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Nambiar M.,Indian Institute of Science | Goldsmith G.,Institute of Bioinformatics and Applied Biotechnology | Moorthy B.T.,Indian Institute of Science | Lieber M.R.,University of Southern California | And 4 more authors.
Nucleic Acids Research | Year: 2011

The t(14;18) translocation in follicular lymphoma is one of the most common chromosomal translocations. Most breaks on chromosome 18 are located at the 3′-UTR of the BCL2 gene and are mainly clustered in the major breakpoint region (MBR). Recently, we found that the BCL2 MBR has a non-B DNA character in genomic DNA. Here, we show that single-stranded DNA modeled from the template strand of the BCL2 MBR, forms secondary structures that migrate faster on native PAGE in the presence of potassium, due to the formation of intramolecular G-quadruplexes. Circular dichroism shows evidence for a parallel orientation for G-quadruplex structures in the template strand of the BCL2 MBR. Mutagenesis and the DMS modification assay confirm the presence of three guanine tetrads in the structure. 1H nuclear magnetic resonance studies further confirm the formation of an intramolecular G-quadruplex and a representative model has been built based on all of the experimental evidence. We also provide data consistent with the possible formation of a G-quadruplex structure at the BCL2 MBR within mammalian cells. In summary, these important features could contribute to the single-stranded character at the BCL2 MBR, thereby contributing to chromosomal fragility. © 2010 The Author(s).

Srivastava M.,Indian Institute of Science | Nambiar M.,Indian Institute of Science | Sharma S.,Indian Institute of Science | Karki S.S.,KLE University | And 12 more authors.
Cell | Year: 2012

DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens. © 2012 Elsevier Inc.

Karthigeyan D.,Jawaharlal Nehru Centre for Advanced Scientific Research | Prasad S.B.B.,Jawaharlal Nehru Centre for Advanced Scientific Research | Shandilya J.,Jawaharlal Nehru Centre for Advanced Scientific Research | Agrawal S.,Institute of Bioinformatics and Applied Biotechnology | Kundu T.K.,Jawaharlal Nehru Centre for Advanced Scientific Research
Medicinal Research Reviews | Year: 2011

The Aurora A kinase belongs to serine/threonine group of kinases, well known for its role in cell cycle, especially in the regulation of mitosis. Numerous substrates of Aurora A kinase have been identified, which are predominantly related to cell cycle progression while some of them are transcription factors. Aurora A-mediated phosphorylation can either directly or indirectly regulate the function of its substrates. There are overwhelming evidences which report overexpression and gene amplification of Aurora A in several human cancers, and suggest that Aurora A could be a bona fide oncogene involved in tumorigenesis. Hence, Aurora A plays wide-ranging roles in both mitosis and its deregulation manifests in cancer progression. These observations have favored the choice of Aurora kinases as a target for cancer therapy. Recently, numerous small molecules have been discovered against Aurora kinases and many have entered clinical trials. Most of these small-molecule modulators designed are specific against either Aurora A or Aurora B, but some are dual inhibitors targeting the ATP-binding site which is highly conserved among the three human homologues of Aurora kinase. In this review, we discuss the physiological functions of Aurora A, interactions between Aurora A kinase and its cellular substrates, tumorigenesis mediated by Aurora A kinase upon overexpression, and small-molecule modulators of Aurora kinase as targets for cancer therapy. © 2010 Wiley Periodicals, Inc.

Jaroslawski S.,Institute of Bioinformatics and Applied Biotechnology | Pai M.,McGill University
Journal of Epidemiology and Global Health | Year: 2012

Serological tests for tuberculosis are inaccurate and WHO has recommended against their use. Although not used by the Revised National TB Control Programme (RNTCP), serodiagnostics are widely used in the private sector in India. A root-cause analysis was undertaken to determine why serological tests are so popular, and seven root causes were identified that can be grouped into three categories: technical/medical, economic, and regulatory. Technical/medical: RNTCP's current low budget does not allow scale-up of the newer, WHO-endorsed technologies. Thus, under the RNTCP, most patients have access to only smear microscopy, a test that is insensitive and underused in the private sector. Because there is no accurate, validated, point-of-care test for TB, serological tests meet a perceived need among doctors and patients. Economic: While imported molecular or liquid culture tests are too expensive, there are no affordable Indian versions on the market, leaving serological tests as the main alternative. Although serological tests are inaccurate, various players along the value chain profit from their use, and this sustains a market for these tests. Regulatory: TB tests are poorly regulated and a large number of serological kits are on the market. Private healthcare in general is poorly regulated, and doctors in the private sector are outside the scope of RNTCP and do not necessarily follow standard guidelines. A clear understanding of these realities should facilitate market-based strategies that can help replace serological tests with accurate, validated tools. © 2012 Ministry of Health, Saudi Arabia.

Chandola U.,Institute of Bioinformatics and Applied Biotechnology | Das R.,Institute of Bioinformatics and Applied Biotechnology | Panda B.,Institute of Bioinformatics and Applied Biotechnology | Panda B.,Initiative of Institute of Bioinformatics and Applied Biotechnology and Strand Life science
Briefings in Functional Genomics | Year: 2015

Epigenetics is a field that encompasses chemical modifications of DNA and histone proteins, both of which alter gene expression without changing the underlying nucleotide sequence. DNA methylation and modifications of histone tails have been studied in detail and are now known to be global gene regulatory mechanisms. An analogous post-transcriptional modification is chemical modification of specific nucleotides in RNA. Study of RNA modifications is a nascent field as yet, and the significance of these marks in controlling cell growth and differentiation is just beginning to be appreciated. The addition of a methyl group to adenosine (N-methyl-6-adenosine) or m6A is the most abundant modification in mammalian mRNAs. Though identified four decades ago, interest in this particular modification was set offby the discovery that the obesity gene FTO was an RNA demethylase. Since then, many studies have investigatedm6A modification in different species. In this review, we summarize the current literature and hypotheses about the presence and function of this ubiquitous RNA modification in mammals, viruses, yeast and plants in terms of the consensus sequence and the methyltransferase/demethylation machinery identified thus far. We discuss its potential role in regulating molecular and physiological processes in each of these organisms, especially its role in RNA splicing, RNA degradation and development. We also enlist the methodologies developed so far, both locus-specific and transcriptome-wide, to study this modification. Lastly, we discuss whether m6A alterations have consequences on modulating disease aetiology, and speculate about its potential role in cancer. © The Author 2014. Published by Oxford University Press. All rights reserved.

Jarosawski S.,Creativ Ceutical | Jarosawski S.,Institute of Bioinformatics and Applied Biotechnology | Toumi M.,University of Lyon
BMC Health Services Research | Year: 2011

Background: Market Access Agreements (MAA) between pharmaceutical industry and health care payers have been proliferating in Europe in the last years. MAA can be simple discounts from the list price or very sophisticated schemes with inarguably high administrative burden. Discussion. We distinguished and defined from the health care payer perspective three kinds of MAA: Commercial Agreements (CA), Payment for Performance Agreements (P4P) and Coverage with Evidence Development (CED). Apart from CA, the agreements assumed collection and analysis of real-life health outcomes data, either from a cohort of patients (CED) or on per patient basis (P4P). We argue that while P4P aim at reducing drug cost to payers without a systematic approach to addressing uncertainty about drugs' value, CED were implemented provisionally to reduce payer's uncertainty about value of a medicine within a defined time period. Summary. We are of opinion that while CA and P4P have a potential to reduce payers' expenditure on costly drugs while maintaining a high list price, CED address initial uncertainty related to assessing the real-life value of new drugs and enable a final HTA recommendation or reimbursement and pricing decisions. Further, we suggest that real cost to health care payers of drugs in CA and P4P should be made publicly available in a systematic manner, to avoid a perverse impact of these MAA types on the international reference pricing system. © 2011 Jarosawski and Toumi; licensee BioMed Central Ltd.

Grover R.,Indian Institute of Science | Grover R.,Institute of Bioinformatics and Applied Biotechnology | Sharathchandra A.,Indian Institute of Science | Ponnuswamy A.,Indian Institute of Science | And 2 more authors.
RNA Biology | Year: 2011

Earlier we have demonstrated the presence of internal ribosome entry site (IRES ) within tumor suppressor p53 mRNA. Here we have mapped the putative secondary structure of p53-IRES RNA using information from chemical probing and nuclease mapping experiments. Additionally, the secondary structure of the IRES element of the wild-type RNA was compared with cancer-derived silent mutant p53 RNAs. These mutations might result in the conformational alterations of p53-IRES RNAs. The results also indicate decreased IRES activities of the mutants as compared to wild-type RNA. Further, it was observed that some of the cytoplasmic trans-acting factors, critical for enhancing IRES function, were unable to bind mutant RNAs as efficiently as to wild-type. Our results suggest that hnRNP C1/C2 binds to p53-IRES and siRNA mediated partial silencing of hnRNP C1/C2 showed appreciable decrease in IRES function and consequent decrease in the level of the corresponding p53 isoform. Interestingly mutant p53 IRES showed lesser binding with hnRNP C1/C2 protein. Finally, upon doxorubicin treatment, the mutant RNAs were unable to show enhanced p53 synthesis to similar extent compared to wild type. Taken together, these observations suggest that mutations occurring in the p53 IRES might have profound implications for de-regulation of its expression and activity. © 2011 Landes Bioscience.

Jaroslawski S.,Institute of Bioinformatics and Applied Biotechnology | Saberwal G.,Institute of Bioinformatics and Applied Biotechnology
BMC Medical Informatics and Decision Making | Year: 2014

Background: India is a country with vast unmet medical needs. eHealth has the potential to improve the quality of health care and reach the unreached. We have sought to understand the kinds of eHealth programmes being offered in India today, the challenges they face and the nature of their financing. Methods. We have adopted an interview-based methodology. The 30 interviews represent 28 organizations, and include designers, implementers, evaluators and technology providers for eHealth programmes. Results: A range of programmes is being run, including point-of-care in rural and urban areas, treatment compliance, data collection and disease surveillance, and distant medical education. Most programmes provide point-of-care to patients or other beneficiaries in rural areas. Technology is not a limiting factor but the unavailability of suitable health personnel is a major challenge, especially in rural areas. We have identified a few factors that help this situation. Financial sustainability is also a concern for most programmes, which have rarely been scaled up. There are recent for-profit efforts in urban areas, but no reliable business model has been identified yet. Government facilities have not been very effective in eHealth on their own, but collaborations between the government and non-profit (in particular) and for-profit organisations have led to impactful programmes. Conclusions: It is unlikely that eHealth will have widespread and sustainable impact without government involvement, especially in rural areas. Nevertheless, programmes run solely by the government are unlikely to be the most effective. © 2014 Jarosławski and Saberwal; licensee BioMed Central Ltd.

Ananth P.,Institute of Bioinformatics and Applied Biotechnology | Goldsmith G.,Institute of Bioinformatics and Applied Biotechnology | Yathindra N.,Institute of Bioinformatics and Applied Biotechnology
RNA | Year: 2013

Non-Watson-Crick pairs like the G·U wobble are frequent in RNA duplexes. Their geometric dissimilarity (nonisostericity) with the Watson-Crick base pairs and among themselves imparts structural variations decisive for biological functions. Through a novel circular representation of base pairs, a simple and general metric scheme for quantification of base-pair nonisostericity, in terms of residual twist and radial difference that can also envisage its mechanistic effect, is proposed. The scheme is exemplified by G·U and U·G wobble pairs, and their predicable local effects on helical twist angle are validated by MD simulations. New insights into a possible rationale for contextual occurrence of G·U and other non-WC pairs, as well as the influence of a G·U pair on other non-Watson-Crick pair neighborhood and RNA-protein interactions are obtained from analysis of crystal structure data. A few instances of RNA-protein interactions along the major groove are documented in addition to the well-recognized interaction of the G·U pair along the minor groove. The nonisostericity-mediated influence of wobble pairs for facilitating helical packing through long-range interactions in ribosomal RNAs is also reviewed. © 2013; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Jaroslawski S.,Institute of Bioinformatics and Applied Biotechnology | Saberwal G.,Institute of Bioinformatics and Applied Biotechnology
BMC Health Services Research | Year: 2013

Background: Over 75% of the medical devices used in India are imported. Often, they are costly and maladapted to low-resource settings. We have prepared case studies of six firms in Bangalore that could contribute to solving this problem. They have developed (or are developing) innovative health care products and therefore are pioneers in the Indian health care sector, better known for its reverse engineering skills. We have sought to understand what enablers and barriers they encountered. Methods. Information for the case studies was collected through semi-structured interviews. Initially, over 40 stakeholders of the diagnostics sector in India were interviewed to understand the sector. However the focus here is on the six featured companies. Further information was obtained from company material and other published resources. Results: In all cases, product innovation has been enabled by close interaction with local medical practitioners, links to global science and technology and global regulatory requirements. The major challenges were the lack of guidance on product specifications from the national regulatory agency, paucity of institutionalized health care payers and lack of transparency and formalized Health Technology Assessment in coverage decision-making. The absence of national evidence-based guidelines and of compulsory continuous education for medical practitioners were key obstacles in accessing the poorly regulated and fragmented private market. Conclusions: Innovative Indian companies would benefit from a strengthened capacity and interdisciplinary work culture of the national device regulatory body, institutionalized health care payers and medical councils and associations. Continuous medical education and national medical guidelines for medical practitioners would facilitate market access for innovative products. © 2013 Jarosławski and Saberwal; licensee BioMed Central Ltd.

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