Coalescent simulations are a widely used approach for simulating sample genealogies, but can become computationally burdensome in large samples. Methods exist to analytically calculate a sample’s ...expected frequency spectrum without simulating full genealogies. However, statistics that rely on the distribution of the length of internal coalescent branches, such as the probability that two mutations of equal size arose on the same genealogical branch, have previously required full coalescent simulations to estimate. Here, we present a sampling method capable of efficiently generating limited portions of sample genealogies using a series of analytic equations that give probabilities for the number, start, and end of internal branches conditional on the number of final samples they subtend. These equations are independent of the coalescent waiting times and need only be calculated a single time, lending themselves to efficient computation. We compare our method with full coalescent simulations to show the resulting distribution of branch lengths and summary statistics are equivalent, but that for many conditions our method is at least 10 times faster.
NOX‐A12 is a PEGylated mirror‐image oligonucleotide (a so‐called Spiegelmer) that binds to CXCL12 (stromal cell–derived factor‐1, SDF‐1) with high affinity thereby inhibiting CXCL12 signaling on both ...its receptors, CXCR4 and CXCR7. In animals, NOX‐A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX‐A12 had a benign safety profile and also dose‐dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half‐life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose‐dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX‐A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long‐lasting mobilization and chemosensitization of hematological cancer cells.
Clinical Pharmacology & Therapeutics (2013); 94 1, 150–157. doi:10.1038/clpt.2013.58
Background and Purpose
Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated ...structured l‐oligoribonucleotide, binds and inactivates hepcidin.
Experimental Approach
We conducted a placebo‐controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg−1.
Key Results
After treatment with lexaptepid, serum iron concentration and transferrin increased dose‐dependently. Iron increased from approximately 20 μmol·L−1 at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg−1 lexaptepid. The pharmacokinetics showed dose‐proportional increases in peak plasma concentrations and moderately over‐proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti‐drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg−1 and with local injection site reactions after s.c. but not after i.v. administration.
Conclusions and Implications
Lexaptepid pegol inhibited hepcidin and dose‐dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease.
Renal Ewing tumors Zöllner, S.; Dirksen, U.; Jürgens, H. ...
Annals of oncology,
09/2013, Letnik:
24, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Renal Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is extremely rare. Clinical symptoms are nonspecific presenting abdominal pain, palpable mass, and hematuria. Owing to advanced ...technology demonstrating the ES-specific EWS/ETS translocation, this differential diagnosis has become feasible.
The German database of GPOH Ewing's sarcoma trials from 1980 to 2009 was searched for kidney as primary site. Twenty-four patients were identified and analyzed. The median time of observation was 3.71 years (range 0.27–8.75 years). Additionally, we carried out a Medline search for renal ES/PNET.
The median age was 24.9 years (range 11–60 years). In 37.5%, patients presented with primary metastases. Tumor thrombi in the adjacent renal vessels occurred in 56.2%. In 90.9%, rearrangements of t(11;22) were found. All patients received a combined chemotherapy according to the EURO-E.W.I.N.G.99 protocol. In accordance, local control consisted predominantly of combined modality surgery and radiation (47%). At 3 years, overall survival (OS) was 0.80 (SE = 0.09), and event-free survival (EFS) 0.66 (SE = 0.11).
ES/PNET should be considered in the differential diagnosis of renal tumors. Patients with renal ES/PNET respond to and benefit from conventional ES treatment according to ES study protocols. Therefore, an accurate diagnostic approach and a guideline-adapted therapy should be facilitated.
We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation ...influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.
Abstract Objective Reactive oxygen and nitrogen species (e.g., peroxynitrite) may trigger neointima formation leading to restenosis. In a rat carotid endarterectomy (CEA) model, we investigated the ...effects of the manganese(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP), a superoxide dismutase (SOD) mimetic and peroxynitrite scavenger on neointima formation. Methods CEA was performed in male Sprague–Dawley rats. Animals received either vehicle (control group; n = 15) or 15 mg kg−1 day−1 MnTBAP intraperitoneally for 3 weeks (treatment group; n = 13). Four groups of carotids were analysed: the left, uninjured carotids (sham) and the right, injured carotids (control CEA) from the control group, the right, injured carotids from the treatment group (CEA + MnTBAP) and an additional group of carotids that were harvested 1 h following endarterectomy. The analysis of carotid arteries was performed by histology, immunohistochemistry and real-time polymerase chain reaction (PCR). Plasma malondialdehyde (MDA) levels were measured by lipid hydroperoxidase assay. Results Stenosis rate (10.5 ± 8.1% vs. 45.4 ± 28.3%), the percentage of proliferating cell nuclear antigen-positive cells (13.4 ± 7.1% vs. 23.3 ± 11.0%) and nitrotyrosine immunoreactivity (5.8 ± 1.9 vs. 8.0 ± 2.0) were significantly reduced in the vascular wall of the CEA + MnTBAP group compared with control CEA group. Ratio of Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive nuclei was significantly lower after antioxidant therapy (41.7 ± 26.7% vs. 64.9 ± 18.5%). Plasma MDA levels increased after endarterectomy (11.7 ± 4.8 vs. 4.1 ± 2.0 μmol l−1 ) and reduced in the treatment group (3.2 ± 2.1 μmol l−1 ). No significant gene regulation after MnTBAP treatment could be noted. Conclusions MnTBAP decreased neointima formation, which was associated with reduced vascular smooth muscle cell proliferation and attenuated local and systemic nitro-oxidative stress.
We present the results of extensive simulations that emulate the development and distribution of linkage disequilibrium (LD) between single-nucleotide polymorphisms (SNPs) and a gene locus that is ...phenotypically stratified into two classes (disease phenotype and wild-type phenotype). Our approach, based on coalescence theory, allows an explicit modeling of the demographic history of the population without conditioning on the age of the mutation, and serves as an efficient tool to carry out simulations. More specifically, we compare the influence that a constant population size or an exponentially growing population has on the amount of LD. These results indicate that attempts to locate single disease genes are most likely successful in small and constant populations. On the other hand, if we consider an exponentially growing population that started to expand from an initially constant population of reasonable size, then our simulations indicate a lower success rate. The power to detect association is enhanced if haplotypes constructed from several SNPs are used as markers. The versatility of the coalescence approach also allows the analysis of other relevant factors that influence the chances that a disease gene will be located. We show that several alleles leading to the same disease have no substantial influence on the amount of LD, as long as the differences between the disease-causing alleles are confined to the same region of the gene locus and as long as each allele occurs in an appreciable frequency. Our simulations indicate that mapping of less-frequent diseases is more likely to be successful. Moreover, we show that successful attempts to map complex diseases depend crucially on the phenotype-genotype correlations of all alleles at the disease locus. An analysis of lipoprotein lipase data indicates that our simulations capture the major features of LD occurring in biological data.
Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex ...differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.
We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.
Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).
In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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