Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients

Introduction: TP53 gene is the most frequently altered tumor suppressor gene in breast cancer. It has been observed that MDM2 plays a central role in regulating the TP53 pathway. This study aimed to investigate the role of TP53 Arg72Pro and MDM2 T309G polymorphisms in breast cancer patients. Material and method: The TP53 (Arg72Pro) and MDM2 (T309G) polymorphisms were studied in a hospital-based case control study by AS-PCR in 100 breast cancer patients and 100 healthy control subjects. Results: It was observed that TP53 Arg72Pro polymorphism was significantly associated with breast cancer (v2 = 9.92, p = 0.007). A significantly increased breast cancer risk was associated with the Proline allele [odds ratio 1.84 (95 % CI: 1.22-2.77), risk ratio 1.34 (95 % CI: 1.11-1.63), p value 0.003], HER2/neu status (p = 0.01) and distant metastasis (p = 0.05). On the other hand, we have found a significant correlation between MDM2 (T309G) polymorphism with HER2/neu status (v2 = 11.14, p = 0.003) and distant metastasis (p value = 0.04). Conclusion: Our finding suggests that TP53 (Arg72Pro) polymorphism may play a significant role as risk factor for breast cancer in north Indian breast cancer patients. While MDM2 (T309G) polymorphism may not be directly associated with the risk of breast cancer occurrence in the same population, but it may play role in disease progression by triggering TP53 (AU)

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The C609T (Pro187Ser) Null Polymorphism of the NQO1 Gene Contributes Significantly to Breast Cancer Susceptibility in North Indian Populations: a Case Control Study.

BACKGROUND: Worldwide, breast cancer is the most common cancer among women and is a leading cause of cancer death. In the present study, we investigated the NQO1 C609T genotypic and allelic distribution in north Indian breast cancer patients. MATERIALS AND METHODS: The genotypic distribution of the NQ01 C609T polymorphism was assessed in 100 invasive ductal carcinoma (IDC) breast cancer patients and 100 healthy controls using allele specific PCR (AS-PCR). RESULTS: A lower frequency of the CC genotype was found in breast cancer patients (24%) than in the controls. On the other hand, TT genotype frequency was also found to be higher in female healthy controls (32%) than the female breast cancer patients (20%). The frequencies of all three genotypes CC, CT, TT in patients were 24%, 56% and 20% and in healthy controls 50%, 22% and 32% respectively. We did not find any significant correlation between the NQO1 C609T polymorphism and age group, grading, menopausal status and distant metastasis. A less significant association was found between the NQ01 C609T polymorphism and the stage of breast cancer (X2=5.931, P=0.05). CONCLUSIONS: The present study shows a strong association between NQO1 C609T polymorphism with the breast cancer risk in the north Indian breast cancer patients so that possible use as a risk factor should be further explored.

Survivin siRNA increases sensitivity of primary cultures of ovarian cancer cells to paclitaxel

Purpose. This aim of this study was to use ovarian cancer cells shed in ascitic fluid to establish primary cultures and subsequently use it to detect drug resistance to paclitaxel. Survivin siRNA was used to down regulate survivin expression and effect on paclitaxel resistance was also evaluated. Methodology. Ascitic fluid along with corresponding primary tumor tissue was collected from twenty untreated epithelial ovarian cancer patients. Ten primary cultures were established from ascites obtained from untreated ovarian cancer patients in MCDB 105 and M199 medium (ratio 1:1). Knockdown of survivin was done using siRNA and sensitivity to paclitaxel was evaluated by MTT assay. Results. Grape-like clusters of ovarian cancer cells present in ascites attached and gave a characteristic cobble stone appearance. Treatment with survivin siRNA resulted in a fivefold decrease in survivin expression in primary cultures. Survivin siRNA treatment significantly increased the sensitivity of the primary ovarian cancer cell cultures to paclitaxel. Conclusion. Ascitic cancer cells reflect the molecular profile of tumor and can be used to diagnose resistance to chemotherapy. This study also establishes that high survivin expression is also responsible for resistance to paclitaxel (AU)

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Epidemiological investigation of an outbreak of chikungunya in hyderabad and nalgonda districts of andhra pradesh, India.

After about three decades, Chikungunya infection has re-emerged in India and the first cases were reported in December, 2005. The outbreak has currently affected about 8 states in the country. Although known to be commonly non fatal, since the present outbreak involved a large population, it has been raised as an issue of public health concern and also attracted wide media attention. The clinico-epidemiological and entomological review of the Chikungunya outbreak situation in Hyderabad and Nalgonda Districts of Andhra Pradesh, which started in December 2005, revealed that it is under control. However, preventive efforts need to continue and disease surveillance for early detection of potential outbreaks further strengthening. Given the significantly high House Index, all the three study areas remain at significant risk of outbreaks in the future if appropriate control measures are not put in place. Community support and participation is also crucial for the prevention of future outbreaks and improving the health and well being of population in the districts.

Oxidative stress and apoptosis.

Apoptosis or programmed cell death, is essential for the normal functioning and survival of most multi-cellular organisms. The morphological and biochemical characteristics of apoptosis, however, are highly conserved during the evolution. It is currently believed that apoptosis can be divided into at least three functionally distinct phases, i.e. induction, effector and execution phase. Recent studies have demonstrated that reactive oxygen species (ROS) and the resulting oxidative stress play a pivotal role in apoptosis. Antioxidants and thiol reductants, such as N-acetylcysteine, and overexpression of manganese superoxide (MnSOD) can block or delay apoptosis. Bcl-2, an endogenously produced protein, has been shown to prevent cells from dying of apoptosis apparently by an antioxidative mechanism. Taken together ROS, and the resulting cellular redox change, can be part of signal transduction pathway during apoptosis. It is now established that mitochondria play a prominent role in apoptosis. During mitochondrial dysfunction, several essential players of apoptosis, including pro-caspases, cytochrome C, apoptosis-inducing factor (AIF), and apoptotic protease-activating factor-1 (APAF-1) are released into the cytosol. The multimeric complex formation of cytochrome C, APAF-1 and caspase 9 activates downstream caspases leading to apoptotic cell death. All the three functional phases of apoptosis are under the influence of regulatory controls. Thus, increasing evidences provide support that oxidative stress and apoptosis are closely linked physiological phenomena and are implicated in pathophysiology of some of the chronic diseases including AIDS, autoimmunity, cancer, diabetes mellitus, Alzheimer's and Parkinson's and ischemia of heart and brain.