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The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.

Soybeans are a rich source of isoflavones that have been linked with anti-inflammatory processes and various health benefits. However, specific mechanisms whereby soy bioactives impact immune cell subsets are unclear. Isoflavones, such as genistein and daidzein, are metabolized by microbes to bioactive metabolites as O-desmethylangolensin (O-DMA) and equol, whose presence has been linked to health benefits. We examined how soy isoflavones and metabolites impact natural killer (NK) cell signaling and function. We observe no impact of isoflavones on viability of healthy donor peripheral blood mononuclear cells (PBMCs) or NK cells, even at high (25 µM) concentrations. However, pre-treatment of PBMCs with physiologically-relevant concentrations of genistein (p = 0.0023) and equol (p = 0.006) decreases interleukin (IL)-12/IL-18-induced interferon-gamma (IFN-γ) production versus controls. Detailed cellular analyses indicate genistein and equol decrease IL-12/IL-18-induced IFN-γ production by human NK cell subsets, but do not consistently alter cytotoxicity. At the level of signal transduction, genistein decreases IL-12/IL-18-induced total phosphorylated tyrosine, and phosphorylation MAPK pathway components. Further, genistein limits IL-12/IL-18-mediated upregulation of IL-18Rα expression on NK cells (p = 0.0109). Finally, in vivo studies revealed that C57BL/6 mice fed a soy-enriched diet produce less plasma IFN-γ following administration of IL-12/IL-18 versus control-fed animals (p < 0.0001). This study provides insight into how dietary soy modulates NK cell functions.

Chronic pancreatitis (CP) is a fibro-inflammatory syndrome in individuals who develop persistent pathological responses to parenchymal injury or stress. Novel therapeutic or dietary interventions that could lessen inflammation in this disease could significantly improve quality of life in patients with CP. Complex dietary foods like soy and tomatoes are composed of active metabolites with anti-inflammatory effects. Data from our group reports that bioactive agents in soy and tomatoes can reduce pro-inflammatory cytokines and suppressive immune populations. Additionally, our team has developed a novel soy-tomato juice currently being studied in healthy individuals with no toxicities, and good compliance and bioavailability. Thus, we hypothesize that administration of a soy-tomato enriched diet can reduce inflammation and severity of CP. C57BL/6 mice were injected intraperitoneally with 50 μg/kg caeurlein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks of caerulein injections, mice were administered a control or a soy-tomato enriched diet for 2 weeks. Disease severity was measured via immunohistochemical analysis of pancreata measuring loss of acini, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were analyzed at the end of the study. Inflammatory factors in the serum and pancreas, and immune populations in the spleen of mice were analyzed by cytokine multiplex detection, qRT-PCR, and flow cytometry respectively. Infra-red (IR) sensing of mice was used to monitor spontaneous activity and distress of mice. Mice fed a soy-tomato enriched diet had a significantly reduced level of inflammation and severity of CP ( p  = 0.032) compared to mice administered a control diet with restored serum lipase and amylase levels ( p  < 0.05). Mice with CP fed a soy-tomato diet had a reduction in inflammatory factors (TNF-α, IL-1β, IL-5) and suppressive immune populations (myeloid-derived suppressor cells; MDSC) compared to control diet fed mice ( p  < 0.05). Infra-red sensing to monitor spontaneous activity of mice showed that soy-tomato enriched diet improved total activity and overall health of mice with CP ( p  = 0.055) and CP mice on a control diet were determined to spend more time at rest ( p  = 0.053). These pre-clinical results indicate that a soy-tomato enriched diet may be a novel treatment approach to reduce inflammation and pain in patients with CP.

Single-cell RNA sequencing (scRNA) has empowered many insights into gastrointestinal microenvironments. However, profiling human biopsies using droplet-based scRNA (D-scRNA) is challenging since it requires immediate processing to minimize epithelial cell damage. In contrast, picowell-based (P-scRNA) platforms permit short-term frozen storage before sequencing. We compared P- and D-scRNA platforms on cells derived from human colon biopsies. Endoscopic rectosigmoid mucosal biopsies were obtained from two adults and conducted D-scRNA (10X Chromium) and P-scRNA (Honeycomb HIVE) in parallel using an individual's pool of single cells (> 10,000 cells/participant). Three experiments were performed to evaluate 1) P-scRNA with cells under specific storage conditions (immediately processed [fresh], vs. frozen at -20C vs. -80C [2 weeks]); 2) fresh P-scRNA versus fresh D-scRNA; and 3) P-scRNA stored at -80C with fresh D-scRNA. Significant recovery of loaded cells was achieved for fresh (80.9%) and -80C (48.5%) P-scRNA and D-scRNA (76.6%), but not -20C P-scRNA (3.7%). However, D-scRNA captures more typeable cells among recovered cells (71.5% vs. 15.8% Fresh and 18.4% -80C P-scRNA), and these cells exhibit higher gene coverage at the expense of higher mitochondrial read fractions across most cell types. Cells profiled using D-scRNA demonstrated more consistent gene expression profiles among the same cell type than those profiled using P-scRNA. Significant intra-cell-type differences were observed in profiled gene classes across platforms. Our results highlight non-overlapping advantages of P-scRNA and D-scRNA and underscore the need for innovation to enable high-fidelity capture of colonic epithelial cells. The platform-specific variation highlights the challenges of maintaining rigor and reproducibility across studies that use different platforms.

Diet and nutrition play major roles either preventing or promoting disease. Epidemiological studies have established links between dietary patterns, nutrients, phytochemicals and cancer risk. The work presented in this dissertation addresses three broad themes: (1) the impact of diet and nutrition on the carcinogenesis process, (2) the interaction of dietary compounds in metabolism, and (3) the interaction of the gut microbiome and the promotion or prevention of cancer. We first investigated the role of tomatoes and the bioactive tomato carotenoid lycopene. Tomatoes and lycopene were associated with reduced risks of prostate cancer in epidemiology studies with a growing body of pre-clinical evidence supporting these findings. We demonstrated that tomatoes with distinct lycopene isomer profiles similarly inhibit prostate carcinogenesis in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model in conjunction with distinct inhibitions of immune and inflammatory pathways. We also show that tomato diets drive plasma metabolomic signatures, and that there are minimal impacts of dietary tomato on gut bacterial diversity. In the second study, we demonstrate the safety of a novel-vitamin D-enriched soy bread in the pre-clinical TRAMP model. Both vitamin D and soy were associated with reduced risk of prostate cancer. We show that dietary levels of vitamin D drive plasma accumulation of 25(OH)D, the circulating biomarker of vitamin D status, with subsequent impacts on vitamin D metabolic gene expression. In addition, we explored the interaction between soy and vitamin D metabolism. Previously, the soy isoflavone genistein showed inhibitory activity against the vitamin D degradation enzyme CYP24A1. We find modest impacts of soy bread on vitamin D metabolism, including no effect on Cyp24a1 expression. Further study is warranted in pre-clinical models to assess anti-prostate cancer potential with translation into human cohorts. The third and final study addresses two questions: does the gut microbiome change in response to an intense dietary intervention, and does red meat have a distinct impact on global gut bacterial signatures? We demonstrate that responses to the dietary intervention are personalized. Global microbiome signatures do not consistently follow a single grouping pattern, yet there was a distinct, individual response to the intervention. In addition, to answer our second question, there appears to be little impact of beef on global signatures of gut microbe populations. This does not prove no effect, rather the impact if there, is not immediately obvious using global microbiome signatures. In summary, dietary patterns and specific dietary compounds convey significant effects on a multitude of physiological processes, from cancer preventative mechanisms, to impacts on vitamin metabolism, and personalized alterations to gut microbial communities. Diet is an important variable that contributes to multiple health outcomes.

To report hip adduction, abduction, and adduction:abduction strength ratio values in NCAA Division I American football players, and to compare strength values across position groups. Cross-sectional study. University training facility. 85 male football players. Isometric hip adduction and abduction strength values in the 0° hip-flexion long-lever and 0° hip-flexion short-lever testing positions, using a ForceFrame. Hip strength values are presented across two testing positions. ANOVA revealed significant differences (p ≤ 0.05) in hip strength between position groups, with medium-to-large effect size (n2 = 0.116–0.284). Skill-position and mid-position players demonstrated significantly greater hip adduction and abduction relative strength in both testing positions, when compared to lineman-position players. In addition, skill-position and mid-position players demonstrated significantly greater hip adduction:abduction strength ratios (0.19–0.20, 24–25%) in the long-lever testing position, when compared to lineman-position players, with large effect size (n2 = 0.178). No significant differences in strength were observed between skill-position and mid-position players. Hip adduction:abduction strength ratios ranged from 0.68 to 0.88 in the long-lever testing position and 1.05 to 1.09 in the short-lever testing position. Significant differences in relative strength exist between position groups of NCAA Division-I football players, in hip adduction, abduction and adduction:abduction ratio. •Hip strength values were reported for NCAA Division I football players.•Significant differences in relative hip strength exist between position groups.•Lineman position players demonstrate notably weaker hip strength to mid and skill position players.

Intraoperative crisis events, such as haemorrhage or iatrogenic perforation, can cause considerable stress in the operating surgeon. Little standardized training exists for managing such events, especially for surgical trainees. Cognitive load (CogL) is the extent to which a task places demands on cognitive resources. Such resources are finite, and when overwhelmed, can lead to stress, which in turn can negatively affect intraoperative technical and non-technical performance. Surgical sabermetrics is a novel field that involves advanced analysis of data obtained from non-invasive physiological sensors measuring surgeon CogL, as well as audiovisual recordings of surgical procedures capturing surgeon technical and non-technical skills. This data-driven approach enhances understanding of factors that can improve, or worsen, surgical performance. ‘Managing Surgical Crises’ is a high-fidelity simulation course which exposes surgical trainees to standardized intraoperative crises with no risk to patient safety. This study aims to apply a sabermetrics framework to the ‘Managing Surgical Crises’ course to gain insight into trainee surgeon CogL and non-technical skills during the introduction and response to crisis events. Surgical trainees will be allocated to a simulated surgical crisis event and tasked with managing the scenario utilizing the Team, Environment, Assess/Analyse/Anticipate, Manage resources (TEAM) algorithm. A sabermetrics framework will be employed to collect quantitative data regarding CogL and non-technical performance. Full ethical approval has been obtained for this study. Dissemination of the results will be through conferences and publications in peer-reviewed journals.