An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality.

BACKGROUND: Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes. METHODS: We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis. RESULTS: Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10(-5)). CONCLUSIONS: We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Genetic architecture of prostate cancer in the Ashkenazi Jewish population.

BACKGROUND: Recently, numerous prostate cancer risk loci have been identified, some of which show association in specific populations. No study has yet investigated whether these single nucleotide polymorphisms (SNPs) are associated with prostate cancer in the Ashkenazi Jewish (AJ) population. METHODS: A total of 29 known prostate cancer risk SNPs were genotyped in 963 prostate cancer cases and 613 controls of AJ ancestry. These data were combined with data from 1241 additional Ashkenazi controls and tested for association with prostate cancer. Correction for multiple testing was performed using the false discovery rate procedure. RESULTS: Ten of twenty-three SNPs that passed quality control procedures were associated with prostate cancer risk at a false discovery rate of 5%. Of these, nine were originally discovered in studies of individuals of European ancestry. Based on power calculations, the number of significant associations observed is not surprising. CONCLUSION: We see no convincing evidence that the genetic architecture of prostate cancer in the AJ population is substantively different from that observed in other populations of European ancestry.

Computational identification of noncoding RNAs in E. coli by comparative genomics.

Some genes produce noncoding transcripts that function directly as structural, regulatory, or even catalytic RNAs [1, 2]. Unlike protein-coding genes, which can be detected as open reading frames with distinctive statistical biases, noncoding RNA (ncRNA) gene sequences have no obvious inherent statistical biases [3]. Thus, genome sequence analyses reveal novel protein-coding genes, but any novel ncRNA genes remain invisible. Here, we describe a computational comparative genomic screen for ncRNA genes. The key idea is to distinguish conserved RNA secondary structures from a background of other conserved sequences using probabilistic models of expected mutational patterns in pairwise sequence alignments. We report the first whole-genome screen for ncRNA genes done with this method, in which we applied it to the "intergenic" spacers of Escherichia coli using comparative sequence data from four related bacteria. Starting from >23,000 conserved interspecies pairwise alignments, the screen predicted 275 candidate structural RNA loci. A sample of 49 candidate loci was assayed experimentally. At least 11 loci expressed small, apparently noncoding RNA transcripts of unknown function. Our computational approach may be used to discover structural ncRNA genes in any genome for which appropriate comparative genome sequence data are available.

Locoregional cancer treatment with magnetic drug targeting.

The specific delivery of chemotherapeutic agents to their desired targets with a minimum of systemic side effects is an important, ongoing challenge of chemotherapy. One approach, developed in the past to address this problem, is the i.v. injection of magnetic particles [ferrofluids (FFs)] bound to anticancer agents that are then concentrated in the desired area (e.g., the tumor) by an external magnetic field. In the present study, we treated squamous cell carcinoma in rabbits with FFs bound to mitoxantrone (FF-MTX) that was concentrated with a magnetic field. Experimental VX-2 squamous cell carcinoma was implanted in the median portion of the hind limb of New Zealand White rabbits (n = 26). When the tumor had reached a volume of approximately 3500 mm3, FF-MTX was injected intraarterially (i.a.; femoral artery) or i.v. (ear vein), whereas an external magnetic field was focused on the tumor. FF-MTX i.a. application with the external magnetic field resulted in a significant (P < 0.05), complete, and permanent remission of the squamous cell carcinoma compared with the control group (no treatment) and the i.v. FF-MTX group, with no signs of toxicity. The intratumoral accumulation of FFs was visualized both histologically and by magnetic resonance imaging. Thus, our data show that i.a. application of FF-MTX is successful in treating experimental squamous cell carcinoma. This "magnetic drug targeting" offers a unique opportunity to treat malignant tumors locoregionally without systemic toxicity. Furthermore, it may be possible to use these magnetic particles as a "carrier system" for a variety of anticancer agents, e.g., radionuclides, cancer-specific antibodies, and genes.

Toward a resolution of the introns early/late debate: only phase zero introns are correlated with the structure of ancient proteins.

We present evidence that a well defined subset of intron positions shows a non-random distribution in ancient genes. We analyze a database of ancient conserved regions drawn from GenBank 101 to retest two predictions of the theory that the first genes were constructed by exon shuffling. These predictions are that there should be an excess of symmetric exons (and sets of exons) flanked by introns of the same phase (positions within the codon) and that intron positions in ancient proteins should correlate with the boundaries of compact protein modules. Both these predictions are supported by the data, with considerable statistical force (P values < 0.0001). Intron positions correlate to modules of diameters around 21, 27, and 33 A, and this correlation is due to phase zero introns. We suggest that 30-40% of present day intron positions in ancient genes correspond to phase zero introns originally present in the progenote, while almost all of the remaining intron positions correspond to introns added, or moved, appearing equally in all three intron phases. This proposal provides a resolution for many of the arguments of the introns-early/introns-late debate.

Photorefractive keratectomy for hyperopic and mixed astigmatism.

BACKGROUND: The correction of astigmatism with photorefractive keratectomy has been recommended in simple and myopic astigmatism. Therefore in this study the excimer laser was used to correct compound hyperopic and mixed astigmatism. METHODS: We present a prospective clinical study of photorefractive keratectomy in 30 eyes of 24 patients with compound hyperopic astigmatism with a mean spherical equivalent of +4.30 D and mean astigmatism of 2.33 D (group I) and in 17 eyes of 15 patients with mixed astigmatism with a mean spherical equivalent refraction of +0.46 D and mean astigmatism of 4.75 D (group II). The excimer laser used in this study was an MEL 60 (Aesculap-Meditec). In both groups an 18-month follow-up study was performed. RESULTS: In the compound hyperopic astigmatism group after 18 months, 14 of 17 treated eyes (82.3%) were within +/-1.00 D, and 11 (64.7%) were within 60.50 D of the intended correction. In the mixed astigmatism group after 18 months, 10 of 11 eyes (90.9%) were within +/-1.00 D, 8 eyes (72.7%) were within +/-0.50 D of the intended correction. In regard to the stability the 1 year regression of spherical equivalent in the compound hyperopic astigmatism group is 0.78 D and in the mixed astigmatism group 0.37 D. At 18 months, spectacle corrected visual acuity in the compound hyperopic astigmatism group was unchanged or improved in 14 eyes (87.5%); 2 eyes (12.5%) had lost one line. In the mixed astigmatism group at 18 months, spectacle corrected visual acuity was unchanged or improved in 9 eyes (81.8 %); 2 eyes (18.1%) lost one line. Preoperatively, the mean uncorrected visual acuity was 20/100 in the compound hyperopic astigmatism group and the mixed astigmatism group. At 18 months, 14 eyes (93.3%) in the compound hyperopic astigmatism group had an uncorrected visual acuity of 20/40 or better; 4 (26.6%) eyes had an uncorrected visual acuity of 20/20 or better. In the mixed astigmatism group, 9 (81.8%) eyes had an uncorrected visual acuity of 20/40 or better; 4 (36.3%) eyes had an uncorrected visual acuity of 20/20 or better. CONCLUSION: Photorefractive keratectomy is an efficient and relatively safe procedure for reducing or eliminating compound hyperopic and mixed astigmatism up to 6.00 D.

Health status indicators: definitions and national data.

In July 1991 the Centers for Disease Control (CDC) released a set of 18 health status indicators and encouraged their use by federal, State, and local health agencies. The indicators were developed in response to Objective 22.1 of Healthy People 2000 through a consensus process described in a previous Statistical Notes. This article recommends detailed definitions, suggests national data sources, and provides national baseline data for each indicator.

Native herpes simplex virus glycoprotein D vaccine: immunogenicity and protection in animal models.

Mice, guinea pigs, and rhesus monkeys were immunized with immunoaffinity-purified native glycoprotein D (gD) derived from herpes simplex virus type 1 (HSV1). The native glycoprotein has evoked significant in vivo responses even at low doses. Thus, mice immunized with doses as low as 1 microgram were significantly protected from the morbidity and mortality of lethal HSV2 challenge and from establishment of latent HSV2 infection. Protection was dose-related and correlated with prechallenge serum neutralizing antibody titres to HSV. Similarly, immunized guinea-pigs demonstrated significant reductions in the frequency, severity and duration of genital lesions induced by HSV2 vaginal challenge. In long term immunogenicity studies, immunized rhesus monkeys exhibited significant serum neutralizing antibody responses to both HSV1 and HSV2. In vitro stimulation of monkey peripheral blood leucocytes with purified gD resulted in a significant cellular proliferative response. The results obtained in these animal models with a gD subunit vaccine provide an appropriate foundation for the initiation of human studies.

Effect of a thymidine kinase inhibitor (L-653,180) on antiviral treatment of experimental herpes simplex virus infection in mice.

Thymidine kinase (TK) inhibitors can block the activity of TK-dependent antiviral drugs in vitro. We have examined the ability of the TK inhibitor (+/-)-9-([(Z)-2-(hydroxymethyl)cyclohexyl] methyl)guanine (L-653,180) to prevent the therapeutic effect of acyclovir (ACV) in experimental herpes simplex virus type 1 (HSV) skin infections of mice. The results showed that ACV given in the drinking water prevents, in a dose-dependent way, the evolution of the viral infection, and that L-653,180 can reverse some of the therapeutic effects of the antiviral drug. Among the parameters used to evaluate the effect of the TK inhibitor mortality was increased compared to ACV treatment alone, only in the presence of low doses of ACV, whereas the establishment of latent infections in sensory ganglia was significantly increased compared to ACV treatment alone, even when high doses of ACV were administered together with L-653,180.

Herpes simple / Herpes simplex

Las infecciones producidas por el virus herpes simple siguen siendo un gran problema de salud publica. Todavia no existe una vacuna eficaz y el tratamiento es casi exclusivamente paliativo

Reinfections and site-specific immunity in herpes simplex virus infections.

Studies with human volunteers and patients suffering from recurrent herpes simplex virus (HSV) infections have shown that reinfections with autologous or heterologous strains, occurring at sites distant from those of the recurrences, are possible in a variable proportion of the subjects. Experiments in animals have shown that mice surviving a primary HSV infection in the lumbo-sacral area, can become latently infected in trigeminal ganglia upon reinfection of the orofacial site. Similar results were obtained after vaccination of mice with a thymidine-kinase negative, non-pathogenic HSV-1 mutant. It was also demonstrated that initial HSV-1 eye infection in rabbits prevents superinfection of trigeminal ganglia by other strains.