Dyspnea is defined as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity”. Dyspnea occurs in approximately 10% to 70% of oncology patients. This broad range in its prevalence rates suggests that dyspnea has a large amount of inter-individual variability. In addition, the risk factors for dyspnea in patients with cancer are likely to be multifactorial. This variability makes it difficult to characterize the “dyspnea experience” of oncology patients and determine factors associated with this symptom. Consequently, dyspnea decreases oncology patients’ quality of life and, in some cases, overall survival. Yet, definitive interventions do not exist. Therefore, the aims of this dissertation research were to: 1) develop the Multifactorial Model of Dyspnea in Patients with Cancer; 2) systematically review studies published since 2009 that evaluated for dyspnea in patients with cancer; 3) identify subgroups of patients with distinct shortness of breath profiles in a sample of outpatients receiving chemotherapy and evaluate for differences in a variety of demographic, clinical, and symptom characteristics; and 4) determine the most influential perturbed inflammatory pathways between patients with and without dyspnea.

In terms of Aim 1, a conceptual paper provides an overview of the physiology of normal breathing; the pathophysiology of dyspnea; and factors that contribute to dyspnea in oncology patients. Specific factors that were included in the Multifactorial Model of Dyspnea in Patients with Cancer were: person, clinical, and cancer-related factors, as well as respiratory muscle weakness, co-occurring symptoms, and stress. While this paper provides a summary of the evidence on the mechanisms and factors associated with dyspnea in patients with cancer, the paucity of research on this symptom suggests numerous areas for investigation. This paper concludes that progress will not be made in the effective management of dyspnea without increased knowledge of its associated risk factors and underlying mechanisms.

In terms of Aim 2, in a systematic review, 117 studies were identified that evaluated for dyspnea in patients with cancer. This systematic review summarized the prevalence, intensity, distress, and impact of dyspnea in oncology patients and identified research gaps. Across these studies, the intensity of dyspnea was the most common symptom dimension that was evaluated followed by impact and distress. Depression and anxiety were the most common symptoms that co-occurred with dyspnea. Future research studies need to use valid and reliable multidimensional measures. In addition, given the paucity of studies on mechanism(s) that underlie dyspnea in patients with cancer, future research is warranted to determine specific biomarkers for dyspnea.

In terms of Aim 3, in outpatients receiving their second or third cycle of chemotherapy, four distinct shortness of breath profiles were identified (None [70.5%]; Decreasing [8.2%]; Increasing [7.8%], High [13.5%]). Findings suggest that risk factors for membership in High class include history of smoking, self-reported diagnosis of lung disease, having lung cancer, and receipt of a higher number of cancer treatments. In terms of symptom dimensions, patients in the High class reported more frequent and severe shortness of breath. In addition, compared to None class, patients in the other three classes reported higher occurrence rates for chest tightness and difficulty breathing. Compared to None class, patients in the Decreasing and High classes reported higher occurrence rates for cough. Regarding the impact of shortness of breath, compared to None class, patients in the High class reported poorer physical, psychological, and social functioning.In addition, we evaluated associations between shortness of breath and global, cancer-specific, and cumulative life stress, as well as resilience and common co-occurring symptoms. Compared to None class, patients in the Decreasing and High classes had higher global and cancer-specific stress scores. Patients in the High class reported higher occurrence rates for several adverse childhood experiences. In addition, our findings suggested that compared to None class, patients in the Decreasing and High classes had higher depression, anxiety, and morning fatigue scores and lower morning energy and cognitive function scores.

In terms of Aim 4, given the paucity of research on underlying mechanism(s) for dyspnea in patients with cancer and the potential contribution of inflammatory mechanisms, whole transcriptome gene expression and pathway impact analyses were done to evaluate for associations between this symptom and perturbations in inflammatory pathways. Among 73 significantly perturbed Kyoto Encyclopedia of Genes and Genomes signaling pathways, 29 were related to inflammatory mechanisms. Findings from this study provide preliminary support for the hypothesis that pulmonary and systemic inflammation contribute to the occurrence of dyspnea in patients receiving chemotherapy.

To evaluate the interconnections between and among these inflammatory pathways, an unweighted knowledge network was created using the specific pathway maps. Three centrality measures (i.e., betweenness, closeness, degree) were calculated to gain insights into the structural importance of each node. The mitogen-activated protein kinase (MAPK) signaling pathway node had the highest closeness, betweenness, and degree scores. The next ten pathways with the highest centrality scores were: Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway; apoptosis, phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, natural killer (NK)-cell mediated cytotoxicity, neutrophil extracellular trap (NET) formation, nuclear factor kappa light chain enhancer of activated B cells (NF-kappa B) signaling pathway, cytokine-cytokine receptor interaction, nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway, Forkhead box O (FoxO) signaling pathway, and chemokine signaling pathway. In addition, five common respiratory disease-related pathways, that may share mechanisms with cancer-related dyspnea, were perturbed. These findings warrant validation. This dissertation concludes with implications for clinical practice and future research.

Cytokine Gene Variations are Associated with Levels of Exercise in Women Prior to Breast Cancer SurgeryBy Nadia Haas Background - Over 90% of women with breast cancer undergo surgery. Although the benefits of exercise prior to and following surgery have been demonstrated, many breast cancer patients exercise below the recommended level. Genetic variation may account for 30-70% of a persons regular level of exercise. Genes associated with exercise include ones involved inflammatory and anti-inflammatory processes. Purpose - The purposes of this study is, in a sample of women evaluated prior to breast cancer surgery were to: evaluate for differences in demographic and clinical characteristics between patients who did (n=78) and those who did not (n=120) exercise on a regular basis and evaluate for associations between exercise group membership and cytokine gene variations. Methods - This study draws its data from a larger longitudinal study on lymphedema and neuropathic pain in women follow breast cancer surgery. Patients completed enrollment questionnaires, and levels of exercise, demographic and clinical characteristics were obtained. Genotype data was obtained DNA isolated from peripheral blood. Three exercise groups were created using guidelines from Healthy People 2020: patients who did not exercise (NoEX, n=120), patients who exercised less than 150 minutes/week (LessEX, n=134), and patients who exercised for the recommended 150 minutes/week (RecEX, n=78). Differences in demographic and clinical characteristics between the NoEX and RecEx groups. Genetic variations of pro-inflammatory, anti-inflammatory and transcriptional regulators were tested for associations with membership in the NoEX and RecEx groups. Results - As compared to the RecEX group, patients in the NoEX group had fewer years of education, were less likely to be White or Asia/Pacific Islander, more like to be Hispanic or of mixed ethnic background, and more likely to report a lower annual household income. Clinically, as compared to the RecEX group, patients in the NoEX group had a higher Body Mass Index (BMI), a lower KPS score, a higher SCQ score, were more likely to self-report a diagnosis of high blood pressure, and were more likely to have received neoadjuvant chemotherapy. In the final multivariate regression models, variations in two SNPs were associated with RecEX or NoEX group membership: IFNGR1 rs9376268 (p-value = 0.021) and NFKB1 rs4648135 (p-value = 0.006). Both loci are in high linkage with missense SNPs located in putative regulatory regions. Conclusions - This study is the first to identify non-modifiable demographic risk factors and modifiable clinical characteristics associated with lack of exercise in patients prior to breast cancer surgery. This exploratory candidate gene study is also the first to identify variations in a cytokine gene and a regulatory gene that are associated with lack of exercise in patients prior to breast cancer surgery. Given the anti-inflammatory effects of exercise can protect against the development of chronic conditions and improve overall health, our findings on the association between exercise and cytokine gene variations may explain some of the beneficial effects of exercise found in studies of patients with and survivors of breast cancer. In addition, given that exercise improves the quality of life of patients with breast cancer, clinicians can use the characteristics identified in this study (e.g. higher BMI, co-morbidities) to identify high risk patients. Furthermore, clinicians should identify barriers to regular exercise and counsel patients on the benefits of regular exercise during and following cancer treatment.

Cognitive changes associated with cancer and its treatments, known as cancer-related cognitive impairment (CRCI), are reported by up to 75% of patients and 60% of those who have completed treatment. Because a number of cognitive domains are impacted, CRCI results in decrements in multiple domains of quality of life. In addition, because of gaps in knowledge regarding its underlying mechanism(s), progress is slow in the development of prevention or mitigation strategies. Equally important, anxiety is a common symptom that co-occurs with CRCI. Despite high prevalence rates for both symptoms, CRCI and anxiety are often evaluated as individual symptoms. However, because anxiety can impact cognitive function and vice versa, an assessment of the co-occurrence of both symptoms warrants evaluation.Therefore, the first three aims of this dissertation were to: 1) develop a comprehensive conceptual model of CRCI; 2) test this newly developed conceptual model; and 3) conduct a scoping review of the literature to describe the depth and breadth of available evidence on blood-based biomarkers of CRCI. In addition, using data from a sample of patients with heterogenous types of cancer with distinct joint CRCI AND anxiety profiles (n=1332), the fourth, fifth, and sixth aims of this dissertation were to: evaluate for differences in demographic and clinical characteristics among the three CRCI AND anxiety latent classes; evaluate for differences in levels of global stress, cancer-specific stress, cumulative life stress, and resilience among the three CRCI AND anxiety latent classes; and evaluate for perturbed pathways associated with membership in the No CRCI AND Low Anxiety class compared to the High CRCI AND High Anxiety class. In terms of Aim 1, an original comprehensive conceptual model of CRCI, named the Multifactorial Model of CRCI (MMCRCI), was developed. The MMCRCI was designed based on a review of the literature that included over 100 review and state of the science papers published between 2017 and 2022. The specific concepts in the conceptual model include social determinants of health, patient-specific factors, co-occurring symptoms, treatment factors, and biologic mechanisms. The model can be used to design pre-clinical and clinical studies of CRCI. In terms of Aim 2, structural regression methods were used to evaluate the MMCRCI using data from a large sample of outpatients receiving chemotherapy for a variety of cancers. The goals were to determine how well the concepts in the MMCRCI predicted CRCI and to determine the relative contribution of each of these concepts to deficits in perceived cognitive function. Of the four MMCRCI concepts evaluated, while co-occurring symptoms explained the largest amount of variance in CRCI, treatment factors explained the smallest amount of variance. These findings suggest that testing individual components of the MMCRCI may provide useful information on the relationships among various risk factors for CRCI, as well as refinements of the model. In terms of Aim 3, a scoping review was done that synthesized the extant literature on associations between subjective and/or objective measures of CRCI and blood-based biomarkers in adults with non-central nervous system cancers. A total of 95 studies were included in this review. Of note, a wide variety of biomarkers were examined. The majority of studies evaluated patients with breast cancer. A variety of cognitive assessment measures were used. The most consistent significant associations were with various subjective and objective measures of CRCI and levels of interleukin-6 and tumor necrosis factor. This review concluded with directions for future research. In terms of Aims 4 and 5, a latent profile analysis identified subgroups of patients with distinct joint CRCI AND anxiety profiles (i.e., latent classes). In addition, differences in demographic and clinical characteristics, as well as levels of global stress, cancer-specific stress, cumulative life stress, and resilience were reported. In terms of the symptom profiles, three latent classes were identified (i.e., No CRCI AND Low Anxiety (57.3%), Moderate CRCI AND Moderate Anxiety (34.5%), and High CRCI AND High Anxiety (8.2%)). All of the stress measures showed a dose response pattern. Higher levels of co-occurring CRCI AND anxiety were associated with several demographic (e.g., age, marital status) and clinical (e.g., functional status, comorbidity burden) characteristics, as well with as with higher levels of stress and lower levels of resilience. Increased knowledge of modifiable characteristics and sources of stress associated with the co-occurrence of these two symptoms will assist clinicians to identify high risk patients, and with the development and testing of interventions. In terms of Aim 6, perturbations in neurodegenerative pathways associated with the CRCI AND High anxiety classes were identified. Five neurodegenerative pathways were significantly perturbed, namely: Amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, Prion disease, and Pathways of neurodegeneration - multiple diseases. Four common biological processes across these perturbed neurodegenerative pathways were identified (i.e., apoptosis, mitochondrial function, endoplasmic stress, oxidative stress). While these findings warrant confirmation, they suggest that these two symptoms may share common mechanisms across patients with cancer and patients with neurodegenerative diseases.

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Oncology patients receiving chemotherapy report on average 14 concurrent symptoms. The co-occurrence of these symptoms is associated with poorer functional status, decrements in quality of life (QOL), and increased mortality. Given that symptoms rarely occur in isolation, the concept of a symptom cluster emerged in the literature in 2001. An increased understanding of how symptoms cluster together and the biological mechanism(s) that underlie them has the potential to lead to the development of targeted interventions to decrease symptom burden. Therefore, the overall aims of this dissertation research were to: 1) review the conceptual basis for using variable-centered versus patient-centered analytic approaches in symptom cluster research; 2) systematically review studies published since 2016 that evaluated for symptom clusters in patients receiving primary or adjuvant chemotherapy; 3) evaluate the stability and consistency of symptom clusters across time and across three symptom dimensions (i.e., occurrence, severity, and distress); 4) identify common and distinct symptom clusters across various types of cancer; and 5) evaluate for associations between psychological and gastrointestinal symptom clusters and epigenetic regulation of inflammatory genes in a heterogeneous sample of oncology patients. In terms of aim 1, a theoretical paper described two conceptual approaches that are used to evaluate symptom clusters; namely: “clustering” symptoms (i.e., variable-centered analytic approach) and “clustering” patients (i.e., person-centered analytic approach). Findings suggest that while each approach has unique strengths and weaknesses, conceptual clarity is needed when a study is designed and the specific research question(s) should guide the selection of the appropriate analytic method. The application of newer analytic approaches (e.g., network analysis (NA), natural language processing (NLP)) to study symptom clusters were reviewed. This paper summarized the paucity of research on the evaluation of the underlying mechanism(s) for symptom clusters. In terms of aim 2, in a systematic review, 23 studies were identified that evaluated for symptom clusters in patients receiving chemotherapy. Across these studies, the Memorial Symptom Assessment Scale (MSAS) was the most common instrument and exploratory factor analysis (EFA) was the most common statistical method used to identify symptom clusters. While psychological, gastrointestinal, and nutritional clusters were the most common clusters identified across studies, only the psychological cluster remained relatively stable over time. A major conclusion from this review was that clear criteria are needed to evaluate the stability of symptom clusters across time and dimensions. In addition, only five studies evaluated for secondary outcomes (e.g., functional status, QOL). Additional research is needed to evaluate the biological mechanism(s) for symptom clusters. In terms of aim 3, prior to the start of their second or third cycle of chemotherapy, outpatients reported an average of 13.9 (±7.2) concurrent symptoms. Lack of energy was both the most common and severe symptom while “I don’t look like myself” was the most distressing. Psychological, gastrointestinal, weight gain, respiratory, and hormonal clusters were the common symptom clusters identified across the three symptom dimensions. Our findings suggest that psychological, gastrointestinal, and weight gain clusters are common across various types of cancer while respiratory and hormonal clusters are cancer specific. In terms of aim 4, across a cycle of chemotherapy, the number of symptoms remained relatively stable over time, with patients reporting 13.9 (±7.2) symptoms prior to, 14.0 (±7.0) at one week after, and 12.2 (±6.8) at two weeks after receipt of chemotherapy. While the psychological, weight gain, respiratory, and gastrointestinal clusters were stable over time and dimensions, only the psychological, weight gain, and respiratory clusters were consistent across time and dimensions. In terms of aim 5, given the paucity of studies on the underlying mechanism(s) for the two most common symptom clusters (i.e., psychological, gastrointestinal), exploratory analyses were done to evaluate for associations between these clusters and epigenetic variation of inflammatory genes. Findings from both studies provide preliminary support for the hypothesis that epigenetic dysregulation of inflammatory processes contributes to the occurrence of psychological and gastrointestinal symptom clusters in patients receiving chemotherapy. For the psychological symptom cluster, cluster of differentiation (CD) 40 was differentially methylated across two independent samples (false discovery rate (FDR) = .017). Six expression-associated CpGs (i.e., eCpG; cg22232207, cg06571407, cg17929951, cg21601405, cg01943874, cg11841529) located in the promoter region of this gene were hypomethylated across both samples. For the gastrointestinal symptom cluster, one trans eCpG locus (i.e., cg03171795) that was associated with expression of the lymphotoxin beta (LTB) gene was associated with the occurrence of the gastrointestinal symptom cluster (FDR = 0.168). These findings warrant validation. This dissertation concludes with implications for clinical practice and future research.

The availability of complete genomes allows for direct and powerful tests of the different processes underlying molecular evolution and quantification of their relative contributions. Here, I evaluate the relative contributions of natural selection and random genetic drift in shaping the evolution of the genome of Strongylocentrotid sea urchins using the assembled genome of the purple sea urchin, Strongylocentrotus purpuratus and by sequencing the entire genome of eight additional closely related species. I use a phylogenomic approach taking advantage of the data provided by 3,848 nuclear genes to obtain a robust and well-resolved phylogeny of the group. I observe that synonymous codon usage is biased in S. purpuratus and that there are five distinct clusters of codon usage. I find evidence that natural selection acts on slightly advantageous mutations through changes in synonymous codon usage bias, involving translational efficiency and/or accuracy as well as mRNA folding stability. Finally, using the comparative genomics of the group and the rates of synonymous and non-synonymous substitutions between species I detected strong evidence for broadly acting purifying selection and extensive signals of positive Darwinian selection (27.6% of genes). Sea urchins have long served as model organisms and have provided key insights into our basic understanding of biology and will continue to continue furthering our understanding of the role of natural selection on shaping the genome in the future.