The importance of herpes simplex viruses (HSV) as human pathogens and the emerging prospect of using mutant derivatives of HSV-1 as potential anti-cancer therapeutics have necessitated a thorough investigation into the molecular basis of host-cell permissiveness to HSV. Here we show that NIH-3T3 cells transformed with the oncogenes v-erbB, activated sos or activated ras become significantly more permissive to HSV-1. Inhibitors of the Ras signalling pathway, such as farnesyl transferase inhibitor 1 and PD98059, effectively suppressed HSV-1 infection of ras-transformed cells. Enhanced permissiveness of the transformed cells was linked to the inhibition of virus-induced activation (phosphorylation) of the double-stranded RNA-activated protein kinase (PKR), thereby allowing viral transcripts to be translated in these cells. An HSV-1-derived oncolytic mutant, R3616, was also found to infect preferentially both transformed cells and PKR-/- (but not PKR+/+) mouse embryo fibroblasts. These observations suggest that HSV-1 specifically targets cells with an activated Ras signalling pathway, and have important ramifications in the use of engineered HSV in cancer therapy, the development of strategies against HSV infections, and the controversial role of HSV in human cancers.

BackgroundColorectal cancer is the third most common cancer in Iran. The increasing trend of colorectal cancer incidence in Iran and the close relationship with the geographical location are the underlying reasons for this study.MethodsData source: Eleven databases, including MEDLINE, EMBASE, SCOPUS, and four other databases, for articles in Persian were searched from April 2014 to October 2014. Additional data were obtained from an online survey of the Central Library of Tabriz Faculty of Medicine. Study eligibility criteria: In this systematic review and meta-analysis, we included studies reporting different measures of incidence, age-standardized incidence rates, and crude incidence rates. All rates (per 100,000 person-years) were standardized to the world standard population. Study appraisal and synthesis methods: A preliminary review of the title and abstracts of these articles was used to exclude any that were clearly irrelevant. The full text review determined whether the article was relevant to our topic. All the potentially relevant manuscripts were reviewed by two other investigators (S.D., M.G.). A total of 39 studies (10 Persian and 29 English articles) from different provinces and diverse areas of Iran, were analyzed in this study using comprehensive meta-analysis software. For accuracy studies, we used estimated rates for males and females with 95 % confidence intervals.ResultsAge-standardized incidence rates were obtained based on the random effects model and were 8.16 (95 % CI: 6.64 to 9.68) and 6.17 (95 % CI: 5.01 to 7.32) for males and females, respectively. The random crude rates were 5.58 (95 % CI: 4.22 to 6.94) for males and 4.01 (95 % CI: 3.06 to 4.97) for females.ConclusionsColorectal cancer incidence rates rise due to individual and environmental risk factors as well as improvement in the registry system and increase in access to health services. A more executed organized and structured system for collecting cancer data, in all cities and rural areas of the country, is an essential priority.

Purpose. The increasing incidence of colorectal cancer (CRC) in the past three decades in Iran has made it a major public health burden. This study aimed to report its epidemiologic features, molecular genetic aspects, survival, heredity, and screening pattern in Iran. Methods. A comprehensive literature review was conducted to identify the relevant published articles. We used medical subject headings, including colorectal cancer, molecular genetics, KRAS and BRAF mutations, screening, survival, epidemiologic study, and Iran. Results. Age standardized incidence rate of Iranian CRCs was 11.6 and 10.5 for men and women, respectively. Overall five-year survival rate was 41%, and the proportion of CRC among the younger age group was higher than that of western countries. Depending on ethnicity, geographical region, dietary, and genetic predisposition, mutation genes were considerably diverse and distinct among CRCs across Iran. The high occurrence of CRC in records of relatives of CRC patients showed that family history of CRC was more common among young CRCs. Conclusion. Appropriate screening strategies for CRC which is amenable to early detection through screening, especially in relatives of CRCs, should be considered as the first step in CRC screening programs.

Mesothelin, a differentiation antigen present in a series of malignancies such as mesothelioma, ovarian, lung and pancreatic cancer, has been studied as a marker for diagnosis and a target for immunotherapy. We, however, were interested in evaluating the effects of direct targeting of Mesothelin on the viability of cancer cells as the first step towards developing a novel therapeutic strategy. We report here that gene specific silencing for Mesothelin by distinct methods (siRNA and microRNA) decreased viability of cancer cells from different origins such as mesothelioma (H2373), ovarian cancer (Skov3 and Ovcar-5) and pancreatic cancer (Miapaca2 and Panc-1). Additionally, the invasiveness of cancer cells was also significantly decreased upon such treatment. We then investigated pro-oncogenic signaling characteristics of cells upon mesothelin-silencing which revealed a significant decrease in phospho-ERK1 and PI3K/AKT activity. The molecular mechanism of reduced invasiveness was connected to the reduced expression of β-Catenin, an important marker of EMT (epithelial-mesenchymal transition). Ero1, a protein involved in clearing unfolded proteins and a member of the ER-Stress (endoplasmic reticulum-stress) pathway was also markedly reduced. Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase. In next step, treatment of ovarian cancer cells (OVca429) with a lentivirus expressing anti-mesothelin microRNA resulted in significant loss of viability, invasiveness, and morphological alterations. Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies.

These experiments provide a rationale for targeting Ras and associated signaling pathways in mesothelioma and also suggest cap-dependent translation as one mechanism by which Ras induces proliferation in this disease.