Godavarthi B.K.S. Prasad

Detection of survivin and p53 in human oral cancer: Correlation with clinicopathologic findings

Survivin, an inhibitor of apoptosis, is overexpressed in cancer. It has been implicated in both prevention of apoptosis and cell cycle regulation. We investigated the distribution of antiapoptotic protein survivin in 29 oral squamous cell carcinoma (OSCC) and 16 oral premalignant lesions. It has been suggested that wild‐type p53 represses survivin expression. Therefore, we investigated the status of p53 in relation to survivin to determine the potential involvement in oral tumorigenesis.

Molecular Diagnostics: Promises and Possibilities

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Induction of Apoptosis and Sensitization of Head and Neck Squamous Carcinoma Cells to Cisplatin by Targeting Survivin Gene Expression

Survivin is known to be highly-expressed in various carcinomas; and is associated with their biologically aggressive characteristics and drug resistance. We have previously reported survivin as an important anti-apototic protein involved in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and providing resistance to conventional cancer therapies. The purpose of present study was to investigate the potential of survivin as a therapeutic target in HNSCC. This study was designed to explore the effect(s) of survivin-siRNA therapy on the apoptosis in HNSCC cells, and its influence on cisplatin-sensitivity. Lentivirus vector was developed to deliver survivin specific siRNA into cancer cells. The data indicates that silencing of survivin-mediated by Lentivirus-siRNA therapy effectively suppressed cancer cell proliferation and induced caspase-dependent apoptosis in HNSCC cells. The study also shows that the response of HNSCC cells to cisplatin drug treatment at clinically relevant level was limited. We observed survivin to be a key factor involved in this cisplatin-resistance mechanism, and down-regulation of survivin significantly increased sensitivity of cancer cells to cisplatin-mediated apoptosis. Thus, this combination therapy acts as a multimodality regimen with significant potential to improve clinical outcomes in head and neck cancers.

Parasite killing in malaria non-vector mosquito Anopheles culicifacies species B: implication of nitric oxide synthase upregulation.

Background Anopheles culicifacies, the main vector of human malaria in rural India, is a complex of five sibling species. Despite being phylogenetically related, a naturally selected subgroup species B of this sibling species complex is found to be a poor vector of malaria. We have attempted to understand the differences between vector and non-vector Anopheles culicifacies mosquitoes in terms of transcriptionally activated nitric oxide synthase (AcNOS) physiologies to elucidate the mechanism of refractoriness. Identification of the differences between genes and gene products that may impart refractory phenotype can facilitate development of novel malaria transmission blocking strategies. Methodology/Principal Findings We conducted a study on phylogenetically related susceptible (species A) and refractory (species B) sibling species of An. culicifacies mosquitoes to characterize biochemical and molecular differences in AcNOS gene and gene elements and their ability to inhibit oocyst growth. We demonstrate that in species B, AcNOS specific activity and nitrite/nitrates in mid-guts and haemolymph were higher as compared to species A after invasion of the mid-gut by P. vivax at the beginning and during the course of blood feeding. Semiquantitative RT-PCR and real time PCR data of AcNOS concluded that this gene is more abundantly expressed in midgut of species B than in species A and is transcriptionally upregulated post blood meals. Dietary feeding of L-NAME along with blood meals significantly inhibited midgut AcNOS activity leading to an increase in oocyst production in An. culicifacies species B. Conclusions/Significance We hypothesize that upregulation of mosquito innate cytotoxicity due to NOS in refractory strain to Plasmodium vivax infection may contribute to natural refractoriness in An. culicifacies mosquito population. This innate capacity of refractory mosquitoes could represent the ancestral function of the mosquito immune system against the parasite and could be utilized to understand the molecular basis of refractoriness in planning effective vector control strategies.

Survivin, a molecular target for therapeutic interventions in squamous cell carcinoma

Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment.

Growth inhibition and chemo-radiosensitization of head and neck squamous cell carcinoma (HNSCC) by survivin-siRNA lentivirus.

BACKGROUND Survivin expression is often associated with aggressive tumor behavior and therapy resistance. In this study, we investigated the effect of survivin knockdown by survivin-siRNA lentiviral vector (Svv-Lent) on the response of HNSCC to chemo-radiotherapy, tumor growth and metastasis. METHODS Four human HNSCC (OSC19, Cal27, Cal33 and FaDu) and one normal HOK cell lines were included in the study, and survivin knockdown was achieved with Svv-Lent treatment. Cell proliferation and apoptosis were measured by MTT and TUNEL assay, respectively. Transwell assays were performed to measure in vitro cell migration and matrigel invasion. Xenograft tumors were developed in nude mice by injecting Cal27 cells subcutaneously and following tail-vein injection of lung and liver metastasis. RESULTS Knockdown of survivin significantly suppressed HNSCC cell proliferation and induced apoptosis in vitro. Survivin inhibition could also significantly reduce in vitro cell migration and matrigel invasion that might be due to inactivation of matrix metalloproteinases. In vivo studies showed significant repression of Cal27 xenograft tumor growth and tissue metastasis leading to improvement in mice survival in the Svv-Lent treated group compared to controls. Our data indicated that survivin expression in HNSCC cells contributed to chemo-radioresistance, and its down-regulation increased anti-cancer effects of paclitaxel, cisplatin and radiation. CONCLUSIONS Our findings suggest that sustained survivin expression facilitates HNSCC tumor growth and confers resistance to chemo-radiotherapy. Svv-Lent therapy may be able to enhance the cytotoxic effect of commonly used anticancer drugs such as cisplatin and paclitaxel, and radiotherapy that could provide a promising strategy for the effective control of resistant head and neck cancer.

Segments of Molecular Diagnostics – Market Place

The molecular diagnostics market is the fastest growing segment in the in vitro diagnostics and is being driven by multiple growth factors. This include the need for automated and easy-to-handle techniques which combine optimized sample preparation, analysis, data evaluation, and the growing availability of molecular diagnostic tests for monitoring the therapeutic efficacy of expensive drugs. Currently immunoassays account for approximately 25% of the global market while molecular diagnostics accounts for about 6%. However, things are about to change as molecular diagnostics is poised to take a larger share of the in vitro diagnostics in the years to come. Infectious diseases market is the largest segment of molecular diagnostics and the segment is expected to grow at an annual rate between 7 and 8% over the next few years and this is followed by cancer and cardiovascular segments. In terms of technological push, genomics and proteomics are the major drivers of the molecular diagnostics market. Nanobiotechnology and biochips are also expected to drive future growth. Introduction of new diagnostics tests, primarily in the infectious disease application area is likely to keep the momentum going for the molecular diagnostics business in the short-term.

Lagenaria siceraria: A Potential Source of Anti-Hyperlipidemic and Other Pharmacological Agents

Lagenaria siceraria, commonly known as bottle gourd, is extensively grown in India and other tropical and sub-tropical regions of the world. The bottle gourd is rich in a number of phytoconstituents, minerals, vitamins, fibre etc. with potent neutraceutical and therapeutic functions. Leaves and roots are used as emetic to reduce baldness and to relieve headache. Flowers are used as antidote in certain kinds of poisons. L. siceraria is reported to exhibit cardioprotective, antihyperlipidemic, antioxidant, antihyperglycemic, analgesic, anti-inflammatory, immunomodulatory and hepatoprotective functions in human subjects as well as in experimental models. The bottle gourd is proved to be a potential source of prophylactic and therapeutic neutraceuticals and can serve as ‘medicinal food’ particularly in metabolic disorders associated with carbohydrate and lipid metabolisms. The objective of this article is to work out the ethnopharmacological and other medicinal applications of L. siceraria along with phytochemical and biochemical composition.

Impact of HGP on Molecular Diagnostics

The Human Genome Project has heralded a whole new era in our understanding of the molecular basis of disease. New opportunities now arise to predict disease by genetic testing, and in some cases to prevent disease through surveillance or other specific interventions. Increasingly it will be possible to test for predisposition to disease, to develop new treatments or to tailor available treatments more specifically to an individual’s genetic make-up.

Introduction to Molecular Diagnostics

Molecular diagnostics has become a growing part of the clinical laboratory. It includes all tests and methods to identify a disease and understand the predisposition for a disease analyzing DNA or RNA of an organism. Rapid advances in molecular diagnostics enable basic research and results in practical diagnostic tests. The basic application is to determine changes in sequence or expression levels in crucial genes involved in disease. The use of molecular diagnostics, such as pre-implantation diagnostics or predictive genetic testing, still has technical problems as well as novel, and to date unclear, social, ethical and legal implications. The scope of molecular diagnostics in molecular medicine could be expanded well beyond current nucleic acid testing. It plays an important role in practice of medicine, public health, pharmaceutical industry, forensics and biological warfare and drug discovery. The molecular diagnostic marketplace offers a growth opportunity given the interest in utilizing molecular tools to precisely target therapeutics.