Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment.

Periostin (POSTN), a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, the molecular mechanisms underlying POSTN function within the tumor microenvironment are poorly understood. In this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that POSTN cooperates with a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53(R175H) mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix. Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in promoting invasion. Furthermore, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors. Overall, these results highlight the novel molecular mechanisms supporting the capacity of POSTN in mediating tumor invasion during ESCC development and have implications of therapeutic strategies targeting the tumor microenvironment.

Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis.

Matricellular proteins have been classified as a family of non-structural matrix proteins capable of modulating a variety of biological processes within the extracellular matrix (ECM). These proteins are expressed dynamically and their cellular functions are highly dependent upon cues from the local environment. Recent studies have shown an increasing appreciation of the key roles these ECM proteins play within the tumour microenvironment. Induced by either tumour cells or tumour stromal components, matricellular proteins initiate downstream signalling events that lead to proliferation, invasion, matrix remodelling and dissemination to pre-metastatic niches in other organs. In this review, we summarise and discuss the current knowledge of the diverse roles these proteins play within the microenvironment that influences tumour progression and potential for future therapies targeting the tumour microenvironment.

One-week ranitidine bismuth citrate, amoxicillin and metronidazole triple therapy for the treatment of Helicobacter pylori infection in Chinese.

BACKGROUND: We have previously shown that ranitidine bismuth citrate-based, clarithromycin-containing triple therapy achieves a higher eradication rate than proton pump inhibitor-based regimens in areas with a high prevalence of metronidazole resistance. AIM: To evaluate whether this higher efficacy of ranitidine bismuth citrate over proton pump inhibitor can be extended to non-clarithromycin-containing regimens. METHODS: Helicobacter pylori-positive dyspeptic patients were randomized to receive either ranitidine bismuth citrate, 400 mg, amoxicillin, 1000 mg, and metronidazole, 400 mg, or omeprazole, 20 mg, amoxicillin, 1000 mg, and metronidazole, 400 mg, each given twice daily for 1 week. H. pylori eradication was confirmed by 13C-urea breath test 5 weeks later. The side-effects of the treatments were documented. RESULTS: Two hundred and twenty-nine patients were eligible for analysis. By intention-to-treat and per protocol analysis, the eradication rates were 77% and 79%, respectively, in the ranitidine bismuth citrate-amoxicillin-metronidazole group and 77% and 82%, respectively, in the omeprazole-amoxicillin-metronidazole group (P = 0.58 and P = 0.65). However, patients in the omeprazole-amoxicillin-metronidazole group reported a significantly higher incidence of minor side-effects when compared to those in the ranitidine bismuth citrate-amoxicillin-metronidazole group (P = 0.001). CONCLUSIONS: Ranitidine bismuth citrate-amoxicillin-metronidazole was equally as effective as omeprazole-amoxicillin-metronidazole triple therapy, and may be considered as an alternative non-clarithromycin-based regimen in the Chinese population.

Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine) and related analogs as potential therapeutic agents for Alzheimer's disease.

A series of novel N-(4-pyridinyl)-1H-indol-1-amines and other heteroaryl analogs was synthesized and evaluated in tests to determine potential utility for the treatment of Alzheimer's disease. From these compounds, N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine, 4c) was selected for clinical development based on in-depth biological evaluation. In addition to cholinomimetic properties based initially on in vitro inhibition of [3H]quinuclidinyl benzilate binding, in vivo reversal of scopolamine-induced behavioral deficits, and subsequently on other results, 4c also displayed enhancement of adrenergic mechanisms as evidenced in vitro by inhibition of [3H] clonidine binding and synaptosomal biogenic amine uptake, and in vivo by reversal of tetrabenazine-induced ptosis. The synthesis, structure-activity relationships for this series, and the biological profile of 4c are reported.

Beneficial effect of a low glycaemic index diet in type 2 diabetes.

Low glycaemic index foods produce low blood glucose and insulin responses in normal subjects, and improve blood glucose control in Type 1 and well-controlled Type 2 diabetic patients. We studied the effects of a low glycaemic index diet in 15 Type 2 diabetic patients with a mean fasting blood glucose of 9.5 mmol l-1 using a randomized, crossover design. Patients were given pre-weighed diets (59% energy as carbohydrate, 21% fat, and 24 g 1000-kcal-1 dietary fibre) for two 2-week periods, with a diet glycaemic index of 60 during one period and 87 during the other. On the low glycaemic index diet, the blood glucose response after a representative breakfast was 29% less than on the high glycaemic index diet (874 +/- 108 (+/- SE) vs 204 +/- 112 mmol min l-1; p less than 0.001), the percentage reduction being almost identical to the 28% difference predicted from the meal glycaemic index values. After the 2-week low glycaemic index diet, fasting serum fructosamine and cholesterol levels were significantly less than after the high glycaemic index diet (3.17 +/- 0.12 vs 3.28 +/- 0.16 mmol l-1, p less than 0.05, and 5.5 +/- 0.4 vs 5.9 +/- 0.5 mmol l-1, p less than 0.02, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effect of low-glycemic index diet in overweight NIDDM subjects.

OBJECTIVE: To determine whether low-glycemic index (GI) diets have clinical utility in overweight patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Six patients with NIDDM were studied on both high- and low-GI diets of 6-wk duration with metabolic diets with a randomized crossover design. Both diets were of similar composition (57% carbohydrate, 23% fat, and 34 g/day dietary fiber), but the low-GI diet had a GI of 58 compared with 86 for the high-GI diet. RESULTS: Small and similar amounts of weight were lost on both diets: 2.5 kg on high-GI diet and 1.8 kg on low-GI diet. On the low-GI diet, the mean level of serum fructosamine, as an index of overall blood glucose control, was lower than on the high-GI diet by 8% (P less than 0.05), and total serum cholesterol was lower by 7% (P less than 0.01). CONCLUSIONS: In overweight patients with NIDDM, reducing diet GI improves overall blood glucose and lipid control.

Metabolic effects of reducing rate of glucose ingestion by single bolus versus continuous sipping.

Modifying the rate of absorption has been proposed as a therapeutic principle of specific relevance to diabetes. To demonstrate clearly the metabolic benefits that might result from reducing the rate of nutrient delivery, nine healthy volunteers took 50 g glucose in 700 ml water on two occasions: over 5-10 min (bolus) and at a constant rate over 3.5 h (sipping). Despite similar 4-h blood glucose areas, large reductions were seen in serum insulin (54 +/- 10%, P less than 0.001) and C-peptide (47 +/- 12%, P less than 0.01) areas after sipping, together with lower gastric inhibitory polypeptide and enteroglucagon levels and urinary catecholamine output. There was also prolonged suppression of plasma glucagon, growth hormone, and free-fatty acid (FFA) levels after sipping, whereas these levels rose 3-4 h after the glucose bolus. An intravenous glucose tolerance test at 4 h demonstrated a 48 +/- 10% (P less than 0.01) more rapid decline in blood glucose (Kg) after sipping than after the bolus. Furthermore, FFA and total branched-chain amino acid levels as additional markers of insulin action were lower over this period despite similar absolute levels of insulin and C-peptide. These findings indicate that prolonging the rate of glucose absorption enhances insulin economy and glucose disposal.

Glycemic index of foods in individual subjects.

We studied 12 subjects with diabetes to determine how well the glycemic index (GI) predicted the ranking of glycemic responses of different foods in individuals. All subjects ate three mixed meals (bread, rice, or spaghetti with GIs of 100, 79, and 61, respectively) four times in a randomized complete block design. The mean glycemic response areas of the different meals ranked according to the predicted GI in every individual. The observed mean +/- SD GI values of the meals were significantly different from each other (bread 100 +/- 7, rice 75 +/- 9, spaghetti 54 +/- 9), with no significant difference in response between subjects. It is concluded that individuals share common mean GI values for different foods. Within confidence limits determined by the variability of glycemic responses, the number of repeated tests conducted, and the expected GI difference, the GI can be used to predict the ranking of the mean glycemic responses of mixed meals taken by individuals.

The glycemic index: variation between subjects and predictive difference.

It is not known whether the variability of the glycemic index (GI) in different subjects is due to within- or between-individual variation. In addition, it is not known how large a difference in GI between different meals is clinically important for individuals with diabetes. Therefore, insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic subjects tested four foods, with each food taken by each subject on two separate occasions. For each food, most of the variation of absolute glycemic responses was due to differences between the subjects. However, when the results were expressed as the GI, there were no significant differences between the subjects, and most of the variation was due to within-individual variation. Using the within-individual variance, we estimated the so-called "predictive difference" of GI values. Its reliability was assessed by consideration of published data from eight studies where different mixed meals were taken by the same group of subjects. There were 37 cases where the difference between the GI of any two meals was greater than the predictive difference. Of these 37 pairs of meals, the GI correctly ranked the glycemic responses in 36 (97%). We conclude that GI values for the same food do not vary significantly between different individuals. For a subject with NIDDM a difference in GI of 34 will predict the ranking of glycemic responses of two meals with 95% probability. The corresponding value for a subject with IDDM is 50.

Relationship between fasting serum tryptophan/large neutral amino acid ratio and reported hunger in subjects with diabetes.

Food intake regulation is influenced by serum amino acid (AA) ratios. The objectives of this study were to determine whether non-obese subjects with diabetes have normal serum AA ratios, and to see if AA ratios relate to perceived hunger. We therefore measured fasting serum AA in nine normal subjects on two occasions and 19 patients with diabetes on four occasions over a two month period. At the time of the blood samples, the subjects with diabetes were asked to rate how hungry they felt on a scale of -3 (very hungry) to +3 (very full). There were no significant differences between the mean AA ratios of normal and diabetic subjects. There was a positive correlation between reported hunger score and the ratio of serum tryptophan (TRP) to the sum of the concentrations of the other large neutral AA (LNAA) (r = 0.286, n = 78, p less than 0.05). The relationships between hunger and other AA ratios were not significant. Variations of the TRP/LNAA ratio within each subject did not relate to differences in hunger from day-to-day. However, there was a positive correlation between the mean TRP/LNAA ratio and mean hunger score of the different subjects (r = 0.495, n = 19, p less than 0.05). The relationships between TRP/LNAA ratio and body weight or hunger score were not significant. It is concluded that the serum AA ratios are normal in patients with diabetes. The data is consistent with the hypothesis that a low serum TRP/LNAA ratio causes increased feelings of hunger in different individuals.

Wholemeal versus wholegrain breads: proportion of whole or cracked grain and the glycaemic response.

STUDY OBJECTIVE: To determine the effect on the glycaemic response to bread of the ratio of whole cereal grains to milled flour. DESIGN: Randomised assignment of groups of diabetic volunteers to test and control meals, taken after an overnight fast. Test foods were also analysed for in vitro digestion with human saliva. SETTING: Tertiary care centre. PATIENTS: Groups of six drawn from pool of 16 volunteers with diabetes mellitus (11 men, five women; mean age 64 (SE 3); 10 taking insulin, five taking oral agents, one controlled by diet; other characteristics comparable). INTERVENTIONS: All patients took standard white bread control meals on three occasions spanning the study and on different mornings took test meals containing varying ratios of whole cereal grains (barley or cracked wheat) to milled flour (75:25, 50:50, 0:100). All meals contained 50 g available carbohydrate and were eaten in 15 minutes. Capillary blood samples were taken for determination of glucose concentrations every 30 minutes for three hours. END POINT: Glycaemic index of foods (= increase in area under blood glucose concentration curve for test food divided by increase in area under curve for white bread control X 100). MEASUREMENTS AND MAIN RESULTS: Significant trend to lower glycaemic index with increasing proportion of whole cereal grains in test bread (p less than 0.05) and lower in vitro digestibility (p less than 0.001). Breads containing up to 75% whole grain were considered palatable. CONCLUSIONS: Breads containing a high proportion of whole cereal grains may be useful in reducing the postprandial blood glucose profile in diabetics because they are more slowly digested. These breads should be called "wholegrain" in distinction to "wholemeal" breads made from milled flour.

Low-glycemic-index starchy foods in the diabetic diet.

Eight patients with noninsulin-dependent diabetes underwent two 2-wk study periods in random order during which they were provided with carbohydrate foods with either a high or low glycemic index (GI). Over both high-GI and low-GI periods there were significant reductions in body weight, serum fructosamine, and cholesterol. Reductions in fasting blood glucose, HbA1c, and urinary c-peptide-to-creatinine ratio were significant only over the low-GI period despite a smaller mean weight loss. Reductions in triglyceride were significant only over the high-GI diet. Inclusion of low-GI foods into diets of patients with diabetes may be an additional measure that favorably influences carbohydrate metabolism without increasing insulin demand.

The glycaemic index: effect of age in insulin dependent diabetes mellitus.

It has been suggested that age effects the glycaemic index value of foods, although there is no data to support this. We therefore studied the blood glucose responses of bread and lentils in seven children (aged 7-17 years) and 10 adults (aged 27-74 years) with insulin dependent diabetes (IDDM). Although there were small differences in the shape of the blood glucose response curves in adults and children, the mean glycaemic index value for lentils was virtually identical in the two groups being 43 +/- 7 in the children and 44 +/- 10 in the adults. We conclude that, in IDDM, the glycaemic index is not affected by age.

The glycemic index: similarity of values derived in insulin-dependent and non-insulin-dependent diabetic patients.

To see whether relative differences in the glycemic responses to different foods were similar in insulin-dependent (IDDM) and non-insulin-dependent diabetic patients (NIDDM) we determined the glycemic index (GI) of a total of 20 foods and mixed test meals in groups of IDDM and NIDDM volunteers. The mean GI values ranged from 32 in NIDDM and 41 in IDDM (pearled barley) to 105 in NIDDM and 111 in IDDM (bread with cheese and tomato). The correlation between the mean GI values in IDDM and NIDDM was highly significant (r = 0.927, p less than 0.001). The mean GI values for 15 of the 20 test meals was greater in IDDM than in NIDDM (mean of GI for all 20 foods, 76 in IDDM compared with 68 in NIDDM, p less than 0.005). However, the difference in GI between IDDM and NIDDM was t statistically significant for 19 of the 20 individual test meals. Greater within-individual variability of glycemic responses in IDDM probably accounts for the slightly greater mean GI value seen in IDDM compared with NIDDM. The addition of 32 g cheddar cheese to four foods which were also fed without cheese had no significant effect on the GI in NIDDM (mean GI of 68 without cheese compared with 72 for the meals with cheese), but had a small effect in IDDM where the mean GI was increased from 72 to 87 (p less than 0.05). However, despite small increases in glycemic response to foods with added cheese, the relative differences between foods were unaffected by the addition of cheese in both IDDM and NIDDM. It is concluded that mean GI values for foods are very similar in IDDM and NIDDM patients.

Low-glycemic index diet in hyperlipidemia: use of traditional starchy foods.

To define those patients most likely to benefit from the hypolipidemic effect of low-glycemic-index (GI) traditional starchy foods, 30 hyperlipidemic patients were studied for 3 mo. During the middle month, low-GI foods were substituted for those with a higher GI with minimal change in dietary macronutrient and fiber content. Only in the group (24 patients) with raised triglyceride levels (types IIb, III, and IV) were significant lipid reductions seen: total cholesterol 8.8 +/- 1.5% (p less than 0.001), LDL cholesterol 9.1 +/- 2.4% (p less than 0.001), and serum triglyceride 19.3 +/- 3.2% (p less than 0.001) with no change in HDL cholesterol. The percentage reduction in serum triglyceride related to the initial triglyceride levels (r = 0.56, p less than 0.01). The small weight loss (0.4 kg) on the low-GI diet did not relate to the lipid changes. Low-GI diets may be of use in the management of lipid abnormalities associated with hypertriglyceridemia.

Effect of canning on the blood glucose response to beans in patients with type 2 diabetes.

Cooked dried legumes have been shown to stimulate low blood glucose responses, and their consumption by individuals with diabetes has been encouraged. However, canned beans are more convenient to use than dried beans. Since the glycaemic effects of canned beans have not been determined, we fed 50 g carbohydrate portions of five varieties of beans, both cooked dried and canned, to groups of diabetic patients and calculated their glycaemic indices (GI). All canned and dried beans tested had significantly lower GIs than that of white bread, which was ascribed a GI of 100. The mean GI of the five types of canned beans, 71 +/- 4, was less than that of bread, 100 (P less than 0.001), and greater than that of the same five varieties of cooked dried beans, 47 +/- 5 (P less than 0.001). It is concluded that the glycaemic effect of dried legumes is increased by the canning process. Nevertheless, canned beans give lower blood glucose responses than bread and may be of use in low glycaemic index diets.

Prediction of glycemic response to mixed meals in noninsulin-dependent diabetic subjects.

Recent studies suggest the glycemic response of different mixed meals cannot be predicted from the glycemic index (GI) of individual carbohydrate foods. Postprandial glucose levels following five different mixed meals in six noninsulin-dependent diabetic volunteers were therefore assessed. Each meal comprised 50% carbohydrate, 30% fat, and 20% protein, varying only in type of carbohydrate. The carbohydrate exchanged in each meal (potato, white bread, rice, spaghetti, or lentils and barley) contributed 37% of total meal calories. The correlation between predicted glucose response and postprandial glucose area was highly significant; estimated meal GI was virtually proportional to the actual mean glycemic response. These results demonstrate that the relative glycemic effects of mixed meals can be predicted from the GI of their carbohydrate components, again stressing the importance of type of carbohydrate in regulating postprandial blood-glucose levels.