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The aryl hydrocarbon receptor (AhR) is overexpressed in many tumor types and exhibits tumor-specific tumor promoter and tumor suppressor-like activity. In colon cancer, most but not all studies suggest that the AhR exhibits tumor suppressor activity which is enhanced by AhR ligands acting as agonists. Our studies investigated the role of the AhR in colon tumorigenesis using wild-type and AhR-knockout mice, the inflammation model of colon tumorigenesis using mice treated with azoxymethane (AOM)/dextran sodium sulfate (DSS) and APCS580/+; KrasG12D/+ mice all of which form intestinal tumors. The effects of tissue-specific AhR loss in the intestine of the tumor-forming mice on colonic stem cells, organoid-initiating capacity, colon tumor formation and mechanisms of AhR-mediated effects were investigated. Loss of AhR enhanced stem cell and tumor growth and in the AOM/DSS model AhR-dependent suppression of FOXM1 and downstream genes was important for AhR-dependent anticancer activity. Furthermore, the effectiveness of interleukin-22 (IL22) in colonic epithelial cells was also dependent on AhR expression. IL22 induced phosphorylation of STAT3, inhibited colonic organoid growth, promoted colonic cell proliferation in vivo and enhanced DNA repair in AOM/DSS-induced tumors. In this mouse model, the AhR suppressed SOCS3 expression and enhanced IL22-mediated activation of STAT3, whereas the loss of the AhR increased levels of SOCS3 which in turn inhibited IL22-induced STAT3 activation. In the APCS580/+; KrasG12D/+ mouse model, the loss of the AhR enhanced Wnt signaling and colon carcinogenesis. Results in both mouse models of colon carcinogenesis were complemented by single cell transcriptomics on colonic intestinal crypts which also showed that AhR deletion promoted expression of FOXM1-regulated genes in multiple colonic cell subtypes. These results support the role of the AhR as a tumor suppressor-like gene in the colon.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Lack of an effect of colonic GFP+ stem cell targeted cre recombinase in the absence of gene floxing.

p53 has been shown to mediate cancer stem–like cell function by suppressing pluripotency and cellular dedifferentiation. However, there have been no studies to date that have addressed the specific effects of p53 loss in colonic adult stem cells. In this study, we investigated the consequences of conditionally ablating p53 in the highly relevant Lgr5+ stem cell population on tumor initiation and progression in the colon. In a mouse model of carcinogen (AOM)-induced colon cancer, tamoxifen-inducible Lgr5-driven deletion of p53 reduced apoptosis and increased proliferation of crypt stem cells, but had no effect on tumor incidence or size. Conversely, in a mouse model of colitis-associated cancer, in which mice are exposed to AOM and the potent inflammation inducer DSS, stem cell–specific p53 deletion greatly enhanced tumor size and incidence in the colon. These novel findings suggest that the loss of p53 function in stem cells enables colonic tumor formation only when combined with DNA damage and chronic inflammation. Furthermore, we propose that stem cell targeting approaches are valuable for interrogating prevention and therapeutic strategies that aim to specifically eradicate genetically compromised stem cells. Cancer Res; 75(24); 5392–7. ©2015 AACR.

Numerous clinical and animal studies show that hormone replacement therapy reduces the risk of colon tumor formation. However, the majority of experiments have shown that estradiol (E2) does not inhibit the growth of malignantly transformed colon epithelia. As such, the presented studies focused on evaluating the effects of E2 in noncancerous colonocytes. E2 treatments (0–10 nmol/L) reduced cell growth and increased apoptotic activity in young adult mouse colonocytes (YAMC), a nonmalignant cell line, in a dose-responsive manner. These effects were lost in the YAMC-Ras cells, an isogenic cell line with a single malignant transformation. Cotreatment with an estrogen receptor (ER) antagonist inhibited the physiologic effects of E2 in YAMC cells, suggesting that the response is ER mediated. To further study the effect of E2 on colonic epithelia, we evaluated the development of preneoplastic lesions in ovariectomized wild-type (WT) and ERβ knockout (ERβKO) mice treated with either vehicle or E2. WT E2-treated animals exhibited significantly fewer aberrant crypt foci and increased apoptotic activity in colonic epithelia when compared with WT control mice or ERβKO animals receiving either treatment. For the first time, we showed that E2 alters the growth of nontransformed colonocytes in vitro and that, through an ERβ-mediated mechanism, E2 influences the physiology of noncancerous colonocytes, resulting in fewer preneoplastic lesions. Collectively, these data show that the protective actions of E2 occur primarily during the initiation/promotion stages of disease development and identify the hormone as an important chemoprotective agent. [Cancer Res 2009;69(23):9118–24]

Legend for Supplemental Figures S1-S5.

Supplementary Figure 1 from Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Hydroxylated chalcones are phytochemicals which are biosynthetic precursors of flavonoids and their 1,3-diaryl-prop-2-en-1-one structure is used as a scaffold for drug development. In this study, the structure-dependent activation of aryl hydrocarbon receptor (AhR)-responsive CYP1A1, CYP1B1, and UGT1A1 genes was investigated in Caco2 colon cancer cells and in non-transformed young adult mouse colonocytes (YAMC) cells. The effects of a series of di- and trihydroxychalcones as AhR agonists was structure dependent with maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells observed for compounds containing 2,2′-dihydroxy substituents and this included 2,2′-dihydroxy-, 2,2′,4′-trihydroxy-, and 2,2′,5′-trihydroxychalcones. In contrast, 2′,4,5′-, 2′3′,4′-, 2′,4,4′-trihydroxy, and 2′,3-, 2′,4-, 2′,4′-, and 2′,5-dihydroxychalcones exhibited low to non-detectable AhR activity in Caco2 cells. In addition, all of the hydroxychalcones exhibited minimal to non-detectable activity in YAMC cells, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells. The activity of AhR-active chalcones was confirmed by determining their effects in AhR-deficient Caco2 cells. In addition, 2,2′-dihydroxychalcone induced CYP1A1 protein and formation of an AhR-DNA complex in an in vitro assay. Simulation and modeling studies of hydroxylated chalcones confirmed their interactions with the AhR ligand-binding domain and were consistent with their structure-dependent activity as AhR ligands. Thus, this study identifies hydroxylated chalcones as AhR agonists with potential for these phytochemicals to impact AhR-mediated colonic pathways.

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout (KO) mice. While young GHS-R KO mice showed marginal changes in Bacteroidetes and Firmicutes, aged GHS-R KO mice exhibited reduced Bacteroidetes and increased Firmicutes, featuring a disease-susceptible microbiome profile. To further study the role of GHS-R in intestinal inflammation in aging, we induced acute colitis in young and aged GHS-R KO mice using dextran sulfate sodium (DSS). The GHS-R KO mice showed more severe disease activity scores, higher proinflammatory cytokine expression, and decreased expression of tight junction markers. These results suggest that GHS-R plays an important role in microbiome homeostasis and gut inflammation during aging; GHS-R suppression exacerbates intestinal inflammation in aging and increases vulnerability to colitis. Collectively, our finding reveals for the first time that GHS-R is an important regulator of intestinal health in aging; targeting GHS-R may present a novel therapeutic strategy for prevention/treatment of aging leaky gut and inflammatory bowel disease.

Background: In the large intestine, tertiary lymphoid tissues (TLTs) serve as localized centers of adaptive immune responses. These structures often form in response to inflammation and infection during adulthood. However, more recently TLTs have become a focal point of colon caner development and progression as their presence is often associated with positive clinical outcomes. Interestingly, several studies have demonstrated that the aryl hydrocarbon receptor (AhR) influences the development of secondary lymphoid tissues, but minimal studies have focused on its role in TLT formation. The purpose of the presented studies was to test the hypothesis that activation of AhR in intestinal epithelial cells (IECs) induces the formation of TLTs in the colon. Methods: Wild type (WT) and IEC-specific AhR knockout (CDX2PCreT2 x AhRf/f- iAhRKO) mice were used in several different experimental models. In the first study, azoxymethane (AOM) was used to induce precancerous lesions in the colon and TLT formation was evaluated in the presence and absence of AhR. Then, experiments were conducted to determine the necessity of AhR expression in IECs to influence the formation of TLTs following induction of acute inflammation induced by Dextran sodium sulfate (DSS) exposure. Finally, the ability of known, naturally occurring and microbial-derived AhR ligands (indole-3-aldehyde (I3A), 3,3ʹ-diindolylmethane (DIM), and indole-3-acetic acid (IAA)) were tested for their ability to induce TLT formation in the colon. Intestinal permeability (FITC-Dextran), expression of IEC-associated genes (real-time qPCR), and TLT formation/composition (H&E staining/Immunofluorescence) were evaluated. Results: Results from the first study demonstrated that IEC-specific AhR KO mice exposed to AOM developed significantly fewer TLTs when compared to WT controls, while expression of Il-22 and other chemokines involved in TLT formation were also significantly downregulated. In the acute inflammation study, sex specific results were found. In females, loss of AhR activity in IECs reduced the formation of TLTs without significant changes in immune cell composition within their TLTs. Conversely, in males, loss of AhR lowered expression of functional-IEC genes (Ocln, Il-22), increased number of TLTs, increased T-cell density, and lower B: T cell ratio. Finally, in the other experiments, I3A induced TLT formation and DIM promoted intestinal barrier integrity through the upregulation of various tight junction genes and genes involved in the signaling associated with TLT formation. Evaluation of IAA which is a microbial-derived, AhR ligand is ongoing. Conclusion: These data indicate that AhR plays a distinct role in the formation of TLTs in the colon and these effects are likely ligand specific and may have a significant effect on colon tumor formation. Citation Format: Kimberly F. Allred, Erika L. Garcia-Villatoro, Jennifer DeLuca, Victoria Tepe, Zachary Bomstein, Arinzechukwu Ufondu, Stephen H. Safe, Robert S. Chapkin, Arul Jayaraman, Clinton D. Allred. Aryl hydrocarbon receptor and its ligands influence the formation of colonic tertiary lymphoid tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3443.

Many of the protective responses observed for flavonoids in the gastrointestinal track resemble aryl hydrocarbon receptor (AhR)-mediated effects. Therefore, we examined the structure–activity relationships of isoflavones and isomeric flavone and flavanones as AhR ligands on the basis of their induction of CYP1A1, CYP1B1, and UGT1A1 gene expression in colon cancer Caco2 cells and young adult mouse colonocyte (YAMC) cells. Caco2 cells were significantly more Ah-responsive than YAMC cells, and this was due, in part, to flavonoid-induced cytotoxicity in the latter cell lines. The structure–activity relationships for the flavonoids were complex and both response and cell context specific; however, there was significant variability in the AhR activities of the isomeric substituted isoflavones and flavones. For example, 4′,5,7-trihydroxyisoflavone (genistein) was AhR-inactive whereas 4′,5,7-trihydroxyflavone (apigenin) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells. In contrast, both 5,7-dihydroxy-4-methoxy substituted isoflavone (biochanin A) and flavone (acacetin) induced all three AhR-responsive genes; 4′,5,7-trimethoxyisoflavone was a potent AhR agonist, and the isomeric flavone was AhR-inactive. These results coupled with simulation studies modeling flavonoid interaction within the AhR binding pocket demonstrate that the orientation of the substituted phenyl ring at C-2 (flavones) or C-3 (isoflavones) on the common 4-H-chromen-4-one ring strongly influences the activities of isoflavones and flavones as AhR agonists.

The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of “cooperation response genes” to modulate the function of cancer “driver” genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell–targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis. Implications: Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.

Human modification of water and nutrient flows has resulted in widespread degradation of aquatic ecosystems. The resulting global water crisis causes millions of deaths and trillions of USD in economic damages annually. Semiarid regions have been disproportionately affected because of high relative water demand and pollution. Many proven water management strategies are not fully implemented, partially because of a lack of public engagement with freshwater ecosystems. In this context, we organized a large citizen science initiative to quantify nutrient status and cultivate connection in the semiarid watershed of Utah Lake (USA). Working with community members, we collected samples from ~200 locations throughout the 7,640 km2 watershed on a single day in the spring, summer, and fall of 2018. We calculated ecohydrological metrics for nutrients, major ions, and carbon. For most solutes, concentration and leverage (influence on flux) were highest in lowland reaches draining directly to the lake, coincident with urban and agricultural sources. Solute sources were relatively persistent through time for most parameters despite substantial hydrological variation. Carbon, nitrogen, and phosphorus species showed critical source area behavior, with 10–17% of the sites accounting for most of the flux. Unlike temperate watersheds, where spatial variability often decreases with watershed size, longitudinal variability showed an hourglass shape: high variability among headwaters, low variability in mid-order reaches, and high variability in tailwaters. This unexpected pattern was attributable to the distribution of human activity and hydrological complexity associated with return flows, losing river reaches, and diversions in the tailwaters. We conclude that participatory science has great potential to reveal ecohydrological patterns and rehabilitate individual and community relationships with local ecosystems. In this way, such projects represent an opportunity to both understand and improve water quality in diverse socioecological contexts.

Lithium fluoride (LiF) is difficult to work with because of its hygroscopic nature (it pulls water out of air). The stability limits of LiF thin films and the nature of their failure when exposed to humid air are poorly understood. We show that LiF films undergo irreversible changes in optical properties and microstructure as determined by ellipsometry and SEM when exposed to dew points greater than 6 C. On the other hand, samples stored at a dew point of -22 C (4% RH at room temperature), showed only small changes in ellipsometric parameters. The ones stored at intermediate humidity 6 C (21% RH at room temperature) showed larger changes in ellipsometric parameters. SEM shows that deliquescence as well as efflorescence is important in LiF thin films. In situ spectroscopic ellipsometric measurements using a controlled variable humidity environment illuminates the changes in LiF thin films moving from moisture absorption to complete deliquescence.

Background Diet, loss of aryl hydrocarbon receptor (AhR) expression and their modification of the gut microbiota community composition and its metabolites affect the development of colorectal cancer (CRC). However, the concordance between fecal microbiota composition and the fecal metabolome is poorly understood. Mice with specific AhR deletion (AhRKO) in intestinal epithelial cell and their wild-type littermates were fed a low-fat diet or a high-fat diet. Shifts in the fecal microbiome and metabolome associated with diet and loss of AhR expression were assessed. Microbiome and metabolome data were integrated to identify specific microbial taxa that contributed to the observed metabolite shifts. Results Our analysis shows that diet has a more pronounced effect on mouse fecal microbiota composition than the impact of the loss of AhR. In contrast, metabolomic analysis showed that the loss of AhR in intestinal epithelial cells had a more pronounced effect on metabolite profile compared to diet. Integration analysis of microbiome and metabolome identified unclassified Clostridiales, unclassified Desulfovibrionaceae, and Akkermansia as key contributors to the synthesis and/or utilization of tryptophan metabolites. Conclusions Akkermansia are likely to contribute to the synthesis and/or degradation of tryptophan metabolites. Our study highlights the use of multi-omic analysis to investigate the relationship between the microbiome and metabolome and identifies possible taxa that can be targeted to manipulate the microbiome for CRC treatment.

We report on a large-area, high-aspect-ratio, carbon nanotube (CNT) forest structure produced at BYU acting as a window/separator for a hollow cathode EUV lamp. The structure has large-surface-area, high light trans-mission, and differential pumping. CNT fabrication allows for variable dimensions, which allows various EUV distributions and pressure gradients to be possible. Theory is presented for predicting such distributions and gradients. Several structures have been fabricated; their dimensions, properties, and predicted distributions and gradients are given.

The aryl hydrocarbon receptor (AhR), a ligand‐activated transcription factor that senses xenobiotics, diet, and gut microbial‐derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5(+) stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal‐specific AhR knockout increases basal stem cell and crypt injury‐induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis‐associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR‐FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior.

Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17β-estradiol (E2). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E2 on glucose homeostasis in male and ovariectomized (OVX) female control and liver-specific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E2 regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E2 implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E2 were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E2 suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E2 action on the suppression of gluconeogenesis. We further demonstrated that E2 suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)α–phosphoinositide 3-kinase–Akt–Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E2 in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ERα can be a potential approach to modulate glucose metabolism and prevent diabetes.

Inflammatory bowel disease is a complex collection of disorders. Microbial dysbiosis as well as exposure to toxins including xenoestrogens are thought to be risk factors for inflammatory bowel disease development and relapse. Bisphenol-A has been shown to exert estrogenic activity in the colon and alter intestinal function, but the role that xenoestrogens, such as bisphenol-A , play in colonic inflammation has been previously described but with conflicting results. We investigated the ability of bisphenol-A to exacerbate colonic inflammation and alter microbiota metabolites derived from aromatic amino acids in an acute dextran sulfate sodium-induced colitis model. Female C57BL/6 mice were ovariectomized and exposed to bisphenol-A daily for 15 days. Disease activity measures include body weight, fecal consistency, and rectal bleeding. Colons were scored for inflammation, injury, and nodularity. Alterations in the levels of microbiota metabolites derived from aromatic amino acids known to reflect phenotypic changes in the gut microbiome were analyzed. Bisphenol-A exposure increased mortality and worsened disease activity as well as inflammation and nodularity scores in the middle colon region following dextran sulfate sodium exposure. Unique patterns of metabolites were associated with bisphenol-A consumption. Regardless of dextran sulfate sodium treatment, bisphenol-A reduced levels of tryptophan and several metabolites associated with decreased inflammation in the colon. This is the first study to show that bisphenol-A treatment alone can reduce microbiota metabolites derived from aromatic amino acids in the colon which may be associated with increased colonic inflammation and inflammatory bowel disease. Impact statement As rates of inflammatory bowel disease rise, discovery of the mechanisms related to the development of these conditions is important. Environmental exposure is hypothesized to play a role in etiology of the disease, as are alterations in the gut microbiome and the metabolites they produce. This study is the first to show that bisphenol-A alone alters tryptophan and microbiota metabolites derived from aromatic amino acids in a manner consistent with autoimmune diseases, specifically inflammatory bowel diseases, regardless of dextran sulfate sodium treatment. These findings indicate a potential mechanism by which bisphenol-A negatively affects gut physiology to exacerbate inflammation.

Background A major toxicity concern in radioembolization therapy of hepatic malignancies is radiation-induced pneumonitis and sclerosis due to hepatopulmonary shunting of 90Y microspheres. Currently, 99mTc macroaggregated albumin (99mTc-MAA) imaging is used to estimate the lung shunt fraction (LSF) prior to treatment. The aim of this study was to evaluate the accuracy/precision of LSF estimated from 99mTc planar and SPECT/CT phantom imaging, and within this context, to compare the corresponding LSF and lung-absorbed dose values from 99mTc-MAA patient studies. Additionally, LSFs from pre- and post-therapy imaging were compared. Results A liver/lung torso phantom filled with 99mTc to achieve three lung shunt values was scanned by planar and SPECT/CT imaging with repeat acquisitions to assess accuracy and precision. To facilitate processing of patient data, a workflow that relies on SPECT and CT-based auto-contouring to define liver and lung volumes for the LSF calculation was implemented. Planar imaging-based LSF estimates for 40 patients, obtained from their medical records, were retrospectively compared with SPECT/CT imaging-based calculations with attenuation and scatter correction. Additionally, in a subset of 20 patients, the pre-therapy estimates were compared with 90Y PET/CT-based measurements. In the phantom study, improved accuracy in LSF estimation was achieved using SPECT/CT with attenuation and scatter correction (within 13% of the true value) compared with planar imaging (up to 44% overestimation). The results in patients showed a similar trend with planar imaging significantly overestimating LSF compared to SPECT/CT. There was no correlation between lung shunt estimates and the delay between 99mTc-MAA administration and scanning, but off-target extra hepatic uptake tended to be more likely in patients with a longer delay. The mean lung absorbed dose predictions for the 28 patients who underwent therapy was 9.3 Gy (range 1.3–29.4) for planar imaging and 3.2 Gy (range 0.4–13.4) for SPECT/CT. For the patients with post-therapy imaging, the mean LSF from 90Y PET/CT was 1.0%, (range 0.3–2.8). This value was not significantly different from the mean LSF estimate from 99mTc-MAA SPECT/CT (mean 1.0%, range 0.4–1.6; p = 0.968), but was significantly lower than the mean LSF estimate based on planar imaging (mean 4.1%, range 1.2–15.0; p = 0.0002). Conclusions The improved accuracy demonstrated by the phantom study, agreement with 90Y PET/CT in patient studies, and the practicality of using auto-contouring for liver/lung definition suggests that 99mTc-MAA SPECT/CT with scatter and attenuation corrections should be used for lung shunt estimation prior to radioembolization.

Scope This study investigates the mechanism of action and functional effects of coffee extracts in colonic cells, on intestinal stem cell growth, and inhibition of dextran sodium sulfate (DSS)-induced intestinal barrier damage in mice. Methods and results Aqueous coffee extracts induced Ah receptor (AhR) -responsive CYP1A1, CYP1B1, and UGT1A1 gene expression in colon-derived Caco2 and YAMC cells. Tissue-specific AhR knockout (AhRf/f x Lgr5-GFP-CreERT2 x Villin-Cre), wild-type (Lgr5-CreERT2 x Villin-Cre) mice are sources of stem cell enriched organoids and both coffee extracts and norharman, an AhR-active component of these extracts inhibited stem cell growth. Coffee extracts also inhibit DSS-induced damage to intestinal barrier function and DSS-induced mucosal inflammatory genes such as IL-6 and TGF-β1 in wild-type (AhR+/+ ) but not AhR-/- mice. In contrast, coffee does not exhibit protective effects in intestinal-specific AhR knockout mice. Coffee extracts also enhanced overall formation of AhR-active microbial metabolites. Conclusions In colon-derived cells and in the mouse intestine, coffee induced several AhR-dependent responses including gene expression, inhibition of intestinal stem cell-enriched organoid growth, and inhibition of DSS-induced intestinal barrier damage. We conclude that the anti-inflammatory effects of coffee in the intestine are due, in part, to activation of AhR signaling.

Oxidation of a ∼1000 A sputter-deposited thorium thin film at 150 °C in 100 ppm of flowing oxygen in argon produces the long-sought solid form of thorium monoxide. Changes in the scattering length density (SLD) distribution in the film over the 700-min experiment measured by in-situ, dynamic neutron reflectometry (NR) shows the densities, compositions and thickness of the various thorium oxides layers formed. Screened, hybrid density-functional theory calculations of potential thorium oxides aid interpretation, providing atomic-level picture and energetics for understanding oxygen migration. NR provided evidence of the formation of substoichiometric thorium oxide, ThOy (y

Consumption of a high-fat diet has been associated with an increased risk of developing colorectal cancer (CRC). However, the effects of the interaction between dietary fat content and the aryl hydrocarbon receptor (AhR) on colorectal carcinogenesis remain unclear. Mainly known for its role in xenobiotic metabolism, AhR has been identified as an important regulator for maintaining intestinal epithelial homeostasis. Although previous research using whole body AhR knockout mice has revealed an increased incidence of colon and cecal tumors, the unique role of AhR activity in intestinal epithelial cells (IECs) and modifying effects of fat content in the diet at different stages of sporadic CRC development are yet to be elucidated. In the present study, we have examined the effects of a high-fat diet on IEC-specific AhR knockout mice in a model of sporadic CRC. Although loss of AhR activity in IECs significantly induced the development of premalignant lesions, in a separate experiment, no significant changes in colon mass incidence were observed. Moreover, consumption of a high-fat diet promoted cell proliferation in crypts at the premalignant colon cancer lesion stage and colon mass multiplicity as well as β-catenin expression and nuclear localization in actively proliferating cells in colon masses. Our data demonstrate the modifying effects of high-fat diet and AhR deletion in IECs on tumor initiation and progression. NEW & NOTEWORTHY Through the use of an intestinal-specific aryl hydrocarbon receptor (AhR) knockout mouse model, this study demonstrates that the expression of AhR in intestinal epithelial cells is required to reduce the formation of premalignant colon cancer lesions. Furthermore, consumption of a high-fat diet and the loss of AhR in intestinal epithelial cells influences the development of colorectal cancer at various stages.

Uranium and thorium oxides have critical roles as fuels in existing nuclear power plants, as well as in proposed reactor concepts. The thermal conductivity of these materials determines their ability to transfer heat from the reactor core to the surrounding coolant. Additionally, these actinide compounds are of interest in condensed matter physics because of the 5f orbitals and unique electron interaction, coupling, and scattering events that can occur. Because of the radioactivity of thorium and uranium, thin film measurements of actinide materials are used to limit the amount of operator exposure, but standard thermal characterization methods are not well suited for thin films. This paper presents the process of depositing thin film UOx and ThOx samples of nm-μm thicknesses and the results of thermal property measurements. Thin films were deposited on silicon and glass substrates via dc-magnetron sputtering using an argon/oxygen mixture as the working gas. The thermal properties of the films were measured by the Thermal Conductivity Microscope (TCM). This uses one laser to generate thermal waves and a second laser to measure the magnitude and phases of the thermal waves to obtain the conductivity of materials. The results of the research show that the UOx film properties are lower than bulk values and that the role of the substrate has a considerable effect on determining the measured properties. Future work aims at improving the deposition process. Epitaxial film growth is planned. Additional understanding of thermal property measurements is targeted.

Pancreatic islets, also called the Islets of Langerhans, are a cluster of endocrine cells which produces hormones for glucose regulation and other important biological functions. The islets primarily consist of five types of hormone-secreting cells: α cells secrete glucagon, β cells secrete insulin, δ cells secrete somatostatin, ε cells secrete ghrelin, and PP cells secrete pancreatic polypeptide. Sixty to 80% of the cells in the islets are β cells, which are the most important cell population to study insulin secretion. Pancreatic islets are a crucial model system to study ex vivo insulin secretion. Acquiring high quality islets is of great importance for diabetes research. Most islet isolation procedures require technically difficult to access site of collagenase injection, harsh and complex digestion procedures, and multiple density gradient purification steps. This paper features a simple high yield mouse islet isolation method with detailed descriptions and realistic demonstrations, showing the following specific steps: 1) injection of collagenase P at the ampulla of Vater, a small area joining the pancreatic duct and the common bile duct, 2) enzymatic digestion and mechanical separation of the exocrine pancreas, and 3) a single gradient purification step. The advantages of this method are the injection of digestive enzyme using the more accessible ampulla of Vater, more complete digestion using combination of enzymatic and mechanical approaches, and a simpler single gradient purification step. This protocol produces approximately 250—350 islets per mouse; and islets are suitable for various ex vivo studies. Possible caveats of this procedure are potentially damaged islets due to enzymatic digestion and/or prolonged gradient incubation, all of which can be largely avoided by careful ad justification of incubation time.

Approximately 10–40% of strokes are cryptogenic (CS). Long-term electrocardiographic (ECG) monitoring has been recommended in these patients to search for atrial fibrillation (AF). An unresolved issue is whether ambulatory ECG (AECG) monitoring should be performed first, followed by an implantable loop recorder (ILR) if AECG monitoring is non-diagnostic, or whether long-term ECG monitoring should be initiated using ILRs from the onset. The purpose of this study was to assess, using an ILR, AF incidence in the first month after CS. We enrolled consecutive CS patients referred for an ILR. All patients were monitored via in-hospital continuous telemetry from admission until the ILR (Medtronic [Minneapolis, MN] LINQ™) was implanted. The duration and overall burden of all AF episodes ≥ 2 min was determined. The cohort included 343 patients (68 ± 11 years, CHA2DS2-VASc 3.5 ± 1.7). The time between stroke and ILR was 3.7 ± 1.5 days. During the first 30 days, only 18 (5%) patients had AF. All episodes were paroxysmal, lasting from 2 min to 67 h and 24 min. The median AF burden was 0.85% (IQR 0.52, 10.75). During 1 year of follow-up, 67 (21%) patients had AF. The likelihood of AF detection by an ILR in the first month post-CS is low. Thus, the diagnostic yield of 30 days of AECG monitoring is likely to be limited. These data suggest a rationale for proceeding directly to ILR implantation prior to hospital discharge in CS patients, as many have AF detected during longer follow-up.

We report optical constants of e-beam evaporated yttrium oxide Y2O3 thin films as determined from angle-dependent reflectance measurements at wavelengths from 5 to 50 nm. Samples were measured using synchrotron radiation at the Advanced Light Source. The experimental reflectance data were fit to obtain values for the index of refraction and thin film roughness. We compare our computed constants with those of previous researchers and those computed using the independent atom approximation from the CXRO website. We found that the index of refraction near 36 nm is much lower than previous data from Tomiki as reported by Palik. The real part of the optical constants is about 10% to 15% below CXRO values for wavelengths between 17 nm and 30 nm. Films were also characterized chemically, structurally, and optically by ellipsometry and atomic force microscopy.

To maintain high, broad-band reflectance, thin transparent fluoride layers, such as MgF2, are used to protect aluminum mirrors against oxidation. In this study, we present, for the first time, combined X-ray photoelectron spectroscopy (XPS) and spectroscopic ellipsometric (SE) studies of aluminum oxidation as a function of MgF2 overlayer thickness (thickness 0-5 nm). Dynamic SE tracks the extent of oxide growth every ca. 2s over a period of several hours after the evaporated Al + MgF2 bilayer is removed from the deposition chamber. Aluminum oxidation changes under the fluoride layer were quantitatively verified with XPS. Changes in chemical state from Al metal to Al oxide were directly observed. Oxide growth is computed from relative XPS peak areas as corrected for electron attenuation through the MgF2 overlayer. An empirical formula fits time-dependent data for aluminum surfaces protected by MgF2 as a function of MgF2 layer thickness: aluminum-oxide thickness = kSE*log(t)+bSE. The slope depends only on MgF2 thickness, decreasing monotonically with increasing MgF2 thickness. This method of employing SE coupled with XPS can be extendable to the study of other metal/overlayer combinations.

An optical fiber thermometer consists of an optical fiber whose tip is coated with a highly conductive, opaque material. When heated, this sensing tip becomes an isothermal cavity that emits like a blackbody. This emission is used to predict the sensing tip temperature. In this work, analytical and experimental research has been conducted to further advance the development of optical fiber thermometry. An inexpensive optical fiber thermometer is developed by applying a thin coating of a high-temperature cement onto the tip of a silica optical fiber. An FTIR spectrometer is used to detect the spectral radiance exiting the fiber. A rigorous mathematical model of the irradiation incident on the detection system is developed. The optical fiber thermometer is calibrated using a blackbody radiator and inverse methods are used to predict the sensing tip temperature when exposed to various heat sources.

U-6Nb is a uranium alloy containing 6 wt% niobium that possesses high corrosion resistance. The structure and composition of the passivating oxide layer formed on air-aged U-6Nb, which gives the material its corrosion resistant properties, was characterized using surface scattering techniques. Stable oxide layers formed on the surface of a set of U-6Nb alloy thin films under ambient conditions were investigated using neutron reflectometry (NR), x-ray reflectometry (XRR) and grazing incidence x-ray diffraction (GIXD). The passivating oxide was composed of approximately 27% U, 5% Nb, and 68% O, primarily consisting of a thin niobium oxide layer (5.5 ± 0.4 nm) separating a thicker UO2 layer (27.1 ± 2.3 nm) from the underlying U-6Nb alloy. A critical density of enriched niobium oxide at the metal-oxide interface is hypothesized to limit oxygen diffusion and confer high corrosion resistance to the alloy.

While no solid barrier layer is transparent below ~103nm, simulations show that ~9.5nm LiF on 8.5nm MgF2 on Al could reflect some hydrogen Lyman lines better than a single fluoride layer does. Experiments are promising.

Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part, owing to a reduction in circulating 17β-estradiol (E2). Fasting hyperglycemia, a feature of diabetes mellitus, is largely derived from dysregulation of hepatic glucose production (HGP), in which hyper-activated Foxo1 induces transcription of genes coding gluconeogenic enzymes. We investigated the E2 action on the regulation of glucose hemostasis in male and ovariectomized (OVX) female of control and liver-specific Foxo1 knockout (L-F1KO) mice, and sought to understand the mechanism by which E2 regulates gluconeogenesis via the interaction with liver Foxo1. E2 subcutaneous implant led to decreased fasting blood glucose and improvement of insulin sensitivity in both male and OVX female mice in parallel with the suppression of gluconeogenesis and hepatic gluconeogenic gene expression, including glucose 6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase 1 (Pck1). Importantly, these effects of E2 were only observed in control mice but disrupted in L-F1KO mice. Moreover, suppression of HGP and gluconeogenesis by E2 only occurred in hepatocytes isolated from control mice and we confirmed that Foxo1 was required for the E2 action on gluconeogenesis. E2 suppressed Foxo1 via activation of ERα and phosphorylation of Akt, while inhibition of both ERα and Akt signaling abolished the effect of E2 on gluconeogenesis. Collectively we demonstrated that the activation of ERα-Akt-Foxo1 signaling serves as an important mechanism of estrogen in control of glucose homeostasis. These results may help explain the gender difference in the incidence of type 2 diabetes and suggest an approach to target ERα to modulate glucose metabolism in diabetic patients. Disclosure H. Yan: None. F. Zhou: None. W. Yang: None. Q. Pan: None. Z. Shen: None. G. Han: None. K. Allred: None. C. Allred: None. Y. Xu: None. S. Guo: None.

Flaxseed and its bioactive components have been associated with a decreased risk of colorectal cancer incidence and progression. This review aims to summarize recent research regarding the role of flaxseed and each of its major dietary bioactive components in reducing colorectal cancer. In both human and animal model experiments, flaxseed consumption had beneficial effects on colon physiology associated with reduction in colorectal cancer risk or occurrence. Considered separately, each of flaxseed’s major bioactive components, including fiber, alpha-linolenic acid, lignans, and other phytochemicals, is also associated with decreased risk of colonic neoplasms and regulation of cell growth through several potential mechanisms. Collectively, experimental data suggests that consumption of flaxseed and/or its bioactive components may reduce colorectal cancer risk by a variety of mechanisms. Future studies should focus on the mechanisms by which whole flaxseed can prevent colorectal cancer.