Hepatocellular carcinoma presenting as neutrophilic leukaemoid reaction--a rare entity

Leukaemoid reaction is a rare, growth factor-driven, paraneoplastic manifestation of hepatocellular carcinoma. It may masquerade as the neutrophilic chronic myeloid leukaemia or as chronic neutrophilic leukaemia. A 52-year-old male presented with hepatosplenomegaly and severe leucocytosis. He had progressive leucocytosis, neutrophil alkaline phosphatase score elevated, liver function tests altered. FNAC from the mass in the liver revealed features of moderately differentiated hepatocellular carcinoma. The patient deteriorated within two weeks and died thereafter.     

Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene

Classical galactosemia is an autosomal recessive disorder caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. Our group developed a disease-specific database containing all of the reported sequence variants in GALT (Available at: http://arup.utah.edu/database/galactosemia/GALT_welcome.php; Last accessed: 13 April 2007). Currently the database contains a total of 229 sequence variants, of which 196 are mutations (including nine novel mutations identified in our laboratory), 31 polymorphisms in both introns and exons, and two variants of unknown or uncertain significance. All sequence variants have been verified for their position within the GALT gene and named following standard nomenclature. Sequence variants are reported with accompanying information on protein effect, classification of mutation vs. polymorphism, mutation type (when applicable) based on how each was first described in the literature, and accompanying link to pertinent publication. Unpublished variants are described with relevant clinical information that supports their classification as causative of the disease vs. polymorphisms. Other features of this database include disease information, relevant links for galactosemia and literature, reference sequences, ability to query by various criteria, and submit of novel variations to the database. This free online scientific resource was developed with the clinical laboratory in mind to serve as a reference and repository for novel findings that are periodically collected, verified, and updated into the database.     

Molecular basis of aggressive disease in chronic lymphocytic leukemia patients with 11q deletion and trisomy 12 chromosomal abnormalities

In B-cell chronic lymphocytic leukemia (CLL), Rai stage, immunoglobulin gene mutational status, chromosomal abnormalities, CD38 and ZAP-70 expression were used as prognostic markers. In this study, to understand the molecular basis of chromosomal abnormalities leading to tumor progression, 90 CLL patients were grouped into poor prognosis (with 11q deletion and trisomy 12) and good prognosis (with normal karyotype and 13q deletion) and their clinical outcome was assessed. Gene expression profiles of 35 CLL samples with poor outcome (11q deletion, n=9; trisomy 12, n=5) and good outcome (13q deletion, n=13; normal karyotype, n=8) were analyzed using oligonucleotide microarray. Significance analysis of microarray (SAM) identified 27 differentially expressed genes between these two subgroups with significant overexpression of ATF5 and underexpression of CDC16, PCDH8, SLAM, MNDA and ATF2 in CLL patients with poor outcome. ATF5 gene expression in CLL was further studied because of its role in the regulation of cell cycle progression/differentiation and apoptosis. The overexpression of ATF5 was confirmed by real-time PCR using 39 CLL samples from the poor and good outcome groups. ATF5 was significantly (p<0.001) overexpressed in the poor outcome group. Furthermore, ATF5 expression was significantly higher in the 11q deletion as well as trisomy 12 group alone compared to the 13q deletion and normal karyotype groups. ATF5 overexpression was also associated with significantly (p=0.04) shorter time to treatment. Similarly, expression of five underexpressed genes also correlated with longer time to treatment. Thus, this report demonstrates that ATF5 may be one of the key genes involved in increased proliferation and survival in 11q deletion or trisomy 12, whereas CD16, CD86, SLAM, MNDA and ATF2 may be involved in the decreased proliferation of CLL cells with 13q deletion or normal karyotype.     

Targeting endothelial cells with heme oxygenase-1 gene using VE-cadherin promoter attenuates hyperglycemia-mediated cell injury and apoptosis

Risk factors for cardiovascular diseases include hyperglycemia, TNF, and reactive oxygen species (ROS), which collectively contribute to vascular endothelial cell dysfunction and apoptosis. We examined, in vascular endothelial cells, whether the selective expression of heme oxygenase-1 (HO-1) offers cytoprotection against glucose- and TNF-mediated cell death. An adenoviral vector expressing human HO-1 was constructed using a VE-cadherin (VECAD) promotor fragment, and cell-specific expression of the recombinant adenovirus was examined using endothelial and vascular smooth muscle cells. The effects of HO-1 transduction (Ad-VECAD-HO-1 gene) on HO-1 expression, HO activity, and the response to TNF and hyperglycemia were studied. Human HO-1 gene was selectively expressed in endothelial cells after infection with the Ad-VECAD-HO-1 vector. Selective expression of HO-1 prevented TNF- and hyperglycemia-mediated superoxide (O2-) formation, DNA degeneration, and upregulation of caspase, but increased the expression of pAkt and Bcl-xL, proteins responsible for endothelial dysfunction in diabetes. These results demonstrate that endothelial cell survival after oxidative stress injury may be enhanced by targeting HO-1 expression, thus blocking inflammation, apoptosis, and thereby attenuating cardiovascular risk factors.     

The application of proteomics and genomics to the study of age-related neurodegeneration and neuroprotection

The present study aimed to acquire more information on aging-related alterations, using proteomic and genomic analyses of hippocampus from young (8 months) and old (27 months) rats. In the old rats, the proteomic analysis identified changes in proteins related to the iron-mediated oxidative stress (OS) pathway, including reduction in antioxidant enzymes (e.g., peroxiredoxin, cytochrome c oxidase) and induction of ferritin. Furthermore, the neurofilament light peptide, associated with neurodegenerative processes, was enhanced and binding/ chaperone proteins were altered in old vs. young rats. At the genes levels, significant molecular changes related to neurodegeneration were identified in aged rat hippocampus. Thus, the effects of the potent neuroprotective compounds, the anti-Parkinson drug, rasagiline and the anti-Alzheimer drug, ladostigil (1 mg/kg, for 30 days) on gene expression in the hippocampus were further investigated. Both drugs reversed the effect of aging on the expression of various mitochondrial and key regulator genes involved in neurodegeneration, cell survival, synaptogenesis, oxidation, and metabolism. These results support the hypothesis that OS and mitochondrial dysfunction may play a pivotal role in aging and age-associated neurodegenerative diseases, and can serve as potential clinical targets for future therapy.