RNASEL (encoding ribonuclease L) has recently been proposed as a candidate for the hereditary prostate cancer (HPC1) gene. We determined that the RNASEL variant Arg462Gln has three times less ...enzymatic activity than the wildtype and is significantly associated with prostate cancer risk (P = 0.007). At least one copy of the mutated allele that causes this substitution is carried by nearly 60% of the men in our study. Men that are heterozygous with respect to the mutated allele have 50% greater risk of prostate cancer than non-carriers, and homozygotes have more than double the risk.
We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32–q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The ...smallest region of allelic imbalance contains the podocalyxin-like (PODXL) gene, which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32–q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense variants and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case–control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.09–4.20, P=0.03 and the presence of two copies of any deletion further increased risk (OR=2.58, 95%CI=1.23–5.45, P=0.01). This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR=3.04 for one deletion (95%CI=1.01–9.15) and OR=4.42 for two deletions (95%CI=1.32–14.85, P=0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR=1.48, 95%CI=1.02–2.14, P=0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32–q33.
Genetic analysis of benign ovarian tumors Thomas, Nicola A.; Neville, Phillippa J.; Baxter, Simon W. ...
International journal of cancer,
1 July 2003, Letnik:
105, Številka:
4
Journal Article
The biologic aggressiveness of prostate tumors is an important indicator of prognosis. Chromosome 7q32-q33 was recently reported to show linkage to more aggressive prostate cancer, based on Gleason ...score, in a large sibling pair study. We report confirmation and narrowing of the linked region using finer-scale genotyping. We also report a high frequency of allelic imbalance (AI) defined within this locus in a series of 48 primary prostate tumors from men unselected for family history or disease status. The highest frequency of AI was observed with adjacent markers D7S2531 (52%) and D7S1804 (36%). These two markers delineated a common region of AI, with 24 tumors exhibiting interstitial AI involving one or both markers. The 1.1-Mb candidate region contains relatively few transcripts. Additionally, we observed positive associations between interstitial AI at D7S1804 and early age at diagnosis (P=.03) as well as a high combined Gleason score and tumor stage (P=.06). Interstitial AI at D7S2531 was associated with a positive family history of prostate cancer (P=.05). These data imply that we have localized a prostate cancer tumor aggressiveness loci to chromosome 7q32-q33 that is involved in familial and nonfamilial forms of prostate cancer.
The gene ST7 has recently been implicated as the broad-range tumor suppressor on human chromosome 7q31.1. We did not detect somatic mutations in ST7 in any of 149 primary ovarian, breast or colon ...carcinomas. These data suggest that epigenetic downregulation or haploinsufficiency, rather than somatic genetic alterations, may be the primary mechanism of abrogation of ST7 function in these tumor types.
The biologic aggressiveness of prostate tumors is an important indicator of prognosis. Chromosome 7g32-q33 was recently reported to show linkage to more aggressive prostate cancer, based on Gleason ...score, in a large sibling pair study. We report confirmation and narrowing of the linked region using finer-scale genotyping. We also report a high frequency of allelic imbalance. (AI) defined within this locus in a series of 48 primary prostate tumors from men unselected for family history or disease status. The highest frequency of AI was observed with adjacent markers D7S2531. (52%) and D7S1804. (36%). These two markers delineated a common region of AI, with 24 tumors exhibiting interstitial AI involving one or both markers. The 1.1-Mb candidate region contains relatively few transcripts. Additionally, we observed positive associations between interstitial AI at D7S1804 and early age at diagnosis. (P=.03) as well as a high combined Gleason score and tumor stage. (P=.06). Interstitial AI at D7S2531 was associated with a positive family history of prostate cancer. (P=.05). These data imply that we have localized a prostate cancer tumor aggressiveness loci to chromosome 7832-q33 that is involved in familial and nonfamilial forms of prostate cancer.
Campylobacters are an unwelcome member of the poultry gut microbiota in terms of food safety. The objective of this study was to compare the microbiota, inflammatory responses, and zootechnical ...parameters of broiler chickens not exposed to Campylobacter jejuni with those exposed either early at 6 days old or at the age commercial broiler chicken flocks are frequently observed to become colonized at 20 days old.
Birds infected with Campylobacter at 20 days became cecal colonized within 2 days of exposure, whereas birds infected at 6 days of age did not show complete colonization of the sample cohort until 9 days post-infection. All birds sampled thereafter were colonized until the end of the study at 35 days (mean 6.1 log
CFU per g of cecal contents). The cecal microbiota of birds infected with Campylobacter were significantly different to age-matched non-infected controls at 2 days post-infection, but generally, the composition of the cecal microbiota were more affected by bird age as the time post infection increased. The effects of Campylobacter colonization on the cecal microbiota were associated with reductions in the relative abundance of OTUs within the taxonomic family Lactobacillaceae and the Clostridium cluster XIVa. Specific members of the Lachnospiraceae and Ruminococcaceae families exhibit transient shifts in microbial community populations dependent upon the age at which the birds become colonized by C. jejuni. Analysis of ileal and cecal chemokine/cytokine gene expression revealed increases in IL-6, IL-17A, and Il-17F consistent with a Th17 response, but the persistence of the response was dependent on the stage/time of C. jejuni colonization that coincide with significant reductions in the abundance of Clostridium cluster XIVa.
This study combines microbiome data, cytokine/chemokine gene expression with intestinal villus, and crypt measurements to compare chickens colonized early or late in the rearing cycle to provide insights into the process and outcomes of Campylobacter colonization. Early colonization results in a transient growth rate reduction and pro-inflammatory response but persistent modification of the cecal microbiota. Late colonization produces pro-inflammatory responses with changes in the cecal microbiota that will endure in market-ready chickens.
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