Background: Micronutrients may protect against colorectal cancer. Especially folate has been considered potentially preventive. However, studies on folate and colorectal cancer have found contradicting results; dietary folate seems preventive, whereas folic acid in supplements and fortification may increase the risk. Objective: To evaluate the association between intake of vitamins C, E, folate and beta-carotene and colorectal cancer risk, focusing on possibly different effects of dietary, supplemental and total intake, and on potential effect modification by lifestyle factors. Design: In a prospective cohort study of 56,332 participants aged 50-64 years, information on diet, supplements and lifestyle was collected through questionnaires. 465 Colon and 283 rectal cancer cases were identified during follow-up. Incidence rate ratios of colon and rectal cancers related to micronutrient intake were calculated using Cox proportional hazard analyses. Results: The present study found a protective effect of dietary but not supplemental folate on colon cancer. No association with any other micronutrient was found. Rectal cancer did not seem associated with any micronutrient. For both colon and rectal cancer, we found an interaction between dietary folate and alcohol intake, with a significant, preventive effect among those consuming above 10g alcohol/day only. Conclusions: This study adds further weight to the evidence that dietary folate protects against colon cancer, and specifies that there is a source-specific effect, with no preventive effect of supplemental folic acid. Further studies should thus take source into account. Vitamins C, E and beta-carotene showed no relation with colorectal cancer.

The role of micronutrients in lung cancer prevention is controversial, as observational and experimental studies have generated contradicting results. These discrepancies between studies may be due to different effects of micronutrients depending on source (diet or supplements). The objective of this study was to evaluate the association between vitamin C, E, folate and beta-carotene and lung cancer risk while focusing on source-specific effects of dietary and supplemental intake. The association was evaluated in a cohort of 55,557 Danes who completed a food frequency questionnaire including information on consumption of vitamin C, E, folate and beta-carotene from diet and supplements. Incidence rate ratios of lung cancer were calculated using Cox proportional hazards models. During a median follow-up of 10.6 years, 721 incident lung cancer cases were diagnosed. We found a significant protective effect of dietary vitamin E intake and a significantly higher lung cancer risk with supplemental beta-carotene and dietary folate intake. All three micronutrients exhibited significant source-specific effects. The harmful effect of dietary folate is, however, most likely to be due to uncontrolled confounding. Our results indicate source-specific effects of vitamin E and beta-carotene in lung cancer prevention with a preventive effect of dietary vitamin E and a harmful effect of supplemental beta-carotene. Future studies on micronutrients and lung cancer should take source into account.

BACKGROUND:. The identification of possible treatment effects against a background of spontaneous recovery is a major challenge to the successful completion of randomized clinical trials (RCTs) in rehabilitation research. Conventional trial outcomes such as the differences between group means of an outcome measure at a fixed time point are inefficient to an extent that is a major problem, particularly for exploratory studies seeking preliminary evidence of efficacy. OBJECTIVE:. To quantitate gains in study power over conventional fixed-end-point designs by using parametric end points derived from the modeling of the time course of recovery after brain injury. METHODS:. Nonlinear mixed effects (NLME) modeling of the recovery trajectories of 103 children rehabilitating after traumatic brain injury (TBI) as reflected in serial WeeFIM scores was performed. Pseudoreplicate data sets were generated replicating the statistical characteristics of the original data set, and these formed the basis of clinical trial simulations to derive robust estimates of study power. RESULTS:. Parametric end points derived from modeling of recovery improve study power (and reduce necessary sample size) by up to 5 times in this example. CONCLUSIONS:. Parametric end points derived from models of recovery trajectories offer an efficient alternative design for exploratory clinical studies of rehabilitation interventions.

ABSTRACT: BACKGROUND: c-Met is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), and both c-Met and its ligand are expressed in a variety of tissues. C-Met/HGF/SF signaling is essential for normal embryogenesis, organogenesis, and tissue regeneration. Abnormal c-Met/HGF/SF signaling has been demonstrated in different tumors and linked to aggressive and metastatic tumor phenotypes. In vitro and in vivo studies have demonstrated inhibition of c-Met/HGF/SF signaling by the small-molecule inhibitor PHA665752 (Pfizer). This study investigated c-Met and HGF expression in two neuroblastoma (NBL) cell lines and tumor tissue from patients with NBL, as well as the effects of PHA665752 on growth and motility of NBL cell lines. The effect of the tumor suppressor protein PTEN on migration and proliferation of tumor cells treated with PHA665752 was also evaluated. METHODS: Expression of c-Met and HGF in NBL cell lines SH-EP and SH-SY5Y and primary tumor tissue was assessed by immunohistochemistry and quantitative RT-PCR. The effect of PHA665752 on c-Met/HGF signaling involved in NBL cell proliferation and migration was evaluated in c-Met-positive cells and c-Met-transfected cells. The transwell chemotaxis assay and the MTT assay were used to measure migration and proliferation/cell-survival of tumor cells, respectively. The PPAR- agonist rosiglitazone was used to assess the effect of PTEN on PHA665752-induced inhibition of NBL cell proliferation and migration RESULTS: High c-Met expression was detected in SH-EP cells and primary tumors from patients with advanced-stage disease. c-Met/HGF signaling induced both migration and proliferation of SH-EP cells. Migration and proliferation were inhibited by PHA665752 in a dose-dependent manner. We also found that induced overexpression of PTEN following treatment with rosiglitazone enhanced the inhibitory effect of PHA665752 on NBL-cell migration and proliferation. CONCLUSIONS: c-Met is highly expressed in most tumors from patients with advanced-stage, metastatic NBL. Using the NBL cell line SH-EP as a model, PHA665752 was shown to inhibit cMet/HGF/SF signaling in vitro, suggesting c-Met inhibitors may have efficacy for blocking local progression and/or metastatic spread of c-Met-positive NBL in vivo. Further studies of agents targeting the c-Met/HGF axis in NBL are warranted.

A high intake of whole-grain foods may protect against endometrial cancer, but the existing literature is both limited and inconsistent. A significant reason for the inconsistent evidence could be methodological problems regarding accurate assessment of whole-grain intake. Alkylresorcinol (AR) has been suggested as a reliable biomarker of whole-grain wheat and rye intake. Our aim was to overcome the methodological problems in previous questionnaire-based studies, by using AR as exposure measurement when studying the incidence of endometrial cancer. ARs were measured by gas chromatography-mass spectrometry in stored plasma samples from 177 endometrial cancer cases and a subcohort of 152 women, all originating from the same prospective cohort study. Incidence of endometrial cancer according to plasma levels of AR was estimated in a Cox regression model. No associations between plasma levels of AR and endometrial cancer were observed. Body mass index or use of hormone replacement therapy of the participants did not modify the association. This is the first study to associate the whole-grain wheat and rye biomarker AR to a cancer endpoint. No association was found, but more studies are warranted to further explore AR as a marker of whole-grain exposure in relation to cancer and other disease endpoints.

ABSTRACT: BACKGROUND: The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness. The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use. METHODS: The following polymorphisms were analyzed; a synonymous MDR1 C3435T (rs1045642) in exon 26, G-rs3789243-A in intron 3, the functional BCRP C421A (rs2231142), the two COX-2 A-1195G (rs689466) and G-765C (rs20417) in the promoter region, and the COX-2 T8473C (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 364 cases and a random cohort sample of 772 participants from the Danish prospective Diet, Cancer and Health study. RESULTS: Carriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR)=1.52, 95 % Confidence Interval (CI): 1.12-2.06). Carriers of the variant allele of MDR1 C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR= 0.71 (CI:0.50-1.00)). There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous MDR1 C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16) whereas variant allele carriers were not at increased risk (p for interaction = 0.02). COX-2 and BCRP polymorphisms were not associated with CRC risk. There was interaction between NSAID use and MDR1 C3435T and COX-2 T8473C (p-values for interaction 0.001 and 0.04, respectively). CONCLUSIONS: Two polymorphisms in MDR1 were associated with CRC risk and there was interaction between these polymorphisms and meat intake in relation to CRC risk. Our results suggest that MDR1 polymorphisms affect the relationship between meat and CRC risk.

Background:With the development of left ventricular pacing for cardiac resynchronization, there is an interest in the possibility of improving ventricular antitachycardia pacing (ATP) efficacy by pacing from the LV electrode(s). Objective:This study assessed the efficacy of pacing delivered from the left coronary vein (LCV) compared to that delivered from the right ventricular apex (RVA) upon ventricular tachycardia (VT) induction and termination. Methods:Sixty patients undergoing provocative ventricular electrophysiology (EP) studies in three centers were enrolled. Multipolar EP catheters were placed in the atrium, the RVA, and LCV. VT induction was attempted from the RVA and LCV in random order. Upon detection of monomorphic VT, burst ATP for up to 10 pulses at 88% VT cycle length was delivered from the RVA or LCV, in a random order, and crossed over when possible. Identical VT morphologies were reinduced to allow paired comparison of RVA versus LCV ATP. Results:Data from 55 patients were analyzed. Thirty-four morphologically distinct monomorphic VT types were induced in 22 patients. ATP succeeded in 18 (55%) and VTs in 13 patients. RVA ATP terminated 15 of 23 (65%) VTs, and LCV ATP terminated 10 of 23 (43%) VTs (P = 0.14). ATP delivered ipsilateral to the earliest activation site required 5.0+/- 2.6 pulses to terminate compared to 4.8 +/- 1.7 pulses when delivered from the contralateral site (P = 0.90). Paired comparison was possible for 13 VT morphologies in 11 patients. Paired RVA and LCV ATP efficacy was identical (54%vs 54%, P = 1.0). Conclusion:ATP delivered from a LCV lead offers no efficacy advantage over pacing from the RVA.(PACE 2009; 1-6).

We investigated characteristics of Yersinia enterocolitica infection in Ontario finisher pig herds. Our specific objectives were to estimate or test: prevalence of Y. enterocolitica shedding in finisher pigs, bioserotype distribution, agreement between the herd-level tests based on sampling pig and pooled fecal samples, whether bioserotypes cluster by farms, and whether Y. enterocolitica-positive herds cluster spatially. In total, 3747 fecal samples were collected from 100 farms over the years 2001, 2002, and 2004 (250 total herd visits). Fecal samples were tested by culture and positive isolates were biotyped and serotyped. Apparent pig-level prevalence of Y. enterocolitica was 1.8%, 3.2%, and 12.5% in 2001, 2002, and 2004, respectively. Estimated true pig-level prevalence of Y. enterocolitica was 5.1%, 9.1%, and 35.1% in 2001, 2002, and 2004, respectively. Herd-level prevalence was 16.3%, 17.9%, and 37.5% in 2001, 2002, and 2004, respectively. In all years, the most common bioserotype was 4, O:3, followed by bioserotype 2, O:5,27. Kappa between herd-level status based on pig and pooled samples ranged between 0.51 and 0.68 for biotype 1A and bioserotype 4, O:3, respectively. For 4, O:3, a significant bias in discordant pairs was detected, indicating that pig samples were more sensitive than pooled samples in declaring a herd as positive. Farms tended to be repeatedly positive with the same bioserotype, but positive study farms did not cluster spatially (suggesting lack of between herd transmission and lack of a common geographic risk factor).

The first layered iron borate, Fe(5)O(5)[B(6)O(10)(OH)(3)].nH(2)O, has been prepared by the boric acid flux method. Its structure, determined by single crystal X-ray diffraction, contains a double FeO(6)-octahedral layer and an unusual [B(6)O(13)] chain. The rigid and cambered [B(6)O(13)] chains bend the octahedral layers, resulting in a wave-like and sandwiched structure. Crystallographic study indicates the structural modulation is mainly from the [B(6)O(13)] chains because of the insertion of water molecules in between. Nevertheless, FeO(6) layers in the average structure, which are well separated by borate chains, is still a reasonable model to understand the two-dimensional magnetism. The strong antiferromagnetic interactions and the complex Fe(3+)-net suggest a possible geometrically magnetic frustration, which may be the reason for the second-order temperature-induced magnetic transition at approximately 125 K. The condensed Fe(3+) layers and the relatively low redox potential at about 1.25 V versus Li(+)/Li show its potentials as an anodic material.

Cancer is a disease of genomic aberration. The hypoxic microenvironment is believed to promote tumor progression via the induction of genetic instability. To understand how hypoxia drives tumor progression, we have shown recently that the hypoxia-inducible transcription factor, HIF-1alpha, is critical for transcriptional repression of DNA repair genes by a noncanonical mode of action referred to as the "HIF-1alpha-c-Myc axis." HIF-1alpha action via the HIF-1alpha-c-Myc axis is independent of its DNA-binding and transactivation domains; instead it requires the PAS-B domain to displace the transcription activator c-Myc from the target gene promoter for gene repression. Owing to the functional compromise on DNA repair, tumor cells with activated HIF-1alpha-c-Myc axis display persistent DNA damage, genetic alterations, and malignant progression. However, apoptosis-proficient cells are resistant to such changes. These findings argue that the hypoxic microenvironment plays a critical role in driving genetic alterations especially in apoptosis-deficient cells for malignant progression.