No SMAD4 hypermethylation in colorectal cancer

The chromosome region 18q21 is frequently deleted in colorectal cancers. Three candidate tumour suppressor genes, DCC, SMAD4 and SMAD2, map to this region. The SMAD4(DPC4) gene was recently identified as a candidate pancreatic cancer suppressor gene. It is also a gene for juvenile polyposis tumour predisposition syndrome. Somatic SMAD4 mutations have been detected in some colorectal carcinomas. However, the frequency of these mutations is relatively low, and whether SMAD4 plays a key role in colorectal tumorigenesis is still unclear. In addition to loss of chromosomal material and intragenic mutations there is a third mechanism, DNA methylation, which may have an important role in gene inactivation. In the present study, we examined whether promoter hypermethylation could be a mechanism for SMAD4 inactivation. In total, 42 colorectal tumours were selected for the methylation analysis and no evidence of promoter hypermethylation was found. Our result suggests that hypermethylation of the SMAD4 promoter region is not a frequent event in colorectal tumorigenesis. © 2000 Cancer Research Campaig

Bone Loss Rate May Interact with Other Risk Factors for Fractures among Elderly Women: A 15-Year Population-Based Study

Aim was to investigate fracture risk (FR) according to bone loss (BL) rate. A random sample of 1652 women aged 53.5 years was measured with dual X-ray absorptiometry in femoral neck in 1989 and 1994 and divided into tertiles of annual BL rate: high >0.84%, moderate 0.13%–0.84%, and low <0.13%. Low trauma energy fractures during following 10 years were recorded. There were no differences in FR between BL tertiles in Cox regression model. Factors predicting lower FR in Cox model were in high tertile: high T-score (HR 0.71; 95% CI 0.54–0.93, P = .012), no sister's fracture (HR 0.35; 0.19–0.64, P = .001), no mother's fracture (HR 0.52; 0.31–0.88, P = .015), in moderate tertile: high T-score (HR 0.69;0.53–0.91, P = .008) and good grip strength (HR 0.98; 0.97–0.99, P = .022). In low tertile there were no predictors for FR. BL predicted FR in women with mother's fracture in univariate and multivariate model (OR 2.6; 1.15–5.7, P = .021) but with sister's fracture this was observed only in multivariate model (OR 2.66; 1.09–6.7, P = .039). Accordingly, the risk factors for postmenopausal fractures, especially mother's fracture, may interact with BL

Dispersion from C^alpha or N^H: 4D experiments for backbone resonance assignment of intrinsically disordered proteins

N-HSQC spectrum. Application of these 4D experiments is demonstrated using BilRI (165 aa), an outer-membrane intrinsically disordered protein from the opportunistic oral pathogen Aggregatibacter actinomycetemcomitans. BilRI amino acid sequence encompasses three very similar repeats with a 13-residue identical stretch in two of them

POSIWID and determinism in design for behaviour change

Copyright @ 2012 Social Services Research GroupWhen designing to influence behaviour for social or environmental benefit, does designers' intent matter? Or are the effects on behaviour more important, regardless of the intent involved? This brief paper explores -- in the context of design for behaviour change -- some treatments of design, intentionality, purpose and responsibility from a variety of fields, including Stafford Beer's "The purpose of a system is what it does" and Maurice Broady's perspective on determinism. The paper attempts to extract useful implications for designers working on behaviour-related problems, in terms of analytical or reflective questions to ask during the design process

Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis - Evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers

Juvenile polyposis syndrome (JPS; OMIM 174900) is a rare disorder which is characterized by the presence of hamartomatous polyps throughout the gastrointestinal tract and an increased risk of gastrointestinal malignancy. Mutations of the SMAD4 gene on chromosome 18q21.1 have been shown to cause a subset of JPS cases, with estimates ranging from 20% to &gt;50%. Characterization of the genes that cause the remainder of JPS cases relies on the certainty that SMAD4 is not the causative gene. We have undertaken a comprehensive analysis of germline SMAD4 mutations in a cohort of JPS patients to define the spectrum of mutations that cause JPS. We have analyzed a series of polyps from these patients for SMAD4 protein expression. We have also performed a blinded assessment of polyp material to look for morphological differences between polyps from patients with and without a germline SMAD4 mutation. The results indicate that almost all germline SMAD4 mutations are readily detectable by screening genomic DNA using polymerase chain reaction-based methods; SMAD4 can be excluded as the causative gene in the majority of our JPS cohort. Loss of SMAD4 expression occurs in most polyps from SMAD4 mutation carriers, even those with missense germline mutations. SMAD4 loss in polyps is, however, not a feature of cases that are not caused by SMAD4 mutations, indicating that these polyps develop along a SMAD4-independent pathway. The morphology of polyps from SMAD4 mutation carriers is subtly different from other JPS polyps, notably including a more prominent epithelial component in the former

Comparison of published orthopaedic trauma trials following registration in Clinicaltrials.gov

<p>Abstract</p> <p>Background</p> <p>After the Food and Drug Administration Modernization Act of 1997, the registration of all clinical trials became mandatory prior to publication. Our primary objective was to determine publication rates for orthopaedic trauma trials registered with ClinicalTrials.gov. We further evaluated methodological consistency between registration and publication.</p> <p>Methods</p> <p>We searched Clinical Trials.gov for all trials related to orthopaedic trauma. We excluded active trials and trials not completed by July 2009, and performed a systematic search for publications resulting from registered closed trials. Information regarding primary and secondary outcomes, intervention, study sponsors, and sample size were extracted from registrations and publications.</p> <p>Results</p> <p>Of 130 closed trials, 37 eligible trials resulted in 16 publications (43.2%). We found no significant differences in publication rates between funding sources for industry sponsored studies and nongovernment/nonindustry sponsored studies (<it>p </it>> 0.05). About half the trials (45%) did not include the NCT ID in the publication. Two (10%) publications had major changes to the primary outcome measure and ten (52.6%) to sample size.</p> <p>Conclusions</p> <p>Registration of orthopaedic trauma trials does not consistently result in publication. When trials are registered, many do not cite NCT ID in the publication. Furthermore, changes that are not reflected in the registry of the trial are frequently made to the final publication.</p

Estimation of the iron bioavailability in green vegetables using an in vitro digestion/Caco-2 cell model

It is estimated that over 30% of the global population is anaemic, half of which is due to iron deficiency. The bioavailability of iron from vegetables is low and variable, and influenced by food composition and matrix. We have therefore determined the relative bioavailability of iron in five types of green vegetable, spinach, broccoli, savoy cabbage, curly kale and green pepper, by measuring the ferritin response in a simulated digestion/Caco-2 cell model. Savoy cabbage gave the highest ferritin response and analysis of the digest showed that the iron was present in low molecular weight fractions which contained glucose, fructose, organic acids and amino acids. The addition of fructose 1,6-biphosphate to the Caco-2 cells increased iron uptake 2-fold. These results demonstrate that cabbage was the best source of bioavailable iron out of the vegetables studied and suggest that the formation of complexes with fructose derivatives contribute to increase the iron bioavailability

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT

Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI) due to dysfunction of the mismatch repair system (MMR). As a consequence of this, MSI tumours tend to accumulate errors in mononucleotide repeats as those in genes implicated in repairing double-strand breaks (DSBs). Previous studies have shown that irinotecan (CPT-11), a chemotherapy agent inducing DSB, is more active in MSI than in microsatellite stable (MSS) CRC. The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC50 and were four- to nine-fold more sensitive to CPT-11 than the MSS line. Cell lines harbouring mutations in both MRE11 and RAD50 were most sensitive to CPT-11. We conclude that MSI cell lines display higher sensitivity to CPT-11 than MSS cells. Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted

TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment