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Glioblastoma multiforme (GBM) is the most malignant and common primary brain cancer in adults, with a 2.5-year survival of only ~8%. In this single case study we have analysed the development of a primary GBM over four years. We performed WGS and RNAseq on three, spatially distinct samples of the treatment naïve primary tumour, the first recurrence and the fatal second recurrence. We observed a massive increase in mutations from the first to the second recurrence, showing predominantly C > T and A > G transitions, which is a pattern typical of TMZ treatment. The fact that the hypermutation did not appear until the second recurrence raises questions about the mechanism of hypermutation. The therapeutic apoptotic action of TMZ relies on the function of the mismatch repair (MMR) pathway. In the second recurrence we observed disruptive mutations of MSH6, MSH2, PMS2 and MLH1 all of which are crucial to the MMR pathway. The pattern of mutations of these genes varied between the samples taken from the second recurrence, however, all three samples showed hypermutation. This suggests that the hypermutation observed after TMZ treatment only occurs if the MMR is damaged, but that this damage does not need to be at a specific locus. Using the CRISPR-Cas9 technology we explored the impact of MMR mutations on patient derived GBM cell lines. Results on MSH2 and MSH6 knockout cell lines treated with TMZ showed the reproduction of the hypermutation phenotype in vitro, but only in MGMT promoter methylated cell lines. Moreover, the DNA analysis of the patient showed one shared mutation in high copy number in all of the nine samples: a mutation in EGFR G598V. We hypothesise that subsequent tumours developed from an original clone bearing this mutation. This mutated oncogene is located on an extrachromosomal circular DNA structure known as a double minute (DM), which is found in an estimated 40% of GBM. We performed linked-read sequencing using the 10X Genomics Chromium technology to reconstruct the DM and shed light on its emergence.

Melanoma is the most lethal type of skin cancer with over 132,000 cases occurring globally each year and continually rising incidence. BRAFV600E inhibitors have led to clinically significant improvements in outcomes for melanoma patients, yet many patients with metastatic melanoma rapidly succumb to the disease due to eventual chemoresistance or insensitivity to the drug. Thus, it is critical to identify new therapies that can act alone, or be combined with available treatments for enhanced efficacy and/or to overcome drug resistance. Evidence from human melanoma indicates that the melanocyte lineage is critical for melanoma survival and contributes to therapeutic resistance. MITF is a highly conserved “master melanocyte transcription factor” with a complex role in melanoma. Our lab has previously developed a temperature sensitive BRAFV600E mitfavc7 zebrafish melanoma model carrying a human oncogene and mitfavc7 splice site mutation that enables the conditional control of its endogenous activity by changes to water temperature. As part of my PhD project, I characterized and compared two new models developed since then: a very aggressive BRAFV600E mitfavc7p53M214K melanoma model with three driving mutations and a slower developing BRAF-independent mitfavc7p53M214K. I showed that the MITF activity is crucial for melanocyte survival in both models and that both mutated BRAF and p53 deficiency are oncogenic with low levels of MITF, and result in fish nevi and melanoma resembling the pathology of human disease. Both models are also relevant to a low-MITF subclass of human melanomas that emerged from a recent classification by The Cancer Genome Atlas Network. In addition, I established that, similarly to the BRAFV600Emitfavc7, complete inhibition of MITF activity leads to rapid tumour regression, but once its activity is restored the melanomas recur at the same site as the original tumour. I used histopathology studies and melanocyte lineage transgenes to identify and visualize subpopulations of cells remaining at the site of regression in these new zebrafish melanoma models. I hypothesised that these are the cells of origin for tumour recurrence (melanoma stem or progenitor cells), showed that some of them express a cancer stem cell marker aldehyde dehydrogenase, and attempted to target these subpopulations using 5-nitrofurans (a prodrug NFN1, shown previously by our lab to target ALDHhigh subpopulations in context of melanoma) in fish after melanoma regression. Finally, I also developed and described a new primary zebrafish melanoma cell line that I derived from one of these zebrafish tumours. This study is still in progress, but the cell line will be a useful tool for further investigation of these proposed melanoma progenitor cells in vitro, with potential applications for lineage tracing and transplantations.

Venous leg ulceration has a high recurrence rate. Patients with healed or frequently recurring venous ulceration are required to perform self-care behaviours to prevent recurrence or promote healing, but many find these difficult to perform. Bandura’s self-efficacy theory is a widely used and robust behaviour change model and underpins many interventions designed to promote self-care in a variety of chronic conditions. By identifying areas where patients may experience difficulty in performing self-care, interventions can be developed to strengthen their self-efficacy beliefs in performing these activities successfully. There are currently a variety of self-efficacy scales available to measure self-efficacy in a variety of conditions; but not a disease-specific scale for use with venous ulcer patients. The aim of this study, therefore, was to develop a disease-specific, patient-focused self-efficacy scale for patients with healed venous leg ulceration. Phase 1 consisted of a qualitative design and used focus group methodology to generate an item pool for potential inclusion into the scale from the patients’ perspective. In phase 2, factor analysis using equamax orthogonal rotation methods was used to reduce the items from 60 to 30, resulting in 5 major domains: general self-care; daily self-care tasks; normal living; developing expertise and avoiding trauma. Preliminary reliability studies indicated that the developed scale, VeLUSET© has good internal consistency, with an overall Cronbach alpha of .929 and a strong test-re-test reliability. Furthermore, correlation with the General Self-Efficacy Scale demonstrated a strong positive relationship between the two scales. These results indicate that the VeLUSET©, although still in the early validation stages, is a reliable instrument to measure venous leg ulcer patients’ self-efficacy in performing self-care tasks within clinical practice. The development of this disease-specific tool has now filled a gap in the research on managing patients with healed venous leg ulceration.

Objective: Adequate physician-patient communication about cancer recurrence is vital to quality of life and to informed decision-making related to survivorship care. The current study was guided by a cognitive-affective framework to examine communication with family and physicians about breast cancer recurrence risk. Methods: A survey of recently-diagnosed, early-stage breast cancer patients in Appalachia investigated physician-patient and familial communication about breast cancer recurrence risk. Results: Over 30% of participants reported not talking to family or physicians about breast cancer recurrence risk. Younger patients reported more conversations, and speaking with physicians was associated with greater perception risk factors associated with recurrence risk. Greater worry about recurrence was associated with more communication with family and plans to talk to family, physicians, and friends about recurrence risk in the future. Conclusion: Additional supports for patients and physicians are needed to improve understanding of breast cancer recurrence risk and risk factors for recurrence. Innovation: Family communication about breast cancer recurrence risk is understudied. The combination of physician and family communication adds novelty to our analysis.

The hero’s journey [or the monomyth] and the perennial philosophy are two conceptions of human experience that popularize a single old idea: a common human plight recurs across time through humanity’s socio-cultural variety. The monomyth highlights this through narrative modes; the perennial philosophy does this through religious modes. Both distillations have garnered a Christian counterattack, being thought to dangerously depart from the gospel in their essence as they nonetheless borrow its language and timbre. Yet, their incorporation of the gospel ventures beyond appropriation. Supposing these secular notions esteem the recurrent human journey with any alacrity, a careful apologetic discerns and utilizes an advantageous middle-area of Christological knowledge that lay between the revealed Christ of Scripture and the shared errors of these two conceptions. The continual reappearance of a mythic-hero and of created religious examples to model them bookend two sides of a puzzle: a portrait of the hero best understood in light of the historical Christ on one side, and a religious mode of dying-to-self summated as the practiced “kenosis” of humanity on the other. However, that hero and their kenosis reflect the salvation found for the human soul through the kenotic exemplar of the revealed, historical Christ. This is the “Natural Christology” of the human race; its abductive propositions are to God the Son as those of natural theology are to God in general. Natural Christology may be apprehended by Christian apologetics from emergences of the perennial philosophy in popular religion and the monomyth in popular stories. Proper discernment allows these destructive manifestations of secular culture to serve the ends of drawing the lost to the only condition that fully satisfies their partial portraits of human character; only the historical reality of a heroic Savior’s death and resurrection may meaningfully grant godly perfection to those who are identified in His kenosis.

Investigating novel treatment approaches to combat Clostridioides difficile Rusha Pal ABSTRACT Clostridioides difficile is the leading cause of antibiotic-induced diarrhea and colitis in hospitals and communities worldwide. The enteric pathogen, classified to be an "urgent threat" by the United States Center for Disease Control and Prevention (CDC), capitalizes on disrupted intestinal microbiome to establish infection with disease symptoms ranging from mild diarrhea to potentially fatal conditions. Disruption of the intestinal microbiome, caused mostly by antibiotic use, enables C. difficile to colonize and proliferate within the host. Paradoxically, antibiotics are used to treat C. difficile infection. These antibiotics decimate the gut microbial community further, thus priming the gastrointestinal tract to become more prone to recurrence of infection. To tackle this clinical setback, we utilized a combination of traditional and non-traditional drug discovery approaches and identified chemical entities and targeted treatment options effective against this toxin-producing intestinal pathogen. Herein, we exploited the strategy of high-throughput screening to identify leads that harbor anticlostridial activity. Our primary phenotypic screen of FDA-approved drugs and natural product libraries led to the identification of novel molecules that were further characterized for their anticlostridial efficacy both in vitro and in vivo. The most potent scaffolds identified were those of mitomycin C, mithramycin A, aureomycin, NP-003875, NAT13-338148, NAT18-355531, and NAT18-355768. Of these, mithramycin A, aureomycin, and NP-003875 were also found to harbor anti-virulence properties as they inhibited toxin production by the pathogen. Furthermore, natural product NP-003875 could confer protection to 100% of the infected mice from clinical manifestations of the disease in a primary infection model of C. difficile. Our final approach has been to develop targeted therapeutics called peptide nucleic acids (PNAs). PNAs are antisense agents capable of inhibiting gene expression in bacteria. In this study, antisense inhibition of the RNA polymerase  subunit gene (rpoA) of C. difficile was found to be bactericidal for the pathogen and could also inhibit the expression of its virulence factors. Additionally, antisense inhibition of the C. difficile rpoA gene was found to be non-deleterious for the tested commensal microflora strains. Given their intriguing anticlostridial properties, it can be concluded that our research opened exciting possibilities that can be further evaluated to uncover new treatments for CDI.

Introduction: Cutaneous squamous cell carcinoma (cSCC) is the second most common cutaneous neoplasm, and its incidence is on the rise. While most cSCCs have an excellent prognosis, certain risk factors, especially immunosuppression, have been associated with higher rates of local recurrence (LR), metastasis, and poor prognosis. This study aims to assess the risk factors for LR and metastasis development in cSCC among solid organ transplant recipients (SOTRs) and compare these rates with those in immunocompetent patients. Materials and Methods: A retrospective observational study included cSCC cases from the University Hospital Reina Sofía in Córdoba, Spain, between 2002 and 2019. Demographic, clinical, and histopathological data were collected. Local recurrence and metastasis rates were analyzed, along with progression-free survival. Univariate analyses were performed to identify prognostic factors in SOTRs. Results: Among 849 cSCC cases, we found higher rates of local recurrence and metastasis in tumors developed by SOTRs compared to those in immunocompetent individuals. However, no significant differences in local recurrence, metastasis, or progression-free survival were observed between the two groups. Risk factors for adverse outcomes in SOTRs included tumor size > 2 cm, depth > 4 mm, and a higher Clark level. A total of 34.4% of SOTRs developed a second primary cSCC during the follow-up. Conclusions: In our study, cSCCs in SOTRs did not exhibit statistically significant differences in the rates of adverse outcomes compared to immunocompetent patients. The prognosis of cSCCs in SOTRs may be more related to other tumor-dependent risk factors than to the immunosuppression status itself. Future studies are needed to refine risk stratification and follow-up protocols to ensure the optimal management of high-risk cSCC cases, particularly among immunosuppressed patients.

Background:Body composition parameters have been reported to be prognostic factors in patients with oncologic diseases. However, the available data on patients with HCC are conflicting. The aim of this study was to assess the impact of body composition on survival in patients with HCC treated with sorafenib or selective internal radioembolization (SIRT) and sorafenib. Methods:This is an exploratory subanalysis of the prospective, randomized controlled SORAMIC trial. Within the palliative arm of the study, patients were selected if a baseline abdominal CT was available. A broad set of skeletal muscle and adipose tissue parameters were measured at the L3 level. Low skeletal muscle mass (LSMM) and density parameters were defined using published cutoffs. The parameters were correlated with overall survival. Results:Of 424 patients in the palliative study arm, 369 patients were included in the analysis. There were 192 patients in the combined sorafenib/SIRT and 177 patients in the sorafenib group. Median overall survival was 9.9 months for the entire cohort and 10.8 and 9.2 months for the SIRT/sorafenib and sorafenib groups, respectively. There was no relevant association of either body composition parameter with overall survival in either the overall cohort or in the SIRT/sorafenib or sorafenib subgroups. Conclusions:This subanalysis of the prospective SORAMIC trial does not suggest a relevant influence of body composition parameters of survival in patients with advanced HCC. Body composition parameters therefore do not serve in patient allocation in this palliative treatment cohort.

Recurrence and multiple recurrence in ergodic theory have deep connections with combinatorics, as observed by Furstenberg in his ergodic-theoretic proof of Szemerédi’s theorem on arithmetic progressions. Motivated by combinatorial problems in groups such as ℤd (the d-dimensional integer lattice), ⊕q (an infinite-dimensional vector space over a finite field q), or (ℚ×,·) (the group of nonzero rational numbers under multiplication), we study recurrence properties of measure-preserving actions of countable discrete abelian groups.This dissertation is broken into two main parts. First, in Chapter 3, we juxtapose single recurrence with the dynamical properties of rigidity and weak mixing. We generalize several recent results about ℤ-actions to general abelian group actions and explore new phenomena that arise in the context of infinitely-generated groups and groups with torsion. Two significant applications presented in this chapter are: (1) constructing weakly mixing systems for which various number-theoretically meaningful sequences are rigidity sequences, and (2) establishing a distinction between recurrence and strong recurrence for abelian group actions.In the second, much longer, part, consisting of Chapters 4–8, we investigate the large intersections property for families of linear or polynomial functions. The results of this portion of the dissertation enhance, generalize, and unify many of the previously known results about large intersections for multiple recurrence. Using Furstenberg’s correspondence principle, we obtain a multitude of combinatorial applications dealing with such diverse situations as triangular patterns in ℤ2, geometric progressions in the integers, and polynomial configurations in rings of integers of number fields.

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration (median time to progression: 5.5 versus 16.0 months [p=0.048]; median time to next surgery: 17.0 months versus 29.0 months [p=0.031]). Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

Randomized studies to assess the efficacy of Mohs micrographic surgery in basal cell and squamous cell carcinomas are limited by methodological and ethical issues and a lack of long follow-up periods. This study presents the "real-life" results of a nationwide 7-years cohort on basal cell carcinoma and squamous cell carcinoma treated with Mohs micrographic surgery. A prospective cohort was conducted in 22 Spanish centres (from July 2013 to February 2020) and a multivariate analysis, including characteristics of patients, tumours, surgeries and follow-up, was performed. A total of 4,402 patients followed up for 12,111 patient-years for basal cell carcinoma, and 371 patients with 915 patient-years of follow-up for squamous cell carcinoma were recruited. Risk factors for recurrence included age, non-primary tumours and more stages or unfinished surgeries for both tumours, and immunosuppression for squamous cell carcinoma. Incidence rates of recurrence were 1.3 per 100 person-years for basal cell carcinoma (95% confidence interval 1.1-1.5) and 4.5 for squamous cell carcinoma (95% confidence interval 3.3-6.1), being constant over time (0-5 years). In conclusion, follow-up strategies should be equally intense for at least the first 5 years, with special attention paid to squamous cell carcinoma (especially in immunosuppressed patients), elderly patients, non-primary tumours, and those procedures requiring more stages, or unfinished surgeries.

Abstract: Background- Crohn's disease (CD) is a type of inflammatory bowel disease that can cause inflammation throughout the alimentary tract. Many individuals diagnosed with CD ultimately require intestinal resection. Unfortunately, disease often recurs following surgery. The pathophysiology of the post-operative recurrence of CD is incompletely understood, but thought to be multifactorial, involving environmental, genetic, microbial, and immunologic factors. Aims- To identify genetic, microbial, or immunologic factors in humans that predict recurrence of CD following intestinal resection, and to modify inflammation following ileocecal resection (ICR) in a murine model using a prebiotic fiber. Methods- Three distinct cohorts of human subjects were analyzed to determine the effect of genetic loci (n=191), microbial populations (n=45), and locoregional immunologic factors (n=26) in recurrent disease following intestinal resection. An interleukin (IL)-10 knockout murine model of ICR was utilized to assess the effect of fructooligosaccaride on post-ICR inflammation and microbial composition. Results- A single nucleotide polymorphism associated with BACH2 (rs1847472) predicted recurrence in our cohort (HR-1.24 CI-1.00-1.54 p

Cancer is not a bounded, self-organized system. Most malignant tumors have heterogeneous growth, leading to disorderly proliferation well beyond the surgical margins. In fact, the impact of certain tumors is observed not just within the visible tumor, but also in the immediate peritumoral, as well as in seemingly normal-appearing adjacent field. Visual inspection is often not a reliable instrument in cancer diagnosis, providing only qualitative analysis of an image, thereby missing subtle disease signatures. These, and other imaging limitations can lead to unnecessary surgical interventions. Computerized image analysis has shown promise in comprehending disease heterogeneity through quantification and detection of sub-visual patterns. In this work, we present novel radiomic tools to identify subtle radiologic cues (radiomic descriptors) and address clinical challenges in cancer diagnosis, prognosis, and treatment-evaluation. The developed tools and techniques are modality- and domain-agnostic. They can be applied in a pan-cancer setting to mine information from radiographic images and discover associations with underlying molecular (radio-genomics) or histological (radio-pathomics) characteristics to provide a holistic characterization of disease. We have demonstrated their efficacy in addressing problems in prognosis and treatment management of brain tumors.The challenges we target specifically include (1) inability to estimate survival at a pre-treatment stage and (2) inability to avoid highly-invasive surgeries in patients with radiation-induced treatment changes that mimic tumor recurrence. Underlying heterogeneity is linked to poor prognosis and tumor recurrence. Cellular level differences associated with the distinct physiological pathways might also manifest at the radiographic (i.e. MRI) length scale. We present two radiomic descriptors, Co-occurrence of Local Anisotropic Gradient Orientations (CoLlAGe) and radiographic-Deformation and Textural Heterogeneity (r-DepTH), which attempt to capture voxel-level textural and structural heterogeneity associated with brain tumors on MRI. These radiomic features are extracted not only from the solid tumor regions, but also from the adjacent tumor habitat and the healthy parenchyma. Subsequently, they are used in a machine learning setting to predict survival on treatment-naive imaging and characterize radiation-induced effects on post-treatment MRI. Further, via human-machine comparison experiments, we demonstrate the utility of radiomic-based frameworks as a second read decision support in cancer management.

Calcium oxalate (CaOx) urolith is the most common urolith in dogs. The exact mechanism for CaOx urolith formation is not well understood but thought to be multifactorial. However, urolith recurrence is common after removal. Knowledge of which group of dogs are greater risk for formation and recurrence, can help veterinarians select effective therapy and prevention, as well as earlier recognize urolith formation or recurrence to increased opportunity for nonsurgical removal, early dietary modification to minimize urolith growth, early removal to avoid urinary obstruction, and early recognition of potential metabolic diseases Dogs which had a greater risk for CaOx urolith formation included; male, small breed (Bichon, Miniature Schnauzer, Lhasa Apso, Yorkshire Terrier, Pomeranian, and Maltese). To minimize the morbidity and mortality due to urolithiasis, these dogs should be prescreened at approximately 5 years-old. The recurrence of CaOx urolith is common. Small breed, male, dogs with history of previous urolithiasis, dogs 6 - 10 years old, and dogs with CaOx dihydrate were greater risk for recurrence. Therefore, intensive prevention therapy of these dogs will be benefit for minimizing recurrence. To detect early CaOx urolith recurrence, the screening by means of medical imaging should be performed at least once a year to minimize morbidity and permit simple non-invasive urolith removal in most. For prevention of recurrence, clinician should promote low urine specific gravity (< 1.030).

BACKGROUND: Advanced stage epithelial ovarian cancer (EOC) presents with an extremely poor prognosis. While some patients respond well to standard treatments of chemotherapy and cytoreductive surgery, the recurrence rate is high and five-year survival is low. The importance of nutritional eating and a healthy lifestyle has been recognized as a protective factor against the development of many cancers. There may be a role for dietary and lifestyle interventions on reducing the recurrence of EOC, thereby prolonging survival. LITERATURE REVIEW FINDINGS: A review of the literature was performed, focusing on dietary and lifestyle patterns and their effects on the development and recurrence of epithelial ovarian cancers. In general, carotenoids, flavonoids, cruciferous vegetables, and flaxseed rich diets have all been proposed to reduce the risk of developing ovarian cancer. Conversely, red and processed meats, and foods with high glycemic index have been associated with an increased risk of ovarian cancer development. Additionally, obesity and high Body Mass Index (BMI) have been linked to increased cancer risk as well as increased mortality rates from cancer. PROPOSE METHODS: Given the broad spectrum of dietary and lifestyle recommendations for prevention of EOC, many providers are not aware of what information they can give to their patients regarding this topic. A Continuing Medical Education (CME) lecture summarizing the most up-to-date literature on the topic of lifestyle interventions to increase EOC survival would be beneficial. A one hour long course will be offered for CME credit to expand the knowledge base of providers and equip them with the resources necessary to educate patients on healthy lifestyle modifications in order to minimize ovarian cancer recurrence. CONCLUSIONS: With a lack of definitive cure and poor overall prognosis for women diagnosed with advanced stage epithelial ovarian cancer, there is a need for alternative treatment options when traditional methods fail. There is promising evidence that a diet high in carotenoids, cruciferous vegetables, flaxseed, and several other nutritional components is beneficial in preventing development of ovarian cancer. A diet containing processed foods, red meats, dairy, and high sugar content has been associated with increased ovarian cancer risk. It is possible that these dietary recommendations may apply to prevention of recurrence of EOC as well. The CME lecture will present the most up-to-date knowledge in the area of lifestyle interventions for the prevention of EOC. A curriculum for primary care and oncology health care providers will provide them with the tools necessary to provide their patients with nutrition and lifestyle recommendations that may prevent cancer recurrence.

Certain hormones and/or receptors influencing normal cellular pathways were detected in breast cancers. The hypothesis is that gene subsets predict risk of breast carcinoma recurrence in patients with primary disease. Gene expression of 55 hormones and 73 receptors were determined by microarray with LCM-procured carcinoma cells of 247 de-identified biopsies. Univariate and multivariate Cox regressions were determined using expression levels of each hormone/receptor gene, individually or as a pair. Significant genes derived for each subset were analyzed to predict risk of cancer recurrence with 1000 LASSO training/test sets. A 14-gene molecular signature was identified for predicting clinical outcome without regard to estrogen or progestin receptor status of biopsies. A three-gene signature was derived for ER+ cancers while a 9-gene signature was deciphered for ER- cancers. Molecular signatures derived were compared with results in public databases. Collectively, results suggest gene subsets in primary breast cancer have been identified that predict recurrence.

Treatment for rectal cancer can be associated with rectal functional impairment, increased morbidity and may impact quality of life. Restorative surgery is the preferred choice of surgery, but in some circumstances, surgery with a permanent stoma is required to ensure tumour clearance. While the aim of treatment for rectal cancer is to ensure cure where possible the long term impact of the functional impact of this treatment is not known. This thesis investigates rectal functional impairment after treatment for rectal cancer in the long-term and its impact on quality of life in rectal cancer compared with age matched colon cancer patients. It also assesses the impact of radiotherapy on this impairment and its effect on quality of life in rectal cancer. In addition, it compares the quality of life in patients with and without a primary stoma after curative surgery for colorectal cancer and determines the impact of country of birth on the perception of a stoma. This thesis finally examines the long term morbidity, local recurrence and survival associated with radiotherapy and provides a protocol for future studies to better evaluate the effects of rectal cancer treatment. Patients treated for rectal cancer have greater rectal functional impairment compared to patients treated for colon cancer. In patients treated for rectal cancer, those receiving radiotherapy had even greater rectal dysfunction. This high rate of rectal dysfunction did not impact on the global quality of life. Patients with a permanent stoma had more restricted physical activity those without a stoma but there were no differences in mental functioning. There were no differences in the overall quality of life associated with country of birth. In this cohort of patients there was no difference in morbidity between those patients who had surgery alone compared with those who had radiotherapy and surgery. The rates of local and distant recurrence were not different between the groups as was overall survival. This thesis has shown that the functional outcomes after treatment for rectal cancer should be an important factor in decision making and that the role of radiotherapy in the treatment of rectal cancer should be re-evaluated.

Glioblastoma (GBM) is a progressive and malignant form of glioma with very poor prognosis. Treatment options for GBM include surgery, chemotherapy, and radiotherapy, with radiotherapy being the focus of this study. GBM is especially hard to treat with radiotherapy due to the fact that the disease often extends microscopically beyond the visible tumor on MRI, leading to high recurrence rates.The widely accepted method of radiotherapy uses a 2cm isotropic expansion from the MRI indicated tumor region in order to capture the microscopic glial cells that protrude beyond the apparent tumor margin. This method, however, is nonspecific as the radiation volume often radiates grey matter regions that not only have a lower probability of tumor growth, but is also responsible for important cognitive functions associated with motor and sensory neuronal cells. Studies have shown that GBM grows preferentially along the white matter tracts of the brain, which plays an integral role in our method of predicting tumor growth. Using patient data from 3 individuals with GBM, we utilized a diffusion tensor imaging (DTI) technique, tractography, to predict tumor growth along white matter tracts. DTI is very quantitative in capturing the anisotropic nature of the diffusion of water molecules in white matter tracts, which will allow us to model the tumor growth using tractography.Ours results were compared against the clinical planned radiation treatment for each of the 3 patients, which showed significantly greater coverage of white matter tracts, areas of high probable tumor recurrence.

Cancer recurrence is an emotionally intense experience. Further information is needed to understand the strategies that recurrence patients use to regulate their emotional responses. An emotion regulation model was tested using prospective data from patients with recurrent breast cancer (N = 146). Participants completed measures of affect at diagnosis (POMS, CES-D, BHS, LOT-R), measures of emotion regulation 4 months later (COPE), and measures of quality of life (QoL) at 12 months (SF-36). Bootstrapped mediation analyses examined the indirect effect of two emotion regulation strategies, engagement coping and disengagement coping, on the relationship between affect and QoL. Significant mediating effects (p

Abstract: Breast cancer is the most common cancer among women in the developed world. The disease results from the combined effects of genetic, environmental, reproductive and lifestyle risk factors. Germline DNA variations identified thus far by linkage and genome-wide association studies (GWASs) account for less than one-third of variability in breast cancer predisposition, suggesting that more variants exist. Furthermore, despite advancements in breast cancer therapies guided by tumor-based prognostic and predictive factors, approximately 30% of breast cancer patients who receive standard guideline-based therapies experience disease recurrence within ten years post diagnosis. Consequently, there is a clear need of additional markers for disease risk assessment as well as markers of potential prognostic values to better guide treatment modalities. In this thesis, I adopted a comprehensive approach utilizing single nucleotide polymorphisms (SNPs) and germline copy number aberrations (copy number variations (CNVs) and copy neutral-loss of heterozygosities (CN-LOHs)) to identify markers for breast cancer susceptibility and disease prognosis. I used a multi-stage association study design that included cumulative sample sizes of 2,795 invasive breast cancer cases and 4,505 healthy controls of predominantly Caucasian in origin selected from Alberta, Canada. I identified a novel breast cancer susceptibility locus on chromosome 4q31.22 showing a strong statistical significance for overall breast cancer (per allele odds ratio=1.28 and P=1.5 x 10-7), adjusted for body mass index (BMI). I also independently confirmed one literature reported association on chromosome 8q24.21-rs13281615 (BMI adjusted-P

Previous studies have shown lymphovascular space invasion (LVSI) to increase the risk for recurrent endometrioid uterine cancer (EC), yet its significance relative to other risk factors and in relation to survival are less well-defined. Our aim was to study prognostic factors for recurrence and survival in women with early stage EC. Women with LVSI, FIGO grade 2 or 3 histology (G2/3), or outer half myometrial invasion (OI) were included in this study. We identified 338 patients, 73% of the patients had a lymphadenectomy. The rate of recurrence was 17.2%. In multivariate analysis only LVSI was a significant independent risk factor for total recurrence OR=2.57, and distant recurrence OR=3.26. LVSI was also a significant poor prognostic factor for progression-free survival, disease-specific survival and overall survival with 5-year survival rates of 66% compared to 88% with and without LVSI. LVSI appears to be an independent poor prognostic factor for recurrence and survival.

The incidence of focal segmental glomerulosclerosis (FSGS), already the second leading cause of end stage renal disease (ESRD) in children, appears to be increasing. Moreover, post-transplant (Tx) FSGS recurrence (R) is a major problem, and there is concern that kidneys from living related donors (LRDs) are more likely to be affected by R than kidneys from deceased donors (DDs). However, prior studies have not accounted for the potentially confounding influence of race on donor type in recurrence risk. AIMS: (1) To study trends in FSGS leading to pediatric ESRD using a national database. (2) To analyze risk factors for FSGS R in the pediatric Tx recipients on a national scale.METHODS: Data from the United Network for Organ Sharing (UNOS) from 1988-2008 was analyzed for number of Tx for a primary diagnosis of FSGS in Tx recipients

Let M(n,s) be the number of nxn matrices with binary entries, row and column sum s, and whose rows are in lexicographical order. Let S(n) be the number of nxn matrices with entries from {0,1,2}, symmetric, with trace 0, and row sum 2. (The sequence S(n) appears as A002137 in N.J.A. Sloane's Online Encyclopedia of Integer Sequences.) We give two proofs to show that M(n,2)=S(n). First, we show they satisfy the same recurrence. Second, we give an explicit bijection between the two sets. We also show that the bijection maintains the cycle structure of our matrices. Let M_s(n,2) be the set of symmetric matrices in M(n,2). We will show M_s(n,2) satisfies the Fibonacci sequence.

OBJECTIVE: To determine if chlorhexidine can be used as an intervention to prolong the time to relapse of oral candidiasis. SUBJECTS AND METHODS: A double-blinded randomized clinical trial was performed in 75 HIV?AIDS subjects with oral candidiasis. Clotrimazole troche was prescribed, and the subjects were re-examined every 2 weeks until the lesions were completely eradicated. The subjects were then randomly divided into two groups; 0.12% chlorhexidine (n = 37, aged 22–52 years, mean 34 years) and 0.9% normal saline (n = 38, aged 22– 55 years, mean 38 years). They were re-examined every 2 weeks until the next episode was observed. RESULTS: The time to recurrence of oral candidiasis between the chlorhexidine and the saline group was not statistically significant (P > 0.05). The following variables were significantly associated with the time of recurrence; frequency of antifungal therapy (P = 0.011), total lymphocyte (P = 0.017), alcohol consumption (P = 0.043), and candidiasis on gingiva (P = 0.048). The subjects with lower lymphocyte showed shorter oral candidiasis-free periods (P = 0.034). CONCLUSIONS: Chlorhexidine showed a small but not statistically significant effect in maintenance of oral candidiasis- free period. This lack of significance may be due to the small sample size. Further study should be performed to better assess the size of the effect, or to confirm our findings.

Objective: To determine predisposing factors and outcomes for recurrent ventilator associated pneumonia (VAP). Design: Retrospective review. Patients: All adult surgical patients mechanically ventilated more than 48 hours between January 2000 and December 2004 were evaluated. VAP was defined as greater than or equal to 10,000 colony forming units/mL in a bronchoalveolar lavage or protected catheter lavage, and recurrence as a positive quantitative culture more than 4 days after initiation of antibiotics. Main Outcome Measures: We analyzed potential risk factors for recurrence, including initial pathogen, APACHE II scores, age, white blood cell count, presence of trauma, and duration of hospital stay before diagnosis. Results: Eighty four of 177 patients (48%) with confirmed VAP developed recurrence, with 68% involving methicillin-resistant S. aureus or nonfermenting gram-negative bacilli. APACHE II score, duration of hospital stay, and age were associated with recurrence (OR 1.06, p=0.04; OR 1.03, p=0.04; OR 1.02, p=0.03). Conclusions: There is a high rate of VAP recurrence in the surgical population with the majority involving drug-resistant organisms. Treatment should include coverage for these pathogens.

The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. The five-year relapse rate is approximately 25-40% and the identification of patients at high risk of recurrence would represent an important strategy for the use of adjuvant chemotherapy. We retrospectively analyzed gene expression profiles in frozen tumor specimens from patients with Dukes' B colorectal cancer by using high density oligonucleotide microarrays. Our results show a subset of 48 genes differentially expressed with an associated probability

This study attempts to explain why some countries experience multiple civil wars while others who have experienced a civil war build long-term stability from the rubble of conflict. The explanation of why civil war recurs focuses on the collective action problem, centering on the rebel leaders' ability to solve the Rebel's Dilemma. I further argue that once the Rebel's Dilemma has been solved once it is much easier for rebel leaders to solve it again and again. The empirical finds suggest that the political situation resulting from the first war plays a strong role in the solutions to the collective action problem and thus the long-term stability following a civil war. Namely, the level of democracy, partition and third party enforcement of the peace all affect the ability of the rebel leaders to solve the collective action problem and the likelihood of another civil war.

Bipolar I (BPI) disorder is a recurrent affective psychiatric disorder with a disruptive and debilitating course. Clinical evidence indicates that the frequency of recurrence is positively associated with a more severe course and progressive functional deterioration. Thus, research is needed to identify the factors that increase the likelihood of recurrence and to assess the mechanisms by which these factors exert their effect. This study examined the psychosocial risk factors associated with increased recurrence in persons with meeting DSM-III-R criteria for a diagnosis of BPI disorder. Using data from the National Comorbidity Survey (NCS), psychosocial correlates of BPI episode recurrence were investigated in a representative population sample of noninstitutionalized Americans between the ages of 15 and 54. The NCS was the first psychiatric epidemiologic survey administered to a nationally representative sample (N = 8098) and was completed with a response rate of 82.4%. In addition to documenting prevalence and incidence of 14 psychiatric disorders, the NCS data included extensive measures on childhood and family risk factors as well as on intrapsychic characteristics and current events and stressors. A diathesis-stress model was tested to ascertain whether adverse experiences during childhood (e.g., parental psychopathology, relationship difficulties, and violence during childhood) create a vulnerability that predisposes the bipolar respondent to increased risk of recurrence, especially in the presence of certain adult characteristics and circumstances (e.g., comorbidity, traumatic events, chronic stressors, and personality characteristic). Two childhood adversities showed robust direct effects on recurrence, parental psychopathology and childhood abuse. Significant adult risk factors were marital difficulties, interpersonal conflicts, and current traumatic events of an aggressive or financial nature. When all significant childhood and adult predictors were placed in one multivariate model, three factors remained strongly predictive of recurrence: childhood abuse, parental psychopathology, and ongoing marital difficulties. No associations between social support and recurrence were found. Remarkably, with each additional risk factor the risk of recurrence more than doubled. None of the childhood effects were mediated through adult adversities, but traumatic events reduced the effect size of other adult predictors, suggesting the need to further examine the possibility of a triggering effect for traumatic events.