A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil

High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the enhancer region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes' C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30–1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52–0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

The Agrodiversity Experiment: three years of data from a multisite study in intensively managed grasslands

Intensively managed grasslands are globally prominent ecosystems. We investigated whether experimental increases in plant diversity in intensively managed grassland communities can increase their resource use efficiency. This work consisted of a coordinated, continental-scale 33-site experiment. The core design was 30 plots, representing 15 grassland communities at two seeding densities. The 15 communities were comprised of four monocultures (two grasses and two legumes) and 11 four-species mixtures that varied in the relative abundance of the four species at sowing. There were 1028 plots in the core experiment, with another 572 plots sown for additional treatments. Sites agreed a protocol and employed the same experimental methods with certain plot management factors, such as seeding rates and number of cuts, determined by local practice. The four species used at a site depended on geographical location, but the species were chosen according to four functional traits: a fast-establishing grass, a slow-establishing persistent grass, a fast-establishing legume, and a slow-establishing persistent legume. As the objective was to maximize yield for intensive grassland production, the species chosen were all high-yielding agronomic species. The data set contains species-specific biomass measurements (yield per species and of weeds) for all harvests for up to four years at 33 sites. Samples of harvested vegetation were also analyzed for forage quality at 26 sites. Analyses showed that the yield of the mixtures exceeded that of the average monoculture in >97% of comparisons. Mixture biomass also exceeded that of the best monoculture (transgressive overyielding) at about 60% of sites. There was also a positive relationship between the diversity of the communities and aboveground biomass that was consistent across sites and persisted for three years. Weed invasion in mixtures was very much less than that in monocultures. These data should be of interest to ecologists studying relationships between diversity and ecosystem function and to agronomists interested in sustainable intensification. The large spatial scale of the sites provides opportunity for analyses across spatial (and temporal) scales. The database can also complement existing databases and meta-analyses on biodiversity–ecosystem function relationships in natural communities by focusing on those same relationships within intensively managed agricultural grasslands

Plant diversity greatly enhances weed suppression in intensively managed grasslands

Weed suppression was investigated in a field experiment across 31 international sites. The study included 15 plant communities at each site, based on two grasses and two legumes, each sown in monoculture and 11 four-species mixtures varying in the relative proportions of the four species. At each site, one grass and one legume species was selected as fast establishing and the other two species were selected for persistence. Average weed biomass in mixtures over the whole experiment was 52% less (95% confidence interval, 30 to 75%) than in the most suppressive monoculture (transgressive suppression). Transgressive suppression of weed biomass persisted over each year for each mixture. Weed biomass was consistently low and relatively similar across all mixtures and years. Average sown species biomass was greater in all mixtures than in any monoculture. The suppressive effect of sown forage species on weeds in mixtures was achieved without any herbicide use. At each site, weed biomass for almost every mixture was lower than the average across the four monocultures. The average proportion of weed biomass in mixtures was less than in the most suppressive monoculture in two thirds of sites. Mixtures outyielded monocultures, and mixture yield comprised far lower weed biomass

Molecular markers of response and toxicity to FOLFOX chemotherapy in metastatic colorectal cancer

BACKGROUND: To investigate three genetic alterations (TP53 mutation, Kras mutation and microsatellite instability (MSI)) and three polymorphisms (methylene tetrahydrofolate reductase (MTHFR) C677T, excision repair cross complementing group 1 (ERCC1)-118 and X-ray repair cross complementing group 1 (XRCC1)-399) for their ability to predict response, survival and toxicity to FOLFOX first line chemotherapy in the treatment of metastatic colorectal cancer (mCRC). METHODS: Tumour tissues from 118 mCRC patients who underwent FOLFOX treatment from three successive phase II trials were evaluated for mutations in TP53 (exons 5–8) and Kras (codons 12 and 13) and for MSI using PCR-based analysis. Genotyping for common single nucleotide polymorphisms in the MTHFR (codon 677), ERCC1 (codon 118) and XRCC1 (codon 399) genes was also carried out using PCR techniques. These genetic markers were correlated with clinical response, survival and toxicity to treatment. RESULTS: Patients with the T allele of ERCC1-118 showed significantly worse progression-free survival in univariate analysis (HR 2.62; 95 % CI 1.14–6.02; P 0.02). None of the genetic alterations or polymorphisms showed significant association with clinical response to FOLFOX. The MTHFR, ERCC1 and XRCC1 polymorphisms showed no associations with overall haematological, gastrointestinal or neurological toxicity to FOLFOX, although MTHFR 677 TT genotype patients showed a significantly higher incidence of grade 3 or 4 diarrhoea (26%) compared with CC or CT genotype patients (6%, P 0.02). CONCLUSIONS: The ERCC1-118 and MTHFR C677T polymorphisms were associated with progression and severe diarrhoea

Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma

BACKGROUND: Cutaneous Malignant Melanoma causes over 75% of skin cancer-related deaths, and it is clear that many factors may contribute to the outcome. Matrix Metalloproteinases (MMPs) play an important role in the degradation and remodeling of the extracellular matrix and basement membrane that, in turn, modulate cell division, migration and angiogenesis. Some polymorphisms are known to influence gene expression, protein activity, stability, and interactions, and they were shown to be associated with certain tumor phenotypes and cancer risk. METHODS: We tested seven polymorphisms within the MMP-9 gene in 1002 patients with melanoma in order to evaluate germline genetic variants and their association with progression and known risk factors of melanoma. The polymorphisms were selected based on previously published reports and their known or potential functional relevance using in-silico methods. Germline DNA was then genotyped using pyrosequencing, melting temperature profiles, heteroduplex analysis, and fragment size analysis. RESULTS: We found that reference alleles were present in higher frequency in patients who tend to sunburn, have family history of melanoma, higher melanoma stage, intransit metastasis and desmoplastic melanomas among others. However, after adjustment for age, sex, phenotypic index, moles, and freckles only Q279R, P574R and R668Q had significant associations with intransit metastasis, propensity to tan/sunburn and primary melanoma site. CONCLUSION: This study does not provide strong evidence for further investigation into the role of the MMP-9 SNPs in melanoma progression

Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk

<p>Abstract</p> <p>Background</p> <p>Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.</p> <p>Methods</p> <p>In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.</p> <p>Results</p> <p>Here, we have shown that the high enzymatic activity genotype of CCND1^High(AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMT^Medium(MetVal) and the high enzymatic activity of COMT^High(ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMT^High(ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: <b>2.22</b>, 95%CI (1.49–3.28)] and Finland [OR: <b>1.73</b>, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.</p> <p>Conclusion</p> <p>Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.</p

Weed suppression greatly increased by plant diversity in intensively managed grasslands: A continental-scale experiment

Publisher's version (útgefin grein)Grassland diversity can support sustainable intensification of grassland production through increased yields, reduced inputs and limited weed invasion. We report the effects of diversity on weed suppression from 3 years of a 31-site continental-scale field experiment. At each site, 15 grassland communities comprising four monocultures and 11 four-species mixtures based on a wide range of species' proportions were sown at two densities and managed by cutting. Forage species were selected according to two crossed functional traits, “method of nitrogen acquisition” and “pattern of temporal development”. Across sites, years and sown densities, annual weed biomass in mixtures and monocultures was 0.5 and 2.0 t DM ha−1 (7% and 33% of total biomass respectively). Over 95% of mixtures had weed biomass lower than the average of monocultures, and in two-thirds of cases, lower than in the most suppressive monoculture (transgressive suppression). Suppression was significantly transgressive for 58% of site-years. Transgressive suppression by mixtures was maintained across years, independent of site productivity. Based on models, average weed biomass in mixture over the whole experiment was 52% less (95% confidence interval: 30%–75%) than in the most suppressive monoculture. Transgressive suppression of weed biomass was significant at each year across all mixtures and for each mixture. Weed biomass was consistently low across all mixtures and years and was in some cases significantly but not largely different from that in the equiproportional mixture. The average variability (standard deviation) of annual weed biomass within a site was much lower for mixtures (0.42) than for monocultures (1.77). Synthesis and applications. Weed invasion can be diminished through a combination of forage species selected for complementarity and persistence traits in systems designed to reduce reliance on fertiliser nitrogen. In this study, effects of diversity on weed suppression were consistently strong across mixtures varying widely in species' proportions and over time. The level of weed biomass did not vary greatly across mixtures varying widely in proportions of sown species. These diversity benefits in intensively managed grasslands are relevant for the sustainable intensification of agriculture and, importantly, are achievable through practical farm-scale actions.We thank the many colleagues who have assisted this work. We thank M. Coll for her early contribution. Co-ordination of this project was supported by the EU Commission through COST Action 852 ‘Quality legume-based forage systems for contrasting environments’. M.T.S., R.L. and A.R. were supported by the Spanish Ministry of the Economy and Competitiveness through projects CARBOAGROPAS (CGL2006-13555- C03- 01/ BOS) and BIOGEI (CGL2013-49142- C2- 1- R) and the Ministry of the Environment through OPS (209/PC08/3-08.2). L.K. was supported by an award from Science Foundation Ireland (09/RFP/EOB2546). A.L., J.A.F., J.C. and M.S. were partly supported by the EU FP7 project ‘AnimalChange’ under grant agreement no. 266018.Peer Reviewe