Atypical D-FISH patterns of BCR/ABL gene rearrangements in 169 chronic myeloid leukemia patients

The Philadelphia (Ph) chromosome, a hallmark chromosomal anomaly observed in 95 percent of chronic myeloid leukemia (CML) cases, is known to involve the Abelson (ABL) proto-oncogene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22, producing BCR/ABL mRNA encoding an abnormal tyrosine kinase protein. In the process of generating BCR-ABL fusion, the deletion of residual BCR or ABL occurs in 15-30 percent of CML patients. In addition, some rearrangements are complex, and do not yield the ABL/BCR fusion due to the involvement of a third chromosome in the rearrangement. The possible role of these deletions and complex rearrangements in disease outcome is an ongoing topic of research. We report our results of cytogenetic analysis with GTG banding and fluorescence in situ hybridization using dual color dual fusion probe (D-FISH) from Vysis Inc, USA in 169 (109 male and 60 female) CML patients registered at The Gujarat Cancer and Research Institute (GC and RI) from April 2004 to December 2005. GTG banding was carried out in 123 cases having analyzable metaphases. Of these 123 cases, D-FISH revealed atypical signal patterns in 57 patients (46%), and 12 cases revealed additional complex translocations indicative of disease progression. Out of 57 cases with atypical FISH patterns, 22 included metaphase FISH results, and the rest had only interphase FISH performed. In addition to the hallmark Philadelphia chromosome, other chromosomal aberrations in CML revealed heterogeneity of molecular events. Pooling of more data may lead to identification of new CML sub-groups and hence help in the analysis of clinical trials. Patients enrolled in our prospective study of prognostic significance will be followed up for disease free and overall survival in correlation with ABL-BCR deletion status.     

Diverse dependencies of developing Merkel innervation on the trkA and both full-length and truncated isoforms of trkC

This study demonstrates that innervation dependent on two different neurotrophin tyrosine kinase (trk) receptors can form the same types of sensory endings (Merkel endings) in the same target (Merkel cells of vibrissa follicles). Some endings transiently express trkA during their initial development, whereas others express trkC throughout their development. Consequently, elimination of kinase domains of either trkA or trkC each result in a partial loss of Merkel endings, whereas absence of kinase domains of both receptors results in a total loss. At the onset of Merkel ending development, at least one kinase-lacking trkC isoform is transiently expressed on all the follicle cells, while neurotrophin 3 is transiently expressed only in the cells at the middle third of the follicle where the Merkel endings and cells develop. This transient non-neuronal expression of truncated trkC is essential for development of any Merkel endings, whereas some Merkel endings and cells still begin to develop in the absence of neurotrophin 3. Therefore, truncated trkC plays a more important role in the development of this innervation than kinase forms of trkA or trkC or of NT3, the only known ligand for trkC receptors.     

Understanding atherosclerosis through mouse genetics

During the past year studies with mouse models have significantly clarified our understanding of atherosclerosis. Noteworthy achievements include: the discovery of a number of novel genes and pathways; new evidence emphasizing the role of lymphocytes in atherogenesis; the development of mouse models exhibiting advanced lesions with evidence of thrombosis; and new results indicating an anti-atherogenic effect of testosterone.     

Thioredoxin-interacting protein deficiency disrupts the fasting-feeding metabolic transition

Through a positional cloning approach, the thioredoxin-interacting protein gene (Txnip) was recently identified as causal for a form of combined hyperlipidemia in mice (Bodnar, J. S., A. Chatterjee, L. W. Castellani, D. A. Ross, J. Ohmen, J. Cavalcoli, C. Wu, K. M. Dains, J. Catanese, M. Chu, S. S. Sheth, K. Charugundla, P. Demant, D. B. West, P. de Jong, and A. J. Lusis. 2002. Positional cloning of the combined hyperlipidemia gene Hyplip1. Nat. Genet. 30: 110-116). We now show that Txnip-deficient mice in the fed state exhibit a metabolic profile similar to fasted mice, including increased levels of plasma ketone bodies and free fatty acids, decreased glucose, and increased hepatic expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and acyl-CoA oxidase. Dramatic differences in the expression of key metabolic enzymes were also observed in other tissues, and the fat-to-muscle ratio of Txnip-deficient mice was increased by approximately 40%. We demonstrate an effect of Txnip on the redox status, as the Txnip-deficient mice in the fed state had a significant increase in the ratio of NADH to NAD(+). Surprisingly, we observed that Txnip-deficient mice and wild-type mice had similar levels of thioredoxin activity, suggesting that the effects of Txnip deficiency may be mediated in part by other interactions. These results indicate a role for Txnip in the metabolic response to feeding and the maintenance of the redox status.     

Synthesis and in vitro antineoplastic evaluation of certain 16-(4-substituted benzylidene) derivatives of androst-5-ene

In a systematic effort aimed at identifying new steroidal cytotoxic agents with potent antiproliferative activity against cancer cells, we synthesized certain 16-[4-(NO2, CN, and i-Pr)substituted]benzylidene derivatives of androst-5-ene, 7-25, with pyrrolidino functionality in the 3beta-position of the steroid nucleus, i.e., 13-18 and 25. The selected compounds were examined for their cytotoxicity against a panel of three human cancer cell lines at the National Cancer Institute (NCI), Bethesda, USA. The results presented herein provide experimental evidence that compounds 7, 9, 10, 12, 16, and 19-21 induced apoptosis in human cancer cells.     

In silico characterization of <Emphasis Type="Italic">Plasmodium falciparum</Emphasis> purinergic receptor: a novel chemotherapeutic target

Serpentine receptors with G-protein coupled receptor like seven transmembrane (7 TM) topology are identified in Plasmodium. A class of 7 TM receptors known as purinergic receptors binds to purines such as ADP, ATP and UTP and mediates important physiological functions including regulation of calcium signaling. Here we performed in silico analysis of Plasmodium falciparum serpentine receptors and found that one of the P. falciparum serpentine receptors, PfSR12 possess nucleotide binding consensus P-loop sequence in addition to seven transmembrane domains. The presence of conserved seven transmembrane domains and a consensus nucleotide binding sequence (P-loop) suggest that PfSR12 is a putative purinergic receptor. On further analysis using docking programmes we found four active binding residues Asn149, Lys150, Asn151 and Gly152 in P-loop of PfSR12, interact with ATP. This work gives insights into the interactions between putative purinergic receptor PfSR12 and its ligand ATP which can be explored in structure based drug designing against malaria.     

Somatic embryogenesis in Leptadenia reticulata (Retz.) Wight and Arn along with assessment of shoot and callus cultures for HPTLC fingerprint and quantification of p-coumaric acid

Plant Cell, Tissue and Organ Culture (PCTOC) - Leptadenia reticulata (Retz.) Wight and Arn is an important medicinal plant of Asclepiadaceae family. In the present study regeneration was attempted...