different histological types of lung cancer may be distinguished from normal tissue based on methylation profiles of specific genes.     

Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas

Over the past two decades, several known genes have been shown to govern important functions in the development of primary and metastatic melanomas. However, from this limited number of genes, it is not possible to establish detailed molecular profiles for the early and advanced stages of melanoma development. To gain insights into the genetic profile of every stage of the melanoma progression pathway, and to determine to what extent these profiles are similar or distinct, we performed whole-genome expression profiling of tissue specimens representing normal skin, benign and atypical nevi, and early and advanced-stage melanomas. The results of this study provide first-time evidence that significant molecular changes occur distinctly at the border of/transition from melanoma in situ to primary melanoma, and that genes involved in mitotic cell cycle regulation and cell proliferation constitute the two leading categories of genes associated with these changes.     

13C-labelling of xanthohumol in hop cones (Humulus lupulus)

Biolabelling conditions in hop cones of xanthohumol (Xn) were studied by feeding [U-13C]glucose, [1-13C]glucose, [ring-13C6]phenylalanine, [2-13C]sodium acetate or [2-13C]malonic acid as biosynthetic precursors to hop sprouts. Quantitative 13C-NMR spectroscopic analysis of the resulting labelled Xn showed different labelling patterns and ratios depending on precursor and feeding concentrations. The highest incorporation rate was achieved with [U-13C]glucose (9.41 +/- 1.22 %). With [ring-13C6]phenylalanine only ring B was labelled (3.51 +/- 0.08 % enrichment). [2-13C]sodium acetate and [2-13C]malonic acid allowed labelling of the A-ring (1.82 +/- 0.02 % and 1.74 +/- 0.03 % enrichment). The specific labelling pattern of the prenyl side chain with [1-13C]glucose (2.36 +/- 0.27 % enrichment) confirmed the biosynthetic origin to be MEP pathway-derived. On the basis of these results radiolabelling of Xn will be performed for in vivo bioavailability studies.     

Lack of clinical efficacy of imatinib in metastatic melanoma

This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day(-1). In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ralpha and -Rbeta expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ralpha in seven out of 12 cases (58%) and for PDGF-Rbeta in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.     

States of emergency. As fiscal challenges increasingly overwhelm their budgets, states brace for the Bush administration's Medicaid plan

With a host of other expensive issues leading President Bush's agenda, officials fear Medicaid could suffer some hard blows. States are already carving out efficiencies, even as enrollment swells. New HHS Secretary Mike Leavitt, left, last week said he saw an opportunity to revamp coverage for some Medicaid recipients. "Wouldn't it be better to give Chevys to everyone, rather than Cadillacs to a few?" he asked.