Longevity is a polygenic trait in which genetic predisposition is particularly important. We hypothesized that among genes differentially expressed in response to caloric restriction, several may be candidate longevity genes. We tested 459 single-nucleotide polymorphisms (SNPs) in 47 genes differentially expressed in calorically restricted mice and 12 other genes for association with longevity. Subjects were American men of Japanese ancestry, 440 aged ≥95 years and 374 with an average life span. Based on a dominant model of inheritance, an association with longevity at the p < .05 level was seen for SNPs in 13 of the genes. Testing by all possible models increased the number of genes to 18. After correction for multiple testing, four genes retained significance, namely, MAP3K5 (p = .00004), SIRT7 (p = .00004), SIRT5 (p = .0007), and PIK3R1 (p = .01). In a dominant model, association with longevity was seen for multiple adjacent SNPs within two of these genes (MAP3K5 and PIK3R1), as well as in FLT1, consistent with linkage disequilibrium with a causative variant in the vicinity of each respective SNP set. MAP3K5 and FLT1 haplotypes were associated with longevity. In conclusion, the present study implicates variation in MAP3K5, FLT1, PIK3R1, SIRT7, and SIRT5 in human longevity.

The variant rs4769613 T/C within the enhancer element near FLT1, an acknowledged gene in preeclampsia, was previously identified as a risk factor for preeclampsia in the genome-wide association study (GWAS) targeting placental genotypes. We aimed to test the robustness of this association in 2 Estonian cohorts. Both placental sample sets HAPPY PREGNANCY (Development of novel non-invasive biomarkers for fertility and healthy pregnancy; preeclampsia, n=44 versus nonpreeclampsia, n=1724) and REPROMETA (REPROgrammed fetal and/or maternal METAbolism; 52/277) exhibited suggestive association between rs4769613[C] variant and preeclampsia (logistic regression adjusted for gestational age and fetal sex, nominal P<0.05). Meta-analysis across 2 samples (96/2001) replicated the genome-wide association study outcome (Bonferroni corrected P=4×10^-3; odds ratio, 1.75 [95% CI, 1.23-2.49]). No association was detected with gestational diabetes mellitus, preterm birth, and newborn parameters. Also, neither maternal nor paternal rs4769613 genotypes predisposed to preeclampsia. The exact role of placental rs4769613 genotype in the preeclampsia pathogenesis is to be clarified as no effect was detected on maternal baseline serum sFlt-1 (soluble fms-related receptor tyrosine kinase 1) levels. However, when placental FLT1 gene expression and maternal serum sFlt-1 measurements were stratified by placental rs4769613 genotypes, significantly higher transcript and biomarker levels were detected in preeclampsia versus nonpreeclampsia cases in the CC- and CT- (Student t test, P≤0.02), but not in the TT-genotype subgroup. We suggest that rs4769613 represents a conditional expression Quantitative Trait Locus, whereby only the enhancer with the C-allele reacts to promote the FLT1 expression in unfavorable placental conditions. The study highlighted that the placental FLT1 rs4769613 C-allele is a preeclampsia-specific risk factor. It may contribute to early identification of high-risk women, for example, when genotyped in the cffDNA available in maternal blood plasma.

Keywords: genotype; placenta; pregnancy; risk factor; women.

Random skin flap (RSF) is commonly used in plastic and reconstructive surgery, but its distal part often occurs ischemia. Type 1 Diabetes mellitus (T1DM), may be detrimental for flap survival by provide sever ischemia. We sought to determine the influence of DM on the relation between mast cells and angiogenesis by examining tryptase and Fms-like tyrosine kinase 1 (Flt-1), a well-known vascular endothelial growth factor receptor (VEGFR-1), in the surviving areas of RSF in healthy and diabetic rats. 16 male rats divided into healthy and diabetic groups. T1DM was created in the diabetic rats, followed by generation of a RSF in both the control and diabetic rat. On day 7, the surviving areas of each RSF were recorded. Then animals were euthanized, and numbers of vessels, mast cells and co-localization of mast cell tryptase and Flt-1 were analyzed. T1DM decreased survival areas in the RSF compared to the healthy rats, with higher percentage of intact and degranulated mast cells. T1DM elevated the expression percentage of tryptase and VEGFR-1in the proximal and middle areas of the survival parts of the RSF in most diabetic rats. Generally, our results showed that mast cell degranulation might have a positive correlation with VEGFR-1 and in this current model of ischemic tissue in diabetic rats, this finding could lead to poor angiogenesis and weakened blood vessel function, which might result in decreased RSF survival. Additional molecular mechanisms that pertain to the effects of DM on ischemic tissues healing such as this RSF model should be determined by further investigations.

Keywords: Angiogenesis; Flap; Ischemia; Vessel.

Long term exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with the increasing risk of lung cancer. To identify differentially hypermethylated genes associated with PAHs-induced carcinogenicity, we performed genome-wide DNA methylation analysis in 20 μM benzo(a)pyrene (BaP)-transformed human bronchial epithelial (HBE) cells at different stages of cell transformation. Several methylated genes (CNGA4, FLT1, GAREM1, SFMBT2, TRIM36) were differentially hypermethylated and their mRNA was suppressed in cells at both pre-transformed and transformed stages. Similar results were observed in HBE cells transformed by 20 μg/mL coke oven emissions (COEs) mixture collected from a coking manufacturing facility. In particular, hypermethylation of TRIM36 and suppression of TRIM36 expression were gradually enhanced over the time of COEs treatment. We developed bisulfite pyrosequencing assay and assessed TRIM36 methylation quantitatively. We found that hypermethylation of TRIM36 and reduced gene expression was prevalent in several types of human cancers. TRIM36 hypermethylation appeared in 90.0% (23/30) of Non-Small Cell Lung Cancer (NSCLCs) tissues compared to their paired adjacent tissues with an average increase of 1.32 fold. Furthermore, an increased methylation rate (5.90% v.s 7.38%) and reduced levels of TRIM36 mRNA were found in peripheral lymphocytes (PBLCs) of 151 COEs-exposed workers. In all subjects, TRIM36 hypermethylation was positively correlated with the level of urinary 1-hydroxypyrene (P < 0.001), an internal exposure marker of PAHs, and the DNA damage (P = 0.013). These findings suggest that aberrant hypermethylation of TRIM36 might be involved in the acquisition of malignant phenotype and could be served as a biomarker for risk assessment of PAHs exposure.

Enhancing differentiation of mesenchymal stem cells (MSCs) to endothelial cells may improve their ability to vascularize tissue and promote wound healing. This study describes a novel role for nitric oxide (NO) in reprogramming MSCs towards an endothelial lineage and highlights the role of Wnt signaling and epigenetic modification by NO. Rat MSCs were transduced with lentiviral vectors expressing endothelial nitric oxide synthase (pLV-eNOS) and a mutated caveolin gene (pLV-CAV-1^F92A ) to enhance NO generation resulting in increased in vitro capillary tubule formation and endothelial marker gene expression. An exogenous source of NO could also stimulate CD31 expression in MSCs. NO was associated with an arterial-specific endothelial gene expression profile of Notch1, Dll4, and Hey2 and significantly reduced expression of venous markers. Wnt signaling associated with NO was evident through increased gene expression of Wnt3a and β-catenin protein, and expression of the endothelial marker Pecam-1 could be significantly reduced by treatment with the Wnt signaling inhibitor Dkk-1. The role of NO as an epigenetic modifier was evident with reduced gene expression of the methyltransferase, DNMT1, and bisulfite sequencing of the endothelial Flt1 promoter region in NO-producing MSCs showed significant demethylation compared to control cells. Finally, subcutaneous implantation of NO-producing MSCs seeded in a biomaterial scaffold (NovoSorb®) resulted in survival of transplanted cells and the formation of blood vessels. In summary, this study describes, NO as a potent endothelial programming factor which acts as an epigenetic modifier in MSCs and may provide a novel platform for vascular regenerative therapy.

The involvement of genes and miRNAs in the development of atherosclerosis is a challenging problem discussed in recent publications. It is necessary to establish which miRNAs affect the expression of candidate genes. We used known candidate atherosclerosis genes to predict associations. The quantitative characteristics of interactions of miRNAs with mRNA candidate genes were determined using the program, which identifies the localization of miRNA binding sites in mRNA, the free energy interaction of miRNA with mRNA. In mRNAs of GAS6 and NFE2L2 candidate genes, binding sites of 21 miRNAs and of 15 miRNAs, respectively, were identified. In IRS2 mRNA binding sites of 25 miRNAs were located in a cluster of 41 nt. In ADRB3, CD36, FASLG, FLT1, PLA2G7, and PPARGC1A mRNAs, clusters of miR-466, ID00436.3p-miR, and ID01030.3p-miR BS were identified. The organization of overlapping miRNA binding sites in clusters led to their compaction and caused competition among the miRNAs. The binding of 53 miRNAs to the mRNAs of 14 candidate genes with free energy interactions greater than -130 kJ/mole was determined. The miR-619-5p was fully complementary to ADAM17 and CD36 mRNAs, ID01593.5p-miR to ANGPTL4 mRNA, ID01935.5p-miR to NFE2L2, and miR-5096 to IL18 mRNA. Associations of miRNAs and candidate atherosclerosis genes are proposed for the early diagnosis of this disease.

Keywords: association; atherosclerosis; binding sites cluster; gene; mRNA; marker; miRNA.

Background: The aim of this study was to find genes with significantly aberrant expression in diabetic nephropathy (DN) and determine their underlying mechanisms.

Methods: GSE30528 and GSE1009 were obtained by querying the Gene Expression Omnibus (GEO) database. The difference in target gene expression between normal renal tissues and kidney tissues in patients with DN was screened by using the GEO2R tool. Using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, differentially expressed genes (DEGs) were analysed by Gene Ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Then, the protein-protein interactions (PPIs) of DEGs were analyzed by Cytoscape with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and the hub genes in this PPI network were recognized by centrality analysis.

Results: There were 110 genes with significant expression differences between normal and DN tissues. The differences in gene expression involved many functions and expression pathways, such as the formation of the extracellular matrix and the construction of the extracellular domain. The correlation analysis and subgroup analysis of 14 hub genes and the clinical characteristics of DN showed that CTGF, ALB, PDPN, FLT1, IGF1, WT1, GJA1, IGFBP2, FGF9, BMP2, FGF1, BMP7, VEGFA, and TGFBR3 may be involved in the progression of DN.

Conclusions: We confirmed the differentially expressed hub genes and other genes which may be the novel biomarker and target candidates in DN.

Keywords: Diabetic nephropathy (DN); bioinformatics analysis; differentially expressed gene (DEG); hub genes; microarray analysis.

BACKGROUND Preeclampsia (PE) remains one of the primary causes of maternal morbidity and mortality worldwide. This study was designed to investigate the relevance of long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) and downstream molecules in trophoblast cell proliferation and apoptosis. MATERIAL AND METHODS NEAT1 expression in the placental tissues of rats with PE was analyzed by reverse transcriptionquantitative polymerase chain reaction. The role of NEAT in trophoblast cell proliferation, migration, invasion, and apoptosis was assessed by transfecting pcDNA-NEAT1 and siRNA-NEAT1 into trophoblast cells. The microRNA (miRNA) binding to NEAT1 and the genes targeted by the screened miRNAs were predicted by Starbase, and the mechanism of action of NEAT1 in PE was further investigated. RESULTS The expression of NEAT1 lncRNA was markedly higher in placental samples of PE than control rats. Ectopic expression of NEAT1 repressed trophoblast cell proliferation, migration, invasion, and colony formation, but facilitated cell apoptosis, whereas NEAT1 downregulation resulted in the opposite effects. NEAT1 was found to act as a molecular sponge for miR-373, regulating Fms-like tyrosine kinase-1 (FLT-1) to modulate PE development. CONCLUSIONS NEAT1 may contribute to PE development by regulating trophoblast cell proliferation and apoptosis. These findings may provide a new perspective for understanding the etiology and pathogenesis of PE.

BACKGROUND

Pyroglutamylation of truncated Aβ peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-Aβ species with enhanced aggregation propensities and resistance to most amino-peptidases and endo-peptidases. pE-Aβ species have been identified as major constituents of Aβ plaques and reduction of pE-Aβ species is associated with improvement of cognitive tasks in animal models of Alzheimer's disease (AD). Pharmacological inhibition of QC has thus emerged as a promising therapeutic approach for AD. Here, we question whether cerebrospinal fluid (CSF) QC enzymatic activity differs between AD patients and controls and whether inflammatory or angiogenesis mediators, some of which are potential QC substrates, and/or Aβ peptides may serve as pharmacodynamic read-outs for QC inhibition.

METHODS

QC activity, Aβ peptides and inflammatory or angiogenesis mediators were measured in CSF of a clinically well-characterized cohort of 20 mild AD patients, 20 moderate AD patients and 20 subjective memory complaints (SMC) controls. Correlation of these parameters with core diagnostic CSF AD biomarkers (Aβ42, tau and p-tau) and clinical features was evaluated.

RESULTS

QC activity shows a tendency to decrease with AD progression (p = 0.129). The addition of QC activity to biomarkers tau and p-tau significantly increases diagnostic power (ROC-AUCTAU = 0.878, ROC-AUCTAU&QC = 0.939 and ROC-AUCpTAU = 0.820, ROC-AUCpTAU&QC = 0.948). In AD and controls, QC activity correlates with Aβ38 (r = 0.83, p < 0.0001) and Aβ40 (r = 0.84, p < 0.0001), angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1, r>> 0.5, p < 0.0001) and core diagnostic biomarkers (r>> 0.35, p = <0.0057). QC activity does not correlate with MMSE or ApoE genotype.

CONCLUSIONS

Aβ38, Aβ40 and angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1) are potential pharmacodynamic markers of QC inhibition, because their levels closely correlate with QC activity in AD patients. The addition of QC activity to core diagnostic CSF biomarkers may be of specific interest in clinical cases with discordant imaging and biochemical biomarker results.

Colorectal cancer (CRC) is one of the most commonly-diagnosed malignancies throughout the world and the fourth-leading cause of cancer deaths globally. Angiogenesis and the resultant tumor neovascularization is a well-known cancer hallmark. Here we investigated the expression of FLT1 and KDR, the influential genes in angiogenesis regulation, in CRC patients.

We assessed FLT1 and KDR mRNA expression in 47 CRC samples and matched adjacent noncancerous tissues (ANCT) by quantitative real-time PCR. The Spearmen correlation coefficient and receiver operating characteristic (ROC) curves were also examined.

Both genes were expressed at significantly greater levels in CRC tissues than in ANCT (p < 0.05). A significant association was found between KDR expression and disease stage and lymph status in CRC patients. Furthermore, the Spearman correlation demonstrated a moderate correlation between FLT1 and KDR expression in CRC samples. Finally, ROC curve analysis demonstrated that FLT1 had the greatest sensitivity (85.1%), while the greatest specificity was achieved by a combination of the two genes.

The dysregulated FLT1 and KDR expression, in addition to the observed correlation and ROC curve results, indicate the critical importance of angiogenesis among the cancer pathways in CRC. These data can broaden our current knowledge of angiogenesis in CRC to improve disease diagnosis and patient treatment.

Background: Lung adenocarcinoma (LUAD) is a common lung cancer with a high mortality, for which microRNAs (miRNAs) play a vital role in its regulation. Multiple messenger RNAs (mRNAs) may be regulated by miRNAs, involved in LUAD tumorigenesis and progression. However, the miRNA-mRNA regulatory network involved in LUAD has not been fully elucidated.

Methods: Differentially expressed miRNAs and mRNA were derived from the Cancer Genome Atlas (TCGA) dataset in tissue samples and from our microarray data in plasma (GSE151963). Then, common differentially expressed (Co-DE) miRNAs were obtained through intersected analyses between the above two datasets. An overlap was applied to confirm the Co-DEmRNAs identified both in targeted mRNAs and DEmRNAs in TCGA. A miRNA-mRNA regulatory network was constructed using Cytoscape. The top five miRNA were identified as hub miRNA by degrees in the network. The functions and signaling pathways associated with the hub miRNA-targeted genes were revealed through Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The key mRNAs in the protein-protein interaction (PPI) network were identified using the STRING database and CytoHubba. Survival analyses were performed using Gene Expression Profiling Interactive Analysis (GEPIA).

Results: The miRNA-mRNA regulatory network consists of 19 Co-DEmiRNAs and 760 Co-DEmRNAs. The five miRNAs (miR-539-5p, miR-656-3p, miR-2110, let-7b-5p, and miR-92b-3p) in the network were identified as hub miRNAs by degrees (>100). The 677 Co-DEmRNAs were targeted mRNAs from the five hub miRNAs, showing the roles in the functional analyses of the GO analysis and KEGG pathways (inclusion criteria: 836 and 48, respectively). The PPI network and Cytoscape analyses revealed that the top ten key mRNAs were NOTCH1, MMP2, IGF1, KDR, SPP1, FLT1, HGF, TEK, ANGPT1, and PDGFB. SPP1 and HGF emerged as hub genes through survival analysis. A high SPP1 expression indicated a poor survival, whereas HGF positively associated with survival outcomes in LUAD.

Conclusion: This study investigated a miRNA-mRNA regulatory network associated with LUAD, exploring the hub miRNAs and potential functions of mRNA in the network. These findings contribute to identify new prognostic markers and therapeutic targets for LUAD patients in clinical settings.

Keywords: bioinformatics; hub genes; lung adenocarcinoma; microRNAs; prognostic marker.

Use of trait-dependent sampling designs in whole-genome association studies of sequence data can reduce total sequencing costs with modest losses of statistical efficiency. In a quantitative trait (QT) analysis of data from the Genetic Analysis Workshop 17 mini-exome for unrelated individuals in the Asian subpopulation, we investigate alternative designs that sequence only 50% of the entire cohort. In addition to a simple random sampling design, we consider extreme-phenotype designs that are of increasing interest in genetic association analysis of QTs, especially in studies concerned with the detection of rare genetic variants. We also evaluate a novel sampling design in which all individuals have a nonzero probability of being selected into the sample but in which individuals with extreme phenotypes have a proportionately larger probability. We take differential sampling of individuals with informative trait values into account by inverse probability weighting using standard survey methods which thus generalizes to the source population. In replicate 1 data, we applied the designs in association analysis of Q1 with both rare and common variants in the FLT1 gene, based on knowledge of the generating model. Using all 200 replicate data sets, we similarly analyzed Q1 and Q4 (which is known to be free of association with FLT1) to evaluate relative efficiency, type I error, and power. Simulation study results suggest that the QT-dependent selection designs generally yield greater than 50% relative efficiency compared to using the entire cohort, implying cost-effectiveness of 50% sample selection and worthwhile reduction of sequencing costs.

Vascular endothelial growth factor (VEGF) is one of the most potent factors in tumor-induced neoangiogenesis. After binding to its specific receptors KDR and FLT-1 on the endothelial cell surface cell proliferation and migration are stimulated. Recently there has been some evidence for the expression of these receptors on tumor cells. We investigated the protein and mRNA expression of KDR and FLT-1 in native tissues and tumor cell cultures from squamous cell carcinomas of the head and neck (HNSCC) and analyzed their in vitro functional significance for tumor cell proliferation and migration. Apart from the expected expression of VEGF receptors on endothelial cells we observed a tumor cell-specific localization of FLT-1 in 29 tumors and KDR in 16 of 37 tumors analyzed. Functional studies in vitro revealed that the addition of VEGF to HNSCC cells inhibited the proliferation and migration of these cells in a dose-dependent manner. Our data suggest a potential negative regulatory loop for VEGF and FLT1 when tumor cells have an insufficient blood supply.

Objectives: The purpose of this study was to propose an integrated strategy for investigating the mechanism of Qiliqiangxin capsule (QLQX) to treat chronic heart failure (CHF). Methods: Pharmacokinetics analysis was performed to screen the active components of QLQX using high-performance liquid chromatography-tandem mass spectrometry techniques. We then constructed the component-target network between the targets of active components in QLQX and CHF using Cytoscape. A network analysis, including topological parameters, clustering, and pathway enrichment, was established to identify the hub targets and pathways. Finally, some of the predicted hub targets were validated experimentally in human cardiac microvascular endothelial cell (HCMEC). Results: We identified 29 active components in QLQX, and 120 consensus potential targets were determined by the pharmacokinetics analysis and network pharmacology approach. Further network analysis indicated that 6 target genes, namely, VEGFA, CYP1A1, CYP2B6, ATP1A1, STAT3, and STAT4, and 10 predicted functional genes, namely, KDR, FLT1, NRP2, JAK2, EGFR, IL-6, AHR, ATP1B1, JAK1, and HIF1A, may be the primary targets regulated by QLQX for the treatment of CHF. Among these targets, VEGFA, IL-6, p-STAT3, and p-JAK2 were selected for validation in the HCMEC. The results indicated that QLQX may inhibit inflammatory processes and promote angiogenesis in CHF via the JAK/STAT signaling pathway. Conclusions: This study provides a strategy for understanding the mechanism of QLQX against CHF by combining pharmacokinetics study, network pharmacology, and experimental validation.

BACKGROUND

Gastroschisis has been assumed to have a low rate of syndromic and primary malformations. We aimed to systematically review and explore the frequency and type of malformations/chromosomal syndromes and to identify significant biological/genetic roles in gastroschisis.

METHODS

Population-based, gastroschisis-associated anomalies/chromosomal defects published 1950-2018 (PubMed/MEDLINE) were independently searched by two reviewers. Associated anomalies/chromosomal defects and selected clinical characteristics were subdivided and pooled by race, system/region, isolated, and associated cases (descriptive analysis and chi-square test were performed). Critical regions/genes from representative chromosomal syndromes including an enrichment analysis using Gene Ontology Consortium/Panther Classification System databases were explored. Fisher's exact test with False Discovery Rate multiple test correction was performed.

RESULTS

Sixty-eight articles and 18525 cases as a base were identified (prevalence of 17.9 and 3% for associated anomalies/chromosomal defects, respectively). There were 3596 associated anomalies, prevailing those cardiovascular (23.3%) and digestive (20.3%). Co-occurring anomalies were associated with male, female, American Indian, Caucasian, prenatally diagnosed, chromosomal defects, and mortality (P < 0.00001). Gene clusters on 21q22.11 and 21q22.3 (KRTAP), 18q21.33 (SERPINB), 18q22.1 (CDH7, CDH19), 13q12.3 (FLT1), 13q22.1 (KLF5), 13q22.3 (EDNRB), and 13q34 (COL4A1, COL4A2, F7, F10) were significantly related to biological processes: blood pressure regulation and/or vessel integrity, angiogenesis, coagulation, cell-cell and/or cell-matrix adhesion, dermis integrity, and wound healing (P < 0.05).

CONCLUSIONS

Our findings suggest that gastroschisis may result from the interaction of several chromosomal regions in an additive manner as a pool of candidate genes were identified from critical regions supporting a role for vascular disruption, thrombosis, and mesodermal deficiency in the pathogenesis of gastroschisis.

OBJECTIVE

The aim of this study was to investigate the effect of scatter and its correction on kinetic parameters in dynamic brain positron emission tomography (PET) tumor imaging. The 2-tissue compartment model was used, and two different reconstruction methods and two scatter correction (SC) schemes were investigated.

METHODS

The gate Monte Carlo (MC) software was used to perform 2 × 15 full PET scan simulations of a voxelized head phantom with inserted tumor regions. The two sets of kinetic parameters of all tissues were chosen to represent the 2-tissue compartment model for the tracer 3'-deoxy-3'-((18)F)fluorothymidine (FLT), and were denoted FLT1 and FLT2. PET data were reconstructed with both 3D filtered back-projection with reprojection (3DRP) and 3D ordered-subset expectation maximization (OSEM). Images including true coincidences with attenuation correction (AC) and true+scattered coincidences with AC and with and without one of two applied SC schemes were reconstructed. Kinetic parameters were estimated by weighted nonlinear least squares fitting of image derived time-activity curves. Calculated parameters were compared to the true input to the MC simulations.

RESULTS

The relative parameter biases for scatter-eliminated data were 15%, 16%, 4%, 30%, 9%, and 7% (FLT1) and 13%, 6%, 1%, 46%, 12%, and 8% (FLT2) for K1, k2, k3, k4, Va, and Ki, respectively. As expected, SC was essential for most parameters since omitting it increased biases by 10 percentage points on average. SC was not found necessary for the estimation of Ki and k3, however. There was no significant difference in parameter biases between the two investigated SC schemes or from parameter biases from scatter-eliminated PET data. Furthermore, neither 3DRP nor OSEM yielded the smallest parameter biases consistently although there was a slight favor for 3DRP which produced less biased k3 and Ki estimates while OSEM resulted in a less biased Va. The uncertainty in OSEM parameters was about 26% (FLT1) and 12% (FLT2) larger than for 3DRP although identical postfilters were applied.

CONCLUSIONS

SC was important for good parameter estimations. Both investigated SC schemes performed equally well on average and properly corrected for the scattered radiation, without introducing further bias. Furthermore, 3DRP was slightly favorable over OSEM in terms of kinetic parameter biases and SDs.