Colorectal cancer risk, screening and treatment: using epidemiological approaches to inform better understanding in cancer control

Colorectal cancer (CRC) is a major public health problem worldwide. Reducing the burden of CRC requires a multi-faceted approach centred on the domains of prevention, screening and treatment. This thesis aims to use various epidemiological approaches to improve current understanding of CRC control. In the first section, a systematic review and meta-analysis of molecular characteristics in serrated polyposis syndrome found that multiple molecular pathways may be implicated in the pathogenesis of this syndrome. The findings form the basis of a potential panel of molecular markers which may be used to guide further studies. In the second section, I examined various aspects of colorectal cancer screening using linked data from large cohort studies. I reported on the level of ever-screening in Australia, either through Australia’s National Bowel Cancer Screening Program or via opportunistic screening. I found that factors associated with non-participation in any CRC screening were smoking, socioeconomic disadvantage and language barriers, whereas family history of CRC was associated with out-of-program screening. I demonstrated the feasibility and validity of using linked hospital data to capture records of colonoscopies performed in the Bowel Cancer Screening Programme in England. Using linked hospital data, I then showed that those who had abnormal screening test had a substantially increased risk of CRC, that conditions other CRC are also associated with a positive screening test, and that examination of linked health records may help to characterise reasons for non-attendance at follow-up colonoscopies. In the last section, data collected in a population-based cancer registry was linked to data from a multi-centre prospective study to investigate whether CRC treatment varied according to the microsatellite instability (MSI) of the tumour. It found that although MSI influenced treatment decisions in younger patients, other prognostic markers such as age and tumour location were independent predictors of treatment. Collectively, this thesis demonstrates that different epidemiological approaches may be used to enhance our understanding of CRC. It showcases how the integration of clinical and molecular information through data linkage may enable researchers to investigate determinants of healthcare access, evaluate outcomes from population-based screening programs and monitor treatment patterns in response to emerging evidence

Using meta-research methods to examine the inclusion of women, pregnant women, and women-specific health outcomes in studies that contributed to the dietary reference intakes for one-carbon metabolism micronutrients

Purpose: Maternal micronutrient deficiencies occurring during periconceptional, pregnancy, and postpartum periods are a leading cause of adverse pregnancy outcomes globally. The Dietary Reference Intakes (DRIs) are a set of reference values used to assess and guide nutrient intakes of healthy individuals. However, the current DRIs for pregnancy and lactation may be limited in their methods and included populations. The present study analyzed the current DRIs for their inclusion of pregnant women and geographic representativeness. Methods: Meta-research methods were applied to the DRI report for vitamins B6, B12, folate, and choline in four steps: search, screening, full-text data extraction, and data analysis. For each target micronutrient, sections that contributed data to setting the average requirement were focused on, “Selection of Indicators for Estimating the Requirement,” “Findings by Life Stage and Gender Group,” and “Tolerable Upper Intake Limit” for adults, pregnancy, and lactation sub-sections. Screening involved reviewing the reference list to determine whether a reference directly contributed to setting the DRI. Full-text data extraction of primary data was conducted in areas of: 1) administrative information; 2) study methods; 3) human population characteristics; and 4) non-human subjects. Descriptive analyses were performed to describe the inclusion of women, pregnant women, geographic patterns, and demographic diversity. Results: For Vitamin B12, 100% of indicator studies and 71% of life stages studies included women, with a total of 3,246 women participants. However, none of the indicator studies and 15% of life stages studies included pregnant women, with a total of 556 pregnant women participants. None of the indicator studies and 8% of life stages studies reported health measurements specific to women, pregnancy, or lactation. Geographically, 54% of studies were conducted in the United States, and 18% took place in low-and middle-income countries. Data analysis is ongoing for the remaining micronutrients. Conclusions: Preliminary findings indicate that the body of evidence informing the current DRIs are limited in their inclusion of women and pregnant women. Numerous adverse pregnancy and birth outcomes are preventable through optimal maternal nutrition. Therefore, it is critical to ensure that the DRIs are suitable for their intended population. Despite their original intent for use in North America, the DRIs are widely adopted globally. Thus, geographic representation of the studies underlying the DRIs have implications for generalizability

NCP activates chloroplast transcription by controlling phytochrome-dependent dual nuclear and plastidial switches.

Phytochromes initiate chloroplast biogenesis by activating genes encoding the photosynthetic apparatus, including photosynthesis-associated plastid-encoded genes (PhAPGs). PhAPGs are transcribed by a bacterial-type RNA polymerase (PEP), but how phytochromes in the nucleus activate chloroplast gene expression remains enigmatic. We report here a forward genetic screen in Arabidopsis that identified NUCLEAR CONTROL OF PEP ACTIVITY (NCP) as a necessary component of phytochrome signaling for PhAPG activation. NCP is dual-targeted to plastids and the nucleus. While nuclear NCP mediates the degradation of two repressors of chloroplast biogenesis, PIF1 and PIF3, NCP in plastids promotes the assembly of the PEP complex for PhAPG transcription. NCP and its paralog RCB are non-catalytic thioredoxin-like proteins that diverged in seed plants to adopt nonredundant functions in phytochrome signaling. These results support a model in which phytochromes control PhAPG expression through light-dependent double nuclear and plastidial switches that are linked by evolutionarily conserved and dual-localized regulatory proteins

Chronic Cavitary Pulmonary Aspergillosis: An Unusual Cause of Chronic Cough, Pleuritic Chest Pain, and Hemoptysis in a 24-Year-Old Coal Mine Worker

Pulmonary Aspergillus infections are caused by the ubiquitous fungus mold when spores found in compost, dust, and plant material are inhaled. Manifestation of the disease is represented by a delicate balance between host and pathogen interactions, making Aspergillus infection more commonly observed in immunocompromised individuals. Chronic cavitary pulmonary aspergillosis (CCPA) is a subtype of pulmonary Aspergillosis associated with history of chronic or prior lung disease. Here we present the case of a non-immunocompromised 24-year-old male with a history of intermittent asthma with chronic pulmonary symptoms and finding of a lung mass on imaging. We describe the diagnostic challenge and surgical treatment of CCPA in medically refractory disease

4-Bromo-N-phenyl­aniline

In the title compound, C12H10BrN, the dihedral angle between the benzene rings is 52.5 (1)°, whereas the pitch angles, or the angles between the mean plane of each aryl group ‘propeller blade’ and the plane defined by the aryl bridging C—N—C angle, are 19.6 (2) and 36.2 (3)°. While the N—H group is not involved in hydrogen-bonding inter­actions, the structure exhibits a network of inter­molecular C—H⋯π and N—H⋯π inter­actions

DDI-CPI, a server that predicts drug–drug interactions through implementing the chemical–protein interactome

Drug–drug interactions (DDIs) may cause serious side-effects that draw great attention from both academia and industry. Since some DDIs are mediated by unexpected drug–human protein interactions, it is reasonable to analyze the chemical–protein interactome (CPI) profiles of the drugs to predict their DDIs. Here we introduce the DDI-CPI server, which can make real-time DDI predictions based only on molecular structure. When the user submits a molecule, the server will dock user's molecule across 611 human proteins, generating a CPI profile that can be used as a feature vector for the pre-constructed prediction model. It can suggest potential DDIs between the user's molecule and our library of 2515 drug molecules. In cross-validation and independent validation, the server achieved an AUC greater than 0.85. Additionally, by investigating the CPI profiles of predicted DDI, users can explore the PK/PD proteins that might be involved in a particular DDI. A 3D visualization of the drug-protein interaction will be provided as well. The DDI-CPI is freely accessible at http://cpi.bio-x.cn/ddi/