Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine – a review

Purpose The impact on patients’ health of radiopharmaceuticals in nuclear medicine diagnostics has not until now been evaluated systematically in a European context. Therefore, as part of the EU-funded Project PEDDOSE. NET (www.peddose.net), we review and summarize the current knowledge on biokinetics and dosimetry of commonly used diagnostic radiopharmaceuticals. Methods A detailed literature search on published biokinetic and dosimetric data was performed mostly via PubMed (www.ncbi.nlm.nih.gov/pubmed). In principle the criteria for inclusion of data followed the EANM Dosimetry Committee guidance document on good clinical reporting. Results Data on dosimetry and biokinetics can be difficult to find, are scattered in various journals and, especially in paediatric nuclear medicine, are very scarce. The data collection and calculation methods vary with respect to the time-points, bladder voiding, dose assessment after the last data point and the way the effective dose was calculated. In many studies the number of subjects included for obtaining biokinetic and dosimetry data was fewer than ten, and some of the biokinetic data were acquired more than 20 years ago. Conclusion It would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the-art equipment and more uniform dosimetry protocols. For easier public access to dosimetry data for diagnostic radiopharmaceuticals, a database containing these data should be created and maintained

Genome-Wide DNA Methylation Scan in Major Depressive Disorder

While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12–15% increased DNAm in MDD (p = 0.0002–0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08

Detailed analysis of X chromosome inactivation in a 49,XXXXX pentasomy

<p>Abstract</p> <p>Background</p> <p>Pentasomy X (49,XXXXX) has been associated with a severe clinical condition, presumably resulting from failure or disruption of X chromosome inactivation. Here we report that some human X chromosomes from a patient with 49,XXXXX pentasomy were functionally active following isolation in inter-specific (human-rodent) cell hybrids. A comparison with cytogenetic and molecular findings provided evidence that more than one active X chromosome was likely to be present in the cells of this patient, accounting for her abnormal phenotype.</p> <p>Results</p> <p>5-bromodeoxyuridine (BrdU)-pulsed cultures showed different patterns among late replicating X chromosomes suggesting that their replication was asynchronic and likely to result in irregular inactivation. Genotyping of the proband and her mother identified four maternal and one paternal X chromosomes in the proband. It also identified the paternal X chromosome haplotype (P), indicating that origin of this X pentasomy resulted from two maternal, meiotic non-disjunctions. Analysis of the <it>HUMANDREC </it>region of the androgen receptor (<it>AR</it>) gene in the patient's mother showed a skewed inactivation pattern, while a similar analysis in the proband showed an active paternal X chromosome and preferentially inactivated X chromosomes carrying the 173 <it>AR </it>allele. Analyses of 33 cell hybrid cell lines selected in medium containing hypoxanthine, aminopterin and thymidine (HAT) allowed for the identification of three maternal X haplotypes (M1, M2 and MR) and showed that X chromosomes with the M1, M2 and P haplotypes were functionally active. In 27 cell hybrids in which more than one X haplotype were detected, analysis of X inactivation patterns provided evidence of preferential inactivation.</p> <p>Conclusion</p> <p>Our findings indicated that 12% of X chromosomes with the M1 haplotype, 43.5% of X chromosomes with the M2 haplotype, and 100% of the paternal X chromosome (with the P haplotype) were likely to be functionally active in the proband's cells, a finding indicating that disruption of X inactivation was associated to her severe phenotype.</p

Molecular basis of targeted therapy in T/NKcell lymphoma/leukemia: A comprehensive genomic and immunohistochemical analysis of a panel of 33 cell lines

T and NK-cell lymphoma is a collection of aggressive disorders with unfavorable outcome, in which targeted treatments are still at a preliminary phase. To gain deeper insights into the deregulated mechanisms promoting this disease, we searched a panel of 31 representative T-cell and 2 NK-cell lymphoma/leukemia cell lines for predictive markers of response to targeted therapy. To this end, targeted sequencing was performed alongside the expression of specific biomarkers corresponding to potentially activated survival pathways. The study identified TP53, NOTCH1 and DNMT3A as the most frequently mutated genes. We also found common alterations in JAK/STAT and epigenetic pathways. Immunohistochemical analysis showed nuclear accumulation of MYC (in 85% of the cases), NFKB (62%), p-STAT (44%) and p-MAPK (30%). This panel of cell lines captures the complexity of T/NK-cell lymphoproliferative processes samples, with the partial exception of AITL cases. Integrated mutational and immunohistochemical analysis shows that mutational changes cannot fully explain the activation of key survival pathways and the resulting phenotypes. The combined integration of mutational/expression changes forms a useful tool with which new compounds may be assayed

Mitigation of phosphorus, sediment and Escherichia coli losses in runoff from a dairy farm roadway

peer reviewedDairy cow deposits on farm roadways are a potential source of contaminants entering streams. Phosphorus (P), suspended sediment (SS) and Escherichia coli (E. coli) loads in 18 runoff events over 12 mo from two-halves of a section of dairy farm roadway that spilt into an adjacent P-impacted stream were measured. The runoff from one half was untreated while the other half was directed through a filter of steel melter slag [termed aluminium chlorohydrate (ACH)-altered slag] sprayed with 1% ACH solution to improve P sorption capacity. An uncertainty analysis was conducted to ascertain potential loads of P lost from roadways considering variation in deposit weight, number and P content. Over the monitoring period, the total load decreased P (92%), SS (98%) and E. coli (76%) from the ACHaltered slag roadway compared to the control. However, uncertainty analysis showed that the amount of dung-P deposited on the roadway could be 10-fold greater

Clinical impact of the loss of chromosome 7q on outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem cell transplantation

We conducted a nationwide retrospective study to evaluate the prognostic influence of +1, der(1;7)(q10;p10) [hereafter der(1;7)] and ?7/del(7q) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for de novo myelodysplastic syndromes (MDS). In this database, 69 MDS patients with der(1;7), 75 with ?7/del(7q), and 511 with normal karyotype (NK) underwent allo-HSCT at advanced disease status. The 3-year overall survival (OS) and cumulative incidence of relapse (CIR) were 50.4 and 19.4% for those with der(1;7), 36.2 and 38.4% for ?7/del(7q),and 51.1 and 20.7% for NK, respectively. In the multivariate analysis, the presence of ?7/del(7q) correlated with a significantly shorter OS (HR [95% CI], 1.38 [1.00?1.89]; P = 0.048) and higher CIR (HR, 2.11 [1.36?3.28]; P = 0.001) than those with NK. There were 23 patients with der(1;7), 29 with ?7/del(7q), and 347 with NK who underwent allo-HSCT at early disease status.The 3-year OS and CIR were as follows: 47.3 and 9.5% for the der(1;7) group, 70.5 and 13.8% for ?7/del(7q), and 70.9 and 5.6% for NK,respectively. No significant differences were observed in OS and CIR among three groups. The impact of the loss of chromosome 7q on OS and CIR may differ based on its type and disease status after allo-HSCT for MDS

Improved measurement of CP violation parameters in Bs0→J/ψK+K− decays in the vicinity of the ϕ(1020) resonance

The decay-time-dependent C P asymmetry in B 0 s → J / ψ ( → μ + μ − ) K + K − decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6     fb − 1 , collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 B 0 s signal decays with an invariant K + K − mass in the vicinity of the ϕ ( 1020 ) resonance, the C P -violating phase ϕ s is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the B 0 s − ¯ B 0 s system, Δ Γ s , and the difference of the average B 0 s and B 0 meson decay widths, Γ s − Γ d . The values obtained are ϕ s = − 0.039 ± 0.022 ± 0.006     rad , Δ Γ s = 0.0845 ± 0.0044 ± 0.0024     ps − 1 , and Γ s − Γ d = − 0.005 6 + 0.0013 − 0.0015 ± 0.0014     ps − 1 , where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase ϕ s is also measured independently for each polarization state of the K + K − system and shows no evidence for polarization dependence