cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5127673.v1
title: Supplementary Material for: Public Perceptions of Disease Severity but Not Actionability Correlate with Interest in Receiving Genomic Results: Nonalignment with Current Trends in Practice

description: <b><i>Purpose:</i></b> Frameworks highlighting disease actionability and severity are evolving to address the need to organize results from genome-wide analyses. This approach represents a paradigm shift from consultations focused on one or more genes to multiple genes for multiple disorders. Empirical input from the general population is lacking, yet seems essential for understanding how to maximize patient autonomy and satisfaction in the decision-making process. <b><i>Methods:</i></b> We conducted a cross-sectional online survey with a representative sample of 900 US adults and assessed the participants' perceptions and attitudes toward disease actionability and severity, ranking hypothetical scenarios for these properties, and explored correlations with interest in learning test results. <b><i>Results:</i></b> Most respondents (&gt;85%) rated actionability and severity as useful concepts; 46.6% indicated actionability alone would be adequate for decision making. Over half of them (53.8%) reported being very/extremely confident in their ability to score for actionability and severity. The participants' scoring of medical scenarios varied significantly between individuals. Scores for severity but not actionability were correlated with interest in learning genetic results. Subsets of the respondents projected wanting all results (30%) or no results (16%). The use of expert-created lists was acceptable to 43%. <b><i>Conclusions:</i></b> The respondents from the general population were confident in making their own decisions. The responses suggested different priorities than current expert-driven approaches. The emphasis on binning genes may be missing a complementary, simplifying approach of grouping patients based upon their all/none interest in genomic results. This study illuminates important differences between the general public and genetic experts.
DOI: 10.6084/m9.figshare.5127652
title: Supplementary Material for: The Role of Rare Variants in Systolic Blood Pressure: Analysis of ExomeChip Data in HyperGEN African Americans

description: Cardiovascular diseases are among the most significant health problems in the United States today, with their major risk factor, hypertension, disproportionately affecting African Americans (AAs). Although GWAS have identified dozens of common variants associated with blood pressure (BP) and hypertension in European Americans, these variants collectively explain &lt;2.5% of BP variance, and most of the genetic variants remain yet to be identified. Here, we report the results from rare-variant analysis of systolic BP using 94,595 rare and low-frequency variants (minor allele frequency, MAF, &lt;5%) from the Illumina exome array genotyped in 2,045 HyperGEN AAs. In addition to single-variant analysis, 4 gene-level association tests were used for analysis: burden and family-based SKAT tests using MAF cutoffs of 1 and 5%. The gene-based methods often provided lower p values than the single-variant approach. Some consistency was observed across these 4 gene-based analysis options. While neither the gene-based analyses nor the single-variant analysis produced genome-wide significant results, the top signals, which had supporting evidence from multiple gene-based methods, were of borderline significance. Though additional molecular validations are required, 6 of the 16 most promising genes are biologically plausible with physiological connections to BP regulation.
DOI: 10.6084/m9.figshare.5127658
title: Supplementary Material for: Relationship between Treatment Effects on Progression-Free Survival and Overall Survival in Multiple Myeloma: A Systematic Review and Meta-Analysis of Published Clinical Trial Data

description: <b><i>Background:</i></b> Demonstrating improved overall survival (OS) with new multiple myeloma (MM) treatments is becoming difficult because of extended survival, so progression-free survival (PFS) is commonly used as a surrogate endpoint for OS. We evaluated PFS as a potential surrogate for OS by examining whether observed treatment effects on PFS are positively associated with treatment effects on OS in MM. <b><i>Methods:</i></b> A systematic literature review identified 21 randomized control trials reporting hazard ratios (HRs) for treatment effects on PFS and OS. Pearson's r estimated the relationship between HRs (HR<sub>PFS</sub> and HR<sub>OS</sub>), and between log-transformed HRs (log(HR<sub>PFS</sub>) and log(HR<sub>OS</sub>)). R<sup>2</sup> values were estimated from linear regression models of the HR and the log(HR) relationships. Sensitivity and subgroup analyses examined the robustness of the HR findings. <b><i>Results:</i></b> Positive correlations were found between HR<sub>PFS</sub> and HR<sub>OS</sub> (r = 0.82; p &lt; 0.0001) and between log(HR<sub>PFS</sub>) and log(HR<sub>OS</sub>) (r = 0.80; p &lt; 0.0001). Linear regression models produced R<sup>2</sup> values of 0.67 and 0.63 when regressing HR<sub>OS</sub> on HR<sub>PFS</sub>, and log(HR<sub>OS</sub>) on log(HR<sub>PFS</sub>), respectively. Sensitivity analyses supported the HR findings. <b><i>Conclusion:</i></b> This analysis provides evidence for a positive association between treatment effects on PFS and OS. Studies involving patient level data are necessary to confirm whether PFS is a valid surrogate for OS in MM.
DOI: 10.6084/m9.figshare.5127661
title: Supplementary Material for: Determinants of Platelet-Leukocyte Aggregation and Platelet Activation in Stroke

description: <b><i>Background:</i></b> Platelet-leukocyte aggregation (PLA) and platelet activation are found to be on the higher side in ischemic stroke patients. The correlation of PLA with clinical features has not been intensively investigated and the influence of genetic factors on PLA is still unexplored. The interaction of platelets with leukocytes is mainly determined by the proteins encoded by six genes: P-Selectin (<i>SELP </i>encodes CD62P) on the thrombocyte binding to P-Selectin-Glycoprotein-Ligand-1 <i>(PSGL1)</i> on the leukocyte, intracellular-adhesion-molecule 2 <i>(ICAM2)</i> interacting with Integrin alpha M (<i>ITGAM</i>) and Glycoprotein 1b-alpha <i>(GP1BA)</i> binding to Integrin alpha L <i>(ITGAL)</i>. <b><i>Methods:</i></b> Seventy-nine patients with acute ischemic stroke and 151 controls without vascular disease from a single German center were enrolled. A neurologist and a neuroradiologist ascertained clinical and radiological features. PLA and platelet activation were analyzed using flow cytometry with various antibodies. Coding as well as tagging SNPs in six genes determining PLA were genotyped. Three groups of parameters were correlated with each other: (i) clinical and radiological parameters, (ii) laboratory parameters, (iii) genetic parameters. For the comparisons, robust nonparametric statistical tests were applicable. <b><i>Results:</i></b> PLA and platelet activation were higher in ischemic stroke patients compared to controls. Both, anticoagulant and antiplatelet treatment in the patient group affected platelet activation but not PLA. PLA correlated weakly with measures of stroke severity but not with thrombus length or stroke etiology. The association of SNP rs2228315 in the P-Selectin Glycoprotein Ligand-1-gene (PSGL1) with ischemic stroke and platelet activation was significant before correction for multiple testing while a trend was observed for the association with PLA. Regression analysis revealed that (i) platelet activation was an independent determinant of stroke, (ii) that PLA correlated with stroke, sex, age and platelet activation and (iii) that platelet activation correlated only with stroke. None of the SNPs survived in the regression analysis for stroke, PLA or platelet activation as dependent variables. <b><i>Conclusions:</i></b> The most important result of our study is that PLA and platelet activation are independent of other vascular risk factors correlated with stroke in our sample. In addition, we identified the missense SNP rs2228315 in the <i>PSGL1</i>-gene as a candidate polymorphism for ischemic stroke-related PLA. Association between this SNP and stroke as well as coronary artery disease has also been shown by two other studies.
DOI: 10.6084/m9.figshare.5127652.v1
title: Supplementary Material for: The Role of Rare Variants in Systolic Blood Pressure: Analysis of ExomeChip Data in HyperGEN African Americans

description: Cardiovascular diseases are among the most significant health problems in the United States today, with their major risk factor, hypertension, disproportionately affecting African Americans (AAs). Although GWAS have identified dozens of common variants associated with blood pressure (BP) and hypertension in European Americans, these variants collectively explain &lt;2.5% of BP variance, and most of the genetic variants remain yet to be identified. Here, we report the results from rare-variant analysis of systolic BP using 94,595 rare and low-frequency variants (minor allele frequency, MAF, &lt;5%) from the Illumina exome array genotyped in 2,045 HyperGEN AAs. In addition to single-variant analysis, 4 gene-level association tests were used for analysis: burden and family-based SKAT tests using MAF cutoffs of 1 and 5%. The gene-based methods often provided lower p values than the single-variant approach. Some consistency was observed across these 4 gene-based analysis options. While neither the gene-based analyses nor the single-variant analysis produced genome-wide significant results, the top signals, which had supporting evidence from multiple gene-based methods, were of borderline significance. Though additional molecular validations are required, 6 of the 16 most promising genes are biologically plausible with physiological connections to BP regulation.
DOI: 10.6084/m9.figshare.5127655
title: Supplementary Material for: Postoperative Intensity-Modulated Radiotherapy Improved Survival in Lymph Node-Positive or Stage III Thoracic Esophageal Squamous Cell Carcinoma

description: <b><i>Background:</i></b> The aim of this study was to retrospectively analyze the effect of postoperative intensity-modulated radiotherapy (IMRT) on recurrence and survival in lymph node-positive or stage III thoracic esophageal squamous cell carcinoma (TESCC) patients, and evaluate its role in TESCC therapy. <b><i>Methods:</i></b> We enrolled 538 patients who underwent radical resection with (S + R) or without (S) postoperative IMRT. The median total postoperative IMRT dose was 60 Gy. The Kaplan-Meier method, log-rank test, and chi-square test were used for survival rate calculation, univariate analysis, and sites of failure analysis, respectively. <b><i>Results:</i></b> The 5-year overall survival (OS) and disease-free survival rates were 32.7 and 27.3%, respectively. The 5-year OS rates of lymph node-positive S and S + R patients were 28.4 and 38.8%, respectively (p &lt; 0.001). The 5-year OS rates of stage III S and S + R patients were 24.0 and 38.0%, respectively (p = 0.001). Postoperative IMRT resulted in significantly decreased intrathoracic and supraclavicular recurrence, and obviously delayed median local recurrence and systemic metastases. Systemic metastases increased following postoperative IMRT. <b><i>Conclusion:</i></b> Postoperative IMRT reduces local recurrence and improves survival in lymph node-positive or stage III TESCC patients, providing a rationale for selection criteria for postoperative IMRT in TESCC.
DOI: 10.6084/m9.figshare.5127658.v1
title: Supplementary Material for: Relationship between Treatment Effects on Progression-Free Survival and Overall Survival in Multiple Myeloma: A Systematic Review and Meta-Analysis of Published Clinical Trial Data

description: <b><i>Background:</i></b> Demonstrating improved overall survival (OS) with new multiple myeloma (MM) treatments is becoming difficult because of extended survival, so progression-free survival (PFS) is commonly used as a surrogate endpoint for OS. We evaluated PFS as a potential surrogate for OS by examining whether observed treatment effects on PFS are positively associated with treatment effects on OS in MM. <b><i>Methods:</i></b> A systematic literature review identified 21 randomized control trials reporting hazard ratios (HRs) for treatment effects on PFS and OS. Pearson's r estimated the relationship between HRs (HR<sub>PFS</sub> and HR<sub>OS</sub>), and between log-transformed HRs (log(HR<sub>PFS</sub>) and log(HR<sub>OS</sub>)). R<sup>2</sup> values were estimated from linear regression models of the HR and the log(HR) relationships. Sensitivity and subgroup analyses examined the robustness of the HR findings. <b><i>Results:</i></b> Positive correlations were found between HR<sub>PFS</sub> and HR<sub>OS</sub> (r = 0.82; p &lt; 0.0001) and between log(HR<sub>PFS</sub>) and log(HR<sub>OS</sub>) (r = 0.80; p &lt; 0.0001). Linear regression models produced R<sup>2</sup> values of 0.67 and 0.63 when regressing HR<sub>OS</sub> on HR<sub>PFS</sub>, and log(HR<sub>OS</sub>) on log(HR<sub>PFS</sub>), respectively. Sensitivity analyses supported the HR findings. <b><i>Conclusion:</i></b> This analysis provides evidence for a positive association between treatment effects on PFS and OS. Studies involving patient level data are necessary to confirm whether PFS is a valid surrogate for OS in MM.
DOI: 10.6084/m9.figshare.5127646
title: Supplementary Material for: A Search for Ribonucleic Antiterminator Sites in Bacterial Genomes: Not Only Antitermination

description: BglG/LicT-like proteins are transcriptional antiterminators that prevent termination of transcription at intrinsic terminators by binding to ribonucleic antiterminator (RAT) sites and stabilizing an RNA conformation which is mutually exclusive with the terminator structure. The known RAT sites, which are located in intergenic regions of sugar utilization operons, show low sequence conservation but significant structural analogy. To assess the prevalence of RATs in bacterial genomes, we employed bioinformatic tools that describe RNA motifs based on both sequence and structural constraints. Using descriptors with different stringency, we searched the genomes of <i>Escherichia</i><i>coli</i> K12, uropathogenic <i>E. coli</i> and <i>Bacillus subtilis</i> for putative RATs. Our search identified all known RATs and additional putative RAT elements. Surprisingly, most putative RATs do not overlap an intrinsic terminator and many reside within open reading frames (ORFs). The ability of one of the putative RATs, which is located within an antiterminator-encoding ORF and does not overlap a terminator, to bind to its cognate antiterminator protein in vitro and in vivo was confirmed experimentally. Our results suggest that the capacity of RAT elements has been exploited during evolution to mediate activities other than antitermination, for example control of transcription elongation or of RNA stability.
DOI: 10.6084/m9.figshare.5127655.v1
title: Supplementary Material for: Postoperative Intensity-Modulated Radiotherapy Improved Survival in Lymph Node-Positive or Stage III Thoracic Esophageal Squamous Cell Carcinoma

description: <b><i>Background:</i></b> The aim of this study was to retrospectively analyze the effect of postoperative intensity-modulated radiotherapy (IMRT) on recurrence and survival in lymph node-positive or stage III thoracic esophageal squamous cell carcinoma (TESCC) patients, and evaluate its role in TESCC therapy. <b><i>Methods:</i></b> We enrolled 538 patients who underwent radical resection with (S + R) or without (S) postoperative IMRT. The median total postoperative IMRT dose was 60 Gy. The Kaplan-Meier method, log-rank test, and chi-square test were used for survival rate calculation, univariate analysis, and sites of failure analysis, respectively. <b><i>Results:</i></b> The 5-year overall survival (OS) and disease-free survival rates were 32.7 and 27.3%, respectively. The 5-year OS rates of lymph node-positive S and S + R patients were 28.4 and 38.8%, respectively (p &lt; 0.001). The 5-year OS rates of stage III S and S + R patients were 24.0 and 38.0%, respectively (p = 0.001). Postoperative IMRT resulted in significantly decreased intrathoracic and supraclavicular recurrence, and obviously delayed median local recurrence and systemic metastases. Systemic metastases increased following postoperative IMRT. <b><i>Conclusion:</i></b> Postoperative IMRT reduces local recurrence and improves survival in lymph node-positive or stage III TESCC patients, providing a rationale for selection criteria for postoperative IMRT in TESCC.
DOI: 10.6084/m9.figshare.5127661.v1
title: Supplementary Material for: Determinants of Platelet-Leukocyte Aggregation and Platelet Activation in Stroke

description: <b><i>Background:</i></b> Platelet-leukocyte aggregation (PLA) and platelet activation are found to be on the higher side in ischemic stroke patients. The correlation of PLA with clinical features has not been intensively investigated and the influence of genetic factors on PLA is still unexplored. The interaction of platelets with leukocytes is mainly determined by the proteins encoded by six genes: P-Selectin (<i>SELP </i>encodes CD62P) on the thrombocyte binding to P-Selectin-Glycoprotein-Ligand-1 <i>(PSGL1)</i> on the leukocyte, intracellular-adhesion-molecule 2 <i>(ICAM2)</i> interacting with Integrin alpha M (<i>ITGAM</i>) and Glycoprotein 1b-alpha <i>(GP1BA)</i> binding to Integrin alpha L <i>(ITGAL)</i>. <b><i>Methods:</i></b> Seventy-nine patients with acute ischemic stroke and 151 controls without vascular disease from a single German center were enrolled. A neurologist and a neuroradiologist ascertained clinical and radiological features. PLA and platelet activation were analyzed using flow cytometry with various antibodies. Coding as well as tagging SNPs in six genes determining PLA were genotyped. Three groups of parameters were correlated with each other: (i) clinical and radiological parameters, (ii) laboratory parameters, (iii) genetic parameters. For the comparisons, robust nonparametric statistical tests were applicable. <b><i>Results:</i></b> PLA and platelet activation were higher in ischemic stroke patients compared to controls. Both, anticoagulant and antiplatelet treatment in the patient group affected platelet activation but not PLA. PLA correlated weakly with measures of stroke severity but not with thrombus length or stroke etiology. The association of SNP rs2228315 in the P-Selectin Glycoprotein Ligand-1-gene (PSGL1) with ischemic stroke and platelet activation was significant before correction for multiple testing while a trend was observed for the association with PLA. Regression analysis revealed that (i) platelet activation was an independent determinant of stroke, (ii) that PLA correlated with stroke, sex, age and platelet activation and (iii) that platelet activation correlated only with stroke. None of the SNPs survived in the regression analysis for stroke, PLA or platelet activation as dependent variables. <b><i>Conclusions:</i></b> The most important result of our study is that PLA and platelet activation are independent of other vascular risk factors correlated with stroke in our sample. In addition, we identified the missense SNP rs2228315 in the <i>PSGL1</i>-gene as a candidate polymorphism for ischemic stroke-related PLA. Association between this SNP and stroke as well as coronary artery disease has also been shown by two other studies.
DOI: 10.6084/m9.figshare.5127643
title: Supplementary Material for: Extracorporeal Virus Elimination for the Treatment of Severe Ebola Virus Disease - First Experience with Lectin Affinity Plasmapheresis

description: Therapeutic options for Ebola virus disease (EVD) are currently limited to (1) best supportive care, and (2) evolving virus-specific therapies, resulting from decades of analyzing one of the world's deadliest diseases. Supportive care ranges from oral or intravenous rehydration therapy and anti-emetics in developing countries to much more extensive life-support interventions in resource-rich countries. Current EVD-specific therapies attempt to either interfere with the earliest steps of viral replication or to elicit a strong immune response against the virus. An entirely new approach is the extracorporeal elimination of viruses and viral glycoproteins by lectin affinity plasmapheresis. Herein, we report for the first time the successful and safe use of lectin affinity plasmapheresis in a patient with severe Ebola virus disease.
DOI: 10.6084/m9.figshare.5127649
title: Supplementary Material for: The Serine Protease Inhibitor Camostat Mesilate Attenuates the Progression of Chronic Kidney Disease through its Antioxidant Effects

description: <b><i>Background/Aims:</i></b> We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model. <b><i>Methods:</i></b> In <i>protocol 1</i>, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In <i>protocol 2</i>, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy. <b><i>Results:</i></b> CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the <i>protocol 2</i>, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro. <b><i>Conclusion:</i></b> Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.