Anthonio Adefuye

Regulation of Inflammatory Pathways in Cancer and Infectious Disease of the Cervix

Cervical cancer is one of the leading gynaecological malignancies worldwide. It is an infectious disease of the cervix, associated with human papillomavirus infection (HPV), infection with bacterial agents such as Chlamydia trachomatis and Neisseria gonorrhoea as well as human immunodeficiency virus (HIV). Furthermore, it is an AIDS-defining disease with an accelerated mortality in HIV-infected women with cervical cancer. With the introduction of robust vaccination strategies against HPV in the developed world, it is anticipated that the incidence of cervical cancer will decrease in the coming years. However, vaccination has limited benefit for women already infected with high-risk HPV, and alternative therapeutic intervention strategies are needed for these women. Many pathological disorders, including cervical cancer, are characterised by the exacerbated activation and maintenance of inflammatory pathways which are considered to be regulated by infectious agents. In cervical cancer, hyperactivation of these inflammatory pathways and regulation of immune infiltrate into tissues can potentially play a role not only in tumorigenesis but also in HIV infection. In this paper we will discuss the contribution of inflammatory pathways to cervical cancer progression and HIV infection and the role of HIV in cervical cancer progression.

The Regulation of Inflammatory Pathways and Infectious Disease of the Cervix by Seminal Fluid

The connection between human papillomavirus (HPV) infection and the consequent sequelae which establishes cervical neoplastic transformation and invasive cervical cancer has redefined many aspects of cervical cancer research. However there is still much that we do not know. In particular, the impact of external factors, like seminal fluid in sexually active women, on pathways that regulate cervical inflammation and tumorigenesis, have yet to be fully understood. HPV infection is regarded as the initiating noninflammatory cause of the disease; however emerging evidence points to resident HPV infections as drivers of inflammatory pathways that play important roles in tumorigenesis as well as in the susceptibility to other infections such as human immunodeficiency virus (HIV) infection. Moreover there is emerging evidence to support a role for seminal fluid, in particular, the inflammatory bioactive lipids, and prostaglandins which are present in vast quantities in seminal fluid in regulating pathways that can exacerbate inflammation of the cervix, speed up tumorigenesis, and enhance susceptibility to HIV infection. This review will highlight some of our current knowledge of the role of seminal fluid as a potent driver of inflammatory and tumorigenic pathways in the cervix and will provide some evidence to propose a role for seminal plasma prostaglandins in HIV infection and AIDS-related cancer.

CCR5 expression is elevated in cervical cancer cells and is up-regulated by seminal plasma

The interplay between inflammation, cervical cancer and HIV acquisition in women is poorly understood. We have previously shown that seminal plasma (SP) can promote cervical tumour cell growth in vitro and in vivo via the activation of potent inflammatory pathways. In this study, we investigated whether SP could regulate expression of chemokine receptors with known roles in HIV infection, in the cervix and in cervical cancer. The expression of CD4 and CCR5 was investigated by RT-PCR analysis and immunohistochemistry. CD4 and CCR5 expression was elevated in cervical cancer tissue compared with normal cervix. Ex vivo studies conducted on cervical tissues and HeLa cells showed that SP significantly increases the expression of CD4 and CCR5 transcripts. Furthermore, it was found that SP also up-regulates CCR5 protein in HeLa cells. The regulation of CCR5 expression was investigated following treatment of HeLa cells with SP in the presence/absence of chemical inhibitors of intracellular signalling, EP2 and EP4 antagonists, prostaglandin (PG) E2 and a cyclooxygenase (COX)-1 doxycycline-inducible expression system. These experiments demonstrated that the regulation of CCR5 expression by SP occurs via the epidermal growth factor receptor (EGFR)-COX-1-PGE2 pathway. This study provides a link between activation of inflammatory pathways and regulation of HIV receptor expression in cervical cancer cells.

Seminal plasma induces the expression of IL-1α in normal and neoplastic cervical cells via EP2/EGFR/PI3K/AKT pathway

Background Cervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women. Exposure of neoplastic cervical epithelial cells to seminal plasma (SP) has been shown to promote the growth of cancer cells in vitro and tumors in vivo by inducing the expression of inflammatory mediators including pro-inflammatory cytokines. IL-1α is a pleotropic pro-inflammatory cytokine induced in several human cancers and has been associated with virulent tumor phenotype and poorer prognosis. Here we investigated the expression of IL-1α in cervical cancer, the role of SP in the regulation of IL-1α in neoplastic cervical epithelial cells and the molecular mechanism underlying this regulation. Methods and results Real-time quantitative RT-PCR confirmed the elevated expression of IL-1α mRNA in cervical squamous cell carcinoma and adenocarcinoma tissue explants, compared with normal cervix. Using immunohistochemistry, IL-1α was localized to the neoplastically transformed squamous, columnar and glandular epithelium in all cases of squamous cell carcinoma and adenocarcinomas explants studied. We found that SP induced the expression of IL-α in both normal and neoplastic cervical tissue explants. Employing HeLa (adenocarcinoma) cell line as a model system we identified PGE2 and EGF as possible ligands responsible for SP-mediated induction of IL-1α in these neoplastic cells. In addition, we showed that SP activates EP2/EGFR/PI3kinase-Akt signaling to induce IL-1α mRNA and protein expression. Furthermore, we demonstrate that in normal cervical tissue explants the induction of IL-1α by SP is via the activation of EP2/EGFR/PI3 kinase-Akt signaling. Conclusion SP-mediated induction of IL-1α in normal and neoplastic cervical epithelial cells suggests that SP may promote cervical inflammation as well as progression of cervical cancer in sexually active women.

Seminal Fluid-Mediated Inflammation in Physiology and Pathology of the Female Reproductive Tract

Inflammation is a multifaceted process involving a host of resident and recruited immune cells that eliminate the insult or injury and initiate tissue repair. In the female reproductive tract (FMRT), inflammation-mediated alterations in epithelial, vascular, and immune functions are important components of complex physiological processes and many local and systemic pathologies. It is well established that intracoital and postcoital function of seminal fluid (SF) goes beyond nutritive support for the spermatozoa cells. SF, in particular, the inflammatory bioactive lipids, and prostaglandins present in vast quantities in SF, have a role in localized immune modulation and regulation of pathways that can exacerbate inflammation in the FMRT. In sexually active women SF-mediated inflammation has been implicated in physiologic processes such as ovulation, implantation, and parturition while also enhancing tumorigenesis and susceptibility to infection. This review highlights the molecular mechanism by which SF regulates inflammatory pathways in the FMRT and how alterations in these pathways contribute to physiology and pathology of the female reproductive function. In addition, based on findings from TaqMan® 96-Well Plate Arrays, on neoplastic cervical cells treated with SF, we discuss new findings on the role of SF as a potent driver of inflammatory and tumorigenic pathways in the cervix.

Omics-based molecular techniques in oral pathology centred cancer: prospect and challenges in Africa

BackgroundThe completion of the human genome project and the accomplished milestones in the human proteome project; as well as the progress made so far in computational bioinformatics and “big data” processing have contributed immensely to individualized/personalized medicine in the developed world.Main bodyAt the dawn of precision medicine, various omics-based therapies and bioengineering can now be applied accurately for the diagnosis, prognosis, treatment, and risk stratification of cancer in a manner that was hitherto not thought possible. The widespread introduction of genomics and other omics-based approaches into the postgraduate training curriculum of diverse medical and dental specialties, including pathology has improved the proficiency of practitioners in the use of novel molecular signatures in patient management. In addition, intricate details about disease disparity among different human populations are beginning to emerge. This would facilitate the use of tailor-made novel theranostic methods based on emerging molecular evidences.ConclusionIn this review, we examined the challenges and prospects of using currently available omics-based technologies vis-à-vis oral pathology as well as prompt cancer diagnosis and treatment in a resource limited setting.

The physician-scientists: rare species in Africa

There is paucity of physician-scientists in Africa, resulting in overt dependence of clinical practice on research findings from advanced “first world” countries. Physician-scientists include individuals with a medical degree alone or combined with other advanced degrees (e.g. MD/MBChB and PhD) with a career path in biomedical/ translational and patient-oriented/evaluative science research. The paucity of clinically trained research scientists in Africa could result in dire consequences as exemplified in the recent Ebola virus epidemic in West Africa, where shortage of skilled clinical scientists, played a major role in disease progression and mortality. Here we contextualise the role of physician-scientist in health care management, highlight factors limiting the training of physician-scientist in Africa and proffer implementable recommendations to address these factors.

Practice of community-service doctors in the assessment and medico-legal documentation of common physical assault cases

Background: In South Africa, allegations of physical assault are managed primarily at the primary healthcare level, where they are attended to by medical officers or community service doctors (CSDs). However, reports that the knowledge and skills provided at undergraduate level are not sufficient to equip these CSDs to deal with evidence in medico-legal examinations in various settings, including in cases of patients who allege being the victims of common physical assault or assault with intent to inflict grievous bodily harm, have been documented in the literature. This study investigates the practice of CSDs in relation to the assessment and medico-legal documentation of allegations of common assault, with a view to identifying gaps in their knowledge of clinical forensic medicine. Method: The study was a cross-sectional descriptive study. A questionnaire with quantitative sections that used an adapted Likert scale was used to gather data. An electronic survey tool was employed to target 150 CSDs countrywide. Percentages are used to display results. Results: A response rate of 59.3% was achieved and results indicate that clinical forensic training in the undergraduate medical programme does not prepare CSDs sufficiently for the task of managing the medico-legal examination and documentation of allegations of assault by patients. Conclusions: The courts rely heavily on medico-legal documentation for success in criminal prosecution. Any substantial flaw in the documentation, including inadequate observations and/or notes made by a medical practitioner, may make proving guilt very difficult. This study revealed an important gap in the knowledge and practice of clinical forensic medicine by CSDs and suggests that the current curriculum should be adapted to allow adequate training of undergraduate medical students in the area of clinical forensic medicine. Appropriate undergraduate training will ensure that medico-legal documentation is completed accurately and that medical practitioners help ensure the administration of justice.

Medico-legal documentation of rape or sexual assault: are community-service doctors equipped for the task?

Abstract Background: Following upon two-year internship, community-service doctors make mistakes when they deal with evidence of medico-legal examinations in various settings. These mistakes result in alleged perpetrators being released by courts. This study investigated undergraduate clinical forensic medicine training, based on experiences and opinions of community-service doctors. This article focuses on incidents of alleged rape cases only. Methods: The study was a quantitative retrospective cohort study that made use of a questionnaire with an adapted Likert scale. An electronic survey tool was employed to target 150 community-service doctors throughout South Africa. Percentages are used to display results. Results: A response rate of 59.3% was achieved. Although 80% of the participants reported that they had undergraduate training on how to manage alleged rape or sexual assault cases, only 11.4% of the participants had hands-on exposure to an alleged rape case during their undergraduate training. In addition, the majority of the participants (77.1%) never had undergraduate training on how to complete the J88 form. These findings indicate that clinical forensic training in the undergraduate medical programme does not adequately prepare community-service doctors to meet the challenges of clinical forensic practice. The current curriculum should be adapted to address these shortcomings. Conclusions: Perpetrators cannot be convicted if evidence collected cannot stand up in court. Proper training of undergraduate medical students prior to their community-service posting will ensure that medico-legal documentation is completed correctly, leading to the presentation of credible evidence in a court of law in order to ensure successful conviction of alleged perpetrators.

Medico-legal aspects regarding drunk driving: experience and competency in practice of community service doctors

Abstract Background: Drunk driving has been reported to increase the risk of road traffic accidents associated with death and severe injury. In South Africa, an increase in blood alcohol concentration of as little as 0.01 g per 100 ml above the legal limit may warrant criminal prosecution or the denial of an insurance claim for damages. However, multiple court cases have been withdrawn because of the incompetence of officials at various stages of the investigation. The scope of the mistakes range from poor scene handling to the incorrect handling of blood samples at the laboratory to eventual laboratory testing of blood samples. Using a group of community service doctors (CSDs) as a cohort study group, this study investigated the competency of medical graduates in relation to the medico-legal aspects of drunk driving. Methods: A self-administered questionnaire-based study was done with 150 CSDs. The questionnaire was administered in Afrikaans and English and was dispatched electronically via e-mail. All potential participants were contacted telephonically to obtain verbal consent. Results are displayed as percentages. Results: A response rate of 59.3% was achieved. The results obtained in this study confirm that some CSDs lack competency in handling medico-legal aspects relating to drunk driving, and are thus unable to serve the communities they have been assigned to adequately. Their lack of skills and knowledge suggests that the present undergraduate Clinical Forensic Medicine curriculum is inadequate. Conclusion: It would be beneficial to revise the curriculum for Clinical Forensic Medicine in undergraduate medical training to address the gap in knowledge and practice of various demands of forensic medicine required from new medical graduates and CSDs.