cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.1569145.v3
title: Integrative analysis of methylome and transcriptome in human blood identifies extensive sex- and immune cell-specific differentially methylated regions

description: The relationship between DNA methylation and gene expression is complex and elusive. To further elucidate these relations, we performed an integrative analysis of the methylome and transcriptome of 4 circulating immune cell subsets (B cells, monocytes, CD4<sup>+</sup>, and CD8<sup>+</sup> T cells) from healthy females. Additionally, in light of the known sex bias in the prevalence of several immune-mediated diseases, the female datasets were compared with similar public available male data sets. Immune cell-specific differentially methylated regions (DMRs) were found to be highly similar between sexes, with an average correlation coefficient of 0.82; however, numerous sex-specific DMRs, shared by the cell subsets, were identified, mainly on autosomal chromosomes. This provides a list of highly interesting candidate genes to be studied in disorders with sexual dimorphism, such as autoimmune diseases. Immune cell-specific DMRs were mainly located in the gene body and intergenic region, distant from CpG islands but overlapping with enhancer elements, indicating that distal regulatory elements are important in immune cell specificity. In contrast, sex-specific DMRs were overrepresented in CpG islands, suggesting that the epigenetic regulatory mechanisms of sex and immune cell specificity may differ. Both positive and, more frequently, negative correlations between subset-specific expression and methylation were observed, and cell-specific DMRs of both interactions were associated with similar biological pathways, while sex-specific DMRs were linked to networks of early development or estrogen receptor and immune-related molecules. Our findings of immune cell- and sex-specific methylome and transcriptome profiles provide novel insight on their complex regulatory interactions and may particularly contribute to research of immune-mediated diseases.
DOI: 10.6084/m9.figshare.1569135.v1
title: Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

description: Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the Vascular Endothelial Growth Factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this <i>in vivo</i> situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation, which initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.
DOI: 10.6084/m9.figshare.1569135.v2
title: Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

description: Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.
DOI: 10.6084/m9.figshare.1569121
title: Pharmacogenetic tests to predict the efficacy of aspirin desensitization in patients with aspirin-exacerbated respiratory diseases; HLA-DQB302

description: This study is aimed at investigating the association of <i>HLA-DRB1,</i><i>HLA-DQA1,</i> and <i>HLA</i>-<i>DQB1</i> variability with the response to aspirin desensitization (AD). A total of 16 patients with aspirin-exacerbated respiratory diseases (AERD, 81.3% were female) with median age of 29 ± 4.3 years were included in this study. Following 6 months, Sino-Nasal Outcome Test-22 (SNOT-22), medication, symptom scores, and forced expiratory volume in 1 s (FEV1) (all p &lt; 0.001) improved significantly. However, only seven patients (43.7%) had clinically significant improvement in all of the medication and symptom scores and FEV1, who were considered responders to AD. Responders to AD had significantly higher symptom scores compared with non-responders at baseline (20 ± 1.18 vs 10 ± 1.27; p = 0.003). <i>HLADQB1*0302</i> was significantly lower in non-responders than in responders to AD (0.12 [0.02–0.76]; p = 0.022). Sensitivity and specificity of HLA-DQB1*0302 to predict response to AD was 71.4% (95% CI: 35.8–91.7) and 81.8% (95% CI: 52.3–94.8). This study introduces <i>HLA-DQB1*0302</i> as a genetic marker for favorable response to AD.
DOI: 10.6084/m9.figshare.1569135.v3
title: Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

description: Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.
DOI: 10.5517/ccdc.csd.cc24r738
title: CCDC 1988529: Experimental Crystal Structure Determination

description: Related Article: Loren C Brown, Andrew Peloquin, Nicholas P. Godman, Gary James Balaich, Scott T Iacono|2020|J.Org.Chem.|85|11116|doi:10.1021/acs.joc.0c01014
DOI: 10.6084/m9.figshare.1569119
title: Self-starting monitoring scheme for Poisson count data with varying population sizes

description: In this paper we consider the problem of monitoring Poisson rates when the population sizes are time-varying and the nominal value of the process parameter is unavailable. Almost all previous control schemes for the detection of increases in the Poisson rate in Phase II are constructed based on assumed knowledge of the process parameters, e.g., the expectation of the count of a rare event when the process of interest is in control. In practice, however, this parameter is usually unknown and not able to be estimated with a sufficiently large number of reference samples. A self-starting EWMA control scheme based on a parametric bootstrap method is proposed. The success of the proposed method lies in the use of probability control limits, which are determined based on the observations during rather than before monitoring. Simulation studies show that our proposed scheme has good in-control and out-of-control performance under various situations. In particular, our proposed scheme is useful in rare event studies during the start-up stage of a monitoring process.
DOI: 10.5517/ccdc.csd.cc24r749
title: CCDC 1988530: Experimental Crystal Structure Determination

description: Related Article: Loren C Brown, Andrew Peloquin, Nicholas P. Godman, Gary James Balaich, Scott T Iacono|2020|J.Org.Chem.|85|11116|doi:10.1021/acs.joc.0c01014
DOI: 10.5517/ccdc.csd.cc24r75b
title: CCDC 1988531: Experimental Crystal Structure Determination

description: Related Article: Loren C Brown, Andrew Peloquin, Nicholas P. Godman, Gary James Balaich, Scott T Iacono|2020|J.Org.Chem.|85|11116|doi:10.1021/acs.joc.0c01014
DOI: 10.5517/ccdc.csd.cc24r76c
title: CCDC 1988532: Experimental Crystal Structure Determination

description: Related Article: Loren C Brown, Andrew Peloquin, Nicholas P. Godman, Gary James Balaich, Scott T Iacono|2020|J.Org.Chem.|85|11116|doi:10.1021/acs.joc.0c01014
DOI: 10.6084/m9.figshare.1569135
title: Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

description: Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.
DOI: 10.6084/m9.figshare.1569135.v4
title: Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

description: Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.
DOI: 10.6084/m9.figshare.1569121.v1
title: Pharmacogenetic tests to predict the efficacy of aspirin desensitization in patients with aspirin-exacerbated respiratory diseases; HLA-DQB302

description: This study is aimed at investigating the association of <i>HLA-DRB1,</i><i>HLA-DQA1,</i> and <i>HLA</i>-<i>DQB1</i> variability with the response to aspirin desensitization (AD). A total of 16 patients with aspirin-exacerbated respiratory diseases (AERD, 81.3% were female) with median age of 29 ± 4.3 years were included in this study. Following 6 months, Sino-Nasal Outcome Test-22 (SNOT-22), medication, symptom scores, and forced expiratory volume in 1 s (FEV1) (all p &lt; 0.001) improved significantly. However, only seven patients (43.7%) had clinically significant improvement in all of the medication and symptom scores and FEV1, who were considered responders to AD. Responders to AD had significantly higher symptom scores compared with non-responders at baseline (20 ± 1.18 vs 10 ± 1.27; p = 0.003). <i>HLADQB1*0302</i> was significantly lower in non-responders than in responders to AD (0.12 [0.02–0.76]; p = 0.022). Sensitivity and specificity of HLA-DQB1*0302 to predict response to AD was 71.4% (95% CI: 35.8–91.7) and 81.8% (95% CI: 52.3–94.8). This study introduces <i>HLA-DQB1*0302</i> as a genetic marker for favorable response to AD.
DOI: 10.6084/m9.figshare.1569135.v6
title: Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

description: Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.
DOI: 10.6084/m9.figshare.1569135.v5
title: Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

description: Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.
DOI: 10.6084/m9.figshare.1569121.v3
title: Pharmacogenetic tests to predict the efficacy of aspirin desensitization in patients with aspirin-exacerbated respiratory diseases; HLA-DQB302

description: This study is aimed at investigating the association of <i>HLA-DRB1,</i><i>HLA-DQA1,</i> and <i>HLA</i>-<i>DQB1</i> variability with the response to aspirin desensitization (AD). A total of 16 patients with aspirin-exacerbated respiratory diseases (AERD, 81.3% were female) with median age of 29 ± 4.3 years were included in this study. Following 6 months, Sino-Nasal Outcome Test-22 (SNOT-22), medication, symptom scores, and forced expiratory volume in 1 s (FEV1) (all p &lt; 0.001) improved significantly. However, only seven patients (43.7%) had clinically significant improvement in all of the medication and symptom scores and FEV1, who were considered responders to AD. Responders to AD had significantly higher symptom scores compared with non-responders at baseline (20 ± 1.18 vs 10 ± 1.27; p = 0.003). <i>HLADQB1*0302</i> was significantly lower in non-responders than in responders to AD (0.12 [0.02–0.76]; p = 0.022). Sensitivity and specificity of HLA-DQB1*0302 to predict response to AD was 71.4% (95% CI: 35.8–91.7) and 81.8% (95% CI: 52.3–94.8). This study introduces <i>HLA-DQB1*0302</i> as a genetic marker for favorable response to AD.
DOI: 10.6084/m9.figshare.1569121.v2
title: Pharmacogenetic tests to predict the efficacy of aspirin desensitization in patients with aspirin-exacerbated respiratory diseases; HLA-DQB302

description: This study is aimed at investigating the association of <i>HLA-DRB1,</i><i>HLA-DQA1,</i> and <i>HLA</i>-<i>DQB1</i> variability with the response to aspirin desensitization (AD). A total of 16 patients with aspirin-exacerbated respiratory diseases (AERD, 81.3% were female) with median age of 29 ± 4.3 years were included in this study. Following 6 months, Sino-Nasal Outcome Test-22 (SNOT-22), medication, symptom scores, and forced expiratory volume in 1 s (FEV1) (all p &lt; 0.001) improved significantly. However, only seven patients (43.7%) had clinically significant improvement in all of the medication and symptom scores and FEV1, who were considered responders to AD. Responders to AD had significantly higher symptom scores compared with non-responders at baseline (20 ± 1.18 vs 10 ± 1.27; p = 0.003). <i>HLADQB1*0302</i> was significantly lower in non-responders than in responders to AD (0.12 [0.02–0.76]; p = 0.022). Sensitivity and specificity of HLA-DQB1*0302 to predict response to AD was 71.4% (95% CI: 35.8–91.7) and 81.8% (95% CI: 52.3–94.8). This study introduces <i>HLA-DQB1*0302</i> as a genetic marker for favorable response to AD.