Environmental Carcinogenesis: Characterization of Rising Incidence and Discovery of Novel Biomarkers of Pathogenesis and Prognosis.

This dissertation applied molecular epidemiology to address the relationship between the environment and cancer. The World Health Organization has identified cancer as the leading cause of death worldwide, and the International Agency for Research on Cancer shows the global burden of cancer lies primarily in low- and middle-income countries (LMICs). It is crucial to understand the effects of the surrounding environment on cancer incidence, induction and outcomes. The first objective of this dissertation was to characterize female breast cancer incidence trends in southern Thailand. Incidence rates of breast cancer increased by almost 300% from 1990 to 2010. Both period and birth cohort effects played a role in shaping the increase in incidence. Three distinct incidence projection methods consistently suggested that incidence rates will continue to increase in the future with incidence for women age 50 and above increasing at a higher rate than for women below 50. The findings from this study identify opportunities for breast cancer prevention and future research by identifying priorities for screening and developing hypotheses for population-based studies. Cadmium is a Class 1 carcinogen (IARC), however its mechanism of toxicity is unknown. My second objective was to determine epigenetic changes associated with this exposure. There are significant areas of environmental cadmium exposure in Thailand. Environmental cadmium exposure is associated with specific DNA methylation, and this relationship depended on the gender of the individual. Identification of these biomarkers of cadmium in a human population is a logical first step to identifying the mechanism of carcinogenesis. The relationship between environmental and epidemiologic factors and these changes is not well understood. Novel relationships were identified between methylation markers, survival and recurrence, and differed based upon etiologic environmental factors. Identification of these significant epigenetic markers should open new horizons for interventions directed at reversible gene alterations and new therapeutic targets. Overall, this research provides an understanding of the environmental contribution to cancer incidence, pathogenesis and prognosis. It offers a basis for future studies aimed at developing targeted interventions to address the rise in cancer incidence in Thailand, toxicity of environmental exposures and determining individualized treatment therapies to promote patient survival.PhDToxicologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108938/1/shamav_1.pd

Stability of methylation markers in head and neck squamous cell carcinoma

BackgroundAs cancer progresses, methylation patterns change to promote the tumorigenic phenotype. However, stability of methylation markers over time and the extent that biopsy samples are representative of larger tumor specimens are unknown. This information is critical for clinical use of such biomarkers.MethodsNinety‐eight patients with tumor specimens from 2 timepoints were measured for DNA methylation in the promoter regions across 4 genes.ResultsThere were no significant differences in overall methylation of CCNA1 (cyclin A1), NDN (necdin), deleted in colorectal carcinoma (DCC), and cluster of differentiation 1a (CD1A) within paired specimens (p values = .56, .17, .66, and .58, respectively). All genes showed strong correlations between paired specimens across time. Methylation was most consistent for CCNA1 and NDN over time.ConclusionThis report provides the first evidence that methylation markers measured in biopsy samples are representative of gene methylation in later specimens and suggests that biopsy markers could be representative biomarkers for use in defining personalized treatment utilizing epigenetic changes. © 2015 Wiley Periodicals, Head Neck 38: E1325–E1331, 2016Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/1/hed24223.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/2/hed24223_am.pd

Squamous cell carcinoma of the oral cavity, oropharynx, and larynx: a scoping review of treatment guidelines worldwide

Head and neck cancer (HNC) treatments have been based on single or multimodal therapies with surgery, radiotherapy (RT), chemotherapy, and immunotherapy. However, treatment recommendations among countries may differ due to technological/human resources and usual local practices. This scoping review aims to identify, compare, and map the clinical practice guidelines (CPGs) for treating squamous cell carcinoma (SCC) of the oral cavity, oropharynx, and larynx worldwide. A search strategy on global CPGs for HNC was performed by using five electronic databases and grey literature. CPGs were selected for inclusion using EndNote-20 and Rayyan online software. No language or publication date restrictions were applied. The results were analyzed descriptively considering the most updated CPG version. In total, 25 CPGs covering the head and neck region (10), the larynx (7), the oral cavity (5), and the oropharynx (3), were found in 13 geographical regions, and 19 were developed by medical societies from 1996 to 2023. Surgery and RT remain the main modalities for early-stage HNC, with surgery preferred in low-resource countries, and RT in selected cases, especially in the larynx/oropharynx aiming to achieve a cure with organ preservation. Human papillomavirus infection for oropharyngeal SCC is not tested in some Asian countries and there is still no consensus to treat p16-positive cases differently from p16-negative. Recommendations for larynx preservation vary according to facilities in each country, however, individualized choice is emphasized. Inequality across countries/continents is evident, with a similar pattern of recommendations among developed as well as developing ones. No CPGs were found in Latin America as well as Oceania countries, where the incidence of HNC is high and limitations of access to treatment may be encountered

Diagnostic Accuracy of HPV16 Early Antigen Serology For HPV-Driven Oropharyngeal Cancer is Independent of Age and Sex

Funding information: This project was funded in part by NIH/NIDCR R01 DE025712 (Paul Brennan, Brenda Diergaarde and Neil Hayes). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). We thank Dr. Wolfgang Ahrens, PhD (Universität Bremen, Germany) for his support in ARCAGE study. The Carolina Head and Neck Cancer Epidemiology (CHANCE) study was supported in part by the National Cancer Institute (R01-CA90731). The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The University of Pittsburgh head and neck cancer case-control study is supported by US National Institutes of Health grants P50CA097190 and P30CA047904. The MSH-PMH study was supported by Canadian Cancer Society Research Institute and Lusi Wong Programs at the Princess Margaret Hospital Foundation.Peer reviewedPublisher PD

INTERNATIONAL JOURNAL OF PURE AND APPLIED RESEARCH IN ENGINEERING AND TECHNOLOGY A PATH FOR HORIZING YOUR INNOVATIVE WORK HANDWRITING RECOGNITION USING NEURAL NETWORKS

Abstract This paper presents a simple learning rule for recognition of handwritten character on our computer screen using artificial neural network. Kohonen self organization map for pattern classification which employs unsupervised learning algorithm is used. One advantage of proposed scheme is that the system is quite tolerant to changing conditions and inputs. Here first the preprocessing is done of the images. These images are then trained using NN .The trained images are then used for classification and recognition

Age, period and cohort analysis of age-specific maternal mortality trend in Ethiopia: A secondary analysis.

BACKGROUND:Maternal mortality (MM) was persistently high for several decades in Ethiopia though it has declined in recent years. The roles of time-varying elements in this decrease are unknown. Analyzing MM with age-period-cohort analysis will provide evidence to policymakers to re-direct resources towards vulnerable age groups. The aim of this analysis was to determine the role of age effect, period effect and birth cohort effect on the trend of age-specific maternal mortality in Ethiopia. METHODS:Age-period-cohort (APC) analysis was applied to examine the effect of age, period and birth cohort on MM in Ethiopia using data from the Ethiopian Demographic and Health Survey (EDHS) from years 2000, 2005, 2011 and 2016. Age-specific maternal mortality rates were calculated using standardized maternal death compared to age-specific population per 100,000 woman-years of exposure and the trend was analyzed. RESULT:In most age groups, the MM rate decreased in 2015 compared with the previous years except for older women. According to the APC analysis, the age-cohort effect explains the MM rate better than age-period effect. The period effect shows the risk ratio of MM after 2005 decreased compared with before. The cohort effect illustrates women born after 1980 has lower risk ratio compared with the older one. CONCLUSION:Maternal mortality in Ethiopia declined overall in recent years. However, certain age groups still face high maternal mortality rates. A national policy on MM reduction interventions for the identified high-risk age groups is required

Trends in Incidence of Two Major Subtypes of Liver and Bile Duct Cancer: Hepatocellular Carcinoma and Cholangiocarcinoma in Songkhla, Southern Thailand, 1989-2030

Background. The incidence of liver and bile duct cancer continues to rise, especially in Thailand. We aimed to project the trends in incidence of this rare but lethal cancer in southern Thailand in order to determine its future disease burden. Methods. Gender-specific trends in age-standardized incidence rates per 100,000 person-years for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) cases in Songkhla province of southern Thailand diagnosed between 1989 and 2013 were estimated and projected up to year 2030 using three different modeling techniques: a joinpoint model, an age-period-cohort model, and a modified age-period-cohort model. Results. Of 2,676 liver and bile duct (LBD) cancer cases identified, 73% were males, 51% were aged between 50 and 69 years, and HCC (44.4%) was slightly more common than CCA (38.1%). The models all predicted an increase in the incidence rate of CCA up to 2025 for both sexes whereas the incidence of HCC is expected to decrease among males and stabilize among females. The incidence rates of HCC and CCA among males in 2030 could reach 6.7 and 9.4 per 100,000 person-years, respectively, whereas the expected rates of HCC and CCA among females are expected to be around 1.5 and 3.9 per 100,000 person-years, respectively. Conclusions. The incidence of cholangiocarcinoma is expected to increase in Songkhla and will contribute a larger proportion of LBD cancers in the future. Future public health efforts and research studies should focus on this increasing trend

Current and Future Burden of Prostate Cancer in Songkhla, Thailand: Analysis of Incidence and Mortality Trends From 1990 to 2030

Purpose: Prostate cancer is the second most common malignancy among men worldwide, and it poses a significant public health burden that has traditionally been limited mostly to developed countries. However, the burden of the disease is expected to increase, affecting developing countries, including Thailand. We undertook an analysis to investigate current and future trends of prostate cancer in the province of Songkhla, Thailand, using data from the Songkhla Cancer Registry from 1990 to 2013. Methods: Joinpoint regression analysis was used to examine trends in age-adjusted incidence and mortality rates of prostate cancer and provide estimated annual percent change (EAPC) with 95% CIs. Age-period-cohort (APC) models were used to assess the effect of age, calendar year, and birth cohort on incidence and mortality rates. Three different methods (Joinpoint, Nordpred, and APC) were used to project trends from 2013 to 2030. Results: Eight hundred fifty-five cases of prostate cancer were diagnosed from 1990 to 2013 in Songkhla, Thailand. The incidence rates of prostate cancer significantly increased since 1990 at an EAPC of 4.8% (95% CI, 3.6% to 5.9%). Similarly, mortality rates increased at an EAPC of 5.3% (95% CI, 3.4% to 7.2%). The APC models suggest that birth cohort is the most important factor driving the increased incidence and mortality rates of prostate cancer. Future incidence and mortality of prostate cancer are projected to continue to increase, doubling the rates observed in 2013 by 2030. Conclusion: It is critical to allocate resources to provide care for the men who will be affected by this increase in prostate cancer incidence in Songkhla, Thailand, and to design context-appropriate interventions to prevent its increasing burden

Delivery type not associated with global methylation at birth

<p><b>Abstract</b></p> <p><b>Background</b></p> <p>Birth by cesarean delivery (CD) as opposed to vaginal delivery (VD) is associated with altered health outcomes later in life, including respiratory disorders, allergies and risk of developing type I diabetes. Epigenetic gene regulation is a proposed mechanism by which early life exposures affect later health outcomes. Previously, type of delivery has been found to be associated with differences in global methylation levels, but the sample sizes have been small. We measured global methylation in a large birth cohort to identify whether type of delivery is associated with epigenetic changes.</p> <p><b>Methods</b></p> <p>DNA was isolated from cord blood collected from the University of Michigan Women’s & Children Hospital and bisulfite-converted. The Luminometric Methylation Assay (LUMA) and LINE-1 methylation assay were run on all samples in duplicate.</p> <p><b>Results</b></p> <p>Global methylation data at CCGG sites throughout the genome, as measured by LUMA, were available from 392 births (52% male; 65% CD), and quantitative methylation levels at LINE-1 repetitive elements were available for 407 births (52% male; 64% CD). LUMA and LINE-1 methylation measurements were negatively correlated in this population (Spearman’s r = −0.13, <it>p</it> =0.01). LUMA measurements were significantly lower for total CD and planned CD, but not emergency CD when compared to VD (median VD = 74.8, median total CD = 74.4, <it>p</it> = 0.03; median planned CD = 74.2, <it>p</it> = 0.02; median emergency CD = 75.3, <it>p</it> = 0.39). However, this association did not persist when adjusting for maternal age, maternal smoking and infant gender. Furthermore, total CD deliveries, planned CD and emergency CD deliveries were not associated with LINE-1 measurements as compared to VD (median VD = 82.2, median total CD = 81.9, <it>p</it> = 0.19; median planned CD = 81.9, <it>p</it> = 0.19; median emergency CD = 82.1, <it>p</it> = 0.52). This lack of association held when adjusting for maternal age, maternal smoking and infant gender in a multivariable model.</p> <p><b>Conclusions</b></p> <p>Type of delivery was not associated with global methylation in our population, even after adjustment for maternal age, maternal smoking, and infant gender. While type of birth may be associated with later health outcomes, our data suggest that it does not do so through changes in global genomic methylation.</p