Geographical and chronological origin and evolution of Hepatitis C Virus.

Hepatitis C Virus (HCV) infection is a major health problem that leads to cirrhosis and hepatocellular carcinoma. World over, more than 270-300 million people are estimated to be infected with the virus. HCV is a positive sense single stranded RNA virus and replicates within the cytoplasm of the hepatocyte using its own RNA dependent RNA polymerase (RdRp). RdRp does not have proof reading capacity, and hence generates mutants of the virus, resulting in a chronic infection, which ultimately ends in hepatocellular carcinoma. Such mutations have given rise to several genotypes, subtypes, strains and variants with significant difference in disease outcomes. The mutation rate varies among genotypes, subtypes, strains or even in different sites of the genome. Yet, the extent of heterogeneity is usually moderate, so that estimates of the time of divergence can be computed. The evolution of variants seems to be influenced by the genetic make-up and the immune response of the host and has geographical significance. Here we used phylogenetic analysis and Computational molecular dating techniques to conclude that the ancestral genotype is 7a and that it originated in Canada 363 years ago. Molecular dating was based on the fact that the rate of mutation across all evolutionary lineages is constant over time. Surprisingly, our analyses show that genotype 1d isolated from Canada5 is the most recent with an evolutionary date of just 33 years. It is evident that HCV is still an emerging virus and demographical parameters seem to have a very strong influence in its evolution. We believe that this emphasises the need for developing drugs that are customised to act against strains that evolve and become geographically endemic

Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity

Over the last three decades, p21-activated kinases (PAKs) have emerged as prominent intracellular nodular signaling molecules in cancer cells with a spectrum of cancer-promoting functions ranging from cell survival to anchorage-independent growth to cellular invasiveness. As PAK family members are widely overexpressed and/or hyperactivated in a variety of human tumors, over the years PAKs have also emerged as therapeutic targets, resulting in the development of clinically relevant PAK inhibitors. Over the last two decades, this has been a promising area of active investigation for several academic and pharmaceutical groups. Similar to other kinases, blocking the activity of one PAK family member leads to compensatory activity on the part of other family members. Because PAKs are also activated by stress-causing anticancer drugs, PAKs are components in the rewiring of survival pathways in the action of several therapeutic agents; in turn, they contribute to the development of therapeutic resistance. This, in turn, creates an opportunity to co-target the PAKs to achieve a superior anticancer cellular effect. Here we discuss the role of PAKs and their effector pathways in the modulation of cellular susceptibility to cancer therapeutic agents and therapeutic resistance

The Revelation of Continuously Organized, Co-Overexpressed Protein-Coding Genes with Roles in Cellular Communications in Breast Cancer

Many human cancers, including breast cancer, are polygenic and involve the co-dysregulation of multiple regulatory molecules and pathways. Though the overexpression of genes and amplified chromosomal regions have been closely linked in breast cancer, the notion of the co-upregulation of genes at a single locus remains poorly described. Here, we describe the co-overexpression of 34 continuously organized protein-coding genes with diverse functions at 8q.24.3(143437655-144326919) in breast and other cancer types, the CanCord34 genes. In total, 10 out of 34 genes have not been reported to be overexpressed in breast cancer. Interestingly, the overexpression of CanCord34 genes is not necessarily associated with genomic amplification and is independent of hormonal or HER2 status in breast cancer. CanCord34 genes exhibit diverse known and predicted functions, including enzymatic activities, cell viability, multipotency, cancer stem cells, and secretory activities, including extracellular vesicles. The co-overexpression of 33 of the CanCord34 genes in a multivariant analysis was correlated with poor survival among patients with breast cancer. The analysis of the genome-wide RNAi functional screening, cell dependency fitness, and breast cancer stem cell databases indicated that three diverse overexpressed CanCord34 genes, including a component of spliceosome PUF60, a component of exosome complex EXOSC4, and a ribosomal biogenesis factor BOP1, shared roles in cell viability, cell fitness, and stem cell phenotypes. In addition, 17 of the CanCord34 genes were found in the microvesicles (MVs) secreted from the mesenchymal stem cells that were primed with MDA-MB-231 breast cancer cells. Since these MVs were important in the chemoresistance and dedifferentiation of breast cancer cells into cancer stem cells, these findings highlight the significance of the CanCord34 genes in cellular communications. In brief, the persistent co-overexpression of CanCord34 genes with diverse functions can lead to the dysregulation of complementary functions in breast cancer. In brief, the present study provides new insights into the polygenic nature of breast cancer and opens new research avenues for basic, preclinical, and therapeutic studies in human cancer

Cyclophilin A Impairs Efferocytosis and Accelerates Atherosclerosis by Overexpressing CD 47 and Down-Regulating Calreticulin

Impairment of efferocytosis in apoptotic macrophages is a known determinant of the severity of atherosclerosis and the vulnerability of plaques to rupture. The precise mechanisms involved in impaired efferocytosis are unclear. Given the well-recognized role of the inflammatory cytokine cyclophilin A (Cyp A) in modulating several atherogenic mechanisms in high-glucose primed monocytes, we investigated the role of Cyp A in macrophage efferocytosis. The efficiency of efferocytosis in RAW 264.7 macrophages grown in vitro and primed with cyclophilin A was assessed using flow cytometry and confocal assays. Cholesterol content in cells was measured using cell-based cholesterol efflux assay. Proteomic analysis and bioinformatics tools were employed to decipher the link between cyclophilin A and the known ligand receptors involved in efferocytosis. Cyclophilin A was found to impair efferocytosis in apoptotic macrophages by reducing ABCA1-mediated cholesterol efflux in foam cells derived from macrophages. Cyclophilin A-primed macrophages showed an increase in expression of the don’t-eat-me signal CD 47 and a decrease in the expression of the eat-me signal, calreticulin. Phagocytosis was restored upon silencing of cyclophilin A. New Zealand white rabbits were fed a high-fat diet, and lesions in their aortae were analyzed histologically for evidence of atherosclerosis and the expression of Cyp A, CD 47 and calreticulin, the ligand receptor involved in efferocytosis. Gene and protein expressions in aortae and macrophages were analyzed by real-time PCR and Western blotting. Cyclophilin A, via its effects on the expression of CD 47 and calreticulin, impairs efferocytosis in apoptotic macrophages. Together with its impact on cholesterol efflux from macrophages, these effects can amplify other mechanisms of Cyp A in accelerating the progression of atherosclerosis

Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types