Risk factors for early-onset colorectal cancer: A Canadian prospective cohort study.

PURPOSE: The incidence of early-onset (<50 years of age) colorectal cancer (eoCRC) has been steadily increasing in high-income countries including Canada. Despite this increase in incidence, the etiology of eoCRC remains unclear and prospective cohort studies of potential risk factors are limited. METHODS: We examined two prospective cohorts of healthy individuals (<50 years of age) who completed baseline questionnaires in the Ontario Health Study and Alberta's Tomorrow Project. We examined the associations between demographic characteristics, chronic health conditions, and lifestyle behaviours with the development of eoCRC using Cox proportional hazard models. Cohorts were analyzed separately and hazard ratios for each risk factor were pooled with random effects meta-analyses. RESULTS: During an average follow-up of 6.63 years, 98 eoCRC cases occurred among study participants (n=127,852). A family history of CRC alone or with a history of other cancer types was associated with an increased risk of developing eoCRC (HR: 2.76, 95% CI: 1.43-5.32), but a family history of a non-CRC cancer only was not (HR: 1.18, 95% CI: 0.61-2.30). Heavy smokers (≥ 10 pack-years) at baseline had a higher risk of eoCRC compared to non-smokers (HR: 1.87, 95% CI: 1.00-3.52). Sex, socioeconomic factors, diabetes, alcohol consumption, among other factors were not significantly associated with the risk of eoCRC. CONCLUSION: Our findings indicate that specific CRC risk factors are also associated with developing eoCRC. The data in the study offers valuable insights that could be integrated in future meta-analyses. Additional prospective cohort studies are required to understand the etiology of eoCRC.

The Association between Red Meat Consumption and Advanced Colorectal Adenomas in a Population Undergoing a Screening-Related Colonoscopy in Alberta, Canada.

The association between red meat consumption and colorectal cancer has been rigorously examined. However, a more comprehensive understanding of how the intake of unprocessed red meat contributes to the development of early precancerous colorectal lesions, such as advanced colorectal adenomas (ACRAs), requires further investigation. We examined the associations between different types of red meat intake and ACRAs in a sample population of 1083 individuals aged ≥ 50 years undergoing an initial screening colonoscopy in Calgary, Alberta, Canada. Associations between grams per day of total, processed, and unprocessed red meat from diet history questionnaires and ACRAs were evaluated with multivariable logistic regression models. We also applied cubic spline models fitted with three knots (10th, 50th, and 90th percentiles) to identify potential nonlinear associations. We did not observe a meaningful association between unprocessed red meat intake and the presence of ACRAs. In contrast, for every 10 g/d increase in total and processed meat intake, we observed an increase in the odds of ACRAs at the screening colonoscopy (adjusted odds ratio (OR) = 1.05, 95% [CI = 1.01-1.09], p = 0.04) and (adjusted OR = 1.11, 95% [CI = 1.02-1.20], p = 0.02), respectively. This study highlights the importance of differentiating between types of red meat consumption in the context of dietary risks associated with ACRAs.

The Association Between Inflammatory and Oxidative Stress Biomarkers and Plasma Metabolites in a Longitudinal Study of Healthy Male Welders.

INTRODUCTION: Human metabolism and inflammation are closely related modulators of homeostasis and immunity. Metabolic profiling is a useful tool to understand the association between metabolism and inflammation at a systemic level. OBJECTIVE: To investigate the longitudinal associations between the concentration of plasma metabolites and biomarkers related to inflammation and oxidative stress. METHODS: We conducted a repeated cross-sectional analysis consisting of 8 short-term panels that included 88 healthy adult male welders in Massachusetts, USA. In each panel, we collected 1-6 repeated measurements of blood and urine. We used a human vascular injury panel assay and custom cytokine/chemokine assay to quantify inflammatory biomarker plasma levels, liquid chromatography-mass spectrometry to quantify the concentrations of 665 plasma metabolites, and a competitive enzyme-linked immunoassay to quantify urinary 8-OHdG and 8-isoprostane levels. We used linear mixed effects models to estimate the longitudinal association between each inflammatory and oxidative stress biomarker and each metabolite. RESULTS: At a 5% FDR threshold, we detected ≥1metabolite association for 8 unique inflammatory and oxidative stress biomarkers: urinary 8-isoprostane, plasma C-reactive protein (CRP), serum amyloid A (SAA), intercellular adhesion molecule 1, circulating vascular cell adhesion molecule-1, interleukin 8 (IL-8), interleukin 10 (IL-10) and vascular endothelial growth factor. Specifically, 3 metabolites in the androgenic steroids pathway were negatively associated with SAA; 3 dihydrosphingomyelins metabolites were positively associated with 1 or more of CRP, SAA, IL-8 and IL-10; 4 metabolites in acyl choline metabolism pathways were negatively associated with IL-8; 7 lysophospholipid metabolites were negatively associated with 1 or more of CRP, SAA and IL-8; 4 sphingomyelins were positively associated with CRP and/or SAA; and 10 metabolites in the xanthine pathway were positively associated with urinary 8-isoprostane. CONCLUSION: We found that metabolites in phospholipid groups had strong associations with multiple inflammatory biomarkers, especially CRP, SAA and IL-8. The mechanism of these associations warrants further investigation.

Remarkable Thermal Conductivity of Epoxy Composites Filled with Boron Nitride and Cured under Pressure.

This work demonstrates that the application of even moderate pressures during cure can result in a remarkable enhancement of the thermal conductivity of composites of epoxy and boron nitride (BN). Two systems have been used: epoxy-thiol and epoxy-diamine composites, filled with BN particles of different sizes and types: 2, 30 and 180 µm platelets and 120 µm agglomerates. Using measurements of density and thermal conductivity, samples cured under pressures of 175 kPa and 2 MPa are compared with the same compositions cured at ambient pressure. The thermal conductivity increases for all samples cured under pressure, but the mechanism responsible depends on the composite system: For epoxy-diamine composites, the increase results principally from a reduction in the void content; for the epoxy-thiol system with BN platelets, the increase results from an improved matrix-particle interface; for the epoxy-thiol system with BN agglomerates, which has a thermal conductivity greater than 10 W/mK at 44.7 vol.% filler content, the agglomerates are deformed to give a significantly increased area of contact. These results indicate that curing under pressure is an effective means of achieving high conductivity in epoxy-BN composites.

Densification: A Route towards Enhanced Thermal Conductivity of Epoxy Composites.

When an amorphous polymer is cooled under pressure from above its glass transition temperature to room temperature, and then the pressure is released, this results in a densified state of the glass. This procedure applied to an epoxy composite system filled with boron nitride (BN) particles has been shown to increase the density of the composite, reduce its enthalpy, and, most importantly, significantly enhance its thermal conductivity. An epoxy-BN composite with 58 wt% BN platelets of average size 30 µm has been densified by curing under pressures of up to 2.0 MPa and then cooling the cured sample to room temperature before releasing the pressure. It is found that the thermal conductivity is increased from approximately 3 W/mK for a sample cured at ambient pressure to approximately 7 W/mK; in parallel, the density increases from 1.55 to 1.72 ± 0.01 g/cm3. This densification process is much more effective in enhancing the thermal conductivity than is either simply applying pressure to consolidate the epoxy composite mixture before curing or applying pressure during cure but then removing the pressure before cooling to room temperature; this last procedure results in a thermal conductivity of approximately 5 W/mK. Furthermore, it has been shown that the densification and corresponding effect on the thermal conductivity is reversible; it can be removed by heating above the glass transition temperature and then cooling without pressure and can be reinstated by again heating above the glass transition temperature and then cooling under pressure. This implies that a densified state and an enhanced thermal conductivity can be induced even in a composite prepared without the use of pressure.

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid.

PURPOSE: The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA. METHODS: A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models. RESULTS: Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours. CONCLUSION: Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies.

Thermal Conductivity and Cure Kinetics of Epoxy-Boron Nitride Composites-A Review.

Epoxy resin composites filled with thermally conductive but electrically insulating particles play an important role in the thermal management of modern electronic devices. Although many types of particles are used for this purpose, including oxides, carbides and nitrides, one of the most widely used fillers is boron nitride (BN). In this review we concentrate specifically on epoxy-BN composites for high thermal conductivity applications. First, the cure kinetics of epoxy composites in general, and of epoxy-BN composites in particular, are discussed separately in terms of the effects of the filler particles on cure parameters and the cured composite. Then, several fundamental aspects of epoxy-BN composites are discussed in terms of their effect on thermal conductivity. These aspects include the following: the filler content; the type of epoxy system used for the matrix; the morphology of the filler particles (platelets, agglomerates) and their size and concentration; the use of surface treatments of the filler particles or of coupling agents; and the composite preparation procedures, for example whether or not solvents are used for dispersion of the filler in the matrix. The dependence of thermal conductivity on filler content, obtained from over one hundred reports in the literature, is examined in detail, and an attempt is made to categorise the effects of the variables and to compare the results obtained by different procedures.

Achieving High Thermal Conductivity in Epoxy Composites: Effect of Boron Nitride Particle Size and Matrix-Filler Interface.

For the thermal management of high watt density circuit layers, it is common to use a filled epoxy system to provide an electrically insulating but thermally conducting bond to a metal substrate. An epoxy-thiol system filled with boron nitride (BN), in the form of 2, 30 and 180 µm platelets, has been investigated with a view to achieving enhanced thermal conductivity. The effect of BN content on the cure reaction kinetics has been studied by differential scanning calorimetry and the thermal conductivity of the cured samples has been measured by the Transient Hot Bridge method. The heat of reaction and the glass transition temperature of the fully cured samples are both independent of the BN content, but the cure reaction kinetics is systematically affected by both BN content and particle size. These results can be correlated with the thermal conductivity of the cured systems, which is found to increase with both BN content and particle size. For a given BN content, the thermal conductivity found here is significantly higher than most others reported in the literature; this effect is attributed to a Lewis acid-base interaction between filler and matrix.

Study of Hyperbranched Poly(ethyleneimine) Polymers of Different Molecular Weight and Their Interaction with Epoxy Resin.

Two different commercial hyperbranched poly(ethyleneimine)s (HBPEI), with molecular weights (MW) of 800 and 25,000 g/mol, and denoted as PEI800 and PEI25000, respectively, as well as the mixtures with a Diglycidyl Ether of Bisphenol-A (DGEBA) epoxy resin, have been studied using thermal analysis techniques (DSC, TGA), dielectric relaxation spectroscopy (DRS), and dynamic mechanical analysis (DMA). Only a single glass transition is observed in these mixtures by DSC. DRS of the HBPEIs shows three dipolar relaxations: γ, ß, and α. The average activation energy for the γ-relaxation is similar for all HBPEIs and is associated with the motion of the terminal groups. The ß-relaxation has the same average activation energy for both PEI800 and PEI25000; this relaxation is attributed to the mobility of the branches. The α-relaxation peak for all the HBPEIs is an asymmetric peak with a shoulder on the high temperature side. This shoulder suggests the existence of ionic charge trapped in the PEI. For the mixtures, the γ- and ß-relaxations follow the behaviour of the epoxy resin alone, indicating that the epoxy resin dominates the molecular mobility. The α-relaxation by DRS is observed only as a shoulder, as a consequence of an overlap with conductivity effects, whereas by DMA, it is a clear peak.

Epoxy-Thiol Systems Filled with Boron Nitride for High Thermal Conductivity Applications.

An epoxy-thiol system filled with boron nitride (BN), in the form of 80 µm agglomerates, has been investigated with a view to achieving enhanced thermal conductivity. The effect of BN content on the cure reaction kinetics has been studied by differential scanning calorimetry (DSC) and the thermal conductivity of the cured samples has been measured by the transient hot bridge method. The heat of reaction and the glass transition temperature of the fully cured samples are both independent of the BN content, but the cure reaction kinetics is not: with increasing BN content, the reaction first advances and is then delayed, this behaviour being more pronounced than for the same system with 6 µm BN particles, investigated previously. This dependence on BN content is attributed to the effects of heat transfer, and the DSC results can be correlated with the thermal conductivity of the cured systems, which is found to increase with both BN content and BN particle size. For a given BN content, the values of thermal conductivity obtained are significantly higher than many others reported in the literature, and achieve a value of over 4.0 W/mK for a BN content of about 40 vol %.

Study of the Molecular Dynamics of Multiarm Star Polymers with a Poly(ethyleneimine) Core and Poly(lactide) Multiarms.

Multiarm star polymers, denoted PEIx-PLAy and containing a hyperbranched poly(ethyleneimine) (PEI) core of different molecular weights x and poly(lactide) (PLA) arms with y ratio of lactide repeat units to N links were used in this work. Samples were preconditioned to remove the moisture content and then characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and dielectric relaxation spectroscopy (DRS). The glass transition temperature, Tg, is between 48 and 50 °C for all the PEIx-PLAy samples. The dielectric curves show four dipolar relaxations: γ, ß, α, and α' in order of increasing temperature. The temperatures at which these relaxations appear, together with their dependence on the frequency, allows relaxation maps to be drawn, from which the activation energies of the sub-Tg γ- and ß-relaxations and the Vogel-Fulcher-Tammann parameters of the α-relaxation glass transition are obtained. The dependence of the characteristic features of these relaxations on the molecular weight of the PEI core and on the ratio of lactide repeat units to N links permits the assignation of molecular motions to each relaxation. The γ-relaxation is associated with local motions of the -OH groups of the poly(lactide) chains, the ß-relaxation with motions of the main chain of poly(lactide), the α-relaxation with global motions of the complete assembly of PEI core and PLA arms, and the α'-relaxation is related to the normal mode relaxation due to fluctuations of the end-to-end vector in the PLA arms, without excluding the possibility that it could be a Maxwell-Wagner-Sillars type ionic peak because the material may have nano-regions of different conductivity.

Molecular Mobility in Hyperbranched Polymers and Their Interaction with an Epoxy Matrix.

The molecular mobility related to the glass transition and secondary relaxations in a hyperbranched polyethyleneimine, HBPEI, and its relaxation behaviour when incorporated into an epoxy resin matrix are investigated by dielectric relaxation spectroscopy (DRS) and dynamic mechanical analysis (DMA). Three systems are analysed: HBPEI, epoxy and an epoxy/HBPEI mixture, denoted ELP. The DRS behaviour is monitored in the ELP system in three stages: prior to curing, during curing, and in the fully cured system. In the stage prior to curing, DRS measurements show three dipolar relaxations: γ, ß and α, for all systems (HBPEI, epoxy and ELP). The α-relaxation for the ELP system deviates significantly from that for HBPEI, but superposes on that for the epoxy resin. The fully cured thermoset displays both ß- and α-relaxations. In DMA measurements, both α- and ß-relaxations are observed in all systems and in both the uncured and fully cured systems, similar to the behaviour identified by DRS.

The correlation between endoscopic and histopathological measurements in colorectal polyps.

AIMS: Colorectal adenomas measuring 10 mm or more are at increased neoplastic risk and therefore undergo more rigorous follow-up. Currently there is no standardized method of assessing polyp size. We aimed to examine the correlation between endoscopic and histopathological measurements to determine the most appropriate method for clinical use. METHODS AND RESULTS: Colorectal polyps removed between November 2008 and January 2009 were identified. Routine endoscopic and histopathological measurements were determined retrospectively from the reports. Glass slide measurements using a ruler and magnified graticule were performed prospectively on all cases. Fifty cases also underwent high-resolution digital scanning and tissue morphometry. After exclusions, 352 polyps from 210 patients were identified, including 235 adenomas, 107 hyperplastic polyps and 10 other lesions. Only 89% of adenomas had a documented endoscopic measurement and 22% a histopathological measurement. The median endoscopic measurement was significantly greater, resulting in 13% of patients being misclassified as high or low risk. CONCLUSIONS: There are significant differences between endoscopic and histopathological measurement, and currently histopathologists frequently fail to accurately measure adenomas. Histopathological measurement should still be considered as the gold standard; however, there must be a hierarchy of measurements to take account of the practical limitations of sample fragmentation.

A New Epoxy-Based Layered Silicate Nanocomposite Using a Hyperbranched Polymer: Study of the Curing Reaction and Nanostructure Development.

Polymer layered silicate (PLS) nanocomposites have been prepared with diglycidyl ether of bisphenol-A (DGEBA) epoxy resin as the matrix and organically modified montmorillonite (MMT) as the clay nanofiller. Resin-clay mixtures with different clay contents (zero, two, five and 10 wt%) were cured, both isothermally and non-isothermally, using a poly(ethyleneimine) hyperbranched polymer (HBP), the cure kinetics being monitored by differential scanning calorimetry (DSC). The nanostructure of the cured nanocomposites was characterized by small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM), and their mechanical properties were determined by dynamic mechanical analysis (DMA) and impact testing. The results are compared with an earlier study of the structure and properties of the same DGEBA-MMT system cured with a polyoxypropylene diamine, Jeffamine. There are very few examples of the use of HBP as a curing agent in epoxy PLS nanocomposites; here, it is found to enhance significantly the degree of exfoliation of these nanocomposites compared with those cured with Jeffamine, with a corresponding enhancement in the impact energy for nanocomposites with the low clay content of 2 wt%. These changes are attributed to the different cure kinetics with the HBP, in which the intra-gallery homopolymerization reaction is accelerated, such that it occurs before the bulk cross-linking reaction.

Comparison of the Nanostructure and Mechanical Performance of Highly Exfoliated Epoxy-Clay Nanocomposites Prepared by Three Different Protocols.

Three different protocols for the preparation of polymer layered silicate nanocomposites based upon a tri-functional epoxy resin, triglycidyl para-amino phenol (TGAP), have been compared in respect of the cure kinetics, the nanostructure and their mechanical properties. The three preparation procedures involve 2 wt% and 5 wt% of organically modified montmorillonite (MMT), and are: isothermal cure at selected temperatures; pre-conditioning of the resin-clay mixture before isothermal cure; incorporation of an initiator of cationic homopolymerisation, a boron tri-fluoride methyl amine complex, BF3·MEA, within the clay galleries. It was found that features of the cure kinetics and of the nanostructure correlate with the measured impact strength of the cured nanocomposites, which increases as the degree of exfoliation of the MMT is improved. The best protocol for toughening the TGAP/MMT nanocomposites is by the incorporation of 1 wt% BF3·MEA into the clay galleries of nanocomposites containing 2 wt% MMT.

Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis.

OBJECTIVE: The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anticolorectal cancer activity in vitro and in preclinical models. The present study tested whether a novel, enteric-coated formulation of EPA, as the free fatty acid (EPA-FFA), has chemopreventative efficacy in patients with familial adenomatous polyposis (FAP), in a randomised, double-blind, placebo-controlled trial. METHODS: Patients undergoing endoscopic surveillance of their retained rectum postcolectomy were randomised to EPA-FFA (SLA Pharma) 2 g daily or placebo for 6 months. The number and size of polyps in an area of mucosa defined by a tattoo were determined before and after intervention. Global rectal polyp burden was scored (-1, 0, +1) by examination of video endoscopy records. Mucosal fatty acid content was measured by gas chromatography-mass spectrometry. RESULTS: 55 patients with FAP were evaluated by an intention-to-treat analysis (EPA-FFA 28, placebo 27). Treatment with EPA-FFA for 6 months was associated with a mean 22.4% (95% CI 5.1% to 39.6%) reduction in polyp number (p=0.012) and a 29.8% (3.6% to 56.1%) decrease in the sum of polyp diameters (p=0.027). Global polyp burden worsened over 6 months in the placebo group (-0.34) unlike the EPA-FFA group (+0.09, difference 0.42 (0.10-0.75), p=0.011). EPA-FFA treatment led to a mean 2.6-fold increase in mucosal EPA levels (p=0.018 compared with placebo). EPA-FFA was well tolerated with an incidence of adverse events similar to placebo. CONCLUSIONS: EPA-FFA has chemopreventative efficacy in FAP, to a degree similar to that previously observed with selective cyclo-oxygenase-2 inhibitors. EPA holds promise as a colorectal cancer chemoprevention agent with a favourable safety profile.

Long-acting somatostatin analogue therapy in obscure-overt gastrointestinal bleeding in noncirrhotic portal hypertension: a case report and literature review.

We describe a case of obscure gastrointestinal bleeding in a male with noncirrhotic portal hypertension who required multiple admissions and repeated blood transfusions over a 5-month period. Upper and lower gastrointestinal endoscopy failed to establish a cause for bleeding which was eventually ascribed to universal portal hypertensive stigmata in stomach, small bowel and colon, which were not amenable to endoscopic therapy. On account of extensive venous thrombosis, neither surgical shunting nor interventional radiology was an option. Initial management with prothrombotic agents failed. Our patient was successfully stabilized on long-acting somatostatin (SMS) analogue therapy using lanreotide, resulting in avoidance of further admissions and blood transfusion and restoration of his independence and quality of life. The use of short-acting SMS analogues is recognised in acute variceal haemorrhage secondary to portal hypertension in cirrhosis, and long-acting SMS analogue therapy has been described in obscure gastrointestinal bleeding though secondary to angiodysplasia. However, the potential role of long-term SMS analogues in noncirrhotic portal hypertensive bleeding of this type has not been reported earlier. This case supports its use in this scenario in the absence of surgical options and when only palliative approaches are available.