There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients ...undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at 'type A' (ESR1, GATA5, HIC1, HPP1, SFRP1) and 'type C' markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. 'Type A' genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. 'Type C' methylation is more specific for neoplasia. The last five 'type C' markers comprise a CIMP panel. The mean 'type A' and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most 'type A' genes showed direct correlations between methylation and age (ESR1, rho=0.66, P<0.0001), with higher methylation distally (ESR1, P<0.0001). On multivariate analysis, 'type A' methylation was inversely associated with colorectal adenomas (odds ratio=0.23, P<0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio=5.1, P=0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.
This study evaluated the effect of a probiotic bacteria ‘Bifidobacterium lactis’, the carbohydrate ‘resistant starch’ (RS) and their combination (synbiotic), on their ability to protect against ...colorectal cancer (CRC). Bifidobacterium lactis has been shown previously to utilize RS as a substrate and up-regulate the acute apoptotic response to a carcinogen in the colon Le Leu et al. (2005) J. Nutr., 135, 996–1001. Sprague–Dawley rats were divided into six equal groups and fed semi-purified diets for 30 weeks. Colonic neoplasms were induced by 2 weekly injections of azoxymethane (15 mg/kg body wt). The experimental groups were as follows: control—no added dietary fibre or RS; RS in two forms—Hi-maize 958 or Hi-maize 260; B.lactis (lyophilized)—added to control and RS diets (six treatment groups in all). Rats fed RS in combination with B.lactis showed significantly lowered incidence and multiplicity of colonic neoplasms (P < 0.01) by >50% compared with the control group. There was a trend for protection by RS alone (P = 0.07), whereas no protection against cancer was seen in the group supplemented with only B.lactis. Fermentation events short-chain fatty acid (SCFA), pH were altered by the inclusion of RS into the diet, whereas the inclusion of B.lactis into the diet had no significant effect on the fermentation parameters. The synbiotic combination of RS and B.lactis significantly protects against the development of CRC in the rat-azoxymethane model. Synbiotic combination of prebiotic and probiotic seems likely to be a superior preventive strategy to prebiotic alone.
Needle-related distress is a common yet poorly recognised and managed problem among haemodialysis (HD) patients. The aim of this pilot study is to test the feasibility and acceptability of the INJECT ...Intervention-an innovative psychology-based intervention to empower patients to self-manage needle distress with the support of dialysis nurses.
This investigator-initiated, single-arm, non-randomised feasibility study will take place in a large dialysis service in Adelaide, Australia. Participants will include patients aged ≥ 18 years, commencing or already receiving maintenance HD, recruited through dialysis physicians and nursing staff as individuals believed to be at risk of needle distress. They will be screened for inclusion using the Dialysis Fear of Injection Questionnaire (DFIQ) and enrolled into the study if the score is ≥ 2. The multi-pronged intervention encompasses (i) psychologist review, (ii) patient self-management program and (iii) nursing education program. The primary aim is to evaluate feasibility and acceptability of the intervention from patient and dialysis nurse perspectives, including recruitment, retention, engagement with the intervention and completion. Secondary exploratory outcomes will assess suitability of various tools for measuring needle distress, evaluate acceptability of the nursing education program and measure cannulation-related trauma and vascular access outcomes.
The results will inform the protocol for larger trials addressing needle distress in HD patients.
Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000229875, approved 4 April 2021, https://www.anzctr.org.au/ .
Fermentation of polysaccharides in the colon seems likely to regulate tumorigenesis but the mechanisms are unclear. A possible mechanism may be through facilitation of the acute apoptotic response to ...genotoxin-induced DNA damage. This study evaluated the effects of selected dietary polysaccharides, resistant starch (supplied as Hi-maize) and nonstarch polysaccharides (supplied as wheat bran and cellulose) on certain biological events relevant to protection against colon cancer (fecal bulk, pH, butyrate and apoptosis). Male Sprague–Dawley rats were fed the different experimental diets for a period of 4 weeks, after which a single azoxymethane injection was given to induce DNA damage; 6 h later the acute apoptotic response was measured. Other measures included short chain fatty acid (SCFA) levels, fecal bulk and pH. All wheat bran treatments significantly (P < 0.05) enhanced carcinogen-induced apoptosis in the distal colon, increased fecal bulk and butyrate levels and reduced fecal pH, when compared with rats fed NF or Cellulose diets. Total SCFA (P < 0.001, r = 0.496) and butyrate levels (P < 0.001, r = 0.353) in the feces correlated positively with the acute apoptotic response in distal colonic crypts. Resistant starch supplementation by this modest amount did not enhance carcinogen-induced apoptosis. While it did significantly increase bulk, SCFA and butyrate levels and lower pH, the magnitude of these effects was not as great as with wheat bran. These findings indicate that wheat bran is the most effective regulator of these biological events of relevance to protection against colon cancer. Assuming that the acute apoptotic response to genotoxic carcinogens acts to remove genetically damaged cells that might otherwise form mutated clones that progress to malignancy, we have identified an additional biological mechanism by which dietary polysaccharides provide protection.
Protein as well as starch is fermented in the colon, but the interaction between protein and starch fermentation and the impact on colonic oncogenesis is unknown. High-protein diets increase delivery ...of protein to the colon and might promote oncogenesis through generation of toxic products. We investigated the interaction of resistant starch (RS) with digestion-resistant potato protein (PP) on colonic fermentation events and their relationship to intestinal tumourigenesis. Male Sprague–Dawley rats were fed an AIN-76A-based diet for 4 weeks and intestinal neoplasms were induced by azoxymethane. Experimental diets included the following: no added RS or PP, 10% high amylose maize starch (source of RS) replacing digestible starch, 15% PP replacing casein and 10% high amylose maize starch + 15% PP. Rats were maintained on diets until killed at 30 weeks. Feeding RS significantly increased short-chain fatty acid (SCFA) levels (P < 0.001) in the caecum and colon. Importantly, butyrate concentration was significantly increased in the distal colon with RS (P < 0.001). Feeding PP increased protein fermentation products, but this effect was reduced by adding RS to the diet. Intestinal neoplasms and colorectal adenocarcinomas were reduced by feeding RS (P < 0.01) regardless of whether PP was fed, whereas PP alone increased the incidence and number of small intestinal neoplasms including the adenocarcinomas (P < 0.01). In conclusion, RS altered the colonic luminal environment by increasing the concentration of SCFAs including butyrate and lowering production of potentially toxic protein fermentation products. These effects of RS not only protected against intestinal tumourigenesis but also ameliorated the tumour-enhancing effects of feeding indigestible protein.
Alterations in folate status may play an important role in carcinogenesis. The aim of this study was to examine the effect of a diminished folate status on azoxymethane (AOM)-induced intestinal ...tumours in Sprague–Dawley rats. A total of 125 weanling male rats were divided into five equal groups and fed semi-purified diets containing either 8 mg/kg folate or no folate. After 4 weeks on experimental diets, all animals received three weekly subcutaneous injections of AOM at a dose rate of 15 mg/kg bodyweight. The animals were necropsied after 26 weeks. Rats with a diminished folate status, evident by significantly reduced blood and colonic folate concentrations and elevated plasma homocysteine levels, had significantly (P < 0.01) lower incidence and number of small intestinal and colonic tumours compared with rats displaying an adequate folate status. There was a significant decrease in the incidence of colonic adenocarcinomas (P < 0.01) and size of colonic tumours observed in the rats displaying a diminished folate status. This study shows that a diminished folate status was associated with a decrease in the development of AOM-induced colorectal cancers. The decrease in risk may be attributed to the known role of folate in cell multiplication.
The impact of different dietary protein sources (whey, casein, soybean, red meat) on the incidence, burden and mass index of intestinal tumors induced by dimethylhydrazine in male Sprague-Dawley rats ...was assessed. A purified diet (based on AIN-76A) with a fat concentration of 20 g/100 g and other proteins substituted for casein (20 g/100 g) was used. Whey and casein diets were more protective against the development of intestinal tumors than were the red meat or soybean diets, as evidenced by a reduced incidence of rats affected (P = 0.15), fewer tumors per treatment group (burden, P < 0.005), and a reduced pooled area of tumors (tumor mass index) that formed (P = 0.39). Intracellular concentration of glutathione, an antioxidant and anticarcinogenic tripeptide, measured in liver, was greatest in whey protein- and casein-fed rats and lowest in soybean-fed animals (P < 0.001). For other tissues (spleen, colon, tumor) the differences were not significant, although the whey-fed animals had the highest concentrations of glutathione (P = 0.8). Whey is a source of precursors (cysteine-rich proteins) for glutathione synthesis and may be important in providing protection to the host by stimulating glutathione synthesis. A positive correlation was observed between mean fecal fat concentrations for rats in each treatment group and large intestinal tumor burden (r2 = 0.898, P = 0.05). Fecal fat could be involved in aiding initiation and/or promotion of carcinogenesis. Whatever the mechanism(s), dairy proteins, and whey proteins in particular, offer considerable protection to the host against dimethylhydrazine-induced tumors relative to the other protein sources examined.
The apoptotic response to DNA damage appears to be an innate biological mechanism for protection against tumourigenesis. It is possible that agents that protect against colorectal cancer act by ...enhancing the apoptotic deletion of cells suffering DNA damage, with consequent removal of those with tumourigenic mutations. We examined the acute apoptotic response to genotoxic carcinogens (`AARGC') in colonic epithelium and the possibility that dietary fibres of different fermentability might regulate AARGC. To fully define the time-course and nature of AARGC in response to the carcinogen azoxymethane (AOM), a single injection of AOM (10 mg/kg) was given to rats and apoptosis monitored in the colon by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining over a 72 h period. Having defined the site and time of maximum response, two groups of eight rats were fed diets containing 10% wheat bran fibre (WB; fermentable) or 10% methylcellulose (MC; poorly fermentable) for 4 weeks. Colonic AARGC was compared by light microscopy; lumenal short chain fatty acids (SCFAs) and pH were measured as indicators of the fermentative environment. AOM-induced AARGC was maximal at 8 h and greater in distal compared with proximal colon. Apoptotic cells were situated predominantly in the lower half of the crypt, with the median at position 9 indicating involvement of daughter as well as stem cells. There was no `second wave' of apoptosis within 72 h as follows irradiation in small intestine. Distal colonic AARGC in rats fed WB was twice that in rats fed MC (P < 0.01). Compared with MC, WB significantly lowered lumenal pH and increased all SCFAs including butyrate, while proliferation did not differ between the fibres. Certainly, dietary fibres can regulate AARGC and further studies are warranted to determine if this biological effect is the way in which dietary factors regulate tumourigenesis. Lumenal generation of butyrate may enhance AARGC as butyrate is proapoptotic in vitro.
The effect of different doses of a type-2 resistant starch (RS) in the form of high amylose cornstarch (HAS) on the intralumenal environment and the acute-apoptotic response to a genotoxic carcinogen ...(AARGC) in the colon was assessed to determine if changes in lumenal conditions were associated with an enhanced apoptotic response to DNA damage. The control diet was a modified form of the AIN-76 diet containing fully digestible starch but no dietary fibre. HAS was added to the control diet at the expense of digestible starch to give 10% HAS, 20% HAS and 30% HAS. Rats were fed the different experimental diets for a period of 4 weeks, after which a single injection of azoxymethane was given to induce DNA damage in the colonic epithelium; 6 h later AARGC was measured. Other measures included fecal and cecal short chain fatty acids (SCFA) and pH, and cell proliferation in the colonic epithelium. In HAS-supplemented rats, fermentation events were significantly increased in both cecum and feces. There was a progressive decrease in pH in both the cecum and feces as the amount of HAS in the diet increased. SCFA concentrations, including butyrate, were significantly elevated by HAS with higher levels being observed in the cecum than in the feces. There was a significant increase in colonic AARGC with HAS doses of 20 and 30% (P < 0.01) but not with 10% HAS. Cell proliferation was not affected by any dose of HAS. Correlations with AARGC, independent of dietary group, were seen for fecal SCFAs and pH, suggesting that fermentation events, might explain the effect of RS on AARGC. Altering amounts of dietary RS changes fermentative activity in the colon. Increased RS is associated with enhanced AARGC. Changes in amount of fermentable substrate are capable of changing the biological response to DNA damage.
Experimental evidence is accumulating from animal models and
in vitro data which shows that dietary proteins can influence cancer expression, some having a promotional influence, others a ...preventative effect relative to an arbitrarily established standard diet. This result will to a degree be determined by the nature of the cancer model under study. Dairy proteins have been shown to be relatively protective when compared with defatted soybean meal and cooked red meat in the rat dimethylhydrazine-induced (DMH) colon cancer model. Some epidemiological evidence supports these experimental observations. Both protein and fat appear to be influencing outcome, with potential for interactive effects. A number of possible mechanisms have been postulated as to how these proteins and closely associated factors could be influencing colon cancer risk, an area that deserves more investigation. Combinations of foods such as dairy foods with cereals and/or probiotic bacteria provide potentially interesting alliances in reducing colon cancer risk. The combining of relatively protective agents deserves more investigation as to its potential, in devising functional foods and diets worthy of further evaluation, in animal models of cancer, and human intervention studies using relevant endpoint markers.
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