BACKGROUND: Elucidation of candidate colorectal cancer biomarkers often begins by comparing the expression profiles of cancerous and normal tissue by performing high throughput gene expression profiling. While many such studies have been performed, the resulting lists of differentially expressed genes tend to be inconsistent with each other, suggesting that there are some false positives and negatives. One logical solution to this problem is to determine the intersection of the lists of differentially expressed genes from independent studies. It is expected that genes that are biologically relevant to cancer tumorigenesis will be reported most often, while sporadically reported genes are due to the inherent biases and limitations of each of the profiling platforms used. However, the statistical significance of the observed intersection among many independent studies is usually not considered. PURPOSE: To address these issues, we developed a computational meta-analysis method that ranked differentially expressed genes based on the following criteria, which are presented in order of importance: the amount of intersection among studies, total tissue sample sizes, and average fold change in expression. We applied this meta-analysis method to 25 independent colorectal cancer profiling studies that compared cancer versus normal, adenoma versus normal, and cancer versus adenoma tissues. RESULTS: We observed that some genes were consistently reported as differentially expressed with a statistically significant frequency (P <.0001) in the cancer versus normal and adenoma versus normal comparisons, but not in the cancer versus adenoma comparison. We performed a review of some of the high ranking candidates and determined that some have previously been shown to have diagnostic and/or prognostic utility in colorectal cancer. More interestingly, the meta-analysis method also identified genes that had yet to be tested and validated as biomarkers. Thus, these candidates are currently being validated at the protein level on colorectal tissue microarrays. CONCLUSION: Our meta-analysis method identified genes that were consistently reported as differentially expressed. Besides identifying new biomarker candidates, our meta-analysis method also provides another filter to remove false positive genes from further consideration. In conclusion, the genes presented here will aid in the identification of highly sensitive and specific biomarkers in colorectal cancer.

In immature Jurassic shales of differing depositional environment from Great Britain (Ro<0.5) the C₃₂ hopane and C₂₉ sterane isomerisation provide an accurate indication of relative maturities. For mature Viking Graben samples (Ro>0.7) a reliable indication of relative maturity is gained if Tmax, Ts(Ts+Tm), C₂₉ββ/(ββ+αα) steranes and the Triaromatic Index are considered together. The most reliable parameters for the determination of depositional redox are pristane/phytane and the C₃₅/C₃₄ homohopane ratio, together with the concentrations of V, Cu, Ni and Mo. In the brackish lagoon of the Brora Coal Formation (BCF) low sulphate availability does not appear to have limited the pyritisation of iron relative to the open marine facies of the Brora Argillaceous Formation (BAF). Despite this δ³⁴Spyrite for BCF samples indicates that sulphate reduction took place in a closed system due to the rapid depletion of available sulphate. Only low concentrations of excess H₂S were available for incorporation within the organic matter, organic sulphur abundances in the BCF being much lower than for the BAF. In open-marine sequences an increase in TOC is associated with an increase in anoxia, the preservation of hydrogen-rich organic matter and the abundance of organic sulphur. A generally correlated increase in pyrite sulphur suggests both these modes of sulphur are associated with increasing concentrations of diagenetic sulphides (H₂S and its partial oxidation products) generated through bacterial sulphate reduction. The greatest abundances of organic sulphur are formed when sulphide concentrations are high whilst sub-oxic surficial sediments are maintained so that polysulphides are generated within the sediment (by partial oxidation of H₂S) for rapid sulphur incorporation. Improved preservation of labile organic matter leads to a increase in the abundance of organic compounds (e.g. sterenes and phytol derivatives) in which suitable functionalities exist for sulphur incorporation.

The aims of this project were to investigate the cellular stress response (CSR) in Enteromorpha spp. and assess the potential of the Stress-70 protein (an indicator of the CSR) as a biomarker of pollutant exposure and acquired tolerance in Enteromorpha spp., compared with conventional physiological endpoints of toxicity. Cross-reactivity of a commercial Stress-70 antibody with E. intestinalis proteins was determined and used to develop an assay for Stress-70. Using this assay E. intestinalis was found to exhibit a typical heat shock response. Stress-70 proved to be a relatively insensitive biomarker of copper exposure and did not appear to be involved in copper tolerance, the genetic basis of which was investigated by growing E. intestinalis using a novel culturing technique. Although growth was variable, it provided a simple, consistent and sensitive measure of copper toxicity. The chlorophyll fluorescence parameter Fv/Fm was insensitive to copper exposure. Nutrient limitation enhanced copper toxicity and significantly impaired growth, Fv/Fm and Stress-70 production in E. intestinalis. In both copper ‘sensitive’ and ‘tolerant’ E. intestinalis, copper exposure did not affect the ability to raise a heat shock response. In ‘sensitive’ algae, copper and heat shock were additive stressors, with heat shock acting as a stronger inducer of Stress-70. Only heat shock affected 'tolerant' algae. Zinc was less toxic than copper but in contrast to copper studies, Stress-70 was a relatively sensitive indicator of zinc exposure, compared to Fv/Fm and growth. Studies of triazine herbicides revealed that on a molarity basis, Irgarol 1051 was more toxic to E. intestinalis than atrazine. Fv/Fm and growth were strongly affected by Irgarol exposure, but Stress-70 levels were unaltered by exposure to the herbicide. Fv/Fm and Stress-70 were poor in situ biomarkers of pollution, but another chlorophyll fluorescence parameter - complementary area - appeared to correlate with levels of organic pollution. Overall, Stress-70 was found not to be a useful biomarker of exposure to copper or triazines in E. intestinalis, or in situ pollution. However, the Stress-70 assay developed has a number of alternative applications and Enteromorpha spp. were deemed to be potentially useful in pollution monitoring with the selection of suitable biomarker responses.

Biological markers (“biomarkers”) may have applications in inflammatory bowel disease (IBD), a chronic disease of the gastrointestinal tract. Clinicians are presented with several challenges when treating IBD. Instead of performing expensive and invasive endoscopic procedures - if even possible, as resources for these procedures can be limited - biomarkers could be used to diagnose, assess disease activity and prognosis, and guide medical therapy, particularly in situations where novel biologics are involved. At this time, the use of biomarkers is limited, since few have been useful in predicting disease severity, prognosis and therapeutic response in IBD. Previous research cohorts studying biomarkers are limited due to varying heterogeneity between subjects that confounds the results since patients have variable disease courses. The main aim of this work was to evaluate the utility of biomarkers in IBD. To do this, biomarkers were included into a composite score with other patient reported outcomes (PRO) to predict endoscopic disease activity. Next, we examined the role of biomarkers in newly diagnosed IBD. Lastly, fecal calprotectin (FC) was evaluated in healthy pregnant and IBD patients, establishing reference values and practicality in this clinical group. We also studied the relationship between biomarkers and environmental factors, such as fecal microbiota. We hypothesized biomarker concentration would be elevated with increased clinical and endoscopic measures, and predictive of response to medical therapy in newly diagnosed patients. Additionally, we theorized the inclusion of biomarkers into composite scores would outperform existing scoring models in predicting endoscopic severity. Furthermore, FC levels would be below the limit of detection in healthy pregnancy and elevated in IBD pregnancy. The inclusion of biomarkers into composite scoring models outperformed existing clinical scores. In newly diagnosed patients, modest relationships were found between biomarkers and clinical and endoscopic markers of disease. Lastly, the presence of FC was elevated in pregnant IBD and not significant in healthy pregnancy; thus, FC is useful in IBD and pregnancy. Our work confirmed the significance of biomarkers in several clinical areas of IBD, along with the issues presented in recruiting newly diagnosed patients in small research centres. Future work will incorporate biomarkers into medical triage and as an endpoint in nutritional interventions.

<b>Background and objectives.</b> Knee osteoarthritis (KOA) is a leading cause of disability in the developed world. Additionally, it is possibly linked with premature mortality. Low-grade inflammation is associated with a high risk of non-traumatic KOA incidence but also with metabolic syndrome. Knee injury is a major risk factor for KOA and is associated with an inflammatory response. Heterogeneity of both the symptoms and progression makes early identification of individuals at risk difficult. The aim of this thesis was to examine the diagnostic value of selected biomarkers to identify microscopic synovitis, examine their predictive value for KOA development and any association with excess premature mortality. <b>Methods.</b> Four serum biomarkers, COMP, resistin, C3M and CRPM, all linked with both knee pain and synovial or systemic inflammation, were selected and an additional sonographic marker was tested. Data from two cohorts has been utilised for the purpose of this thesis: the Oxford Knee Injury Cohort, a prospective study of NHS patients with recent ACL and/or meniscal injuries, and the Chingford women's study, a community-based prospective cohort with over 23 years of follow-up. <b>Results.</b> Cross-sectionally, sonographic markers correspond well with microscopically defined post-traumatic synovitis. Two biomarkers, COMP and resistin, were associated with development of incident radiographic KOA (RKOA), while two others, C3M and CRPM, predicted development of painful RKOA independently to age and BMI. High C3M levels and presence of painful RKOA were associated with premature mortality. Knee pain alone, especially in presence of RKOA was an independent predictor of mortality, but RKOA without pain was not. <b>Conclusion.</b> These results support the use of the studied biomarkers in complex predictive models for development of KOA and associated premature mortality. Taking the competing risk of death into account is an important consideration in this field.

Des marqueurs pleuraux pouvant discriminer les pleurésies bénignes et malignes sont nécessaires. Parmi les possibles biomarqueurs, les microparticules (MPs) ont été décrites dans les compartiments biologiques humains ; mais peu de données existent sur leur existence dans le liquide pleural. Etant donné que les cellules tumorales produisent un grand nombre de MPs, nous avons fait l’hypothèse de la présence de MPs tumoraux (TMPs) dans les pleurésies et de leur implication dans la carcinogénèse.Donc, pour la première fois nous avons montré de nombreuses MPs pleurales produites par des cellules normales et malignes et nous avons caractérisé leur cellule d’origine.De plus, nous avons montré des TMPs pleurales exprimant l’antigène EpCAM : ce travail donne les bases pour l’utilisation de ce prometteur biomarqueur pour classifier les pleurésies. Nous avons décrit des cas cliniques de patients avec cytologie négative, mais positifs à la présence de MPs pleurales EpCAM+ : donc, les MPs EpCAM+ peuvent être un outil complémentaire à la cytologie, pour améliorer le diagnostic des MPEs. Ce travail ouvre aussi de nouvelles perspectives pour un monitorage mini-invasif et pour une médecine personnalisée avec une cible EpCAM.Etant donné que les TMPs ont de nombreuses activités, il est possible que les MPs EpCAM+ jouent un rôle majeur dans la carcinogenèse au niveau du microenvironnement pleural.Ces résultats donnent les bases pour la détection des TMPs par cytométrie en flux comme possibles biomarqueurs non-invasif pour la classification des épanchements pleuraux. / Pleural biomarkers which could discriminate benign and malignant pleural effusion are needed.Among candidate biomarkers, microparticles (MPs), have been reported in human body fluids, but little is known about their existence in pleural fluid. Because tumor cells produce high numbers of MPs, we hypothesized the presence of tumor-derived MPs (TMP) in pleuresy and their involvement in carcinogenesis.Therefore, for the first time, we report the presence of high amounts of MPs originating from normal and malignant cells in pleural fluids, and we characterizes their cellular origin. Moreover, we showed pleural TMPs expressing the EpCAM antigen from carcinoma patients : this work establishes the basis for using this promising biomarker to distinguish benign and MPE. We showed clinical cases of cancer patients, negative at cytology, but positive for pleural EpCAM+MPs : thus, EpCAM+MPs may be considered as a complementary tool with the cytology to classify pleurisies. This work also opens new directions about mini-invasive monitoring and personalized medicine targeting EpCAM. Since TMPs also carry various features and genetic signatures implicated in malignacy, it can be assumed that EpCAM+MPs could behave as relevant players of carcinogenesis in the pleural microenvironment. Although the sensitivity and specificity of a diagnosis by TMPs should be established in larger multicenter cohorts, this study establishes the basis for the detection of TMPs by flow cytometry as potential biomarkers for the classification of pleural effusions.

No description available.

BACKGROUND: Elucidation of candidate colorectal cancer biomarkers often begins by comparing the expression profiles of cancerous and normal tissue by performing high throughput gene expression profiling. While many such studies have been performed, the resulting lists of differentially expressed genes tend to be inconsistent with each other, suggesting that there are some false positives and negatives. One logical solution to this problem is to determine the intersection of the lists of differentially expressed genes from independent studies. It is expected that genes that are biologically relevant to cancer tumorigenesis will be reported most often, while sporadically reported genes are due to the inherent biases and limitations of each of the profiling platforms used. However, the statistical significance of the observed intersection among many independent studies is usually not considered. PURPOSE: To address these issues, we developed a computational meta-analysis method that ranked differentially expressed genes based on the following criteria, which are presented in order of importance: the amount of intersection among studies, total tissue sample sizes, and average fold change in expression. We applied this meta-analysis method to 25 independent colorectal cancer profiling studies that compared cancer versus normal, adenoma versus normal, and cancer versus adenoma tissues. RESULTS: We observed that some genes were consistently reported as differentially expressed with a statistically significant frequency (P <.0001) in the cancer versus normal and adenoma versus normal comparisons, but not in the cancer versus adenoma comparison. We performed a review of some of the high ranking candidates and determined that some have previously been shown to have diagnostic and/or prognostic utility in colorectal cancer. More interestingly, the meta-analysis method also identified genes that had yet to be tested and validated as biomarkers. Thus, these candidates are currently being validated at the protein level on colorectal tissue microarrays. CONCLUSION: Our meta-analysis method identified genes that were consistently reported as differentially expressed. Besides identifying new biomarker candidates, our meta-analysis method also provides another filter to remove false positive genes from further consideration. In conclusion, the genes presented here will aid in the identification of highly sensitive and specific biomarkers in colorectal cancer. / Science, Faculty of / Graduate

Introduction with Hypothesis/Objective: Management of long-term conditions requires a holistic approach, which places equal emphasis on the biomedical and the psychosocial. In chronic kidney disease (CKD), whilst biochemical and haematological parameters are routinely measured in accordance with UK Renal Association Standards and Guidelines this is not the case for health-related quality of life (HRQoL).There is evidence that achieving Renal Association biochemical/haematological targets improves mortality & morbidity. However, little evidence is available on whether achieving these targets enhances health-related quality of life (HRQoL). This study’s primary aim was, therefore, to determine whether there was any association between the extent to which patients achieved Renal Association biochemical and haematological targets and their HRQoL. A secondary aim was to explore the association between demographic and other treatment-related factors and HRQoL.Methods: A cross-sectional postal survey was conducted, involving 301 adult maintenance haemodialysis patients (age 18 + yrs.) in North-west England. HRQoL data were collected using the KDQoL-SF and patient records were searched for demographic variables and key biochemical/haematological markers derived from the UK Renal Association Standards and Guidelines. Biomarker achievement was categorised as ‘low achievers’ (patients who reached 0 – 2 Renal Association targets), ’medium achievers’ (3 – 5 targets) and ‘high achievers’ (6 – 8 targets). Data were initially analysed descriptively then using univariate and multivariate (multiple regression) analysis. Results: Participants were older (mean age 63.4 years), mostly male (64.0%) and predominantly white (87.0%); they had been on HD for a mean of 42.0 months (median 28.0). Patients typically had low scores for most aspects of HRQoL. For Renal Association targets, 5.6 % of the sample were ‘low achievers’, 57.1% ‘medium achievers’ and 35.2% ‘high achievers’. Apart from the KDQoL-SF subscale of symptom/problem list (medium achievers p<0.012, high achievers p<0.009), there was no association between HRQoL and the level of RA biomarkers achieved. Being Asian was negatively associated with several KDQoL-SF subscales. Increased age was positively associated with many subscales, suggesting a better toleration of poor health in older patients. The individual biomarker albumin was negatively associated with a number of the KDQoL subscales. Conclusion: The study’s findings demonstrate little association between achievement of Renal Association biochemical/haematological targets and HRQoL. A more holistic approach is required to address other aspects of physical and psychological health. Guidelines are needed that contain recommendations for routine monitoring of HRQoL scores. There is a need for better recognition of HRQoL as a specific treatment goal.

This study examined the acute and chronic responses of brain-derived neurotrophic factor (BDNF), cathepsin B (CatB), insulin-like growth factor-1 (IGF-1), and interleukin-6 (IL-6) and if changes in these biomarkers were correlated during resistance training. Fourteen resistance trained men performed resistance training 3 days per week for 6 weeks in two groups. The only difference between groups was the proximity to failure of each set (4-6 repetitions in reserve or 1-3 repetitions in reserve). Serum was collected immediately before and after training on day 1 of weeks 1 and 6. There were no significant group interactions for any of the biomarkers assessed, there were no main effects for time (p>0.05), and no significant correlations were observed between any of the biomarkers. However, a significant main effect for exercise for BDNF (p=0.03) and IL-6 (p=0.003) was observed. For CatB, a significant exercise × time (p=0.002) interaction was observed, indicating differences in the acute change of CatB in week 6 (+15.78%; g=0.25) vs. week 1 (-7.46%; g=0.13). In summary, these results suggest that multi-joint resistance exercise far from failure can confer a BDNF response. This investigation is the first to demonstrate the potential for acute resistance exercise to elicit a transient increase in CatB. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection