With the increased interest in computer-aided image analysis methods, there is a greater need for objective methods of algorithm evaluation. Validation of in vivo MRI studies is complicated by a lack ...of reference data and the difficulty of constructing anatomically realistic physical phantoms. The authors present here an extensible MRI simulator that efficiently generates realistic three-dimensional (3-D) brain images using a hybrid Bloch equation and tissue template simulation that accounts for image contrast, partial volume, and noise. This allows image analysis methods to be evaluated with controlled degradations of image data.
Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ...ovarian cancer risk have been inconclusive.
We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided.
Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval CI = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91).
Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.
Unusual gold-colored onions were selected from a F3 family originating from a cross between US-type yellow and Brazilian yellow onions. HPLC analysis showed that the gold onions contained a ...significantly reduced amount of quercetin, the most abundant flavonoid in onions. This result indicated that an early step in the flavonoid biosynthesis pathway might be abnormal in these onions. The expression of flavonoid synthesis genes isolated from onions was examined in gold onions and compared to that in onions of other colors by RT-PCR. The results showed that all genes were transcribed in gold onions as in red onions. In order to identify any critical mutations in flavonoid synthesis genes encoding enzymes involved in early steps of the pathway, the genomic sequence of chalcone isomerase (CHI) was obtained. A premature stop codon and a subsequent single base-pair addition causing a frameshift were identified in the coding region of the CHI gene in the gold onions. Co-segregation of the mutant allele of the CHI gene and the gold phenotype was investigated in the original F2 segregating population. Genotyping of three color groups (red, yellow and gold) of F2 onions revealed perfect co-segregation of the mutant CHI allele with the gold phenotype. All tested gold F2 onions were homozygous for the mutant CHI allele. This perfect co-segregation implies that the presence of a premature stop codon in the gold CHI gene results in an inactive CHI. Inactivation of CHI results in a block in the flavonoid biosynthesis pathway and the accumulation of chalcone derivatives, including a yellow pigment which might be responsible for the gold color in onions.
Flavonoid and limonoid glycosides influence taste properties as well as marketability of Citrus fruit and products, particularly grapefruit. In this work, nine grapefruit putative natural product ...glucosyltransferases (PGTs) were resolved by either using degenerate primers against the semiconserved PSPG box motif, SMART-RACE RT-PCR, and primer walking to full-length coding regions; screening a directionally cloned young grapefruit leaf EST library; designing primers against sequences from other Citrus species; or identifying PGTs from Citrus contigs in the harvEST database. The PGT proteins associated with the identified full-length coding regions were recombinantly expressed in Escherichia coli and/or Pichia pastoris and then tested for activity with a suite of substrates including flavonoid, simple phenolic, coumarin, and/or limonoid compounds. A number of these compounds were eliminated from the predicted and/or potential substrate pool for the identified PGTs. Enzyme activity was detected in some instances with quercetin and catechol glucosyltransferase activities having been identified.
There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for ...susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.
A new locus conditioning a pink trait in onions was identified. Unusual pink onions were found in haploid populations induced from an F(1) hybrid between yellow and dark red parents and in F(3) ...populations originating from the same cross. Segregation ratios of red to pink in F(2), backcross, and F(3) populations indicated that this pink trait is determined by a single recessive locus. RT-PCR was carried out to look for any differential expression of anthocyanin synthesis genes between dark red and pink F(3) lines. The transcript level of anthocyanidin synthase (ANS) was significantly reduced in the pink line. To determine whether this reduced transcription is caused by other regulatory factors or by mutations in the ANS gene itself, ANS gene sequences from both dark red and pink F(3) lines were compared to detect any polymorphisms. Polymorphisms were identified, and subsequently utilized as molecular markers for the selection of ANS alleles. Absolute co-segregation of the pink allele and the ANS allele from the pink line was observed in parents, F(1) and F(3) populations. These results indicate that reduced transcription of the ANS gene caused by mutations in a cis -acting element is likely to result in the pink trait in onions.
Serine repeat antigen 5 (SERA5) is an abundant antigen of the human malaria parasite Plasmodium falciparum and is the most strongly expressed member of the nine-gene SERA family. It appears to be ...essential for the maintenance of the erythrocytic cycle, unlike a number of other members of this
family, and has been implicated in parasite egress and/or erythrocyte invasion. All SERA proteins possess a central domain
that has homology to papain except in the case of SERA5 (and some other SERAs), where the active site cysteine has been replaced
with a serine. To investigate if this domain retains catalytic activity, we expressed, purified, and refolded a recombinant
form of the SERA5 enzyme domain. This protein possessed chymotrypsin-like proteolytic activity as it processed substrates
downstream of aromatic residues, and its activity was reversed by the serine protease inhibitor 3,4-diisocoumarin. Although
all Plasmodium SERA enzyme domain sequences share considerable homology, phylogenetic studies revealed two distinct clusters across the
genus, separated according to whether they possess an active site serine or cysteine. All Plasmodia appear to have at least
one member of each group. Consistent with separate biological roles for members of these two clusters, molecular modeling
studies revealed that SERA5 and SERA6 enzyme domains have dramatically different surface properties, although both have a
characteristic papain-like fold, catalytic cleft, and an appropriately positioned catalytic triad. This study provides impetus
for the examination of SERA5 as a target for antimalarial drug design.
The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study.
All 106 XP ...patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up.
In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10,000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)-a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02).
This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.
The binding affinities of 9-cis-retinoic acid (9-cis-RA) and all-trans-retinoic acid (t-RA) for retinoic acid receptors (RAR) alpha, beta, and gamma and for retinoid X receptors (RXR) alpha, beta, ...and gamma were determined using the recombinant receptor proteins and were compared with each hormone's ability to activate transcription through the receptors in mammalian and yeast cell systems. 9-cis-RA bound to both the RXRs (Kd values = 1.4-2.4 nM) and the RARs (Kd values = 0.2-0.8 nM). The ability of 9-cis-RA to bind to the RARs and RXRs correlated with its ability to produce similar transactivation profiles with these receptors in mammalian and yeast cell assays. t-RA bound to the RARs (Kd values = 0.2-0.4 nM) and activated transcription through the RARs in mammalian and yeast cells. In contrast, while t-RA did not bind to the RXRs, it did activate the RXRs, albeit less potently than 9-cis-RA, in mammalian cells. In yeast, however, the RXRs activated transcription only in the presence of 9-cis-RA, not with t-RA. While RAR gamma is activated in yeast by either t-RA or 9-cis-RA, the overall level of transcription was increased upon the addition of hormone-occupied RXR. Metabolism studies suggest that while there was no cell-dependent interconversion between t-RA and 9-cis-RA in yeast, there was cell-dependent conversion of 9-cis-RA to t-RA in mammalian cells corrected.
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