cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5126647
title: Supplementary Material for: Using Gene Genealogies to Detect Rare Variants Associated with Complex Traits

description: <b><i>Background and Objective:</i></b> Standard population genetic theory says that deleterious genetic variants are likely rare and fairly recently introduced. However, can this expectation lead to more powerful tests of association between diseases and rare genetic variation? The gene genealogy describes the relationships between haplotypes sampled from the general population. Although ancestral tree-based methods, inspired by the gene genealogy concept, have been developed for finding associations with common genetic variants, here we ask whether gene genealogies can help in identifying genomic regions containing multiple rare causal variants. <b><i>Methods:</i></b> With data simulated under several demographic models and using known gene genealogies, we developed and compared several tree-based statistics to determine which, if any, could detect the type of clustering expected with rare causal variants and whether the genealogic tree provides additional information about disease associations. <b><i>Results and Conclusions:</i></b> We found that a novel statistic based on the scaled distance between the tips of a tree performed better than other tree-based statistics. When data were simulated with mild population growth, this statistic outperformed two standard non-tree-based methods, showing that an ancestral tree-based approach has potential for rare variant discovery.
DOI: 10.6084/m9.figshare.5126650.v1
title: Supplementary Material for: Cutaneous or Respiratory Exposures to Peanut Allergens in Mice and Their Impacts on Subsequent Oral Exposure

description: <b><i>Background:</i></b> Recent data suggested that non-gastrointestinal exposure can lead to sensitisation to food allergens. We thus assessed the immune impact of respiratory or cutaneous exposure to peanut proteins on non-altered epithelium and investigated the effect of such pre-exposure on subsequent oral administration of peanut. <b><i>Methods:</i></b> BALB/cJ<b> </b>mice were exposed to purified Ara h 1 or to a non-defatted roasted peanut extract (PE) by simple deposit of allergens solutions on non-altered skin or in the nostrils. Exposures were performed 6 times at weekly intervals. Pre-exposed mice then received intra-gastric administrations of PE alone or in the presence of the Th2 mucosal adjuvant cholera toxin (CT). The specific humoral and cellular immune response was assessed throughout the protocol. <b><i>Results:</i></b> Both<b> </b>cutaneous and respiratory exposures led to the production of specific IgG1. Local and systemic IL-5 and IL-13 production were also evidenced, demonstrating activation of specific Th2 cells. This effect was dose-dependent and most efficient via the respiratory route. Moreover, these pre-exposures led to the production of specific IgE antibodies after gavage with PE, whatever the presence of CT. <b><i>Conclusions:</i></b> Cutaneous or respiratory exposures to peanut induce Th2 priming in mice. Moreover, pre-exposures promote further sensitisation via the oral route without the use of CT; this proposes a new adjuvant-free experimental model of sensitisation to food that may reflect a realistic exposure pattern in infants. These results also suggest that non-gastrointestinal peanut exposure should be minimised in high-risk infants, even those with non-altered skin, to potentially reduce allergic sensitisation to this major food allergen.
DOI: 10.6084/m9.figshare.5126656.v1
title: Supplementary Material for: The Impact of a Tumor Diagnosis on Patients' Attitudes toward Advance Directives

description: <b><i>Background:</i></b> Although advance care planning and the completion of advance directives (ADs) are important tools to avoid unwanted aggressive care once patients have lost their decision-making capacity, only a minority of cancer patients are admitted with completed ADs, and little is known about patients' wishes regarding AD consultations. <b><i>Methods:</i></b> For 1 year, every new patient admitted to the hematology/oncology outpatient clinic of the University Hospital Regensburg received a self-administered questionnaire comprising a self-evaluation of AD knowledge and questions about preferences regarding consultation partners and the time of consultation. Disease-related data were collected from medical records. Statistics were calculated with SPSS. <b><i>Results:</i></b> Of the 500 questionnaires handed out, 394 (75%) were evaluable and analyzed. Twenty-eight percent of the participants had completed an AD (living will or health care proxy). Ninety-two percent of the participants without ADs had never received a consultation offer from any professional involved. Only 20% perceived a clear relation between cancer and AD consultations. More than 50% of the participants without ADs were in favor of consultations ‘now' or ‘in a few weeks', while more than 40% objected to AD consultations. <b><i>Conclusions:</i></b> Oncology patients have a large unmet demand for AD consultations. However, a relevant percentage of these patients object to AD consultations. Structured and early AD consultation offers should be made, and early discussions about indications for aggressive treatment should take place.
DOI: 10.6084/m9.figshare.5126641
title: Supplementary Material for: Meta-Analyses of the Effect of <b><i>CYP1A1</i></b> and <b><i>CYP2D6</i></b> Polymorphisms on the Risk of Head and Neck Squamous Cell Carcinoma

description: <b><i>Background: </i></b><i>CYP1A1</i> and <i>CYP2D6</i> are important genes encoding enzymes involved in the metabolism of toxic chemicals and carcinogens. However, inconclusive results for the association between <i>CYP1A1</i> and <i>CYP2D6</i> polymorphisms and the risk of head and neck squamous cell carcinoma (HNSCC) have been reported. We conducted a meta-analysis to evaluate the association of <i>CYP1A1</i> and <i>CYP2D6</i> polymorphisms with the risk of HNSCC. <b><i>Methods: </i></b>A database search yielded 19 relevant studies. 3 polymorphisms were included in the meta-analysis: <i>CYP1A1</i>, <i>CYP2D6*4</i> and <i>CYP2D6*10</i>. Random or fixed effect models were used in the analysis. <b><i>Results: </i></b>The <i>CYP1A1</i> polymorphism was associated with HNSCC (for m1m1 vs. m1m2: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.030-1.542, p<sub>heterogeneity</sub> = 0.025; for the recessive model: OR = 1.316, 95% CI = 1.065-1.625, p<sub>heterogeneity</sub> = 0.001). The analysis showed evidence for association between the <i>CYP2D6*4</i> polymorphism and HNSCC in Asian populations; however, negative results were also observed in other models. A significant association was also observed between <i>CYP2D6*10</i> polymorphism and HNSCC risk. <b><i>Conclusions: </i></b>The current study demonstrates that the <i>CYP1A1</i> and CYP2D6 polymorphisms are associated with susceptibility to both development and progression of HNSCC.
DOI: 10.6084/m9.figshare.5126644
title: Supplementary Material for: Sorafenib in the Treatment of Early Breast Cancer: Results of the Neoadjuvant Phase II Study - SOFIA*

description: <b><i>Background: </i></b>Sorafenib was tested for neoadjuvant treatment with an anthracycline/taxane-based chemotherapy in the open-label, multicentre, single-arm phase II study, ‘SOFIA'. <b><i>Patients and Methods: </i></b>Inclusion criteria were: HER2 negative, cT3, cT4 or cT2 cN+, M0 primary breast cancer. Patients received 4 × epirubicin 90 mg/m<sup>2</sup> and cyclophosphamide 600 mg/m<sup>2</sup> (EC) intravenously (i.v.) in 3-weekly cycles followed or preceded by 12 weeks of paclitaxel (Pw) 80 mg/m<sup>2</sup>. In cohort 1, sorafenib started at 800 mg daily with chemotherapy. An initial daily sorafenib dose of 200 mg was escalated, based on individual toxicities, every 3 weeks in cohort 2 (starting with EC) and every 2 weeks in cohort 3 (starting with Pw). The primary objective was to identify the most feasible regimen; secondary objectives were safety, pathological complete response (pCR) at surgery and pharmacokinetics. <b><i>Results: </i></b>Of the 36 recruited patients, 7/12 patients completed the study in cohort 1 and 24/24 patients in cohorts 2 and 3. The median cumulative sorafenib dose per patient was 37%, 65% and 46% in cohorts 1, 2 and 3, respectively. The main grade 3-4 toxicities were neutropenia and hand-foot syndrome. The pCR (ypT0/is) rate was 27.7%. No pharmacokinetic interaction was observed between sorafenib and epirubicin. <b><i>Conclusion: </i></b>Sorafenib EC-Pw is feasible if the starting dose is 200 mg, escalated every 3 weeks based on the patients' individual toxicities.
DOI: 10.6084/m9.figshare.5126635
title: Supplementary Material for: Pharmacokinetics and Pharmacodynamics following Intravenous Administration of Recombinant Human Hepatocyte Growth Factor in Rats with Renal Injury

description: <b><i>Background/Aim:</i></b> Hepatocyte growth factor (HGF) plays a role in the regeneration and protection of the kidney, but little information is available concerning the pharmacokinetics of therapeutic treatment with HGF. In this study, HGF was administered after the onset of renal injury, and pharmacokinetic analysis was performed simultaneously with an efficacious dose. <b><i>Methods:</i></b> For the study of pharmacodynamics, recombinant human HGF was intravenously administered to rats with glycerol-induced acute kidney injury (AKI). In the pharmacokinetic study, rats subjected to glycerol injection or renal ischemia-reperfusion were used as models of AKI, and rats subjected to 5/6 nephrectomy were used as models of chronic kidney disease (CKD). <b><i>Results:</i></b> After intravenous administration of HGF at doses of 0.5-2.0 mg/kg, the elevation of blood urea nitrogen was suppressed, indicating that HGF had a pharmacodynamic effect. However, no significant difference was seen in the pharmacokinetic parameters such as clearance, distribution volume and half-life between the normal, AKI and CKD groups. <b><i>Conclusion:</i></b> The intravenous administration of HGF after the onset of renal dysfunction exerted a pharmacological effect on AKI, and renal injury did not affect the clearance of plasma HGF. This unaffected profile may serve as a base for the safety of HGF during therapeutic administration.
DOI: 10.6084/m9.figshare.5126638
title: Supplementary Material for: Snoring Amplifies the Risk of Heart Failure and Mortality in Dialysis Patients

description: <b><i>Background:</i></b> Snoring, an indicator of sleep-disordered breathing (SDB), associates with all-cause and cardiovascular (CV) mortality in high-risk conditions such as chronic heart failure (HF). Because SDB and HF are exceedingly frequent in end-stage kidney disease (ESKD), we hypothesized that SDB as detected by snoring may impact upon the relationship between chronic HF and all-cause and CV mortality in these patients. <b><i>Methods:</i></b> We tested this hypothesis in a cohort of 827 ESKD patients, followed up for 2.3 years. <b><i>Results:</i></b> In this population, snoring was a strong modifier of the risk of chronic HF for all-cause and CV death. In fully adjusted Cox models, the hazard ratio (HR) associated to chronic HF for the study outcomes was highest in heavy snorers [all-cause death: HR 2.6 (95% CI 1.6-4.3, p &lt; 0.001); CV death: HR 4.0 (95% CI 2.1-7.6, p &lt; 0.001)], intermediate in moderate snorers [all-cause death: HR 1.6 (95% CI 1.1-2.2, p = 0.01); CV death: HR 1.8 (95% CI 1.2-2.8, p = 0.01)], and lowest and not significant in non-snorers [all-cause death: HR 0.9 (95% CI 0.6-1.6, p = NS); CV death: HR 0.8 (95% CI 0.4-1.6, p = NS)]. <b><i>Conclusions:</i></b> Snoring is a strong and independent effect modifier of the relationship between chronic HF and all-cause and CV mortality in ESKD. Since SDB and snoring are in part attributable to reversible pharyngeal oedema, intensified surveillance and treatment of chronic HF snorers on dialysis may translate into better clinical outcomes in this very high-risk population, an issue which remains to be tested in specifically designed clinical trials.
DOI: 10.6084/m9.figshare.5126647.v1
title: Supplementary Material for: Using Gene Genealogies to Detect Rare Variants Associated with Complex Traits

description: <b><i>Background and Objective:</i></b> Standard population genetic theory says that deleterious genetic variants are likely rare and fairly recently introduced. However, can this expectation lead to more powerful tests of association between diseases and rare genetic variation? The gene genealogy describes the relationships between haplotypes sampled from the general population. Although ancestral tree-based methods, inspired by the gene genealogy concept, have been developed for finding associations with common genetic variants, here we ask whether gene genealogies can help in identifying genomic regions containing multiple rare causal variants. <b><i>Methods:</i></b> With data simulated under several demographic models and using known gene genealogies, we developed and compared several tree-based statistics to determine which, if any, could detect the type of clustering expected with rare causal variants and whether the genealogic tree provides additional information about disease associations. <b><i>Results and Conclusions:</i></b> We found that a novel statistic based on the scaled distance between the tips of a tree performed better than other tree-based statistics. When data were simulated with mild population growth, this statistic outperformed two standard non-tree-based methods, showing that an ancestral tree-based approach has potential for rare variant discovery.
DOI: 10.6084/m9.figshare.5126632
title: Supplementary Material for: Association of Common Genetic Variants with Diabetes and Metabolic Syndrome Related Traits in the Arizona Insulin Resistance Registry: A Focus on Mexican American Families in the Southwest

description: <b><i>Background/Aims:</i></b> The increased occurrence of type 2 diabetes and its clinical correlates is a global public health issue, and there are continued efforts to find its genetic determinant across ethnically diverse populations. The aims of this study were to determine the heritability of diabetes and metabolic syndrome phenotypes in the Arizona Insulin Resistance (AIR) registry and to perform an association analysis of common single nucleotide polymorphisms (SNPs) identified by GWAS with these traits. All study participants were Mexican Americans from the AIR registry. <b><i>Methods:</i></b> Metabolic, anthropometric, demographic and medical history information was obtained on the 667 individuals enrolled in the registry. <b><i>Results:</i></b> The heritability estimates were moderate to high in magnitude and significant, indicating that the AIR registry is well suited for the identification of genetic factors contributing to diabetes and the metabolic syndrome. From the 30 GWAS genes selected (some genes were represented by multiple SNPs), 20 SNPs exhibited associations with one or more of the diabetes related traits with nominal significance (p ≤ 0.05). In addition, 25 SNPs were nominally significantly associated with one or more of the metabolic phenotypes tested (p ≤ 0.05). Most notably, 5 SNPs from 5 genes [body mass index (BMI), hip circumference: rs3751812/FTO; fasting plasma glucose, hemoglobin A1c: rs4607517/GCK; very-low-density lipoprotein: rs10830963/MTNR1B; BMI: rs13266634/SLC30A8, and total cholesterol, low-density lipoprotein: rs7578597/THADA] were significantly associated with obesity, glycemic, and lipid phenotypes when using the multiple testing significance threshold of 0.0015. <b><i>Conclusion:</i></b> These findings extend previous work on Mexican Americans to suggest that metabolic disease is strongly influenced by genetic background in this high-risk population.
DOI: 10.6084/m9.figshare.5126632.v1
title: Supplementary Material for: Association of Common Genetic Variants with Diabetes and Metabolic Syndrome Related Traits in the Arizona Insulin Resistance Registry: A Focus on Mexican American Families in the Southwest

description: <b><i>Background/Aims:</i></b> The increased occurrence of type 2 diabetes and its clinical correlates is a global public health issue, and there are continued efforts to find its genetic determinant across ethnically diverse populations. The aims of this study were to determine the heritability of diabetes and metabolic syndrome phenotypes in the Arizona Insulin Resistance (AIR) registry and to perform an association analysis of common single nucleotide polymorphisms (SNPs) identified by GWAS with these traits. All study participants were Mexican Americans from the AIR registry. <b><i>Methods:</i></b> Metabolic, anthropometric, demographic and medical history information was obtained on the 667 individuals enrolled in the registry. <b><i>Results:</i></b> The heritability estimates were moderate to high in magnitude and significant, indicating that the AIR registry is well suited for the identification of genetic factors contributing to diabetes and the metabolic syndrome. From the 30 GWAS genes selected (some genes were represented by multiple SNPs), 20 SNPs exhibited associations with one or more of the diabetes related traits with nominal significance (p ≤ 0.05). In addition, 25 SNPs were nominally significantly associated with one or more of the metabolic phenotypes tested (p ≤ 0.05). Most notably, 5 SNPs from 5 genes [body mass index (BMI), hip circumference: rs3751812/FTO; fasting plasma glucose, hemoglobin A1c: rs4607517/GCK; very-low-density lipoprotein: rs10830963/MTNR1B; BMI: rs13266634/SLC30A8, and total cholesterol, low-density lipoprotein: rs7578597/THADA] were significantly associated with obesity, glycemic, and lipid phenotypes when using the multiple testing significance threshold of 0.0015. <b><i>Conclusion:</i></b> These findings extend previous work on Mexican Americans to suggest that metabolic disease is strongly influenced by genetic background in this high-risk population.
DOI: 10.6084/m9.figshare.5126638.v1
title: Supplementary Material for: Snoring Amplifies the Risk of Heart Failure and Mortality in Dialysis Patients

description: <b><i>Background:</i></b> Snoring, an indicator of sleep-disordered breathing (SDB), associates with all-cause and cardiovascular (CV) mortality in high-risk conditions such as chronic heart failure (HF). Because SDB and HF are exceedingly frequent in end-stage kidney disease (ESKD), we hypothesized that SDB as detected by snoring may impact upon the relationship between chronic HF and all-cause and CV mortality in these patients. <b><i>Methods:</i></b> We tested this hypothesis in a cohort of 827 ESKD patients, followed up for 2.3 years. <b><i>Results:</i></b> In this population, snoring was a strong modifier of the risk of chronic HF for all-cause and CV death. In fully adjusted Cox models, the hazard ratio (HR) associated to chronic HF for the study outcomes was highest in heavy snorers [all-cause death: HR 2.6 (95% CI 1.6-4.3, p &lt; 0.001); CV death: HR 4.0 (95% CI 2.1-7.6, p &lt; 0.001)], intermediate in moderate snorers [all-cause death: HR 1.6 (95% CI 1.1-2.2, p = 0.01); CV death: HR 1.8 (95% CI 1.2-2.8, p = 0.01)], and lowest and not significant in non-snorers [all-cause death: HR 0.9 (95% CI 0.6-1.6, p = NS); CV death: HR 0.8 (95% CI 0.4-1.6, p = NS)]. <b><i>Conclusions:</i></b> Snoring is a strong and independent effect modifier of the relationship between chronic HF and all-cause and CV mortality in ESKD. Since SDB and snoring are in part attributable to reversible pharyngeal oedema, intensified surveillance and treatment of chronic HF snorers on dialysis may translate into better clinical outcomes in this very high-risk population, an issue which remains to be tested in specifically designed clinical trials.
DOI: 10.6084/m9.figshare.5126644.v1
title: Supplementary Material for: Sorafenib in the Treatment of Early Breast Cancer: Results of the Neoadjuvant Phase II Study - SOFIA*

description: <b><i>Background: </i></b>Sorafenib was tested for neoadjuvant treatment with an anthracycline/taxane-based chemotherapy in the open-label, multicentre, single-arm phase II study, ‘SOFIA'. <b><i>Patients and Methods: </i></b>Inclusion criteria were: HER2 negative, cT3, cT4 or cT2 cN+, M0 primary breast cancer. Patients received 4 × epirubicin 90 mg/m<sup>2</sup> and cyclophosphamide 600 mg/m<sup>2</sup> (EC) intravenously (i.v.) in 3-weekly cycles followed or preceded by 12 weeks of paclitaxel (Pw) 80 mg/m<sup>2</sup>. In cohort 1, sorafenib started at 800 mg daily with chemotherapy. An initial daily sorafenib dose of 200 mg was escalated, based on individual toxicities, every 3 weeks in cohort 2 (starting with EC) and every 2 weeks in cohort 3 (starting with Pw). The primary objective was to identify the most feasible regimen; secondary objectives were safety, pathological complete response (pCR) at surgery and pharmacokinetics. <b><i>Results: </i></b>Of the 36 recruited patients, 7/12 patients completed the study in cohort 1 and 24/24 patients in cohorts 2 and 3. The median cumulative sorafenib dose per patient was 37%, 65% and 46% in cohorts 1, 2 and 3, respectively. The main grade 3-4 toxicities were neutropenia and hand-foot syndrome. The pCR (ypT0/is) rate was 27.7%. No pharmacokinetic interaction was observed between sorafenib and epirubicin. <b><i>Conclusion: </i></b>Sorafenib EC-Pw is feasible if the starting dose is 200 mg, escalated every 3 weeks based on the patients' individual toxicities.
DOI: 10.6084/m9.figshare.5126620
title: Supplementary Material for: Nephrectomy in Autosomal Dominant Polycystic Kidney Disease: A Patient with Exceptionally Large, Still Functioning Kidneys

description: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is characterized by progressive cyst formation in both kidneys, often leading to end-stage kidney disease. Indications for surgical removal of an ADPKD kidney include intractable pain, hematuria, infection, or exceptional enlargement and small abdominal cavity hampering implantation of a donor kidney. We report the case of an extraordinarily large ADPKD kidney weighing 8.7 kg (19.3 lb) with a maximal length of 48 cm (19 inch), and with cysts filled with both clear and bloody fluid.