Polymorphisms in Toll-like receptor genes influence antibody responses to cytomegalovirus glycoprotein B vaccine

<p>Abstract</p> <p>Background</p> <p>Congenital Cytomegalovirus (CMV) infection is an important medical problem that has yet no current solution. A clinical trial of CMV glycoprotein B (gB) vaccine in young women showed promising efficacy. Improved understanding of the basis for prevention of CMV infection is essential for developing improved vaccines.</p> <p>Results</p> <p>We genotyped 142 women previously vaccinated with three doses of CMV gB for single nucleotide polymorphisms (SNPs) in TLR 1-4, 6, 7, 9, and 10, and their associated intracellular signaling genes. SNPs in the platelet-derived growth factor receptor (PDGFRA) and integrins were also selected based on their role in binding gB. Specific SNPs in TLR7 and IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) were associated with antibody responses to gB vaccine. Homozygous carriers of the minor allele at four SNPs in TLR7 showed higher vaccination-induced antibody responses to gB compared to heterozygotes or homozygotes for the common allele. SNP rs1953090 in IKBKE was associated with changes in antibody level from second to third dose of vaccine; homozygotes for the minor allele exhibited lower antibody responses while homozygotes for the major allele showed increased responses over time.</p> <p>Conclusions</p> <p>These data contribute to our understanding of the immunogenetic mechanisms underlying variations in the immune response to CMV vaccine.</p

Validation of a blood protein signature for non-small cell lung cancer

Background: CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. Results: Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. Conclusions: Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules

Risk Factors for and Clinical Outcome of Congenital Cytomegalovirus Infection in a Peri-Urban West-African Birth Cohort

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the most prevalent congenital infection worldwide. Epidemiology and clinical outcomes are known to vary with socio-economic background, but few data are available from developing countries, where the overall burden of infectious diseases is frequently high. METHODOLOGY/PRINCIPAL FINDINGS: As part of an ongoing birth cohort study in The Gambia among term infants, urine samples were collected at birth and tested by PCR for the presence of CMV DNA. Risk factors for transmission and clinical outcome were assessed, including placental malaria infection. Babies were followed up at home monthly for morbidity and anthropometry, and at one year of age a clinical evaluation was performed. The prevalence of congenital CMV infection was 5.4% (40/741). A higher prevalence of hepatomegaly was the only significant clinical difference at birth. Congenitally infected children were more often first born babies (adjusted odds ratio (OR) 5.3, 95% confidence interval (CI) 2.0-13.7), more frequently born in crowded compounds (adjusted OR 2.9, 95%CI 1.0-8.3) and active placental malaria was more prevalent (adjusted OR 2.9, 95%CI 1.0-8.4). These associations were corrected for maternal age, bed net use and season of birth. During the first year of follow up, mothers of congenitally infected children reported more health complaints for their child. CONCLUSIONS/SIGNIFICANCE: In this study, the prevalence of congenital CMV among healthy neonates was much higher than previously reported in industrialised countries, and was associated with active placental malaria infection. There were no obvious clinical implications during the first year of life. The effect of early life CMV on the developing infant in the Gambia could be mitigated by environmental factors, such as the high burden of other infections.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Optimum porphyrin accumulation in epithelial skin tumours and psoriatic lesions after topical application of δ-aminolaevulinic acid

Photodynamic therapy with topically applied δ-aminolaevulinic acid is used to treat skin tumours by employing endogenously formed porphyrins as photosensitizers. This study examines the time course of porphyrin metabolite formation after topical application of δ-aminolaevulinic acid. Porphyrin biosynthesis in human skin tumours (basal cell carcinoma, squamous cell carcinoma), in psoriatic lesions, and in normal skin was investigated. Skin areas were treated with δ-aminolaevulinic acid, and levels of total porphyrins, porphyrin metabolites and proteins were measured in samples excised after 1, 2, 4, 6, 9, 12 and 24 h. There was an increase in porphyrin biosynthesis in all tissues with maximum porphyrin levels in tumours between 2 and 6 h and in psoriatic lesions 6 h after treatment. The pattern of porphyrins showed no significant difference between normal and neoplastic skin, protoporphyrin being the predominant metabolite. The results suggest that optimum irradiation time for superficial epithelial skin tumours may be as soon as 2 h after application of δ-aminolaevulinic acid, whereas for treatment of psoriatic lesions an application time of 6 h is more suitable. © 1999 Cancer Research Campaig

Beak and feather disease virus in wild and captive parrots: an analysis of geographic and taxonomic distribution and methodological trends

Psittacine beak and feather disease (PBFD) has emerged in recent years as a major threat to wild parrot populations and is an increasing concern to aviculturists and managers of captive populations. Pathological and serological tests for screening for the presence of beak and feather disease virus (BFDV) are a critical component of efforts to manage the disease and of epidemiological studies. Since the disease was first reported in the mid-1970s, screening for BFDV has been conducted in numerous wild and captive populations. However, at present, there is no current and readily accessible synthesis of screening efforts and their results. Here, we consolidate information collected from 83 PBFD- and BFDV-based publications on the primary screening methods being used and identify important knowledge gaps regarding potential global disease hotspots. We present trends in research intensity in this field and critically discuss advances in screening techniques and their applications to both aviculture and to the management of threatened wild populations. Finally, we provide an overview of estimates of BFDV prevalence in captive and wild flocks alongside a complete list of all psittacine species in which the virus has been confirmed. Our evaluation highlights the need for standardised diagnostic tests and more emphasis on studies of wild populations, particularly in view of the intrinsic connection between global trade in companion birds and the spread of novel BFDV strains into wild populations. Increased emphasis should be placed on the screening of captive and wild parrot populations within their countries of origin across the Americas, Africa and Asia

Cryptanalyses of Branching Program Obfuscations over GGH13 Multilinear Map from the NTRU Problem

In this paper, we propose cryptanalyses of all existing indistinguishability obfuscation ($iO$) candidates based on branching programs (BP) over GGH13 multilinear map for all recommended parameter settings. To achieve this, we introduce two novel techniques, program converting using NTRU-solver and matrix zeroizing, which can be applied to a wide range of obfuscation constructions and BPs compared to previous attacks. We then prove that, for the suggested parameters, the existing general-purpose BP obfuscations over GGH13 do not have the desired security. Especially, the first candidate indistinguishability obfuscation with input-unpartitionable branching programs (FOCS 2013) and the recent BP obfuscation (TCC 2016) are not secure against our attack when they use the GGH13 with recommended parameters. Previously, there has been no known polynomial time attack for these cases. Our attack shows that the lattice dimension of GGH13 must be set much larger than previous thought in order to maintain security. More precisely, the underlying lattice dimension of GGH13 should be set to $n=\tilde\Theta( \kappa^2 \lambda)$ to rule out attacks from the subfield algorithm for NTRU where $\kappa$ is the multilinearity level and $\lambda$ the security parameter

Bioinformatic and statistical analysis of the optic nerve head in a primate model of ocular hypertension

<p>Abstract</p> <p>Background</p> <p>The nonhuman primate model of glaucomatous optic neuropathy most faithfully reproduces the human disease. We used high-density oligonucleotide arrays to investigate whole genome transcriptional changes occurring at the optic nerve head during primate experimental glaucoma.</p> <p>Results</p> <p>Laser scarification of the trabecular meshwork of cynomolgus macaques produced elevated intraocular pressure that was monitored over time and led to varying degrees of damage in different samples. The macaques were examined clinically before enucleation and the myelinated optic nerves were processed post-mortem to determine the degree of neuronal loss. Global gene expression was examined in dissected optic nerve heads with Affymetrix GeneChip microarrays. We validated a subset of differentially expressed genes using qRT-PCR, immunohistochemistry, and immuno-enriched astrocytes from healthy and glaucomatous human donors. These genes have previously defined roles in axonal outgrowth, immune response, cell motility, neuroprotection, and extracellular matrix remodeling.</p> <p>Conclusion</p> <p>Our findings show that glaucoma is associated with increased expression of genes that mediate axonal outgrowth, immune response, cell motility, neuroprotection, and ECM remodeling. These studies also reveal that, as glaucoma progresses, retinal ganglion cell axons may make a regenerative attempt to restore lost nerve cell contact.</p

Amphipathic DNA polymers exhibit antiviral activity against systemic Murine Cytomegalovirus infection

<p>Abstract</p> <p>Background</p> <p>Phosphorothioated oligonucleotides (PS-ONs) have a sequence-independent, broad spectrum antiviral activity as amphipathic polymers (APs) and exhibit potent in vitro antiviral activity against a broad spectrum of herpesviruses: HSV-1, HSV-2, HCMV, VZV, EBV, and HHV-6A/B, and in vivo activity in a murine microbiocide model of genital HSV-2 infection. The activity of these agents against animal cytomegalovirus (CMV) infections in vitro and in vivo was therefore investigated.</p> <p>Results</p> <p>In vitro, a 40 mer degenerate AP (REP 9) inhibited both murine CMV (MCMV) and guinea pig CMV (GPCMV) with an IC₅₀of 0.045 μM and 0.16 μM, respectively, and a 40 mer poly C AP (REP 9C) inhibited MCMV with an IC₅₀of 0.05 μM. Addition of REP 9 to plaque assays during the first two hours of infection inhibited 78% of plaque formation whereas addition of REP 9 after 10 hours of infection did not significantly reduce the number of plaques, indicating that REP 9 antiviral activity against MCMV occurs at early times after infection. In a murine model of CMV infection, systemic treatment for 5 days significantly reduced virus replication in the spleens and livers of infected mice compared to saline-treated control mice. REP 9 and REP 9C were administered intraperitoneally for 5 consecutive days at 10 mg/kg, starting 2 days prior to MCMV infection. Splenomegaly was observed in infected mice treated with REP 9 but not in control mice or in REP 9 treated, uninfected mice, consistent with mild CpG-like activity. When REP 9C (which lacks CpG motifs) was compared to REP 9, it exhibited comparable antiviral activity as REP 9 but was not associated with splenomegaly. This suggests that the direct antiviral activity of APs is the predominant therapeutic mechanism <it>in vivo</it>. Moreover, REP 9C, which is acid stable, was effective when administered orally in combination with known permeation enhancers.</p> <p>Conclusion</p> <p>These studies indicate that APs exhibit potent, well tolerated antiviral activity against CMV infection in vivo and represent a new class of broad spectrum anti-herpetic agents.</p

Maintenance of Large Subpopulations of Differentiated CD8 T-Cells Two Years after Cytomegalovirus Infection in Gambian Infants

BACKGROUND: In a previously published study, we found that large differentiated subpopulations of CD8 T-cells emerged rapidly after CMV infection in young infants and persisted throughout the following year. Here we describe a follow-up study conducted on the same infants to establish whether the differentiated subpopulations continued through the second year post-infection. METHODOLOGY / PRINCIPAL FINDINGS: CMV-specific cells identified using tetramers remained more activated and differentiated than the overall CD8 population. The large subpopulation of differentiated cytotoxic (CD28(-)CD62L(-)Bcl-2(low)CD95(+)perforin(+)) cells that emerged rapidly after infection remained stable after two years. No similar subpopulation was found in CMV-uninfected infants indicating that two years after infection, CMV remained a major factor in driving CD8 T-cell differentiation. Although markers of activation (CD45R0 and HLA-D) declined throughout the first year, HLA-D expression continued to decline during the second year and CD45R0 expression increased slightly. The age-related increase in IFNgamma response observed during the first year continued but was non-significant during the second year, indicating that the rate of functional improvement had slowed substantially. CONCLUSIONS / SIGNIFICANCE: The large differentiated subpopulations of CD8 T-cells that had emerged immediately after CMV infection persisted through the second year post-infection, while levels of activation and functional capacity remained fairly constant.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe