Pathogenesis of Human Papillomavirus – Immunological Responses to HPV Infection

Papillomavirus is an oncogenic virus which infects mucosal and cutaneous epithelia where it induces benign hyperproliferative lesions. Few studies have been conducted on the causative factors associated with the development of cancer. Infections by high-risk human papillomaviruses (HPVs) have been implicated as causative agents in a variety of cancers such as anogenital, and head and neck cancers. HPVs appear to have evolved mechanisms resulting in escape from host immune surveillance and delay of resolution of infection. The HPV E5 oncoprotein is one of the possible effectors that allows the virus to escape from host immune system through the downregulation of surface classical major histocompatibility complex class I (MHC I) and not the nonclassical MHC I. Lack of classical MHC I in infected cells expressing E5 would allow evasion of cytotoxic T lymphocytes (CTLs) killing and thus establishment and persistence of viral infection

Mutational Analysis of the Transforming Protein E8 of Bovine Papillomavirus Type-4 (BPV-4)

The transforming genes of bovine papillomavirus type 4 (BPV-4) are encoded by the E7 and E8 open reading frames (ORFs). E7 is the transforming gene of BPV-4, in that, in co-operation with activated ras, it induces morphological transformation of primary bovine fibroblasts (PalF) in the absence of other viral genes, but the acquisition of anchorage independent growth requires the additional presence of E8. The BPV-4 E8 is a small transforming protein localized to cellular membrane. It consists of two domains: a very hydro'phobic region encompassing the first 30 amino acids of the protein, and a second region of mainly hydrophilic amino acids comprising the C terminal 12 residues. The results in this thesis demonstrated that in addition to the ability of E8 to grow independently of anchorage, PalF cells expressing E8 lose gap junction intercellular communication (GJIC), can grow in low serum, and are not contact inhibited. E8 also transactivates the cyclin A promoter in PalF cells. Mutant forms of E8 were generated to establish if the transforming functions of the protein could be segregated and therefore to define its functional domains. Mutations were introduced both in the hydrophobic domain and in the hydrophilic C-terminal tail, and chimeras with BPV-1 E5 were constructed. Cells expressing either E8 wild type or its mutants were analysed for their ability to: morphological transformation, anchorage independent growth, focus formation, cell population growth in low serum, tumorigenicity in nude mice, trans-activation of the cyclin A promoter, binding to ductin and down regulation of GJIC. The analysis of E8 mutants and chimeras constructed with BPV-1 E5 show that the multiple transforming function of E8 can be segregated and that both the hydrophobic domain and the hydrophilic C-terminal tail of E8 are critical for its functions and for the transactivation of the cyclin A promoter. These results support the hypothesis that the different aspects of cellular transformation produced by E8 might be due to interaction with different cellular targets. The observation from the analysis of the transformation parameters of E8 and BPV-1 E5 expressing cells suggest that E8 acts differently from E5. This study also demonstrates that the separate domains of E5 and E8 are not functionally interchangeable. The short term co-transfection analysis of E8 mutants suggest that substitution of alanine with proline, which is expected to alter the conformation of the hydrophobic domain, may have an effect on cell transformation. Also the short-term co-transfection experiments of E8 mutants in the putative casein kinase II site support the possibility that BPV-4 E8 might be phosphorylated by CKII and that this phosphorylation could have an effect on the biological activities of this protein

Similarities and differences between the E5 oncoproteins of bovine papillomaviruses type 1 and type 4: Cytoskeleton, motility and invasiveness in E5-transformed bovine and mouse cells

Bovine papillomaviruses (BPVs) are oncogenic viruses. In cattle, BPV-1/2 is associated with urinary bladder cancer and BPV-4 with upper GI tract cancer. BPV E5 is a small hydrophobic protein localised in the endoplasmic reticulum (ER) and Golgi apparatus (GA). E5 is the major transforming protein of BPVs, capable of inducing cell transformation in cultured mouse fibroblasts and, in cooperation with E7, in primary bovine cells. E5-induced cell transformation is accompanied by activation of several cellular protein kinases, including growth factor receptors, and alkalinisation of endosomes and GA. We have reported that BPV E5 causes swelling and fragmentation of the GA and extensive vacuolisation of the cytoplasm. We now show that E5 from both BPV-1 and BPV-4 disturbs the actin cytoskeleton and focal adhesions in transformed bovine cells, where these morphological and behavioural characteristics are accompanied by hyperphosphorylation of the cellular phosphotyrosine kinase c-src. Both BPV-1 and BPV-4 E5 increase the motility of transformed mouse cells, but only BPV-1 E5 causes transformed mouse cells to penetrate a matrigel matrix. BPV-1 transformed mouse cells, but not BPV-4 transformed mouse cells, have hyperhpsphorylated c-src

Three rare cases of anthrax arising from the same source

Anthrax is an acute bacterial infection caused by Bacillus anthracis. Humans become infected under natural conditions by contact with infected animals or contaminated animal products. About 95% of human anthrax is cutaneous and 5% respiratory. Gastrointestinal anthrax is very rare, and has been reported in less than 1% of all cases. Anthrax meningitis is a rare complication of any of the other three forms of disease. We report three rare cases of anthrax (gastrointestinal, oropharyngeal and meningitis) arising from the same source. The three patients were from a single family and were admitted with different clinical pictures after the ingestion of half-cooked meat from a sick sheep. These cases emphasize the need for awareness of anthrax in the differential diagnosis in areas where the disease remains endemic

Non-alcoholic fatty liver disease is not independent risk factor for cardiovascular disease event : a cohort study

There are no consistent results between previous studies for an independent association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) events. To determine if there is an independent association between NAFLD and CVD events. In the present study, valid outcome data of 4808 subjects were available for phase 2 of our cohort study. These subjects had been followed up for seven years from phase 1, beginning in 2009-2010 to phase 2 during 2016-2017. Simple and multiple Cox proportional models were used to determine the association between NAFLD in the primary phase of the cohort and subsequent fatal and non-fatal CVD events during follow-up. The incidence of non-fatal CVD events in males with NAFLD was significantly higher ( = 0.004) than in males without NAFLD. A positive association was demonstrated between NAFLD and non-fatal CVD events in males (Hazard ratio = 1.606; 95%CI: 1.166-2.212; = 0.004) by the simple Cox proportional hazard model, but no independent association was detected between these in the multiple Cox models. No independent association was detected between NAFLD and CVD. It is likely that diabetes mellitus and age may be the principle mediators in this regard. [Abstract copyright: ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.

Prevalence and type distribution of high-risk Human Papillomavirus (HPV) in breast cancer : a Qatar based study

Human papillomavirus (HPV) has been implicated in the etiology of a variety of human cancers. Studies investigating the presence of high-risk (HR) HPV in breast tissue have generated considerable controversy over its role as a potential risk factor for breast cancer (BC). This is the first investigation reporting the prevalence and type distribution of high-risk HPV infection in breast tissue in the population of Qatar. A prospective comparison blind research study herein reconnoitered the presence of twelve HR-HPV types’ DNA using multiplex PCR by screening a total of 150 fresh breast tissue specimens. Data obtained shows that HR-HPV types were found in 10% of subjects with breast cancer; of which the presence of HPV was confirmed in 4/33 (12.12%) of invasive carcinomas. These findings, the first reported from the population of Qatar, suggest that the selective presence of HPV in breast tissue is likely to be a related factor in the progression of certain cases of breast cancer

Signal transduction pathway mutations in gastrointestinal (GI) cancers : a systematic review and meta-analysis

The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3–8%), 12% (95% CI: 8–18%), 17% (95% CI: 14–20%), and 20% (95% CI: 5–41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14–33%) and 20% (95% CI, 17–24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations

Prevalence and type distribution of high-risk human papillomavirus in patients with cervical cancer: a population-based study.

BACKGROUND: Cervical cancer is the greater cause of cancer death in women in many developing countries. Persistent infection with human papilloma virus (HPV), primarily high risk types 16 and 18, is recognized as a causal and essential factor for the development of cervical cancer. We aimed to determine the distribution of high-risk HPV genotypes in archival biopsies with cervical carcinoma in patients from Mazandaran Province, Northern Iran. METHODS: A total of 98 paraffin-embedded cervical samples consisted of 63 Squamous Cell Carcinomas (SCC), 4 Adenocarcinomas, 19 Cervical Interaepithelial Neoplasia grade I (CIN-I), 4 CIN-II and 8 CIN-III diagnosed during 2009-2011, were selected to perform high risk HPV genotyping using AmpliSens(R) HPV HCR DNA genotyping kit. The prevalence of HPV infections was assessed in low and high grade cervical lesions by age. RESULTS: Of the 98 cervical samples analysed by DNA PCR, 78 (79.59%) were positive for HPV DNA. HPV was detected in the 52 of SCC, 4 of Adenocarcinomas, 14 of CIN-I, 4 of CIN-II, and 4 of CIN-III for HPV. From the 78 HPV positive samples, 23 (29.5%) samples were positive for HPV type 16, 32 (41%) were positive for HPV 18, 19 (24.4%) were positive for HPV 45, and 4 (5.1%) of cervical specimens were positive for HPV 39. CONCLUSIONS: This study provides valuable baseline data for future assessment of the impact of current prophylactic vaccination programs that is protective against the two most common oncogenic types of HPV found in cervical cancer, HPV-16 and HPV-18, but not against other high-risk mucosal HPVs, 39 and 45, reported in this population