Papers by Nicholas Davidson
Evidence suggests a relationship between dietary fat intake, obesity, and colorectal cancer, impl... more Evidence suggests a relationship between dietary fat intake, obesity, and colorectal cancer, implying a role for fatty acid metabolism in intestinal tumorigenesis that is incompletely understood. Liver fatty acidbinding protein (L-Fabp), a dominant intestinal fatty acid-binding protein, regulates intestinal fatty acid trafficking and metabolism, and L-Fabp deletion attenuates diet-induced obesity. Here, we examined whether changes in intestinal fatty acid metabolism following L-Fabp deletion modify adenoma development in Apc Min/þ mice. Compound L-Fabp À/À Apc Min/þ mice were generated and fed a 10% fat diet balanced equally between saturated, monounsaturated, and polyunsaturated fat. L-Fabp À/À Apc Min/þ mice displayed significant reductions in adenoma number and total polyp area compared with Apc Min/þ controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp À/À Apc Min/þ mice exhibited reductions in cellular proliferation, high-grade dysplasia, and nuclear b-catenin translocation. Intestinal fatty acid content was increased in L-Fabp À/À Apc Min/þ mice, and lipidomic profiling of intestinal mucosa revealed significant shifts to polyunsaturated fatty acid species with reduced saturated fatty acid species. L-Fabp À/À Apc Min/þ mice also showed corresponding changes in mRNA expression of enzymes involved in fatty acid elongation and desaturation. Furthermore, adenomas from L-Fabp À/À Apc Min/þ 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 fatty acid trafficking and metabolic compartmentalization as an important pathway linking dietary fat intake, obesity, and intestinal tumor formation. Cancer Prev Res; 6(10); 1026-37. Ó2013 AACR.
Digestive Diseases and Sciences, Jan 7, 2020
Background: Few studies have examined the metabolic consequences of short bowel syndrome (SBS) an... more Background: Few studies have examined the metabolic consequences of short bowel syndrome (SBS) and its effects on body composition in adults. We hypothesized that body composition of SBS patients is altered compared to a normal age, race, and sex-matched population, regardless of parenteral nutrition (PN) dependence. To compare the body composition of adult patients with SBS to age, sex and race matched healthy controls. Methods: Twenty patients with SBS underwent body composition analysis using the GE Lunar iDXA scanner. Patients were age, sex and race matched to controls from the National Health and Nutrition Examination Survey (1999)(2000)(2001)(2002)(2003)(2004). Mean differences in body mass index, fat free mass, fat mass, percent body fat, visceral adipose tissue mass and volume, and bone mineral density were measured. Statistical analysis was performed using SAS 9.4 software. Results: Fifty-five percent of subjects had a history of PN use and 30% were current PN users. Mean percent body fat for SBS patients was 35.1% compared to 30.9% for healthy controls (p=0.043). Fat free mass was reduced in SBS (p=0.007). Patients with reduced bone mass had a Terms of use and reuse: academic research for non-commercial purposes, see here for full terms.
Journal of Clinical Investigation, Apr 20, 2020
Figure 1. ASXL2 regulates weight gain and metabolic homeostasis. (A-C) RNA-seq analysis of bone m... more Figure 1. ASXL2 regulates weight gain and metabolic homeostasis. (A-C) RNA-seq analysis of bone marrow macrophages derived from Asxl2 fl/fl and Asxl2 ΔLysM mice. (A) Principal component analysis of all differentially expressed genes. Shaded ellipses are 95% confidence intervals for each group. (B) Heatmap of the top 30 most differentially expressed genes in macrophages based on log(fold change) > 1.3 with adjusted P < 0.001. (C) Gene Ontology (GO) term analysis of all genes significantly downregulated (negative enrichment, blue bar) or upregulated (positive enrichment, red bar) in Asxl2 ΔLysM macrophages. (D-K) Two-month-old control and Asxl2 ΔLysM mice were fed chow diet or HFD for 8 weeks. (D) Body weight with time. (E) Weight of gonadal WAT (gWAT) and inguinal WAT (iWAT) depots at sacrifice. (F) Size of WAT adipocytes at sacrifice. (G) DXA scans at time of sacrifice. (H) DXA-determined percentage body fat at sacrifice. (I) Glucose tolerance test performed before sacrifice. (J) Insulin tolerance test performed before sacrifice. (K) Hematoxylin and eosin-stained liver of control and Asxl2 ΔLysM mice after 8 weeks on HFD. Scale bar: 400 μm. Data are presented as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; as determined by 2-way ANOVA with Holm-Sidak post hoc analysis for multiple comparisons (D-F and H-J).
Scientific Reports, May 11, 2021
Patients with locally advanced colon cancer have worse outcomes. Guidelines of various organizati... more Patients with locally advanced colon cancer have worse outcomes. Guidelines of various organizations are conflicting about the use of laparoscopic colectomy (LC) in locally advanced colon cancer. We determined whether patient outcomes of LC and open colectomy (OC) for locally advanced (T4) colon cancer are comparable in all colon cancer patients, T4a versus T4b patients, obese versus non-obese patients, and tumors located in the ascending, descending, and transverse colon. We used data from the 2013-2015 American College of Surgeons' National Surgical Quality Improvement Program. Patients were diagnosed with nonmetastatic pT4 colon cancer, with or without obstruction, and underwent LC (n = 563) or OC (n = 807). We used a composite outcome score (mortality, readmission, re-operation, wound infection, bleeding transfusion, and prolonged postoperative ileus); length of stay; and length of operation. Patients undergoing LC exhibited a composite outcome score that was 9.5% lower (95% CI -15.4; -3.5) versus those undergoing OC. LC patients experienced a 11.3% reduction in postoperative ileus (95% CI -16.0; -6.5) and an average of 2 days shorter length of stay (95% CI -2.9; -1.0). Patients undergoing LC were in the operating room an average of 13.5 min longer (95% CI 1.5; 25.6). We found no evidence for treatment heterogeneity across subgroups (p > 0.05). Patients with locally advanced colon cancer who receive LC had better overall outcomes and shorter lengths of stay compared with OC patients. LC was equally effective in obese/nonobese patients, in T4a/T4b patients, and regardless of the location of the tumor.
American Journal of Physiology-endocrinology and Metabolism, Apr 1, 2019
Studies show maternal obesity is a risk factor for metabolic syndrome and nonalcoholic fatty live... more Studies show maternal obesity is a risk factor for metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in offspring. Here we evaluated potential mechanisms underlying these phenotypes. Female C57Bl6 mice were fed chow or an obesogenic high-fat/high-sucrose (HF/HS) diet with subsequent mating of F 1 and F2 female offspring to lean males to develop F 2 and F3 generations, respectively. Offspring were fed chow or fibrogenic (high transfat, cholesterol, fructose) diets, and histopathological, metabolic changes, and bile acid (BA) homeostasis was evaluated. Chow-fed F 1 offspring from maternal HF/HS lineages (HF/HS) developed periportal fibrosis and inflammation with aging, without differences in hepatic steatosis but increased BA pool size and shifts in BA composition. F 1, but not F2 or F3, offspring from HF/HS showed increased steatosis on a fibrogenic diet, yet inflammation and fibrosis were paradoxically decreased in F 1 offspring, a trend continued in F 2 and F3 offspring. HF/HS feeding leads to increased periportal fibrosis and inflammation in chow-fed offspring without increased hepatic steatosis. By contrast, fibrogenic diet-fed F 1 offspring from HF/HS dams exhibited worse hepatic steatosis but decreased inflammation and fibrosis. These findings highlight complex adaptations in NAFLD phenotypes with maternal diet. bile acid metabolism; fatty liver; liver fibrosis; maternal high-fat/highsucrose diet
medRxiv (Cold Spring Harbor Laboratory), Jun 7, 2021
Objective: Early-onset colorectal cancer (CRC) is increasing in many developed countries. Type 2 ... more Objective: Early-onset colorectal cancer (CRC) is increasing in many developed countries. Type 2 diabetes mellitus has increased substantially in younger adults; however, its role in early-onset CRC remains unidentified. We conducted a claims-based nested case-control study using IBM® MarketScan® Commercial Database (2006-2015). Incident early-onset CRC diagnosed at ages 18-49 were identified by ICD-9-CM diagnosis code, and the first coded diagnostic pathology date was assigned as the index date. Controls were frequency matched with cases. Type 2 diabetes, stratified by severity, was identified through ICD-9-CM using the Klabunde algorithm. Multivariate logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (Cls). Results: A total of 6001 early-onset CRC and 52104 controls were included. Type 2 diabetes was associated with an increased risk of early-onset CRC (5.0% in cases vs. 3.7% in controls; OR 1.24; 95% CI 1.09 to 1.41). The positive association was more pronounced for uncontrolled (OR 1.37; 95% CI 1.12 to 1.67) or complicated (OR 1.59; 95% CI 1.08-2.35) type 2 diabetes compared to controlled diabetes (OR 1.13; 95% CI 0.94 to 1.36). The positive association was driven by proximal (OR 1.35; 95% CI 1.03 to 1.77) and distal (OR 1.67; 95% CI 1.30 to 2.15) colon cancer but not rectal cancer. Conclusions: Individuals with type 2 diabetes have a higher risk of early-onset CRC, with stronger associations for uncontrolled/complicated diabetes. The rising prevalence of type 2 diabetes among younger adults in the US may partially contribute to the increasing incidence of early-onset CRC.
Diseases of the Colon & Rectum, 2017
BACKGROUND: Surgical resection is the primary treatment for colon cancer, but use of laparoscopic... more BACKGROUND: Surgical resection is the primary treatment for colon cancer, but use of laparoscopic approaches varies widely despite demonstrated short- and long-term benefits. OBJECTIVE: The purpose of this study was to identify characteristics associated with laparoscopic colon cancer resection and to quantify variation based on patient, hospital, and geographic characteristics. DESIGN: Bayesian cross-classified, multilevel logistic models calculated adjusted ORs and CIs for patient, surgeon, hospital, and geographic characteristics and unexplained variability (predicted vs. observed values) using adjusted median odds ratios for hospitals and counties. SETTINGS: The Surveillance, Epidemiology, and End Results–Medicare claims database (2008–2011) supplemented with county-level American Community Survey (2008–2012) demographic data was used. PATIENTS: A total of 10,618 patients ≥66 years old who underwent colon cancer resection were included. MAIN OUTCOME MEASURES: Nonurgent/nonemerge...
BMJ Open, 2015
Objectives: We examined the utility of January 2004 to April 2014 Google Trends data from informa... more Objectives: We examined the utility of January 2004 to April 2014 Google Trends data from information searches for cancer screenings and preparations as a complement to population screening data, which are traditionally estimated through costly population-level surveys. Setting: State-level data across the USA. Participants: Persons who searched for terms related to cancer screening using Google, and persons who participated in the Behavioral Risk Factor Surveillance System (BRFSS). State-level Google Trends data, providing relative search volume (RSV) data scaled to the highest search proportion per week (RSV100) for search terms over time since 2004 and across different geographical locations. (2) RSV of new screening tests, free/low-cost screening for breast and colorectal cancer, and new preparations for colonoscopy (Prepopik). (3) State-level breast, cervical, colorectal and prostate cancer screening rates. Results: Correlations between Google Trends and BRFSS data ranged from 0.55 for ever having had a colonoscopy to 0.14 for having a Pap smear within the past 3 years. Free/low-cost mammography and colonoscopy showed higher RSV during their respective cancer awareness months. RSV for Miralax remained stable, while interest in Prepopik increased over time. RSV for lung cancer screening, virtual colonoscopy and three-dimensional mammography was low. Conclusions: Google Trends data provides enormous scientific possibilities, but are not a suitable substitute for, but may complement, traditional data collection and analysis about cancer screening and related interests.
Journal of Gastroenterology and Hepatology, 2013
A 69-year-old Liberian female with no significant past medical history was referred for screening... more A 69-year-old Liberian female with no significant past medical history was referred for screening colonoscopy. Notably, she immigrated from Liberia to the United States 7 years prior to presentation, since which time she has had regular primary care visits and has been asymptomatic. On presentation, she had a negative review of systems and her physical examination was normal.
GenomeBiology.com (London. Print), 2014
Background: RNA editing encompasses a post-transcriptional process in which the genomically templ... more 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 apolipoprotein B 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′ 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 for 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.
Type 2 Diabetes and Risk of Early-Onset Colorectal Cancer
Gastro Hep Advances, 2022
Diseases of the Colon & Rectum, 2020
BACKGROUND: Patients with (versus without) diabetes mellitus who develop colon cancer are at incr... more BACKGROUND: Patients with (versus without) diabetes mellitus who develop colon cancer are at increased risk of dying within 30 days after surgery. OBJECTIVE: The purpose of this study was to identify potential mediators of the effect of diabetes mellitus on all-cause 30-day mortality risk after surgery for colon cancer. DESIGN: A retrospective cohort study was conducted using the 2013–2015 National Surgical Quality Improvement Program data. SETTING: The study was conducted at various hospitals across the United States (from 435 to 603 hospitals). PATIENTS: Patients who underwent resection for colon cancer with or without obstruction based on the National Surgical Quality Improvement Program colectomy module were included. Patients who had ASA physical status classification V or metastatic disease and those who presented emergently were excluded. Patients were classified as “no diabetes,” “diabetes not requiring insulin,” or “diabetes requiring insulin.” Potential reasons for increas...
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Papers by Nicholas Davidson