Development of Pluoronic nanoparticles of fluorocoxib A for endoscopic fluorescence imaging of colonic adenomas.

Significance: Current white light colonoscopy suffers from many limitations that allow 22% to 32% of preneoplastic lesions to remain undetected. This high number of false negatives contributes to the appearance of interval malignancies, defined as neoplasms diagnosed between screening colonoscopies at a rate of 2% to 6%. Aim: The shortcomings of today's white light-based colorectal cancer screening are addressed by colonoscopic fluorescence imaging of preneoplastic lesions using targeted fluorescent agents to enhance contrast between the lesion and the surrounding normal colonic epithelium. Approach: We describe the development of Pluronic® nanoparticles of fluorocoxib A (FA), a fluorescent cyclooxygenase-2 (COX-2) inhibitor that enables targeted imaging of inflammation and cancer in numerous animal models, for endoscopic florescence imaging of colonic adenomas. Results: We formulated FA, a fluorescent COX-2 inhibitor, or fluorocoxib negative control (FNC), a nontargeted fluorophore and a negative control for FA, in micellar nanoparticles of FDA approved Pluronic tri-block co-polymer using a bulk solvent evaporation method. This afforded FA-loaded micellar nanoparticles (FA-NPs) or FNC-loaded micellar nanoparticles (FNC-NPs) with the hydrodynamic diameters ( D h ) of 45.7 ± 2.5 nm and 44.9 ± 3.8 nm and the zeta potentials ( ζ ) of - 1.47 ± 0.3 mV and - 1.64 ± 0.5 mV , respectively. We intravenously injected B6;129 mice bearing colonic adenomas induced by azoxymethane and dextran-sodium sulfate with FA-loaded Pluronic nanoparticles (FA-NPs). The diffusion-mediated local FA release and its binding to COX-2 enzyme allowed for clear detection of adenomas with high signal-to-noise ratios. The COX-2 targeted delivery and tumor retention were validated by negligible tumor fluorescence detected upon colonoscopic imaging of adenoma-bearing mice injected with Pluronic nanoparticles of FNC or of animals predosed with the COX-2 inhibitor, celecoxib, followed by intravenous dosing of FA-NPs. Conclusions: These results demonstrate that the formulation of FA in Pluronic nanoparticles overcomes a significant hurdle to its clinical development for early detection of colorectal neoplasms by fluorescence endoscopy.

Multi-organ carcinogenicity by inhalation exposure to 2-Bromopropane in rats.

OBJECTIVE: The purpose of this study was to investigate the carcinogenicity of 2-bromopropane (2-BP) in rats. METHODS: Male and female F344 rats were exposed by whole body inhalation to 2-BP vapor at concentrations of 0, 67, 200, and 600 ppm for 6 h/day, 5 days/week for 2 years. RESULTS: All rats of both sexes exposed to 600 ppm died or became moribund within 85 weeks. Death/moribundity was caused by 2-BP induced tumors. In males, significantly increased tumors were malignant Zymbal's gland tumors; sebaceous adenoma and basal cell carcinoma of the skin/appendage; adenocarcinoma of the small/large intestine; follicular cell adenoma of the thyroid; fibroma of the subcutis, and malignant lymphoma of the lymph node. In addition, an increased trend in tumor incidence was found in the preputial gland, lung, forestomach, pancreas islet, brain, and spleen. In females, significantly increased tumors were adenocarcinoma and fibroadenoma of the mammary gland, squamous cell papilloma of the vagina, and large granular lymphocytic leukemia of the spleen. In addition, an increased trend in tumor incidence was found in Zymbal's gland, the clitoral gland, skin, large intestine, pancreas islet, uterus, and subcutis. Particularly, malignant Zymbal's gland tumors were induced even in males exposed to the lowest concentration, 67 ppm. CONCLUSION: Two-year inhalation exposure to 2-BP resulted in multi-organ carcinogenicity in rats. Based on sufficient evidence of carcinogenicity in this study, 2-BP has the potential to be a human carcinogen.

Taking Oral Sulfate Tablets with Simethicone for Bowel Preparation Leads to Higher Adenoma Detection Rate than Polyethylene Glycol: A Propensity Score Analysis.

BACKGROUND: Efficient bowel preparation is essential for preventing colorectal cancer by improving endoscopic adenoma detection. Tablet for bowel preparation containing sulfate salts, OSTs (oral sulfate tablets), has been developed and it is gaining more popularity. However, its efficacy compared to standard preparation agent, PEG-AA (polyethylene glycol), has not been well discovered. We assessed the efficacy of PEG and OSTs using a real-time clinical data warehouse (CDW) model. METHODS: We performed a propensity score-matched (PSM) analysis of consecutive adult patients undergoing colonoscopy who received PEG-AA or OSTs prior to colonoscopy at a tertiary academic hospital. The endoscopic records of 992 adult patients were retrospectively analyzed. The clinical data warehouse collected data including bowel preparation, insertion time, observation time, and the detection of polyps and adenomas. Multivariate regression analysis was performed to reveal the factors associated with endoscopic outcomes. RESULTS: Among 992 patients included in the study, 770 and 222 patients received PEG-AA and OSTs, respectively. Among the propensity score-matched population (n = 1897), OSTs resulted in better bowel cleansing quality (8.16 vs 7.84, p = 0.014) and a higher adenoma detection rate (38.6% vs 27.1%, p = 0.003). Using PEG-AA, older age, inadequate bowel preparation (BBPS score < 6) and endoscopy by fellows were found to be factors associated with poor adenoma detection. In the elderly over 65 years of age, a significant difference in cleansing quality between the two groups (7.21 vs 8.19, p < 0.001) was found, but its impact on ADR was not prominent (49.5% vs 45.4%, p = 0.653). CONCLUSIONS: OSTs with simethicone achieved better endoscopic cleanliness, improving adenoma detection rate compared to the conventional PEG-AA protocol. The synergistic effect of both the convenience of taking tablets and the reduction of intraluminal bubble by adjunctive simethicone improves the clinical efficacy of colonoscopy.

[Shenbai Jiedu Fang inhibits AOM/DSS-induced colorectal adenoma formation and carcinogenesis in mice via miRNA-22-mediated regulation of the PTEN/PI3K/AKT signaling pathway].

OBJECTIVE: To observe the inhibitory effect of Shenbai Jiedu Fang (SBJDF, a compound recipe of traditional Chinese herbal drugs) on chemically induced carcinogenesis of colorectal adenoma in mice and explore the role of PTEN/PI3K/AKT signaling pathway in mediating this effect. METHODS: Four-week-old male C57BL/6 mice were randomly divided into control group (n=10), AOM/DSS model group (n=20), low-dose (14 g/kg) SBJDF group (n=10) and high-dose (42 g/kg) SBJDF group (n= 10). In the latter 3 groups, the mice were treated with azoxymethane (AOM) and dextran sodium sulphate (DSS) to induce carcinogenesis of colorectal adenoma. In the two SBJDF treatment groups, SBJDF was administered daily by gavage during the modeling. The survival rate, body weight, general condition of the mice, and intestinal adenoma formation and carcinogenesis were observed. The expressions of proteins associated with the PTEN/PI3K/AKT signaling pathway in the intestinal tissue were detected using immunohistochemistry. RESULTS: Compared with those in the model group, the mice treated with SBJDF, especially at the high dose, showed a significantly lower incidence of intestinal carcinogenesis and had fewer intestinal tumors with smaller tumor volume. Pathological examination showed the occurrence of adenocarcinoma in the model group, while only low-grade and high-grade neoplasia were found in low-dose SBJDF group; the mice treated with high-dose SBJDF showed mainly normal mucosal tissues in the intestines with only a few lesions of low-grade neoplasia of adenoma. Compared with those in the control group, the mice in the model group had significantly elevated plasma miRNA-222 level (P < 0.05), which was obviously lowered in the two SBJDF groups (P < 0.01). The results of immunohistochemistry revealed that compared with the model group, the two SBJDF groups, especially the high-dose group, had significantly up-regulated expressions of PTEN, P-PTEN and GSK-3ß and down-regulated expressions of p-GSK-3 ß, PI3K, AKT, P-AKT, ß-catenin, c-myc, cyclinD1 and survivin in the intestinal tissues. CONCLUSION: SBJDF can significantly inhibit colorectal adenoma formation and carcino-genesis in mice possibly through regulating miRNA-222 and affecting PTEN/PI3K/AKT signaling pathway.

6- shogaol suppresses AOM/DSS-mediated colorectal adenoma through its antioxidant and anti-inflammatory effects in mice.

Colorectal adenoma appears as benign lesions and is a precursor of colorectal adenocarcinoma. The effect of 6-Shogaol (6-[S]), a bioactive agent from ginger, in early colonic adenoma growth is unknown. As a result, this study examines the effect of 6-[S] in a mouse colorectal adenoma model induced by Azoxymethane (AOM) and dextran sulfate sodium (DSS). Adult male mice served as control in Group 1. Group 2 was treated orally with 6-[S] extract (20 mg/kg BW). Group 3 was exposed to AOM (25 mg/kg BW, ip) and one cycle of DSS (2.5%) in drinking water alone while Group 4 was co-treated with 6-[S] for twenty-one (21) days. The body weight gain, organ weight and length, oxidative stress indices, inflammatory markers and histological examination were estimated. Our findings show that 6-[S] co-treatment reversed AOM/DSS-induced elevation in colon weight, colon length, nitric oxide (NO), myeloperoxidase (MPO), hydrogen peroxidase (H2 O2 ), and tumor necrosis factor-alpha (TNF-α). However, the antioxidant enzyme activities measured namely catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and glutathione-S-transferase were significantly increased in 6-[S] treated mice. Taken together, the protective effect of 6-[S] on oxidative burden, inflammation, and histological aberration observed in the colon of the AOM/DSS model of adenoma growth in mice is mediated primarily owing to its anti-inflammatory and anti-oxidative properties. Thus, this study reveals 6-[S] as a useful agent in the possible clinical intervention of colorectal adenoma. PRACTICAL APPLICATIONS: Certain spices have been reported to have numerous phytochemicals with numerous medicinal purposes. However, no studies have been conducted to investigate the role of 6-[S], a phytochemical found in ginger, in the treatment of colorectal adenoma. The study's findings show that 6-[S] is protective in early colonic cancer development, as it manages colorectal adenoma cancer models of AOM/DSS. As a result, 6-[S]'s ability to reduce oxidative stress and inflammation in the colon may be a potential nutritional therapeutic adjuvant for colorectal adenoma.

A Prospective Pooled Analysis of Meat Mutagens and Colorectal Adenoma and Cancer in the US and EPIC Studies: Findings with an Emphasis on Improving Exposure Measurements.

BACKGROUND: In animal studies, heterocyclic amines (HCAs) are recognized as having strong carcinogenicity, therefore we have hypothesized that HCAs might be associated with the risk of colorectal adenoma (CRA) and cancer (CRC). METHODS: We used the Keywords of "Heterocyclic amines and colorectal cancer" to search, there were showing published articles (n=200). After reviews of titles, abstracts, and full articles, seven prospective cohort studies were included in the pooled analysis. Exposures to HCAs 2-amino-3,8-dimethylimidazo(4,5-j)quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), 2-amino-3,4,8-trimethylimidazo(4,5-f)quinoxaline (DiMeIQx), meat-derived mutagenicity (MDM), and the risk of CRA and CRC were examined. The estimated HCA intake as ng/day and ng/1,000 kcal/day by participants and by studies were examined. The ln(HR) and se(ln(HR)) were estimated from the multivariable-adjusted HR, 95%CI derived from seven published prospective studies in the US and EPIC. The random pooled multivariable-adjusted HR, 95%CI was analyzed using ln(HR) and se(ln(HR)) by STATA-10. RESULTS: For CRC and HCA intake, the null association was observed for MDM, the random pooled multivariable-adjusted HR, (95%CI): 1.11, (1.00, 1.23); for PhIP: 1.00, (0.91, 1.09); and for DiMeIQx: 1.03, (0.87, 1.22). A significant positive association was seen for MeIQx, the random pooled multivariable-adjusted HR, (95%CI):1.12, (1.03, 1.22). For CRA and HCA intake, the null association was observed for MDM, randomly pooled multivariable-adjusted HR, (95%CI): 1.15, (0.99, 1.34), and for DiMeIQx: 1.09, (0.97, 1.23). A significant positive association was seen for PhIP, the random pooled multivariable-adjusted HR, (95%CI): 1.19, (1.02, 1.39), and for MeIQx: 1.17, (1.01, 1.35). The major instances of HCAs were contributed by chicken (54%-74%) for PhIP and by red meat (83%-92%) for MeIQx. However, the estimated PhIP intake (ng/1,000 kcal/day) was remarkably different between studies. CONCLUSIONS: We observed a positive association between exposures to MeIQx and the risk of both CRC and CRA which supports the hypothesis of the role of HCAs in developing CRA and CRC. Improving the quality of the estimated HCA intake would be highly concerned for further investigation.

Nurse-led reinforced education by mobile messenger improves the quality of bowel preparation of colonoscopy in a population-based colorectal cancer screening program: A randomized controlled trial.

BACKGROUND: Adequate bowel preparation is an important colonoscopy quality indicator. Reinforced education is effective in improving bowel preparation quality of colonoscopy with mixed indications. However, it remains unclear whether such improvement can be consistently observed in pre- and post-irrigation during colonoscopy in screening population. OBJECTIVE: We aimed to study the effectiveness of nurse-led reinforced education delivered via mobile messenger (WhatsApp Messenger) on pre- and post-irrigation bowel preparation adequacy in colonoscopies for positive fecal immunochemical test in a population-based colorectal cancer screening program. DESIGN: Randomized controlled trial. SETTING: A hospital-based endoscopy centre in Hong Kong, China. PARTICIPANTS: Patients undergoing colonoscopy for positive fecal immunochemical test in a population-based colorectal cancer screening program. METHODS: The recruited patients were randomized to receive either WhatsApp Reinforced Education (WRE) or No Reinforced Education (NRE) (1:1). Patients in WRE group received one-off reinforced education of bowel preparation in text and video formats via WhatsApp Messenger four days prior to colonoscopy sent by investigator while NRE group received standard-of-care only. Primary outcome was the bowel preparation adequacy rate as evaluated by Aronchick Scale. Secondary outcomes included bowel preparation adequacy rate as evaluated by Boston Bowel Preparation Scale, adenoma detection rate and risk factors of bowel preparation inadequacy. Continuous variables were described as means with standard deviation (SD) and analyzed with Student's t-test. The Pearson Chi Square Test or Fisher Exact Test was used to assess categorical variables when appropriate. Risk factors were determined by logistic regression. RESULTS: From July 2017 to April 2019, 685 eligible patients were randomized to WRE (n = 343) and NRE (n = 342) groups. Patients in WRE group had higher bowel preparation adequacy rate as evaluated by Aronchik Scale (83.4% vs 75.4%, p = 0.010) and Boston Bowel Preparation Scale (94.2% vs 88.9%, p = 0.013). Adenoma detection rate was higher in WRE group but without statistical significance (71.4% vs 67.5%, p = 0.27). In logistic regression, WhatsApp Reinforced Education reduced the inadequate bowel preparation risk (Adjusted odds ratio: 0.564; 95% confidence interval: 0.371-0.856, p = 0.007). Male gender (Adjusted odds ratio [AOR]: 1.638; 95% confidence interval [CI]: 1.054-2.546, p = 0.028) and diabetes (AOR: 2.062; 95% CI: 1.215-3.497, p = 0.007) were risk factors of bowel preparation inadequacy. CONCLUSIONS: Nurse-led mobile messenger-initiated reinforced education improves both pre- and post-irrigation bowel preparation quality of screening colonoscopy following positive fecal immunochemical test. It is readily incorporable in clinical practice because of its low setup cost. REGISTRATION NUMBER: Registered on 4 July 2017 on https://clinicaltrials.gov/ (NCT03209739).

Persistent remission of acromegaly in a patient with GH-secreting pituitary adenoma: Effect of treatment with pasireotide long-acting release and consequence of treatment withdrawal.

WHAT IS KNOWN AND OBJECTIVE: Somatostatin analogues (SSAs) have been used for the treatment of acromegaly for several decades. However, a unified conclusion on the duration of SSAs therapy or the possibility of medication withdrawal is still missing. We aimed to report a case of acromegaly cured by pasireotide long-acting release (PAS-LAR) and provide some information on the withdrawal of SSAs after stable regression in acromegalic patients. CASE SUMMARY: A 55-year-old male patient, who was diagnosed with acromegaly and refused surgery and received PAS-LAR as initial treatment, had maintained stability for ten years under the regular treatment with PAS-LAR. The pituitary microadenoma was also decreased during the treatment. After the PAS-LAR discontinuation for 21 months, no evidence of biochemical or clinical recurrence was found in this patient. WHAT IS NEW AND CONCLUSION: The use of PAS-LAR in a subset of naive-treatment patients is promising to induce long-term regression. A subgroup of patients with mild and well-controlled acromegaly might hope for perpetual remission after the withdrawal of medication.

Oral Contraceptive and Menopausal Hormone Therapy Use and Risk of Pituitary Adenoma: Cohort and Case-Control Analyses.

CONTEXT: No prospective epidemiologic studies have examined associations between use of oral contraceptives (OCs) or menopausal hormone therapy (MHT) and risk of pituitary adenoma in women. OBJECTIVE: Our aim was to determine the association between use of OC and MHT and risk of pituitary adenoma in two separate datasets. METHODS: We evaluated the association of OC/MHT with risk of pituitary adenoma in the Nurses' Health Study and Nurses' Health Study II by computing multivariable-adjusted hazard ratios (MVHR) of pituitary adenoma by OC/MHT use using Cox proportional hazards models. Simultaneously, we carried out a matched case-control study using an institutional data repository to compute multivariable-adjusted odds ratios (MVOR) of pituitary adenoma by OC/MHT use. RESULTS: In the cohort analysis, during 6 668 019 person-years, 331 participants reported a diagnosis of pituitary adenoma. Compared to never-users, neither past (MVHR = 1.05; 95% CI, 0.80-1.36) nor current OC use (MVHR = 0.72; 95% CI, 0.40-1.32) was associated with risk. For MHT, compared to never-users, both past (MVHR = 2.00; 95% CI, 1.50-2.68) and current use (MVHR = 1.80; 95% CI, 1.27-2.55) were associated with pituitary adenoma risk, as was longer duration (MVHR = 2.06; 95% CI, 1.42-2.99 comparing more than 5 years of use to never, P trend = .002). Results were similar in lagged analyses, when stratified by body mass index, and among those with recent health care use. In the case-control analysis, we included 5469 cases. Risk of pituitary adenoma was increased with ever use of MHT (MVOR = 1.57; 95% CI, 1.35-1.83) and OC (MVOR = 1.27; 95% CI, 1.14-1.42) compared to never. CONCLUSION: Compared to never use, current and past MHT use and longer duration of MHT use were positively associated with higher risk of pituitary adenoma in 2 independent data sets. OC use was not associated with risk in the prospective cohort analysis and was associated with only mildly increased risk in the case-control analysis.

The Impact of Patient Education Level on Split-Dose Colonoscopy Bowel Preparation for CRC Prevention.

INTRODUCTION: AGA guidelines emphasize split-dose bowel preparation (BP) to ensure high-quality colonoscopy for the prevention of colorectal cancer (CRC). Split dose results in higher-quality preparation, but understanding instructions might be more difficult. Lower education levels may negatively influence BP quality. The confounding role of education level on BP quality was investigated. METHODS: This was a cross-sectional study of 60 patients given split-dose BP. Patients consented and were asked three Likert scale questions based on BP instructions before the procedure. Compliance was self-reported. BP adequacy and the number of adenomas were recorded. BP was characterized as adequate (excellent, good) or inadequate (fair, poor). Data was analyzed with chi-square, odds ratio, Mann-Whitney, and regression analysis. RESULTS: Thirty-one (52%) patients were high school graduates, 21 (38%) completed some college, and 6 (10%) were college graduates. College-educated patients had adequate BP (72%) more often than high school graduates (51%) (p = 0.02). Adenoma findings were not significantly different. The Likert scale mean ranks for patient understanding and reviewing of instructions were comparable between the two groups. Patient rating of scheduler explanations of the importance of following instructions was significantly better in the college group (mean ranks 2.59 and 1.83, respectively; p = 0.018). DISCUSSION: Patient education level significantly affected the success of BP. Split BP can be more complex to comprehend, and instructions should consider patient education level. Specific intervention programs should be implemented to advise patients with less education that poor preparation may result in missed advanced neoplasias and subsequent procedures.

Proton Pump Inhibitor Omeprazole Suppresses Carcinogen-induced Colonic Adenoma Progression to Adenocarcinoma in F344 Rat.

Colorectal cancer causes over 53,000 deaths annually in the United States. Its rising incidences worldwide and particularly in young adults is a major concern. Here, we evaluated the efficacy of omeprazole that is clinically approved for treating acid reflux, to enable its repurposing for colorectal cancer prevention. In the azoxymethane-induced rat colorectal cancer model, dietary omeprazole (250 and 500 ppm) was administered at early adenoma stage (8 weeks after azoxymethane) to assess the progression of early lesions to adenocarcinoma. Administration of omeprazole at 250 or 500 ppm doses led to suppression of total colon adenocarcinoma incidence by 15.7% and 32% (P < 0.01), respectively. Importantly, invasive carcinoma incidence was reduced by 59% (P < 0.0005) and 90% (P < 0.0001) in omeprazole-administered rats in a dose-dependent manner. There was also a strong and dose-dependent inhibition in the adenocarcinoma multiplicity in rats exposed to omeprazole. Administration of 250 and 500 ppm omeprazole inhibited total colon adenocarcinoma multiplicity by approximately 49% and approximately 65% (P < 0.0001), respectively. While noninvasive adenocarcinomas multiplicity was suppressed by approximately 34% to approximately 48% (P < 0.02), the invasive carcinomas multiplicity was reduced by approximately 74% to approximately 94% (P < 0.0001) in omeprazole-exposed rats in comparison with the untreated rats. Biomarker analysis results showed a decrease in cell proliferation and anti-apoptotic/pro-survival proteins with an increase in apoptosis. Transcriptome analysis of treated tumors revealed a significant increase in adenocarcinoma inhibitory genes (Olmf4; Spink4) expression and downregulation of progression promoting genes (SerpinA1, MMP21, IL6). In summary, omeprazole showed significant protection against the progression of adenoma to adenocarcinoma. PREVENTION RELEVANCE: Preventing colon cancer is urgently needed because of its high incidence and mortality rates worldwide. Toward this end, preventive efficacy of omeprazole, a common medication, was evaluated in animal model of colorectal cancer and was found to suppress colonic adenoma progression to carcinoma. These findings warrant its further evaluation in humans.

Antibiotic use and colorectal neoplasia: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the third most common cancer for women and men and the second leading cause of cancer death in the USA. There is emerging evidence that the gut microbiome plays a role in CRC development, and antibiotics are one of the most common exposures that can alter the gut microbiome. We performed a systematic review and meta-analysis to characterise the association between antibiotic use and colorectal neoplasia. METHODS: We searched PubMed, EMBASE, and Web of Science for articles that examined the association between antibiotic exposure and colorectal neoplasia (cancer or adenoma) through 15 December 2019. A total of 6031 citations were identified and 6 papers were included in the final analysis. We assessed the association between the level of antibiotic use (defined as number of courses or duration of therapy) and colorectal neoplasia using a random effects model. RESULTS: Six studies provided 16 estimates of the association between level of antibiotic use and colorectal neoplasia. Individuals with the highest levels of antibiotic exposure had a 10% higher risk of colorectal neoplasia than those with the lowest exposure (effect size: 1.10, 95% CI 1.01 to 1.18). We found evidence of high heterogeneity (I2=79%, p=0.0001) but not of publication bias. CONCLUSIONS: Higher levels of antibiotic exposure is associated with an increased risk of colorectal neoplasia. Given the widespread use of antibiotics in childhood and early adulthood, additional research to further characterise this relationship is needed.

Intestinal Growth in Glucagon Receptor Knockout Mice Is Not Associated With the Formation of AOM/DSS-Induced Tumors.

Treatment with exogenous GLP-2 has been shown to accelerate the growth of intestinal adenomas and adenocarcinomas in experimental models of colonic neoplasia, however, the role of endogenous GLP-2 in tumor promotion is less well known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) display an increase in circulating GLP-1 and GLP-2. Due to the intestinotrophic nature of GLP-2, we hypothesized that Gcgr-/- mice would be more susceptible to colonic dysplasia in a model of inflammation-induced colonic carcinogenesis. Female Gcgr-/- mice were first characterized for GLP-2 secretion and in a subsequent study they were given a single injection with the carcinogen azoxymethane (7.5 mg/kg) and treated with dextran sodium sulfate (DSS) (3%) for six days (n=19 and 9). A cohort of animals (n=4) received a colonoscopy 12 days following DSS treatment and all animals were sacrificed after six weeks. Disruption of glucagon receptor signaling led to increased GLP-2 secretion (p<0.0001) and an increased concentration of GLP-2 in the pancreas of Gcgr-/- mice, coinciding with an increase in small intestinal (p<0.0001) and colonic (p<0.05) weight. Increased villus height was recorded in the duodenum (p<0.001) and crypt depth was increased in the duodenum and jejunum (p<0.05 and p<0.05). Disruption of glucagon receptor signaling did not affect body weight during AOM/DSS treatment, neither did it affect the inflammatory score assessed during colonoscopy or the number of large and small adenomas present at the end of the study period. In conclusion, despite the increased endogenous GLP-2 secretion Gcgr-/- mice were not more susceptible to AOM/DSS-induced tumors.

Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma.

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers' impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host-microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

Carcinogenicity and chronic toxicity of acrolein in rats and mice by two-year inhalation study.

The carcinogenicity and chronic toxicity of acrolein was examined by whole body inhalation to groups of 50 F344/DuCrlCrlj rats and 50 B6D2F1/Crlj mice of both sexes for two years. The concentration of acrolein was 0, 0.1, 0.5 or 2 ppm (v/v) for male and female rats; and 0, 0.1, 0.4 or 1.6 ppm for male and female mice. Two-year administration of acrolein induced the squamous cell carcinomas in nasal cavity which is rare tumor in one male and two female rats. In females, rhabdomyoma in nasal cavity was observed in four rats exposed to 2 ppm. In mice, since the survival rate of male and female of mice control group were lowered than 25% in late of the administration periods due to renal lesion and/or amyloid deposition, the mice study was terminated at 93rd week in males, and was terminated at 99th week in females. The incidences of adenomas in nasal cavity were observed in 16 females and significantly increased only in female mice. Thus, acrolein is carcinogenic in two species, i.e. rats and mice. Additionally, non-neoplastic nasal cavity lesions in rats and mice were observed.

Glucosamine and Chondroitin Supplements and Risk of Colorectal Adenoma and Serrated Polyp.

BACKGROUND: Studies have shown an inverse association between use of glucosamine and chondroitin supplements and colorectal cancer risk. However, the association with the precursor lesion, colorectal adenoma and serrated polyp, has not been examined. METHODS: Analyses include 43,163 persons from the Nurses' Health Study (NHS), Health Professionals Follow-up Study (HPFS), and NHS2 who reported on glucosamine/chondroitin use in 2002 and who subsequently underwent ≥1 lower gastrointestinal endoscopy. By 2012, 5,715 conventional (2,016 high-risk) adenomas were detected, as were 4,954 serrated polyps. Multivariable logistic regression for clustered data was used to calculate OR and 95% confidence intervals (CI). RESULTS: Glucosamine/chondroitin use was inversely associated with high risk and any conventional adenoma in NHS and HPFS: in the pooled multivariable-adjusted model, glucosamine + chondroitin use at baseline was associated with a 26% (OR = 0.74; 95% CI, 0.60-0.90; P heterogeneity = 0.23) and a 10% (OR = 0.90; 95% CI, 0.81-0.99; P heterogeneity = 0.36) lower risk of high-risk adenoma and overall conventional adenoma, respectively. However, no association was observed in NHS2, a study of younger women (high-risk adenoma: OR = 1.09; 95% CI, 0.82-1.45; overall conventional adenoma: OR = 1.00; 95% CI, 0.86-1.17), and effect estimates pooled across all three studies were not significant (high-risk: OR = 0.83; 95% CI, 0.63-1.10; P heterogeneity = 0.03; overall conventional adenoma: OR = 0.93; 95% CI, 0.85-1.02; P heterogeneity = 0.31). No associations were observed for serrated polyps. CONCLUSIONS: Glucosamine/chondroitin use was associated with lower risks of high-risk and overall conventional adenoma in older adults; however, this association did not hold in younger women, or for serrated polyps. IMPACT: Our study suggests that glucosamine and chondroitin may act on early colorectal carcinogenesis in older adults.

Food-grade titanium dioxide (E171) induces anxiety, adenomas in colon and goblet cells hyperplasia in a regular diet model and microvesicular steatosis in a high fat diet model.

Food-grade titanium dioxide (E171) is a white additive widely used in solid and liquid food products. There is still debate about E171 toxic effects after oral consumption since this additive is deposited in colon, liver, spleen, testis and brain. The consumption of E171 commonly occurs with Western diets that are characterized by a high fat content. Thus, E171 could worsen adverse effects associated with a high fat diet (HFD) such as anxiety, colon diseases and testicular damage. We aimed to evaluate the effects of E171 on anxiety-like behavior, colon, liver and testis and to analyze if the administration of a HFD could exacerbate adverse effects. E171 was administered at ~5 mg/kgbw by drinking water for 16 weeks and mice were fed with a Regular Diet or a HFD. E171 promoted anxiety, induced adenomas in colon, goblet cells hypertrophy and hyperplasia and mucins overexpression, but had no toxic effects on testicular tissue or spermatozoa in regular diet fed-mice. Additionally, E171 promoted microvesicular steatosis in liver in HFD fed-mice and the only HFD administration decreased the spermatozoa concentration and motility. In conclusion, E171 administration increases the number of adenomas in colon, induces hypertrophy and hyperplasia in goblet cells and microvesicular steatosis.

Patients with acromegaly might not be at higher risk for dopamine agonist-induced impulse control disorders than those with prolactinomas.

OBJECTIVE: To evaluate the prevalence of impulse control disorders (ICD) and psychiatric symptoms in patients with acromegaly receiving dopamine agonists (DA) in comparison with those with prolactinoma, nonfunctioning pituitary adenomas (NFA), and healthy controls (HC). DESIGN: Forty patients with acromegaly, 40 with prolactinoma, 38 with NFA, and 32 HCs were included. All patients and controls were evaluated using the revised version of the Minnesota Impulsive Disorders Interview (MIDI-R), Symptom Check List (SCL-90-R) questionnaire, Barratt Impulsiveness Scale (BIS-11), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS: We detected ICD associated with DAs in two patients with acromegaly (5%) and three patients (7.5%) with prolactinoma. All patients' symptoms resolved after discontinuation of the drug. While the mean DA dose was higher in patients with acromegaly than prolactinomas (p < 0.05), no difference was detected in terms of ICD prevalence between two groups (p > 0.05). SCL-90 depression and interpersonal sensitivity subscale positivity was higher in patients with NFA than HCs. Patients with prolactinoma had higher obsession and interpersonal sensitivity positivity and those with NFA had higher somatization, interpersonal sensitivity, and depression positivity as compared to patients with acromegaly (p < 0.05 for all). CONCLUSIONS: Although DA dose was significantly higher in patients with acromegaly, there was no significant difference in the prevalence of DA-related ICD. The higher prevalence of positive screening in SCL-90 in patients with NFA in comparison to HCs supports the hypothesis that the presence of a pituitary adenoma per se might cause significant psychiatric symptoms.

Association between dietary sugar intake and colorectal adenoma among cancer screening examinees in Japan.

Although intake of highly sugary foods is considered to be a potential risk factor for colorectal cancer through hyperinsulinemia, the association of sugar intake and colorectal adenoma, a precursor lesion to most colorectal cancer, is poorly understood, particularly in Asian populations. We undertook a cross-sectional study in a Japanese population to investigate the association between dietary sugar intake and the prevalence of colorectal adenoma. Study subjects were selected from participants who underwent magnifying colonoscopy with dye spraying as part of a cancer screening program and who responded to a self-administered questionnaire before the colonoscopy. A total of 738 cases with colorectal adenoma and 697 controls were enrolled. Dietary intakes of glucose, fructose, galactose, sucrose, maltose, lactose, and total sugars (sum of these six mono- or disaccharides) were calculated from a food frequency questionnaire, and divided into quartiles based on the distribution among controls. Odds ratios and 95% confidence intervals of colorectal adenoma were estimated using unconditional logistic regression models, with adjustment for potential confounding factors. Total sugar intake was not significantly associated with the prevalence of colorectal adenoma (odds ratio for the highest intake group compared to reference group = 1.18; 95% confidence interval, 0.81-1.73; P for trend = .34). Furthermore, no statistically significant positive associations were observed for any of the six mono- or disaccharides. Findings were similar on additional analyses by site, size, and number of adenomas. Our findings do not support an association between high sugar intake and increased odds ratios of colorectal adenoma.