cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5128456
title: Supplementary Material for: Ultrasound Characteristics of Symptomatic Carotid Plaques: A Systematic Review and Meta-Analysis

description: <b><i>Background:</i></b> Ultrasound is the most commonly used imaging modality for assessing carotid artery stenosis. A number of studies have demonstrated that surface irregularities, heterogeneous echotexture and hypoechoic plaques are risk factors for acute ischemic stroke. We performed a systematic review and meta-analysis of the literature to better define the risk of stroke based on the sonographic characteristics of carotid plaques. <b><i>Materials and Methods:</i></b> We performed a comprehensive search for studies reporting imaging findings of symptomatic and asymptomatic carotid plaques on ultrasound using MEDLINE and EMBASE. We included both case-control and cohort studies examining the relationship between complex plaque and acute ischemic stroke or transient ischemic attack. Complex plaque was defined as plaque that had any of the following characteristics: heterogeneous echogenicity, echolucency, neovascularization, surface irregularity, ulceration, and intraplaque motion. Meta-analyses using the random-effects model were performed for complex plaque and each of the individual complex plaque characteristics. p &lt; 0.05 was considered statistically significant. We explored the impact of publication bias by constructing funnel plots and testing their symmetry. We conducted the meta-analysis using Comprehensive Meta-analysis version 2.2, Englewood, N.J., USA. <b><i>Results:</i></b> A total of 1,013 articles were screened and 23 studies with 6,706 carotid plaques were included. Ultrasound plaque characteristics with a higher prevalence in individuals with symptomatic compared to asymptomatic carotid artery stenosis included plaque neovascularity (OR = 19.68, 95% CI = 3.14-123.16), complex plaque (OR = 5.12, 95% CI = 3.42-7.67), plaque ulceration (OR = 3.58, 95% CI = 1.66-7.71), plaque echolucency (OR = 3.99, 95% CI = 3.06-5.19) and intraplaque motion (OR = 1.57, 95% CI = 1.02-2.41). Variables not associated with symptom status included heterogenous echotexture (OR = 2.68, 95% CI = 0.56-12.80) and surface irregularity without ulceration (OR = 2.38, 95% CI = 0.70-8.11). No evidence of publication bias was observed based on Eggers test (p value of 0.05 for complex plaque and 0.53 for plaque echolucency). The remaining plaque features had insufficient data to assess for publication bias. <b><i>Conclusions:</i></b> Our meta-analysis and systematic review of the literature demonstrated that plaques with complex features, particularly those with echolucency, neovascularization, ulceration and intraplaque motion are associated with ischemic symptoms. Assessment of carotid plaque on ultrasound may provide stroke risk information beyond measurement of luminal stenosis. Thus, sonographic evaluation of carotid artery stenosis should focus on the detection of these plaque characteristics in addition to quantifying the degree of stenosis.
DOI: 10.6084/m9.figshare.5128459
title: Supplementary Material for: Pre-Transplant Weight Loss and Survival after Kidney Transplantation

description: <b><i>Background/Aims:</i></b> We examined post-transplant survival among obese kidney candidates who were temporarily designated waitlist inactive (status 7) due to their weight. <b><i>Methods:</i></b> Using OPTN/United Network for Organ Sharing data, patient and graft survival of adult status 7 recipients with a registration body mass index (BMI) ≥30 kg/m<sup>2</sup> (n = 328) were compared to all others (controls; n = 74,066). Status 7 recipients were then matched to controls to assess whether pre-transplant weight loss was associated with a survival benefit. <b><i>Results:</i></b> Median BMI at registration (38 vs. 27 kg/m<sup>2</sup>, p &lt; 0.001) and transplant (36 vs. 27 kg/m<sup>2</sup>, p &lt; 0.001) and reduction in BMI while waitlisted (-5.0 vs. 0.0%, p &lt; 0.001) were higher among status 7 than controls. Patient (status 7: 87.3%; control: 89.3%; p = 0.90) and graft survival (status 7: 82.9%; control: 81.6%; p = 0.75) were similar over 4 years. There was no association between status 7 and mortality (HR 0.96, 95% CI 0.59-1.57) or graft loss (HR 0.95, 95% CI 0.66-1.38) in the overall population nor between matched status 7 recipients and controls (patient survival: 86.0 vs. 87.5%, p = 0.20; graft survival: 82.6 vs. 77.2%, p = 0.61). <b><i>Conclusion:</i></b> Among obese status 7 kidney candidates previously considered too obese for transplant, patient and graft survival were comparable to the general transplant population. No difference in survival was observed with pre-transplant weight loss.
DOI: 10.6084/m9.figshare.5128453
title: Supplementary Material for: Biochemical and Pharmacokinetic Properties of PEGylated Cystathionine γ-Lyase from <b><i>Aspergillus carneus</i></b> KF723837

description: Cystathionine γ-lyase (CGL) was purified to its electrophoretic homogeneity from<i> Aspergillus carneus</i> by various chromatographic approaches. The purified enzyme has four identical subunits of 52 kDa based on SDS and native PAGE analyses. To improve its structural stability, purified CGL was modified by covalent binding to polyethylene glycol moieties. The specific activity of free-CGL and PEG-CGL was 59.71 and 48.71 U/mg, respectively, with a PEGylation yield of 81.5 and 70.7% modification of surface ε-amino groups. Free- and modified CGL have the same pattern of pH stability (8.0-9.0). At 50°C, the thermal stability [half-life time (T<sub>1/2</sub>)] of PEG-CGL was increased by 40% in comparison to free-CGL. The activity of CGL was completely inhibited by hydroxylamine and Hg<sup>+2</sup>, with no effect by EDTA. Free-CGL (0.04 mM<sup>-1</sup>s<sup>-1</sup>) and PEG-CGL (0.03 mM<sup>-1</sup>s<sup>-1</sup>) have a similar catalytic efficiency to L-cystathionine as a substrate. The inhibition constant values of propargylglycine were 0.31 and 0.52 µM for the free- and PEG-CGL, respectively. By in vitro proteolysis, PEG-CGL retains &gt;50% of its initial activity compared to &lt;10% of the free-CGL for acid protease for 30 min. From in vivo pharmacokinetics in New Zealand white rabbits, the T<sub>1/2</sub> was 19.1 and 28.9 h for the Holo free-CGL and PEG-CGL, respectively, ensuring the role of PEGylation on shielding the CGL surface from proteolytic attack, reducing its antigenicity, and stabilizing its internal Schiff base. By external infusion of pyridoxal 5′-phosphate (10 µM), the T<sub>1/2</sub> of free- and PEG-CGL was prolonged to 24 and 33 h, respectively, so dissociation of pyridoxal 5′-phosphate was one of the main causes of loss of enzyme activity. The biochemical and hematological responses of rabbits to free- and PEG-CGL were assessed, with relative similarity to the negative control, confirming the nil toxicity of enzymes. The titer of IgG was duplicated in response to free- versus PEG-CGL after 45 days. To the best of our knowledge, this is the first report concerned with purification and PEGylation of CGL from fungi, with higher affinity for L-cystathionine. With further molecular studies, CGL will be a promising enzyme against various cardiovascular diseases and antioxidant deficiency, as well as for generation of a neurotransmitter (H<sub>2</sub>S).
DOI: 10.6084/m9.figshare.5128450
title: Supplementary Material for: TNFAIP2 Inhibits Early TNFa-Induced NF-κB Signaling and Decreases Survival in Septic Shock Patients

description: During septic shock, tumor necrosis factor alpha (TNFa) is an early response gene and induces a plethora of genes and signaling pathways. To identify robust signals in genes reliably upregulated by TNFa, we first measured microarray gene expression in vitro and searched methodologically comparable, publicly available data sets to identify concordant signals. Using tag single-nucleotide polymorphisms in the genes common to all data sets, we identified a genetic variant of the <i>TNFAIP2</i> gene, rs8126, associated with decreased 28-day survival and increased organ dysfunction in an adult cohort in the Vasopressin and Septic Shock Trial. Similar to this cohort, we found that an association with rs8126 and increased organ dysfunction is replicated in a second cohort of septic shock patients in the St. Paul's Hospital Intensive Care Unit. We found that TNFAIP2 inhibits NF-κB activity, impacting the downstream cytokine interleukin (IL)-8. The minor G allele of TNFAIP2 rs8126 resulted in greater TNFAIP2 expression, decreased IL-8 production and was associated with decreased survival in patients experiencing septic shock. These data suggest that TNFAIP2 is a novel inhibitor of NF-κB that acts as an autoinhibitor of the TNFa response during septic shock.
DOI: 10.6084/m9.figshare.5128438
title: Supplementary Material for: A Case Study of Fixed-Effects and Random-Effects Meta-Analysis Models for Genome-Wide Association Studies in Celiac Disease

description: <b><i>Background/Aims:</i></b> Amongst the many approaches to genome-wide association study (GWAS) meta-analysis (MA), the most popular methods are based on fixed-effects (FE) modeling because it tends to be the statistically most powerful approach in the absence of heterogeneity. However, FE-based MA ignores the potential heterogeneity that may exist between studies. The purpose of our analysis was to test whether results from random effects (RE)-based methods that account for heterogeneity differed significantly from the results that were originally published. <b><i>Methods:</i></b> We reanalyzed two GWAS FE-based MAs of celiac disease with RE-based methods: (1) a two-stage GWAS MA that includes 9,451 celiac disease cases and 16,434 controls from 12 collections and (2) a single-stage GWAS MA using a custom dense genotyping platform to capture low-frequency and rare variants in 12,041 cases and 12,228 controls from 7 collections. <b><i>Results:</i></b> We present evidence that SNPs at loci that were previously reported to be genome-wide significant (GWS; p &lt; 5 × 10<sup>-8</sup>) in either the two-stage GWAS MA or the single-stage GWAS MA were not GWS when heterogeneity was accounted for by an RE MA method. <b><i>Conclusion:</i></b> This case study highlights the strengths of RE MA methods in the presence of heterogeneity and of pooled FE methods.
DOI: 10.6084/m9.figshare.5128441
title: Supplementary Material for: Association Study of GWAS-Derived Loci with Height in Brazilian Children: Importance of <b><i>MAP3K3, MMP24</i></b> and <b><i>IGF1R</i></b> Polymorphisms for Height Variation

description: <b><i>Background/Aim:</i></b> The single nucleotide polymorphisms (SNPs) rs2282978 <i>(CDK6)</i>, rs2425019 <i>(MMP24)</i>, rs8081612 <i>(MAP3K3)</i>, rs2871865 <i>(IGF1R)</i> and rs3782415 <i>(SOCS2)</i> were among the SNPs most strongly associated with height in a meta-analysis of 47 genome-wide association studies (GWAS) involving 114,223 adults from six ethnic groups. The present study aimed to examine associations between these SNPs and height in Brazilian children. <b><i>Methods:</i></b> Cross-sectional heights of 1,008 healthy unrelated 4.4- to 9.7-year-old children were evaluated. All genotypes were determined by allele-specific polymerase chain reactions. Height standard deviation scores (SDS) were generated for this population and regressed on allele counts. Linear regressions were performed to estimate the effect of individual SNPs or a polygenic allelic score on height. <b><i>Results:</i></b> The T allele of rs8081612 <i>(MAP3K3)</i>, the C allele of rs2871865 <i>(IGF1R)</i> and the G allele of rs2425019 <i>(MMP24)</i> were significantly associated with a 0.091-SDS greater height (95% CI 0.089-0.093, p = 0.001) by polygenic analysis. The mean height SDS difference between children with 2 ‘tall' alleles and children with 4 ‘tall' alleles was 0.24 SDS (95% CI 0.05-0.43, p = 0.01). The observed allelic effect is consistent with that found in previous GWAS. <b><i>Conclusions:</i></b> Polymorphisms in <i>MAP3K3, MMP24 </i>and<i> IGF1R</i> act additively on height in children of an admixed population. These results demonstrate the importance of these loci for children's height.
DOI: 10.6084/m9.figshare.5128444
title: Supplementary Material for: The Effects of All-Trans Retinoic Acid on the Induction of Oral Tolerance in a Murine Model of Bronchial Asthma

description: <b><i>Background:</i></b> Active suppression induced by regulatory T (Treg) cells is reported to be one of the mechanisms involved in oral tolerance. All-trans retinoic acid (ATRA) has been reported to affect Treg cell differentiation. The present study examined the effects of ATRA on the induction of oral tolerance in a murine model of bronchial asthma. <b><i>Methods:</i></b> BALB/c mice were sensitized to and challenged with ovalbumin (OVA) through feeding followed by OVA challenges. In some study groups ATRA was orally administered concomitantly with OVA feeding either in the presence or absence of the retinoic acid receptor antagonist LE135. Lung CD4<sup>+</sup> T cells were isolated from mice exposed to ATRA and/or OVA, and transferred to control mice. Airway hyperresponsiveness (AHR), cell counts and cytokine levels in bronchoalveolar lavage (BAL) fluid, and lung histology were assessed. <b><i>Results:</i></b> Concomitant administration of ATRA with OVA ameliorated AHR, airway eosinophilia, elevation of cytokines in BAL fluid and goblet cell metaplasia. The proportion of Treg cells in the lungs was increased in mice treated with OVA and ATRA, as compared to those treated with OVA only. Transfer of lung CD4<sup>+</sup> T cells from mice treated with OVA and ATRA induced suppression of AHR and airway inflammation. LE135 completely reversed the effects of ATRA on AHR, airway allergic inflammation and the number of Treg cells in the lungs. <b><i>Conclusion:</i></b> These data suggested that oral administration of ATRA with OVA had the potential to enhance oral tolerance in this murine model of bronchial asthma. These effects were mediated, at least in part, by Treg cell expansion.
DOI: 10.6084/m9.figshare.5128447
title: Supplementary Material for: Inflammation-Induced Expression of the Alarmin Interleukin 33 Can Be Suppressed by Galacto-Oligosaccharides

description: <b><i>Background:</i></b> The alarmin interleukin 33 (IL-33) and its receptor ST2 play an important role in mucosal barrier tissues, and seem to be crucial for Th2-cell mediated host defense. Galacto-oligosaccharides (GOS), used in infant formulas, exhibit gut and immune modulatory effects. To enhance our understanding of the immunomodulatory capacity of GOS, this study investigated the impact of dietary GOS intervention on IL-33 and ST2 expression related to intestinal barrier dysfunction and asthma. <b><i>Methods:</i></b> B6C3F<sub>1</sub> and BALB/c mice were fed a control diet with or without 1% GOS. To simulate intestinal barrier dysfunction, B6C3F<sub>1</sub> mice received a gavage with the mycotoxin deoxynivalenol (DON). To mimic asthma-like inflammatory airway responses, BALB/c mice were sensitized on day 0 and challenged on days 7-11 with house-dust mite (HDM) allergen. Samples from the intestines and lungs were collected for IL-33 and ST2 analysis by qRT-PCR, immunoblotting and immunohistochemistry. <b><i>Results:</i></b> Dietary GOS counteracted the DON-induced IL-33 mRNA expression and changed the IL-33 distribution pattern in the mouse small intestine. The IL-33 mRNA expression was positively correlated to the intestinal permeability. A strong positive correlation was also observed between IL-33 mRNA expression in the lung and the number of bronchoalveolar fluid cells. Reduced levels of IL-33 protein, altered IL-33 distribution and reduced ST2 mRNA expression were observed in the lungs of HDM-allergic mice after GOS intervention. <b><i>Conclusions:</i></b> Dietary GOS mitigated IL-33 at the mucosal surfaces in a murine model for intestinal barrier dysfunction and HDM-induced asthma. This promising effect may open up new avenues to use GOS not only as a prebiotic in infant nutrition, but also as a functional ingredient that targets inflammatory processes and allergies associated with IL-33 expression.
DOI: 10.6084/m9.figshare.5128450.v1
title: Supplementary Material for: TNFAIP2 Inhibits Early TNFa-Induced NF-κB Signaling and Decreases Survival in Septic Shock Patients

description: During septic shock, tumor necrosis factor alpha (TNFa) is an early response gene and induces a plethora of genes and signaling pathways. To identify robust signals in genes reliably upregulated by TNFa, we first measured microarray gene expression in vitro and searched methodologically comparable, publicly available data sets to identify concordant signals. Using tag single-nucleotide polymorphisms in the genes common to all data sets, we identified a genetic variant of the <i>TNFAIP2</i> gene, rs8126, associated with decreased 28-day survival and increased organ dysfunction in an adult cohort in the Vasopressin and Septic Shock Trial. Similar to this cohort, we found that an association with rs8126 and increased organ dysfunction is replicated in a second cohort of septic shock patients in the St. Paul's Hospital Intensive Care Unit. We found that TNFAIP2 inhibits NF-κB activity, impacting the downstream cytokine interleukin (IL)-8. The minor G allele of TNFAIP2 rs8126 resulted in greater TNFAIP2 expression, decreased IL-8 production and was associated with decreased survival in patients experiencing septic shock. These data suggest that TNFAIP2 is a novel inhibitor of NF-κB that acts as an autoinhibitor of the TNFa response during septic shock.
DOI: 10.6084/m9.figshare.5128441.v1
title: Supplementary Material for: Association Study of GWAS-Derived Loci with Height in Brazilian Children: Importance of <b><i>MAP3K3, MMP24</i></b> and <b><i>IGF1R</i></b> Polymorphisms for Height Variation

description: <b><i>Background/Aim:</i></b> The single nucleotide polymorphisms (SNPs) rs2282978 <i>(CDK6)</i>, rs2425019 <i>(MMP24)</i>, rs8081612 <i>(MAP3K3)</i>, rs2871865 <i>(IGF1R)</i> and rs3782415 <i>(SOCS2)</i> were among the SNPs most strongly associated with height in a meta-analysis of 47 genome-wide association studies (GWAS) involving 114,223 adults from six ethnic groups. The present study aimed to examine associations between these SNPs and height in Brazilian children. <b><i>Methods:</i></b> Cross-sectional heights of 1,008 healthy unrelated 4.4- to 9.7-year-old children were evaluated. All genotypes were determined by allele-specific polymerase chain reactions. Height standard deviation scores (SDS) were generated for this population and regressed on allele counts. Linear regressions were performed to estimate the effect of individual SNPs or a polygenic allelic score on height. <b><i>Results:</i></b> The T allele of rs8081612 <i>(MAP3K3)</i>, the C allele of rs2871865 <i>(IGF1R)</i> and the G allele of rs2425019 <i>(MMP24)</i> were significantly associated with a 0.091-SDS greater height (95% CI 0.089-0.093, p = 0.001) by polygenic analysis. The mean height SDS difference between children with 2 ‘tall' alleles and children with 4 ‘tall' alleles was 0.24 SDS (95% CI 0.05-0.43, p = 0.01). The observed allelic effect is consistent with that found in previous GWAS. <b><i>Conclusions:</i></b> Polymorphisms in <i>MAP3K3, MMP24 </i>and<i> IGF1R</i> act additively on height in children of an admixed population. These results demonstrate the importance of these loci for children's height.
DOI: 10.6084/m9.figshare.5128435
title: Supplementary Material for: Patients Tested at a Laboratory for Hereditary Cancer Syndromes Show an Overlap for Multiple Syndromes in Their Personal and Familial Cancer Histories

description: <b><i>Objective:</i></b> Hereditary cancer testing guidelines are based on the premise that the common hereditary cancer syndromes have distinct, recognizable phenotypes. However, many syndromes present with overlapping cancers. The aim of this analysis was to identify the proportion of patients tested for Lynch syndrome (LS) or hereditary breast and ovarian cancer (HBOC) who met testing criteria for the other syndrome. <b><i>Method:</i></b> We analyzed a commercial laboratory database of patients tested for LS and HBOC in a clinical setting from 2006 to 2013. Patient cancer histories were analyzed using the 2012 NCCN criteria for LS and the 2013 NCCN criteria for HBOC. <b><i>Results:</i></b> In all, 7% of the patients tested for HBOC met criteria for LS testing. The majority of these patients had a family history of colorectal (30.9%) and/or endometrial cancer (22.7%). Conversely, 29.5% of the patients tested for LS met criteria for HBOC testing. In this group, 30.5% of the patients had a personal history of breast cancer, and 12.6% had a personal history of ovarian cancer. <b><i>Conclusions:</i></b> Our data demonstrate a substantial phenotypic overlap among patients for multiple common inherited cancer syndromes, which likely complicates diagnosis and test selection. This supports the value of multigene panels to identify pathogenic mutations in the absence of a clinically specific phenotype.
DOI: 10.6084/m9.figshare.5128438.v1
title: Supplementary Material for: A Case Study of Fixed-Effects and Random-Effects Meta-Analysis Models for Genome-Wide Association Studies in Celiac Disease

description: <b><i>Background/Aims:</i></b> Amongst the many approaches to genome-wide association study (GWAS) meta-analysis (MA), the most popular methods are based on fixed-effects (FE) modeling because it tends to be the statistically most powerful approach in the absence of heterogeneity. However, FE-based MA ignores the potential heterogeneity that may exist between studies. The purpose of our analysis was to test whether results from random effects (RE)-based methods that account for heterogeneity differed significantly from the results that were originally published. <b><i>Methods:</i></b> We reanalyzed two GWAS FE-based MAs of celiac disease with RE-based methods: (1) a two-stage GWAS MA that includes 9,451 celiac disease cases and 16,434 controls from 12 collections and (2) a single-stage GWAS MA using a custom dense genotyping platform to capture low-frequency and rare variants in 12,041 cases and 12,228 controls from 7 collections. <b><i>Results:</i></b> We present evidence that SNPs at loci that were previously reported to be genome-wide significant (GWS; p &lt; 5 × 10<sup>-8</sup>) in either the two-stage GWAS MA or the single-stage GWAS MA were not GWS when heterogeneity was accounted for by an RE MA method. <b><i>Conclusion:</i></b> This case study highlights the strengths of RE MA methods in the presence of heterogeneity and of pooled FE methods.