Background: Carcinoma of uterine cervix is the second most common cancers among women worldwide. Combined radiation and chemotherapy is the choice of treatment for advanced stages of the disease. The prognosis is poor, with a five-year survival rate ranging from about 20-65%, depending on stage of the disease. Therefore, genetic characterization is essential for understanding the biology and clinical heterogeneity in cervical cancer (CC).

BackgroundCervical cancer (CC), a leading cause of cancer-related deaths in women worldwide, has been causally linked to genital human papillomavirus (HPV) infection. Although a host of genetic alterations have been identified, molecular basis of CC development is still poorly understood.ResultsWe examined the role of promoter hypermethylation, an epigenetic alteration that is associated with the silencing tumor suppressor genes in human cancer, by studying 16 gene promoters in 90 CC cases. We found a high frequency of promoter methylation in CDH1, DAPK, RARB, and HIC1 genes. Correlation of promoter methylation with clinical characteristics and other genetic changes revealed the following: a) overall promoter methylation was higher in more advanced stage of the disease, b) promoter methylation of RARB and BRCA1 predicted worse prognosis, and c) the HIC1 promoter methylation was frequently seen in association with microsatellite instability. Promoter methylation was associated with gene silencing in CC cell lines. Treatment with methylation or histone deacetylation-inhibiting agents resulted in profound reactivation of gene expression.ConclusionsThese results may have implications in understanding the underlying epigenetic mechanisms in CC development, provide prognostic indicators, and identify important gene targets for treatment.

This manuscript details the strategy employed for categorising food items based on their processing levels into the four NOVA groups. Semi-quantitative food frequency questionnaires (FFQs) from the Nurses’ Health Studies (NHS) I and II, the Health Professionals Follow-up Study (HPFS) and the Growing Up Today Studies (GUTS) I and II cohorts were used. The four-stage approach included: (i) the creation of a complete food list from the FFQs; (ii) assignment of food items to a NOVA group by three researchers; (iii) checking for consensus in categorisation and shortlisting discordant food items; (iv) discussions with experts and use of additional resources (research dieticians, cohort-specific documents, online grocery store scans) to guide the final categorisation of the short-listed items. At stage 1, 205 and 315 food items were compiled from the NHS and HPFS, and the GUTS FFQs, respectively. Over 70 % of food items from all cohorts were assigned to a NOVA group after stage 2. The remainder were shortlisted for further discussion (stage 3). After two rounds of reviews at stage 4, 95⋅6 % of food items (NHS + HPFS) and 90⋅7 % items (GUTS) were categorised. The remaining products were assigned to a non-ultra-processed food group (primary categorisation) and flagged for sensitivity analyses at which point they would be categorised as ultra-processed. Of all items in the food lists, 36⋅1 % in the NHS and HPFS cohorts and 43⋅5 % in the GUTS cohorts were identified as ultra-processed. Future work is needed to validate this approach. Documentation and discussions of alternative approaches for categorisation are encouraged.

Introductory note by Alfredo MorabiaThis article closes the series of contributions on the history of epidemiologic methods and concepts. It traces, in some epidemiology textbooks published in the 20 th century, the evolution of the way five main topics have been taught: study designs (cohort studies and case-control studies), confounding, bias, interaction, and causal inference. These correspond to the topics covered by the other papers in the series. The only exception is the concept of interaction, for which I had not been able to find an author. This final paper has been sent to review and/or comment to all the living authors of the textbooks. Three authors opted for commentaries which are also published in this issue of Social and Preventive Medicine and two for reviews. Our publisher, Birkhäuser, has been kind enough to let us post the pdfs of all these papers on the website: www.epidemiology.ch (choose history). A revised version of these papers accompanied by a substantial introduction, pooled bibliography and index will appear in 2004 as a book entitled "The history of epidemiological methods and concepts" (Birkhäuser). SummaryTextbooks are an expression of the state of development of a discipline at a given moment in time. By reviewing eight epidemiology textbooks published over the course of a century, we have attempted to trace the evolution of five epidemiologic concepts and methods: study design (cohort studies and case-control studies), confounding, bias, interaction and causal inference. Overall, these eight textbooks can be grouped into three generations. Greenwood (1935) Miettinen (1985) and Rothman (1986)'s textbooks belong to a third generation, "modern epidemiology", presenting an integrated perspective on study designs and their measures of outcome, as well as distinguishing and formalizing the concepts of confounding and interaction. Our review demonstrates that epidemiology, as a scientific discipline, is in constant evolution and transformation. It is likely that new methodological tools, able to assess the complexity of the causes of human health, will be proposed in future generations of textbooks.