Nicholas O Davidson

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (218)1643.69 Total impact

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    ABSTRACT: Apolipoprotein (apo) B is an obligatory component of very low-density lipoprotein (VLDL), whose co- and posttranslational modifications are important in VLDL synthesis, secretion and hepatic lipid homeostasis. ApoB100 contains 25 cysteine residues and 8 disulfide bonds. Although these disulfide bonds were suggested to be important in maintaining apoB100 function, neither the specific oxidoreductase involved nor the direct role of these disulfide bonds in apoB100-lipidation are known. Herein, we used RNA knockdown to evaluate both MTP-dependent and -independent roles of PDI1 in apoB100 synthesis and lipidation in McA-RH7777 cells. Pdi1-knockdown did not elicit any discernible detrimental effect under normal, unstressed conditions. However, it decreased apoB100 synthesis with attenuated MTP activity, delayed apoB100 oxidative folding and reduced apoB100 lipidation, leading to defective VLDL secretion. The oxidative folding-impaired apoB100 was secreted mainly associated with LDL instead of VLDL particles from PDI1-deficient cells, a phenotype which was fully rescued by overexpression of wildtype but not a catalytically inactive PDI1 that fully restored MTP activity. Further, we demonstrate that PDI1 directly interacts with apoB100 via its redox-active CXXC motifs and assist in the oxidative folding of apoB100. Taken together, these findings reveal an unsuspected, yet, key role for PDI1 in oxidative folding of apoB100 and VLDL assembly. © 2014 by The American Society for Cell Biology.
    Molecular Biology of the Cell 12/2014; · 4.55 Impact Factor
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    ABSTRACT: Disparities by race and neighborhood socioeconomic status exist for many colorectal cancer (CRC) outcomes, including screening use and mortality. We used population-based data to determine if disparities also exist for emergency CRC diagnosis and surgery. We examined two emergency CRC outcomes using 1992-2005 population-based U.S. SEER-Medicare data. Among CRC patients aged >=66 years, we examined racial (African American vs. white) and neighborhood poverty disparities in two emergency outcomes defined as: 1) newly diagnosed CRC or 2) CRC surgery associated with: obstruction, perforation, or emergency inpatient admission. Multilevel logistic regression (patients nested in census tracts) analyses adjusted for sociodemographic, tumor, and clinical covariates. Of 83,330 CRC patients, 29.1% were diagnosed emergently. Of 55,046 undergoing surgery, 26.0% had emergency surgery. For both outcomes, race and neighborhood poverty disparities were evident. A significant race by poverty interaction (p < .001) was noted: poverty rate was associated with both outcomes among African Americans, but not whites. Compared to whites in low poverty (<10%) neighborhoods, African Americans in high poverty (>=20%) neighborhoods had increased odds of emergency diagnosis (AOR: 1.50, 95% CI: 1.38-1.63) and surgery (AOR: 1.63, 95% CI: 1.47-1.81). Emergency CRC outcomes are associated with high poverty residence among African Americans in this population-based study, potentially contributing to observed disparities in CRC morbidity and mortality. Targeted efforts to increase CRC screening among African Americans living in high poverty neighborhoods could reduce preventable disparities.
    BMC Cancer 12/2014; 14(1):927. · 3.32 Impact Factor
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    ABSTRACT: APOBEC1 is a cytidine deaminase involved in cholesterol metabolism that has been linked to retrovirus restriction, analogous to the evolutionarily-related APOBEC3 proteins. In particular, murine APOBEC1 was shown to inhibit Friend retrovirus (FV) in vitro, generating high levels of C-to-T and G-to-A mutations. These observations raised the possibility that FV infection might be altered in APOBEC1-null mice. To examine this question directly, we infected wild-type and APOBEC1-null mice with FV complex and evaluated acute infection levels. Surprisingly, APOBEC1-null mice exhibited similar cellular infection levels and plasma viremia relative to wild-type mice. Moreover, next-generation sequencing analyses revealed that in contrast to APOBEC3, APOBEC1 did not enhance retroviral C-to-T and G-to-A mutational frequencies in genomic DNA. Thus, APOBEC1 neither inhibited nor significantly drove the molecular evolution of FV in vivo. Our findings reinforce that not all retrovirus restriction factors characterized as potent in vitro may be functionally relevant in vivo.
    Virology 10/2014; 468-470C:601-608. · 3.28 Impact Factor
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    ABSTRACT: To develop a prognostic model to predict 30-day mortality following colorectal cancer (CRC) surgery using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data and to assess whether race/ethnicity, neighborhood, and hospital characteristics influence model performance.
    Cancer Causes and Control 08/2014; · 2.96 Impact Factor
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    ABSTRACT: HuR is a ubiquitous nucleocytoplasmic RNA binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur IKO mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of ApcMin mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a 3-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis and decreased expression of transcripts encoding anti-apoptotic HuR target RNAs. Similarly, Hur IKO mice subjected to an inflammatory colon carcinogenesis protocol (AOM-DSS administration) exhibited a 2-fold decrease in tumor burden. Hur IKO mice showed no change in ileal Asbt expression, fecal bile acid excretion or enterohepatic pool size that might explain the phenotype. Moreover, none of the HuR targets identified in Apc Min/+Hur IKO were altered in AOM-DSS treated Hur IKO mice, the latter of which exhibited increased apoptosis of colonic epithelial cells where elevation of a unique set of HuR-targeted pro-apoptotic factors was documented. Taken together, our results promote the concept of epithelial HuR as a contextual modifier of pro-apoptotic gene expression in intestinal cancers, acting independently of bile acid metabolism to promote cancer. In the small intestine, epithelial HuR promotes expression of pro-survival transcripts that support Wnt-dependent tumorigenesis, whereas in the large intestine epithelial HuR indirectly downregulates certain pro-apoptotic RNAs to attenuate colitis-associated cancer.
    Cancer Research 08/2014; · 9.28 Impact Factor
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    ABSTRACT: Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis.
    PLoS ONE 07/2014; 9(7):e101828. · 3.53 Impact Factor
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    ABSTRACT: Background RNA editing encompasses a post-transcriptional process in which the genomically templated sequence is enzymatically altered and introduces a modified base into the edited transcript. Mammalian C-to-U RNA editing represents a distinct subtype of base modification, whose prototype is intestinal apolipoproteinB mRNA, mediated by the catalytic deaminase Apobec-1. However, the genome-wide identification, tissue-specificity and functional implications of Apobec-1 mediated C-to-U RNA editing remain incompletely explored. Results Deep sequencing, data filtering and Sanger-sequence validation of intestinal and hepatic RNA from wild-type and Apobec-1 deficient mice revealed 56 novel editing sites in 54 intestinal mRNAs and 22 novel sites in 17 liver mRNAs, all within 3[prime] untranslated regions. Eleven of 17 liver RNAs shared editing sites with intestinal RNAs, while 6 sites are unique to liver. Changes in RNA editing lead to corresponding changes in intestinal mRNA and protein levels in 11 genes. Analysis of RNA editing in vivo following tissue-specific Apobec-1 adenoviral or transgenic Apobec-1 overexpression reveals that a subset of targets identified in wild-type mice are restored in Apobec-1 deficient mouse intestine and liver following Apobec-1 rescue. We find distinctive polysome profiles for several RNA editing targets and demonstrate novel exonic editing sites in nuclear preparations from intestine but not hepatic apolipoprotein B RNA. RNA editing is validated using cell-free extracts from wild-type but not Apobec-1 deficient mice, demonstrating that Apobec-1 is required. Conclusions These studies define selective, tissue-specific targets of Apobec-1 dependent RNA editing and show the functional consequences of editing are both transcript- and tissue-specific.
    Genome Biology 06/2014; · 10.47 Impact Factor
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    ABSTRACT: The presence of advanced adenomas in younger individuals is a criterion for Lynch syndrome (LS). However, the utility of screening advanced adenomas for loss of mismatch repair (MMR) protein expression to identify suspected LS remains unclear.
    Digestive Diseases and Sciences 06/2014; · 2.55 Impact Factor
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    ABSTRACT: Colorectal cancer (CRC) incidence and mortality are higher in African Americans (AAs) than in Caucasian Americans (CAs) and microRNAs (miRNAs) have been found to be dysregulated in colonic and other neoplasias. The aim of this exploratory study was to identify candidate miRNAs that could contribute to potential biological differences between AA and CA colon cancers. Total RNA was isolated from tumor and paired adjacent normal colon tissue from 30 AA and 31 CA colon cancer patients archived at Stony Brook University (SBU) and Washington University (WU)‑St. Louis Medical Center. miRNA profiles were determined by probing human genome-wide miRNA arrays with RNA isolated from each sample. Using repeated measures analysis of variance (RANOVA), miRNAs were selected that exhibited significant (p<0.05) interactions between race and tumor or significant (fold change >1.5, p<0.05) main effects of race and/or tumor. Quantitative polymerase chain reaction (q-PCR) was used to confirm miRNAs identified by microarray analysis. Candidate miRNA targets were analyzed using immunohistochemistry. RANOVA results indicated that miR-182, miR152, miR-204, miR-222 and miR-202 exhibited significant race and tumor main effects. Of these miRNAs, q-PCR analysis confirmed that miR-182 was upregulated in AA vs. CA tumors and exhibited significant race:tumor interaction. Immunohistochemical analysis revealed that the levels of FOXO1 and FOXO3A, two potential miR-182 targets, are reduced in AA tumors. miRNAs may play a role in the differences between AA and CA colon cancer. Specifically, differences in miRNA expression levels of miR-182 may contribute to decreased survival in AA colon cancer patients.
    International Journal of Oncology 05/2014; · 2.77 Impact Factor
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    ABSTRACT: The purpose of this study was to describe hospital and geographic variation in 30-day risk of surgical complications and death among colorectal cancer (CRC) patients and the extent to which patient-, hospital-, and census-tract-level characteristics increased risk of these outcomes. We included patients at least 66 years old with first primary stage I-III CRC from the 2000-2005 National Cancer Institute's Surveillance, Epidemiology, and End Results data linked with 1999-2005 Medicare claims. A multilevel, cross-classified logistic model was used to account for nesting of patients within hospitals and within residential census tracts. Outcomes were risk of complications and death after a complication within 30 days of surgery. Data were analyzed for 35,946 patients undergoing surgery at 1,222 hospitals and residing in 12,187 census tracts; 27.2 % of patients developed complications, and of these 13.4 % died. Risk-adjusted variability in complications across hospitals and census tracts was similar. Variability in mortality was larger than variability in complications, across hospitals and across census tracts. Specific characteristics increased risk of complications (e.g., census-tract-poverty rate, emergency surgery, and being African-American). No hospital characteristics increased complication risk. Specific characteristics increased risk of death (e.g. census-tract-poverty rate, being diagnosed with colon (versus rectal) cancer, and emergency surgery), while hospitals with at least 500 beds showed reduced death risk. Large, unexplained variations exist in mortality after surgical complications in CRC across hospitals and geographic areas. The potential exists for quality improvement efforts targeted at the hospital and/or census-tract levels to prevent complications and augment hospitals' ability to reduce mortality risk.
    Annals of Surgical Oncology 04/2014; · 3.94 Impact Factor
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    ABSTRACT: The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression-as observed in inflammatory bowel disease-may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
    Nature 04/2014; · 42.35 Impact Factor
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    ABSTRACT: Objective To assess hospital and geographic variability in 30-day mortality after surgery for CRC and examine the extent to which sociodemographic, area-level, clinical, tumor, treatment, and hospital characteristics were associated with increased likelihood of 30-day mortality in a population-based sample of older CRC patients.Data Sources/Study SettingLinked Surveillance Epidemiology End Results (SEER) and Medicare data from 47,459 CRC patients aged 66 years or older who underwent surgical resection between 2000 and 2005, resided in 13,182 census tracts, and were treated in 1,447 hospitals.Study DesignAn observational study using multilevel logistic regression to identify hospital- and patient-level predictors of and variability in 30-day mortality.Data Collection/Extraction Methods We extracted sociodemographic, clinical, tumor, treatment, hospital, and geographic characteristics from Medicare claims, SEER, and census data.Principal FindingsOf 47,459 CRC patients, 6.6 percent died within 30 days following surgery. Adjusted variability in 30-day mortality existed across residential census tracts (predicted mortality range: 2.7–12.3 percent) and hospitals (predicted mortality range: 2.5–10.5 percent). Higher risk of death within 30 days was observed for CRC patients age 85+ (12.7 percent), census-tract poverty rate >20 percent (8.0 percent), two or more comorbid conditions (8.8 percent), stage IV at diagnosis (15.1 percent), undifferentiated tumors (11.6 percent), and emergency surgery (12.8 percent).Conclusions Substantial, but similar variability was observed across census tracts and hospitals in 30-day mortality following surgery for CRC in patients 66 years and older. Risk of 30-day mortality is driven not only by patient and hospital characteristics but also by larger social and economic factors that characterize geographic areas.
    Health Services Research 03/2014; · 2.49 Impact Factor
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    ABSTRACT: Comanagement of surgical patients has increased, but information regarding detailed characteristics of patients receiving comanagement during hospitalization for colorectal cancer (CRC) surgery is lacking. To examine the use of and characteristics associated with comanagement of patients hospitalized for CRC surgery. This study used a population-based cross-sectional design. We used the linked 2000 to 2005 Surveillance, Epidemiology, and End Results and Medicare claims data. We included 37,065 patients aged 66 years or older, hospitalized for definitive CRC surgery following stage I to III diagnosis. The outcome of interest was comanagement during hospitalization for CRC surgery, and we examined the association between several patient and hospital characteristics. Comanagement was defined as having a relevant physician (ie, internal medicine hospitalist/generalist) submit a claim for evaluation and management services on 70% or more of the days of hospitalization of the patient. During hospitalization for CRC surgery, 27.6% of patients were comanaged, but this percentage varied widely across hospitals (from 1.9% to 83.2%). Several patient and hospital characteristics were associated with the use of comanaged care, of which important characteristics included older age at diagnosis, presence of comorbidity, emergency surgery, and hospital volume. Extensive variability existed in comanagement use across patients and hospitals, likely reflecting the lack of evidence for its clinical effectiveness. Journal of Hospital Medicine 2014. © 2014 Society of Hospital Medicine.
    Journal of Hospital Medicine 02/2014; · 2.08 Impact Factor
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    ABSTRACT: Previous studies demonstrated that L-Fabp knockout mice are more susceptible to LD induced gallstones because of altered hepatic cholesterol metabolism and increased canalicular cholesterol secretion. Other studies demonstrated that liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) reduced lithogenic diet (LD) induced gallstone formation by increasing biliary phospholipid secretion. Here we show that mice with combined deletion (ie DKO mice) are protected from LD induced gallstone formation. Following two weeks LD feeding, 73% of wild-type (WT) and 100% of L-Fabp knockout mice developed gallstones versus 18% of Mttp-LKO and 23% of DKO mice. This phenotype was recapitulated in both WT and L-Fabp knockout mice treated with an Mttp antisense oligonucleotide (M-ASO). Biliary cholesterol secretion was increased in LD fed L-Fabp knockout mice and decreased in DKO mice. However, phospholipid secretion was unchanged in LD fed Mttp-LKO and DKO mice as well as in M-ASO treated mice. Expression of the canalicular export pump ABCG5/G8 was reduced in LD fed DKO mice and in M-ASO treated L-Fabp knockout mice. We conclude that liver-specific Mttp deletion not only eliminates apical lipoprotein secretion from hepatocytes but also attenuates canalicular cholesterol secretion, which in turn decreases LD induced gallstone susceptibility.
    The Journal of Lipid Research 01/2014; · 4.73 Impact Factor
  • Cancer Prevention Research 01/2014; 5(11_Supplement):A94-A94. · 5.27 Impact Factor
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    Soghra Jarvandi, Nicholas O Davidson, Mario Schootman
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    ABSTRACT: Poor diet increases the risk of both colorectal cancer and type 2 diabetes. We investigated the role of diet in the association between diabetes and colorectal cancer. We analyzed data from 484,020 individuals, aged 50-71 years who participated in the prospective National Institutes of Health-AARP Diet and Health Study and were cancer free at baseline (1995-1996). History of diabetes was self-reported. Diet quality was measured with the Healthy Eating Index-2005 (HEI-2005), using a self-administered food-frequency questionnaire. Cox regression models were constructed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of first primary incident colorectal cancer, overall and by anatomical location. During an average follow-up of 9.2 years, we identified 7,598 new cases of colorectal cancer. After controlling for non-dietary confounders, diabetes was associated with increased risk of colorectal cancer (HR 1.27, 95% CI: 1.18, 1.36). Further adjustment for diet quality did not attenuate this association. Diabetes was associated with a HR of 1.23 (95% CI: 1.07, 1.40) in individuals with good diet (quartile 4 of HEI-2005) and 1.58 (95% CI: 1.34, 1.86) in those with poor diet (quartile 1 of HEI-2005), compared to those with no diabetes and good diet. Moreover, diabetes was associated with a stronger risk of proximal than distal colon cancer (HR: 1.33 vs. HR: 1.20), while poor diet was associated with a weaker risk of proximal colon cancer (HR: 1.18 vs. HR: 1.46). Diabetes and poor diet, independently and additively are associated with the increased risk of colorectal cancer.
    PLoS ONE 09/2013; 8(9):e74616. · 3.53 Impact Factor
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    ABSTRACT: Bile acid synthesis is regulated by nuclear receptors including farnesoid X receptor (FXR) and small heterodimer partner (SHP), and by fibroblast growth factor15/19 (FGF15/19). Because bile acid synthesis involves amino acid conjugation, we hypothesized that hepatic cysteine sulfinic acid decarboxylase (CSAD) (a key enzyme in taurine synthesis) is regulated by bile acids. To investigate CSAD regulation by bile acids and CSAD regulatory mechanisms. Mice were fed a control diet or a diet supplemented with either 0.5% cholate or 2% cholestyramine. To gain mechanistic insight into CSAD regulation, we utilized GW4064 (FXR agonist), FGF19, or T-0901317 (LXR agonist) and Shp(-/-) mice. Tissue mRNA expression was determined by qRT-PCR. Amino acids were measured by HPLC. Mice supplemented with dietary cholate exhibited reduced hepatic CSAD mRNA expression while those receiving cholestyramine exhibited increased hepatic CSAD mRNA expression. Activation of FXR suppressed CSAD mRNA expression whereas hepatic CSAD mRNA expression was increased in Shp(-/-) mice. Hepatic hypotaurine concentration (the product of CSAD) was higher in Shp(-/-) mice with a corresponding increase in serum (but not hepatic) taurine-conjugated bile acids. FGF19 administration suppressed hepatic CYP7A1 mRNA but did not change CSAD mRNA expression. LXR activation induced CYP7A1 mRNA yet failed to induce CSAD mRNA expression. CSAD mRNA expression is physiologically regulated by bile acids in a feedback fashion via mechanisms involving SHP and FXR but not FGF15/19 or LXR. These novel findings implicate bile acids as regulators of CSAD mRNA via mechanisms shared in part with CYP7A1.
    Hepatology Research 08/2013; · 2.22 Impact Factor
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    ABSTRACT: Evidence suggests a relationship between dietary fat intake, obesity and colorectal cancer, implying a role for fatty acid (FA) metabolism in intestinal tumorigenesis that is incompletely understood. Liver fatty acid binding protein (L-Fabp), a dominant intestinal FA binding protein, regulates intestinal FA trafficking and metabolism and L-Fabp deletion attenuates diet-induced obesity. Here we examined whether changes in intestinal FA metabolism following L-Fabp deletion modify adenoma development in ApcMin/+ mice. Compound L-Fabp-/-ApcMin/+ mice were generated and fed a 10% fat diet balanced equally between saturated, monounsaturated and polyunsaturated fat. L-Fabp-/-ApcMin/+ mice displayed significant reductions in adenoma number and total polyp area compared to ApcMin/+controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp-/-ApcMin/+ mice exhibited reductions in cellular proliferation, high-grade dysplasia and nuclear β-catenin translocation. Intestinal FA content was increased in L-Fabp-/-ApcMin/+ mice and lipidomic profiling of intestinal mucosa revealed significant shifts to polyunsaturated FA species with reduced saturated FA species. L-Fabp-/-ApcMin/+mice also demonstrated corresponding changes in mRNA expression of enzymes involved in FA elongation and desaturation. Furthermore, adenomas from L-Fabp-/-ApcMin/+mice displayed significant reductions in mRNA abundance of nuclear hormone receptors involved in cellular proliferation and in enzymes involved in lipogenesis. These findings collectively implicate L-Fabp as an important genetic modifier of intestinal tumorigenesis and identify FA trafficking and metabolic compartmentalization as an important pathway linking dietary fat intake, obesity and intestinal tumor formation.
    Cancer Prevention Research 08/2013; · 4.89 Impact Factor
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    ABSTRACT: BACKGROUND: Using 1998-2005 SEER-Medicare data, we examined the effect of diagnostic and treatment delays on all-cause and colorectal cancer (CRC)-specific death among US adults aged ≥ 66 years with invasive colon or rectal cancer. We hypothesized that longer delays would be associated with a greater risk of death. METHODS: We defined diagnostic and treatment delays, respectively, as days between (1) initial medical consult for CRC symptoms and pathologically confirmed diagnosis (maximum: 365 days) and (2) pathologically confirmed diagnosis and treatment (maximum: 120 days). Cases (CRC deaths) and controls (deaths due to other causes or censored) were matched on survival time. Logistic regression analyses adjusted for sociodemographic, tumor, and treatment factors. RESULTS: Median diagnostic delays were 60 (colon) and 40 (rectal) days and treatment delays were 13 (colon) and 16 (rectal) days in 10,663 patients. Colon cancer patients with the longest diagnostic delays (8-12 months vs. 14-59 days) had higher odds of all-cause (aOR: 1.31 CI: 1.08-1.58), but not CRC-specific death. Colon cancer patients with the shortest treatment delays (<1 vs. 1-2 weeks) had higher odds of all-cause (aOR: 1.23 CI: 1.01-1.49), but not CRC-specific death. Among rectal cancer patients, delays were not associated with risk of all-cause or CRC-specific death. CONCLUSIONS: Longer delays of up to 1 year after symptom onset and 120 days for treatment did not increase odds of CRC-specific death. There may be little clinical benefit in detecting and treating existing symptomatic disease earlier. Screening prior to symptom onset must remain the primary goal to reduce CRC incidence, morbidity, and mortality.
    Cancer Causes and Control 02/2013; · 3.20 Impact Factor
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    ABSTRACT: Activation of hepatic stellate cells (HSCs) is crucial to the development of fibrosis in nonalcoholic fatty liver disease. Quiescent HSCs contain lipid droplets (LDs), whose depletion upon activation induces a fibrogenic gene program. Here we show that liver fatty acid-binding protein (L-Fabp), an abundant cytosolic protein that modulates fatty acid (FA) metabolism in enterocytes and hepatocytes also modulates HSC FA utilization and in turn regulates the fibrogenic program. L-Fabp expression decreased 10-fold following HSC activation, concomitant with depletion of LDs. Primary HSCs isolated from L-FABP(-/-) mice contain fewer LDs than wild type (WT) HSCs, and exhibit upregulated expression of genes involved in HSC activation. Adenoviral L-Fabp transduction inhibited activation of passaged WT HSCs and increased both the expression of prolipogenic genes and also augmented intracellular lipid accumulation, including triglyceride and FA, predominantly palmitate. Freshly isolated HSCs from L-FABP(-/-) mice correspondingly exhibited decreased palmitate in the free FA pool. To investigate whether L-FABP deletion promotes HSC activation in vivo, we fed L-FABP(-/-) and WT mice a high fat diet supplemented with trans-fatty acids and fructose (TFF). TFF-fed L-FABP(-/-) mice exhibited reduced hepatic steatosis along with decreased LD abundance and size compared to WT mice. In addition, TFF-fed L-FABP(-/-) mice exhibited decreased hepatic fibrosis, with reduced expression of fibrogenic genes, compared to WT mice. Conclusion: L-FABP deletion attenuates both diet-induced hepatic steatosis and fibrogenesis, despite the observation that L-Fabp paradoxically promotes FA and LD accumulation and inhibits HSC activation in vitro. These findings highlight the importance of cell-specific modulation of hepatic lipid metabolism in promoting fibrogenesis in nonalcoholic fatty liver disease. (HEPATOLOGY 2013.).
    Hepatology 02/2013; · 11.19 Impact Factor

Publication Stats

5k Citations
1,643.69 Total Impact Points

Institutions

  • 2000–2014
    • Washington University in St. Louis
      • • Department of Medicine
      • • Division of Gastroenterology
      San Luis, Missouri, United States
  • 2013
    • Saint Louis University
      • School of Medicine
      Saint Louis, MI, United States
    • University of Texas Southwestern Medical Center
      • Department of Clinical Sciences
      Dallas, TX, United States
  • 2000–2012
    • University of Washington Seattle
      • • Department of Pediatrics
      • • Department of Medicine
      • • Division of Gastroenterology
      • • Division of General Internal Medicine
      Seattle, WA, United States
  • 2010
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1988–2000
    • University of Chicago
      • • Department of Medicine
      • • Department of Pediatrics
      Chicago, IL, United States
  • 1988–1999
    • University of Illinois at Chicago
      • Department of Medicine (Chicago)
      Chicago, Illinois, United States
  • 1996
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1991
    • The University of Chicago Medical Center
      Chicago, Illinois, United States