Human telomerase reverse transcriptase (hTERT) gene is a biomarker for the targeted therapy in various cancers. Presence of increased telomerase activity is a common feature of all cancers including glioblastoma. Both RNA and catalytic subunits of hTERT are the target sites for blocking its activity. The current study focuses on the expression of hTERT in glioblastoma and its regulation using two different novel siRNAs (small interfering RNA). Our patient data demonstrated increased expression of hTERT, which could be correlated with carcinogenesis in glioma. In vitro studies in siRNA transfected LN18 cells confirmed significant cell death (p \ 0.05) as evidenced by MTT and trypan blue exclusion assay. These results were further supported by flow cytometry data, which showed significant increase in early and late apoptosis. The hTERT mRNA expression was effectively downregulated by 45 and 39 % with siRNA1 and siRNA2, respectively. These results were further confirmed by immunoblotting analysis (p \ 0.05). Our results suggest that both the siRNAs effectively down regulated the expression of hTERT at mRNA and protein levels, thereby decreasing cell viability and proliferation rate. Hence siRNA mediated downregulation of hTERT could be a potential therapeutic avenue in glioblastoma.

Mutations in the adenomatous polyposis coli (APC) gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP) have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC+/− stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may therefore be worth undertaking.

Epidemiological studies have shown that 70-90 % of all cancers are caused due to the chemicals present in environment. Exogenous exposure to carcinogens and their interaction with genetic sequences and endogenous factors, like exposures to products of metabolism which lead to acute stress, disruption of hormones and inflammation of tissues, are triggering factors. Due to relatively small risk of cancer following immediate exposure, the precise quantification of the burden of human cancer attributed to environmental exposure remains ambiguous, thereby leading to an assumption that a causal relationship is relatively large. Research suggests that 90-95 % of all cancers have their roots in the environmental effects on the DNA leading to genetic defects, whereas only 5-10 % can be attributed to inherited genetic defects. The hypothesis of the present review is that response of the cells to the environmental stimulants could be an evolutionary process of adaptation of the DNA. Carcinogenesis is considered as a process of adaptation of mammalian cells to sustained stress environment (SSE) by means of epigenetic alteration (EA) of the genome, mutations which arise due to EA and finally, natural selection of originated mutant cells evading apoptosis. Process of adaptation to SSE involves the emergence of senescent epigenetically reprogrammed cells with specific cancerrelated EA in the genome.

Over the years, deletions of CDKN2A (p16) tumor suppressor gene has been studied using FISH and multiplex PCR, with major focus on exon 2 in various cancers, and the frequency of mutation is found to be varied in different studies. In this study, we analyzed the deletion status of all three exons of p16 and frequency of exon 2 somatic point mutations in glioma from the Indian population and its clinical implications. Multiplex PCR was carried out in order to check deletion of all 3 exons in 50 glioma samples. Nonconventional PCR-SSCP analysis and sequencing was done to identify mutations in 48 cases. Deletion of at least one of the three exons of p16 INK4A was observed in ten cases (20 %). The frequencies of exon-wise deletions were 10 % for exon 1, 4 % for exon 2, and 8 % for exon 3. Two out of 48 samples were positive for mutations in p16 exon 2. One sample had a transition of G to C on position 147 with a codon change TGG to TGC which does not contribute to the protein structure. Another sample had a transversion of A to G on the position 154 with a codon change ATG to GTG with change in amino acid methionine to valine in 52nd position. Deletion pattern was found to be varied in three exons. Frequency of p16 gene mutation was less in the Indian population (4.2 %), and this mutation does not contribute to any remarkable change in protein structure.

In the process of interpreting simulation results, new post-processing techniques are developed. This work presents a post-processing method that analyzes the solidification pattern formed by simulation of the solidification process of molten metal in a mold to produce shaped castings. Simulations generally involve numerical solutions of differential equations which are discretized by dividing the three-dimensional computational domain into small finite volume elements using a 3D grid. The locations of the grid points and values of the solidification time at these locations are used to divide the spatial data into 3D sections such that starting from a hotspot location within the section that has high solidification time, there is a gradient outwards with lower values of solidification time. Each section is assumed to be fed by one or more feeders that must freeze only after the section has solidified completely. The volume of a feeder can be determined from the volume of the section it is supposed to feed. The volume and surface area of sections are determined approximately to calculate feeder size and dimensions. The post-processing algorithm is a simulation-based quantitative approach to feeder design which in conventional foundry practice has been more of an art than science. It is also general enough for use in other 3D segmentation applications.