Mouse Chromosome 11

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46996/1/335_2004_Article_BF00648429.pd

A var gene promoter controls allelic exclusion of virulence genes in Plasmodium falciparum malaria

Mono-allelic expression of gene families is used by many organisms to mediate phenotypic variation of surface proteins. In the apicomplexan parasite Plasmodium falciparum, responsible for the severe form of malaria in humans, this is exemplified by antigenic variation of the highly polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1)1, 2. PfEMP1, encoded by the 60-member vargene family3, 4, 5, 6, represents a major virulence factor due to its central role in immune evasion and intravascular parasite sequestration. Mutually exclusive expression of PfEMP1 is controlled by epigenetic mechanisms involving chromatin modification and perinuclear var locus repositioning7, 8. Here we show that a var promoter mediates the nucleation and spreading of stably inherited silenced chromatin. Transcriptional activation of this promoter occurs at the nuclear periphery in association with chromosome-end clusters. Additionally, the var promoter sequence is sufficient to infiltrate a transgene into the allelic exclusion programme of var gene expression, as transcriptional activation of this transgene results in silencing of endogenous var gene transcription. These results show that a var promoter is sufficient for epigenetic silencing and mono-allelic transcription of this virulence gene family, and are fundamental for our understanding of antigenic variation in P. falciparum. Furthermore, the PfEMP1 knockdown parasites obtained in this study will be important tools to increase our understanding of P. falciparum-mediated virulence and immune evasion

Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies

Background Fruit and vegetable intakes have been associated with a reduced risk of colon cancer; however, in more recent studies associations have been less consistent. Statistical power to examine associations by colon site has been limited in previous studies. Methods Fruit and vegetable intakes in relation to colon cancer risk were examined in the Pooling Project of Prospective Studies of Diet and Cancer. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated separately in 14 studies using Cox proportional hazards model and then pooled using a random- effects model. Intakes of total fruits and vegetables, total fruits, and total vegetables were categorized according to quintiles and absolute cutpoints. Analyses were conducted for colon cancer overall and for proximal and distal colon cancer separately. All statistical tests were two-sided. Results Among 756 217 men and women followed for up to 6 to 20 years, depending on the study, 5838 were diagnosed with colon cancer. The pooled multivariable RRs (95% CIs) of colon cancer for the highest versus lowest quintiles of intake were 0.91 (0.82 to 1.01, Ptrend =.19) for total fruits and vegetables, 0.93 (0.85 to 1.02, Ptrend =.28) for total fruits, and 0.94 (0.86 to 1.02, P trend =.17) for total vegetables. Similar results were observed when intakes were categorized by identical absolute cut points across studies (pooled multivariable RR = 0.90, 95% CI = 0.77 to 1.05 for 800 or more versus <200 g/day of total fruits and vegetables, Ptrend =.06). The age-standardized incidence rates of colon cancer for these two intake categories were 54 and 61 per 100 000 person-years, respectively. When analyzed by colon site, the pooled multivari- able RRs (95% CIs) comparing total fruit and vegetable intakes of 800 or more versus less than 200 g/day were 0.74 (0.57 to 0.95, Ptrend =.02) for distal colon cancers and 1.02 (0.82 to 1.27, Ptrend =.57) for proximal colon cancers. Similar site-specific associations were observed for total fruits and total vegetables. Conclusion Fruit and vegetable intakes were not strongly associated with colon cancer risk overall but may be associated with a lower risk of distal colon cancer

Methods for pooling results of epidemiologic studies: the Pooling Project of Prospective Studies of Diet and Cancer

With the growing number of epidemiologic publications on the relation between dietary factors and cancer risk, pooled analyses that summarize results from multiple studies are becoming more common. Here, the authors describe the methods being used to summarize data on diet-cancer associations within the ongoing Pooling Project of Prospective Studies of Diet and Cancer, begun in 1991. In the Pooling Project, the primary data from prospective cohort studies meeting prespecified inclusion criteria are analyzed using standardized criteria for modeling of exposure, confounding, and outcome variables. In addition to evaluating main exposure-disease associations, analyses are also conducted to evaluate whether exposure-disease associations are modified by other dietary and nondietary factors or vary among population subgroups or particular cancer subtypes. Study-specific relative risks are calculated using the Cox proportional hazards model and then pooled using a random- or mixed-effects model. The study-specific estimates are weighted by the inverse of their variances in forming summary estimates. Most of the methods used in the Pooling Project may be adapted for examining associations with dietary and nondietary factors in pooled analyses of case-control studies or case-control and cohort studies combined