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Review of the current knowledge on the epidemiology, pathogenesis, and prevention of human papillomavirus infection.

Human papillomavirus (HPV) infection is a central and necessary, although not sufficient, cause of cervical cancer. Besides HPV, the additional multiple risk factors related with the onset of cervical cancer are early-age sexual activities; high number of sexual partners, which is the most salient risk factor; suppression and alteration of the immune status; long-term use of oral contraceptives; and other hormonal influences. The tumor-suppressor proteins p53 and pRb are degraded and destabilized through ubiquitination by viral oncoproteins E6 and E7. Over 95% of cervical cancer cases worldwide test positive for oncogenic HPV DNA. Although cervical screening procedures have been successful in reducing the disease burden associated with HPV infection because of lack of resources or inadequate infrastructure many countries have failed to reduce cervical cancer mortality. Therefore, prevention may be a valuable strategy for reducing the economic and disease burden of HPV infection. At present, two successful prophylactic HPV vaccines are available, quadrivalent (HPV16/18/6/11) ‘Gardasil’ and bivalent (HPV16/18) ‘Cervarix’ for vaccinating young adolescent girls at or before the onset of puberty. Recent data indicate that vaccination prevents the development of cervical lesions in women who have not already acquired the vaccine-specific HPV types. Moreover, several therapeutic vaccines that are protein/peptide-based, DNA-based, or cell-based are in clinical trials but are yet to establish their efficacy; these vaccines are likely to provide important future health benefits. The therapeutic vaccination mode of prevention is a promising area of research, as revealed in preclinical trials; however, clinical trials based on large populations are warranted before reaching a valid conclusion. This review summarizes the studies on the epidemiology of HPV infection, the pathogenesis of viral oncoproteins in the oncogenesis of cervical cancer, the economic and health burden of HPV-related diseases, and, finally, focuses on the results of recent clinical vaccination trials.

Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

BACKGROUND Aberrant promoter hypermethylation has been recognized in human breast carcinogenesis as a frequent molecular alteration associated with the loss of expression of a number of key regulatory genes and may serve as a biomarker. The E-cadherin gene (CDH1), mapping at chromosome 16q22, is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. The aim of our study was to assess the methylation pattern of CDH1 and to correlate it with the expression of E-cadherin, clinicopathological parameters and hormone receptor status in breast cancer patients of Kashmir. MATERIALS AND METHODS Methylation specific PCR (MSP) was used to determine the methylation status of CDH1 in 128 invasive ductal carcinomas (IDCs) paired with the corresponding normal tissue samples. Immunohistochemistry was used to study the expression of E-cadherin, ER and PR. RESULTS CDH1 hypermethylation was detected in 57.8% of cases and 14.8% of normal adjacent controls. Reduced levels of E-cadherin protein were observed in 71.9% of our samples. Loss of E-cadherin expression was significantly associated with the CDH1 promoter region methylation (p<0.05, OR=3.48, CI: 1.55-7.79). Hypermethylation of CDH1 was significantly associated with age at diagnosis (p=0.030), tumor size (p=0.008), tumor grade (p=0.024) and rate of node positivity or metastasis (p=0.043). CONCLUSIONS Our preliminary findings suggest that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression. We found significant differences in tumor-related CDH1 gene methylation patterns relevant to tumor grade, tumor size, nodal involvement and age at diagnosis of breast tumors, which could be extended in future to provide diagnostic and prognostic information.

Nephroprotective action of Peucedanum grande against cadmium chloride induced renal toxicity in Wistar rats

Cadmium is a known industrial pollutant which accumulates in the kidney and its exposure leads to the production of reactive oxygen species (ROS). The present study was carried out to evaluate the protective effects of Peucedanum grande against CdCl2 induced renal toxicity in Wistar rats. Wistar rats were subjected to oral pre-treatment of P. grande (60 and 120 mg/kg b.wt) against the renal toxicity induced by administration of CdCl2 (3mg/kg b.wt). Efficacy of P. grande against the renal toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities and histopathological changes. P. grande pretreatment prevented deteriorative effects induced by CdCl2 through a protective mechanism that involved reduction of increased oxidative stress as well as by restoration of histopathological changes against CdCl2 administration.

Prevalence of human papillomavirus infection in a Kashmiri ethnic female population.

Human papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection and is one of the causal factors in cervical cancer. Understanding the epidemiology of this infection is an important step toward developing strategies for its prevention. Cervical samples from 210 healthy women with normal and abnormal cytomorphology were studied for the detection of HPV DNA by polymerase chain reaction (PCR), utilizing the two most commonly used consensus primer sets. The primers; MY09/MY11 and GP5+/GP6+ located within the L1 region of HPV genome, amplified a broad spectrum of HPV genotypes in a single reaction. The PCR amplification of HPV genomes is a sensitive method that is used for the detection of cervicovaginal HPV. With the aim of identifying the HPV types, samples were also subjected to PCR using specific primers for HPV types 16 and 18. In addition, basic demographic information, sociodemographic characteristics, and sexual behavior were recorded. HPV was detected in 13.8% of the study population aged 18 to 57 years using PCR. HPV16 (6.6%) was more commonly detected than HPV18 (3.8%). The highest prevalence of HPV infection was seen in women below 27 years old, and then, a new increase was seen higher than the age of 48. In conclusion, our study demonstrated that younger age at marriage, economic status, parity, and dwelling are the major risk factors determining HPV infection.

Noncoding RNAs in DNA Damage Response: Opportunities for Cancer Therapeutics

DNA repair machinery preserves genomic integrity, which is frequently challenged through endogenous and exogenous toxic insults, and any sort of repair machinery malfunctioning ultimately manifests in the form of several types of terrible human diseases such as cancers (Hoeijmakers, Nature 411(6835): 366-374, 2001). Noncoding RNAs (ncRNAs) are crucial players of DNA repair machinery in a cell and play a vital role in maintaining genomic stability, which is essential for its survival and normal functioning thus preventing tumorigenesis. To preserve the integrity of the genome, cells initiate a specific cellular response, recognized as DNA damage response (DDR), which includes several distinct DNA repair pathways. These repair pathways permit normal cells to repair DNA damage or induce apoptosis and cell cycle arrest in case the damage is irreparable. Disruption of these pathways in cancer leads to an increase in genomic instability and mutagenesis. Recently, emerging evidence suggests that ncRNAs play a critical role in the regulation of DDR. There is an extensive crosstalk between ncRNAs and the canonical DDR signaling pathway. DDR-induced expression of ncRNAs can provide a regulatory mechanism to accurately control the expression of DNA damage responsive genes in a spatio-temporal manner. DNA damage alters expression of a variety of ncRNAs at multiple levels including transcriptional regulation, post-transcriptional regulation, and RNA degradation and vice versa, wherein ncRNAs can directly regulate cellular processes involved in DDR by altering expression of their targeting genes, with a particular emphasis on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Relationship between the defects in the DDR and deregulation of related ncRNAs in human cancers is one of the established, which is growing stronger with the advent of high-throughput sequencing techniques such as next-generation sequencing. Understanding of the mechanisms that explain the association between ncRNAs and DDR/DNA repair pathways will definitely increase our understanding on human tumor biology and on different responses to diverse drugs. Different ncRNAs interact with distinct DDR components and are promising targets for improving the effects to overcome the resistance to conventional chemotherapeutic agents. In this chapter, we will focus the role of ncRNAs in the DNA damage, repair, and cancer.

MicroRNAs in Breast Cancer: Diagnostic and Therapeutic Potential

MicroRNAs (miRNAs) are a large family of small, approximately 20-22 nucleotide, noncoding RNAs that regulate the expression of target genes, at the post-transcriptional level. miRNAs are involved in virtually diverse biological processes and play crucial roles in cellular processes, such as cell differentiation, proliferation, and apoptosis. Accumulating lines of evidence have indicated that miRNAs play important roles in the maintenance of biological homeostasis and that aberrant expression levels of miRNAs are associated with the onset of many diseases, including cancer. It is possible that the diverse roles that miRNAs play, have potential to provide valuable information in a clinical setting, demonstrating the potential to act as both screening tools for the stratification of high-risk patients, while informing the treatment decision-making process. Increasing evidence suggests that some miRNAs may even provide assistance in the diagnosis of patients with breast cancer. In addition, miRNAs may themselves be considered therapeutic targets, with inhibition or reintroduction of a particular miRNA capable of inducing a response in-vivo. This chapter discusses the role of miRNAs as oncogenes and tumor suppressors in breast cancer development and metastasis . It focuses on miRNAs that have prognostic, diagnostic, or predictive potential in breast cancer as well as the possible challenges in the translation of such observations to the clinic.

Anticonvulsant activity of methanolic and aqueous extracts of Melissa parviflora in experimentally induced Swiss albino mice

The aim of the present study was to evaluate the anticonvulsant effect of whole plant extracts of Melissa parviflora using MES and PTZ induced seizures models. The dried whole plant was subjected to extraction in methanol and water. The extracts were subjected to phytochemical tests and the carbohydrate, flavonols, coumarins, glycosides and steroid were found to be present. The methanolic and aqueous extracts of the plant of Melissa parviflora were observed for their anticonvulsant activity by Maximal Electroshock seizures (MES) test and Pentylenetetrazole (PTZ) test using Swiss albino mice. Both the extracts showed significant activity in MES and PTZ induced convulsions in comparison to control. From the literature surveys as well experiments performed, it can be said that Melissa parviflora does pose anticonvulsant property.