On defining partition entropy by inequalities

Partition entropy is the numerical metric of uncertainty within a partition of a finite set, while conditional entropy measures the degree of difficulty in predicting a decision partition when a condition partition is provided. Since two direct methods exist for defining conditional entropy based on its partition entropy, the inequality postulates of monotonicity, which conditional entropy satisfies, are actually additional constraints on its entropy. Thus, in this paper partition entropy is defined as a function of probability distribution, satisfying all the inequalities of not only partition entropy itself but also its conditional counterpart. These inequality postulates formalize the intuitive understandings of uncertainty contained in partitions of finite sets.We study the relationships between these inequalities, and reduce the redundancies among them. According to two different definitions of conditional entropy from its partition entropy, the convenient and unified checking conditions for any partition entropy are presented, respectively. These properties generalize and illuminate the common nature of all partition entropies

Evaluating the role of neurotensin and its receptors in colorectal cancers and polyps

Importance Colorectal Cancer (CRC) accounts for 9% of cancer deaths globally. The clinical role of hormones is well established in some cancers but remains unclear in CRC. Neurotensin (NTS) and its receptors 1 and 3 (NTSR1 and NTSR3) are implicated in CRC carcinogenesis and growth. This thesis hypothesises that NTS and its receptors have the potential to be used as novel diagnostic and prognostic biomarkers for CRC. Such biomarkers could improve early detection and risk stratification of CRC. Furthermore, it could allow the personalisation of CRC treatment through novel therapeutic pathways. Objectives The up to date evidence for the role NTS plays in CRC is systematically reviewed. Two studies were then carried out to test the hypothesis. Firstly, the accuracy of plasma NTS concentration as a diagnostic biomarker for colorectal polyp and cancer is assessed. The second study characterised and quantified the protein expression of NTS, NTSR1 and NTSR3 in human CRC specimens. It then evaluated the association between NTS, NTSR1 and NTSR3 expression, histological grade of CRC and cancer survival. Design, Setting, and Participants Two separate multicentre prospective cohort studies were set up. The first study recruited 180 patients to evaluate the diagnostic accuracy of plasma NTS concentration for colorectal polyps and cancers in patients with high-risk symptoms. Plasma samples were collected from the participants who then underwent diagnostic colonoscopy or computerised tomographic virtual colonography. The plasma concentration of NTS was quantified using enzyme-linked immunoassay. The diagnostic accuracy of plasma NTS was assessed using receiver operator characteristics curve analysis. The finding of the prospective study was then validated using 100 plasma samples stored in a tissue bank. The second study recruited 64 patients with CRC who underwent surgical resection with curative intent. The protein expression of NTS, NTSR1 and NTSR3 in the cancer resection specimens and surrounding normal epithelium was visualised using immunohistochemical staining. The intensity and proportion of expression of all three markers were quantified using the hybrid scoring (H-score) system. The relationship between the expression of these proteins and histopathological, clinical, and survival outcomes was evaluated. Results In the first study, of the 180 participants, 165 were eligible. Of these, 46 had colorectal polyps or cancer. Significantly higher plasma NTS was found in patients with colorectal polyps or cancers compared to those without (603.6 pg/ml vs 407.2 pg/ml, p < 0.01). Loge (plasma NTS concentration) was a significant independent risk factor for the presence of colorectal polyps or cancers (odds ratio, 2.73; 95% CI, 1.33–5.59, p < 0.01). Plasma NTS had an optimal sensitivity of 70.8% and specificity of 59.5% for the diagnosis of colorectal polyps and cancers. Similar diagnostic accuracy was obtained in the validation group. In the second study, of the 64 patients enrolled, 58 participants’ specimen blocks were immunostained. There was significantly higher expression of NTS in CRC of higher T stages (p<0.01), N stages (p=0.03), and AJCC clinical stages (p=0.04). There was significantly higher expression of NTS in cancer tissue compared to surrounding normal epithelium (median H-score 163.5 vs 97.3, p<0.01). There was significantly shorter disease-free survival (DFS) in individuals with CRC which expressed high levels of NTS compared to low levels of NTS (32.8 months 95% CI: 26.8 – 38.8 months vs 41.0 months 95% CI: 37.7–44.4 months respectively, p=0.01). Above median NTS expression in cancer tissue was a significant risk factor for disease recurrence (hazard ratio 5.60, 95% CI 1.22 – 25.6, p=0.03, Cox proportional regression). Conclusions and Relevance Plasma NTS has the potential to be a non-invasive biomarker for colorectal neoplasia. It appears to have better accuracy than existing blood markers and is unique in being able to also detect precancerous polyps. Furthermore, high tissue expression of NTS appears to be associated with more advanced CRC and shorter DFS. NTS expression level can potentially aid postoperative selection for conventional adjuvant therapy and identify individuals for novel therapies targeting the neurotensinergic pathways. These findings support the overarching hypothesis of this work; NTS has the potential to be both a diagnostic and prognostic marker of CRC.Open Acces

Assessment of field effect in the cancerous prostate

Prostate cancer is the second leading cause of cancer death in men. Prostate Specific Antigen (PSA) is the current indicator of prostate health, and needle core biopsy of the prostate is the standard of cancer diagnosis. However, PSA is not a specific indicator of cancer, and biopsy may miss actual tumor cells, leading to both false positive and false negative results, respectively. Therefore, better indicators of prostate cancer need to be identified. Field effect is the term used to describe the existence of genetically altered, although histologically normal, cells that surround an area of frank cancer. Better understanding and characterization of this field should provide more sensitive means of detecting prostate cancer independent of histological biopsy findings that may miss the tumor. This study furthers field characterization by analyzing various types of genomic and epigenetic alterations, including gene promoter methylation, mRNA expression profiling, changes in telomeres, and genomic instability as reflected by random sites of allelic imbalance. Results demonstrate that this field is predictably altered in cancer

Enhanced detection of circulating tumor DNA by fragment size analysis.

Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and the EPSRC (CRUK grant numbers A11906 (NR), A20240 (NR), A22905 (JDB), A15601 (JDB), A25177 (CRUK Cancer Centre Cambridge), A17242 (KMB), A16465 (CRUK-EPSRC Imaging Centre in Cambridge and Manchester)). The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 337905. The research was supported by the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre and Hutchison Whampoa Limited. This research is also supported by Target Ovarian Cancer and the Medical Research Council through their Joint Clinical Research Training Fellowship for Dr Moore. The CALIBRATE study was supported by funding from AstraZeneca

Evaluation of quality of life in Greek colorectal cancer survivors

Survival from cancer is becoming a reality for more people in the world each year. Survival rate from colorectal cancer disease is approximately 80% one year after diagnosis, but falls to 62% at 5 years from diagnosis. Quality of life research in colorectal cancer to date has focused on investigating patients' experience during the diagnostic or treatment phase while the experiences of those who have survived this cancer have been ignored. Based on the concept of Health-Related Quality of Life (HRQOL) this study was focused on understanding and assessing the impact of colorectal cancer disease and its treatment on Greek patients' HRQOL over time. Also, this study sought to identify multiple factors (related either to patient or disease characteristics) that contributed to patients' HRQOL in both specific and general domains. Age, gender, stage at diagnosis, time elapse since diagnosis, income, education, colostomy appliance, disease recurrence, depression and communication between couples were examined for their effect on HRQOL over time. 145 Greek outpatients (male 87, female 58) completed the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) Quality of Life Instrument and the Mental Component of the Short Form 36 Health Survey questionnaire measuring both generic and disease-specific HRQOL, as well as the Center for Epidemiologic Studies Depression Scale (CES-D) to detect depressive symptoms, and the Enriching & Nurturing Relationship Issues, Communication & Happiness (ENRICH) scale to assess communication between couples, at an interval of either one year or more than 5 years since diagnosis. Statistical significance was set at (p<0.05) and data were analysed using the Statistical Package for the Social Sciences (SPSS). The findings suggest that patients who survived colorectal cancer experienced an overall high quality of life independent of the stage of disease at diagnosis or time since diagnosis. Among those factors that had a negative effect on patients overall HRQOL over time depression was the most prevalent. Stoma patients experienced an overall lower HRQOL than non-stoma patients. Most domains of HRQOL assessment such as physical, emotional and role functioning of stoma patients were negatively affected, but these did not reach statistical significance. Notably, stoma patients in this sample showed significantly more dissatisfaction with body image than patients without a stoma – a finding that was more prevalent in women. This may suggest that stoma formation negatively affects sexual function and body image. Finally, patients with lower incomes and a recurrence or metastatic disease also experienced a poorer HRQOL. It is recommended that a practice-based strategy is developed in Greece to assess the HRQOL and psychosocial functioning of these patients as well as the recommendation that in the preoperative stage, after surgery and in the rehabilitation phase for stoma patients to be assessed and supported by a specialist Stoma Care nurse. Other suggestions for future research are also proposed

When is remission remission? Elucidating the remission state in Ulcerative Colitis: a multimodal exploration

Ulcerative Colitis (UC) is a chronic, inflammatory disease of the colon that has a relapsing-remitting characteristic. The disease management consists of prolonging periods of remission and reducing relapse frequency. There is currently no universally accepted definition of remission in UC. There are different methods of establishing if a patient is in remission, but the lack of definition and knowledge make it difficult to know which method to use. The majority of these methods are poorly described for remission patients representing a substantial knowledge gap. This thesis explored the remission term by investigating the mucosal transcriptional profile in UC remission patients and the utility of histology and transcripts as evaluation modalities. We found that several of the gene transcripts investigated were differently expressed in UC remission patients in comparison to healthy controls. These genes were largely related to pro-inflammatory mechanisms and barrier dysfunction, indicating that despite an apparent normal mucosa in endoscopy, the mucosa differed on a transcriptional level. We then investigated if histology could detect inflammation and consistently classify a patient as in remission using the different scoring indices. The results showed that histology could detect inflammation not apparent on endoscopy, but the histologic scores varied too much to be accurate in a categorical classification. The main source of variance was the histologic raters. Lastly, we investigated if any of the clinical, endoscopic, histologic, or transcriptional variables could predict impending relapse in a survival analysis. The results showed that patients with a low ratio between two transcripts had 5.3 times higher risk of relapse. Histologic factors did not turn out to be predictive of relapse. The conclusion was that several gene transcripts were differently regulated in UC remission patients compared to healthy controls. Some of these may be able to predict relapse and have potential use as biomarkers to improve the current treatment regimes

Multi-omics analysis of DNMT3A- and NPM1-mutated acute myeloid leukemia

Acute myeloid leukemia (AML) represents a genetically heterogeneous group of aggressive myeloid malignancies arising from clonal expansion of aberrant, myeloid-primed hematopoietic stem or progenitor cells. Intensive chemotherapy efficiently targets proliferating blasts and achieves remission in the majority of patients. However, most patients relapse, likely due to persisting, slowly proliferating leukemic stem cells (LSCs). A novel flow cytometry sorting strategy was recently developed in-house to enrich five different leukemic populations, two of them enriched for LSCs (GPR56+NKG2DL-). This strategy was applied to a genetically harmonized DNMT3A and NPM1 double-mutant AML cohort. Despite identical driver mutations, one group presented with early relapse (ER) while the other achieved long-term remission (LTR). Multi-omics profiling (RNA-seq, DNA methylation, and genetic information) allowed me to deeply characterize these sorted leukemic populations and identify biological processes associated with ER. This analysis confirmed xenotransplantation experiments and demonstrated that the LSC-enriched populations exhibited indeed more stem-like characteristics. Still, LSC-enriched populations showed a higher cell cycle activity compared to non-engrafting, more differentiated AML populations. The LSC-enriched populations were transcriptionally similar, but the CD34+ population retained also healthy hematopoietic stem cells (HSCs) while the CD34- population contained exclusively leukemic (stem) cells. This was particularly reflected by the distinct mutant allele frequencies of the DNMT3A- and NPM1-mutations. By analyzing the LSC-enriched populations, I demonstrated a higher transcriptomic instability in ER LSCs compared to LTR LSCs that may be initiated by increasing hypomethylation associated with an earlier onset of the DNMT3A mutation. Moreover, ER LSCs exhibited a more stem-like phenotype, characterized by higher activity of mitochondrial oxidative phosphorylation compared to LTR LSCs, which presented enhanced glycolytic activity instead. The difference in energy metabolism was partially confirmed by untargeted metabolomics analyses. In a technical development project, I also implemented an interactive R shiny app (MetaboExtract) and an R package (MetAlyzer) to infer suitable extraction protocols for metabolomics studies. In addition, I trained an outcome prediction expression signature to stratify patients based on their risk of relapse and hence long-term chemotherapy sensitivity. This signature was highly predictive in different AML cohorts and was able to stratify AML patients with poor and more favorable overall survival. In summary, my work revealed biological mechanisms associated with an early relapse in LSC-enriched AML populations and generated a novel outcome prediction signature to stratify patients

Development of a Systemic Lupus Erythematosus Knowledge Questionnaire: The Relationship Among Disease Proximity, Educational Exposure and Knowledge

There are an estimated 1.5 million people living with systemic lupus erythematosus (SLE), a multisystem autoimmune disorder with a high risk of co-morbid health concerns. The psychological consequences of an SLE diagnosis result in increased daily stress, anticipated stigma, fears of rejection, and increased self-consciousness, all of which can decrease a patient’s quality of life. In order to combat these negative experiences, attempts to increase accurate knowledge of SLE and extinguish SLE misconceptions must be made. The current study aimed to 1) create a medically informed SLE knowledge questionnaire; 2) determine the rate of community members’ SLE knowledge; and 3) determine the relation that disease proximity and educational exposure have on community members’ knowledge of SLE. This novel study is the first to create an SLE knowledge questionnaire and provide evidence that having a closer personal relation to SLE increases SLE knowledge, as does having learned about SLE in an educational setting