32 results on '"David Nickle"'
Search Results
2. Gene expression network analysis provides potential targets against SARS-CoV-2
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Ana I. Hernández Cordero, Xuan Li, Chen Xi Yang, Stephen Milne, Yohan Bossé, Philippe Joubert, Wim Timens, Maarten van den Berge, David Nickle, Ke Hao, and Don D. Sin
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Medicine ,Science - Abstract
Abstract Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets. Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions. ACE2 was in a module of 681 co-expressed genes; 10 genes with moderate-high correlation with ACE2 (r > 0.3, FDR
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- 2020
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3. 389 Combining transcriptomic- and tissue-based immune biomarkers to evaluate GB1275, a CD11b modulator, as a single agent or with pembrolizumab in patients with advanced solid tumors
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Laura Carter, Andrea Wang-Gillam, Johanna Bendell, Wungki Park, Wells Messersmith, Drew Rasco, Lei Zhou, Jean-Marie Bruey, Beatrice Ferguson, Jakob Dupont, Marya Chaney, Johann De Bono, David Nickle, and Anna Galkin
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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4. Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment
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Judong Shen, Devan V. Mehrotra, Mary Beth Dorr, Zhen Zeng, Junhua Li, Xun Xu, David Nickle, Emily R. Holzinger, Aparna Chhibber, Mark H. Wilcox, Rebecca L. Blanchard, and Peter M. Shaw
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Clostridium difficile ,antibacterials ,bezlotoxumab ,genomics ,Microbiology ,QR1-502 - Abstract
ABSTRACT Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II). IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.
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- 2020
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5. Genome-wide interaction study of gene-by-occupational exposures on respiratory symptoms
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Xiang Zeng, Judith M. Vonk, Diana A. van der Plaat, Alen Faiz, Peter D. Paré, Philippe Joubert, David Nickle, Corry-Anke Brandsma, Hans Kromhout, Roel Vermeulen, Xijin Xu, Xia Huo, Kim de Jong, and H. Marike Boezen
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Environmental sciences ,GE1-350 - Abstract
Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm. As identification cohort LifeLines I (n = 7976 subjects) was used. Job-specific exposure was estimated using the ALOHA + job exposure matrix. SNP-by-occupational exposure interactions on respiratory symptoms were tested using logistic regression adjusted for gender, age, and current smoking. SNP-by-exposure interactions with a p-value
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- 2019
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6. Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease
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Julie Weidner, Linnea Jarenbäck, Kim de Jong, Judith M. Vonk, Maarten van den Berge, Corry-Anke Brandsma, H. Marike Boezen, Don Sin, Yohan Bossé, David Nickle, Jaro Ankerst, Leif Bjermer, Dirkje S. Postma, Alen Faiz, and Ellen Tufvesson
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Chronic obstructive pulmonary disease ,Lung fibroblast ,Single nucleotide polymorphism ,Sputum ,Sulfatase modifying factor 1 ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background It has been observed that mice lacking the sulfatase modifying factor (Sumf1) developed an emphysema-like phenotype. However, it is unknown if SUMF1 may play a role in Chronic Obstructive Pulmonary Disease (COPD) in humans. The aim was to investigate if the expression and genetic regulation of SUMF1 differs between smokers with and without COPD. Methods SUMF1 mRNA was investigated in sputum cells and whole blood from controls and COPD patients (all current or former smokers). Expression quantitative trait loci (eQTL) analysis was used to investigate if single nucleotide polymorphisms (SNPs) in SUMF1 were significantly associated with SUMF1 expression. The association of SUMF1 SNPs with COPD was examined in a population based cohort, Lifelines. SUMF1 mRNA from sputum cells, lung tissue, and lung fibroblasts, as well as lung function parameters, were investigated in relation to genotype. Results Certain splice variants of SUMF1 showed a relatively high expression in lung tissue compared to many other tissues. SUMF1 Splice variant 2 and 3 showed lower levels in sputum cells from COPD patients as compared to controls. Twelve SNPs were found significant by eQTL analysis and overlapped with the array used for genotyping of Lifelines. We found alterations in mRNA expression in sputum cells and lung fibroblasts associated with SNP rs11915920 (top hit in eQTL), which validated the results of the lung tissue eQTL analysis. Of the twelve SNPs, two SNPs, rs793391 and rs308739, were found to be associated with COPD in Lifelines. The SNP rs793391 was also confirmed to be associated with lung function changes. Conclusions We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD.
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- 2017
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7. Human Lung Tissue Transcriptome: Influence of Sex and Age.
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Matteo Dugo, Chiara E Cotroneo, Emilie Lavoie-Charland, Matteo Incarbone, Luigi Santambrogio, Lorenzo Rosso, Maarten van den Berge, David Nickle, Peter D Paré, Yohan Bossé, Tommaso A Dragani, and Francesca Colombo
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Medicine ,Science - Abstract
Sex and age strongly influence the pathophysiology of human lungs, but scarce information is available about their effects on pulmonary gene expression.We followed a discovery-validation strategy to identify sex- and age-related transcriptional differences in lung.We identified transcriptional profiles significantly associated with sex (215 genes; FDR < 0.05) and age at surgery (217 genes) in non-involved lung tissue resected from 284 lung adenocarcinoma patients. When these profiles were tested in three independent series of non-tumor lung tissue from an additional 1,111 patients, we validated the association with sex and age for 25 and 22 genes, respectively. Among the 17 sex-biased genes mapping on chromosome X, 16 have been reported to escape X-chromosome inactivation in other tissues or cells, suggesting that this mechanism influences lung transcription too. Our 22 age-related genes partially overlap with genes modulated by age in other tissues, suggesting that the aging process has similar consequences on gene expression in different organs. Finally, seven genes whose expression was modulated by sex in non-tumor lung tissue, but no age-related gene, were also validated using publicly available data from 990 lung adenocarcinoma samples, suggesting that the physiological regulatory mechanisms are only partially active in neoplastic tissue.Gene expression in non-tumor lung tissue is modulated by both sex and age. These findings represent a validated starting point for research on the molecular mechanisms underlying the observed differences in the course of lung diseases among men and women of different ages.
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- 2016
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8. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women
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Jean-Christophe Bérubé, Nathalie Gaudreault, Emilie Lavoie-Charland, Laura Sbarra, Cyndi Henry, Anne-Marie Madore, Peter D. Paré, Maarten van den Berge, David Nickle, Michel Laviolette, Catherine Laprise, Louis-Philippe Boulet, and Yohan Bossé
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Diseases of the respiratory system ,RC705-779 - Abstract
Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL) mapping study (n=1035). Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P=7.90E-10). The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients.
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- 2016
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9. Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction.
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Louise V Wain, Ian Sayers, María Soler Artigas, Michael A Portelli, Eleftheria Zeggini, Ma'en Obeidat, Don D Sin, Yohan Bossé, David Nickle, Corry-Anke Brandsma, Anders Malarstig, Ciara Vangjeli, Scott A Jelinsky, Sally John, Iain Kilty, Tricia McKeever, Nick R G Shrine, James P Cook, Shrina Patel, Tim D Spector, Edward J Hollox, Ian P Hall, and Martin D Tobin
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Genetics ,QH426-470 - Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We hypothesised that these "resistant smokers" may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the "resistant smokers" and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34 × 10(-4)) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke.
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- 2014
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10. Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls.
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Maxime Lamontagne, Christian Couture, Dirkje S Postma, Wim Timens, Don D Sin, Peter D Paré, James C Hogg, David Nickle, Michel Laviolette, and Yohan Bossé
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Medicine ,Science - Abstract
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD.
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- 2013
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11. Supplementary Table 2 and Supplemental Figures from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
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Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
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Table S2: Odds ratio and 95% confidence limits for cancers associated with variants with pleiotropic associations. Figure S1: Flowchart showing analysis steps. Figure S2. Manhattan plots by chromosome for individual cancer sites. Figure S3. Results for rs11571833. Figure S4: Conditional QQ-plots.
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- 2023
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12. Data from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
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Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
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Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.
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- 2023
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13. Supplementary Material: Funding, Acknowledgements, Consortia, and Bioinformatics Tools Funding sources from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
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Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
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Funding sources, acknowledgements, consortia involved in study and bioinformatics tools used
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- 2023
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14. Supplementary Table 1 from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
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Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
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Variants selected for replication
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- 2023
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15. Genetic Associations and Architecture of Asthma-COPD Overlap
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Catherine John, Anna L. Guyatt, Nick Shrine, Richard Packer, Thorunn A. Olafsdottir, Jiangyuan Liu, Lystra P. Hayden, Su H. Chu, Jukka T. Koskela, Jian’an Luan, Xingnan Li, Natalie Terzikhan, Hanfei Xu, Traci M. Bartz, Hans Petersen, Shuguang Leng, Steven A. Belinsky, Aivaras Cepelis, Ana I. Hernández Cordero, Ma’en Obeidat, Gudmar Thorleifsson, Deborah A. Meyers, Eugene R. Bleecker, Lori C. Sakoda, Carlos Iribarren, Yohannes Tesfaigzi, Sina A. Gharib, Josée Dupuis, Guy Brusselle, Lies Lahousse, Victor E. Ortega, Ingileif Jonsdottir, Don D. Sin, Yohan Bossé, Maarten van den Berge, David Nickle, Jennifer K. Quint, Ian Sayers, Ian P. Hall, Claudia Langenberg, Samuli Ripatti, Tarja Laitinen, Ann C. Wu, Jessica Lasky-Su, Per Bakke, Amund Gulsvik, Craig P. Hersh, Caroline Hayward, Arnulf Langhammer, Ben Brumpton, Kari Stefansson, Michael H. Cho, Louise V. Wain, Martin D. Tobin, University of Helsinki, Institute for Molecular Medicine Finland, Faculty Common Matters (Faculty of Social Sciences), Department of Public Health, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Groningen Research Institute for Asthma and COPD (GRIAC), and Epidemiology
- Subjects
Pulmonary and Respiratory Medicine ,HAY-FEVER ,Pulmonary Disease, Chronic Obstructive/complications ,Smoking/genetics ,Respiratory System ,spirometry ,LOCI ,Asthma/diagnosis ,Critical Care and Intensive Care Medicine ,OBSTRUCTIVE PULMONARY-DISEASE ,Pulmonary Disease, Chronic Obstructive ,BLOOD EOSINOPHIL COUNT ,immune system diseases ,Humans ,COPD ,GENOME-WIDE ASSOCIATION ,Lung ,RISK ,genome-wide association study ,HERITABILITY ,Smoking ,1103 Clinical Sciences ,asthma ,3126 Surgery, anesthesiology, intensive care, radiology ,respiratory tract diseases ,EXACERBATIONS ,3121 General medicine, internal medicine and other clinical medicine ,epidemiology ,Cardiology and Cardiovascular Medicine ,Genome-Wide Association Study - Abstract
Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.
- Published
- 2022
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16. Sustained Clinical Response to Immunotherapy Followed by BET Inhibitor in a Patient with Unresectable Sinonasal NUT Carcinoma
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Harriet Herbison, Sidney Davis, David Nickless, Andrew Haydon, and Malaka Ameratunga
- Subjects
nut carcinoma ,bet inhibitor ,radiation ,immunotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
NUT carcinomas (NCs) are a group of rare tumors that can occur anywhere in the body and are defined by the fusion of the nuclear protein in testis (NUTM1) resulting in increased transcription of proto-oncogenes. NCs have a poor prognosis that varies according to the site of origin with an urgent need to develop new treatment strategies. Case reports on immunotherapy in pulmonary NC have been published, and bromodomain and extraterminal (BET) inhibitors have shown activity in NC in phase I/II trials. We present the case of a 27-year-old woman with an unresectable sinonasal NC who had a sustained clinical response to both immunotherapy and BET inhibitor therapy. This is the first reported case of immunotherapy in sinonasal NC, and it highlights the different responses to a range of treatments including BET inhibitor therapy. This case supports the theory that NCs arising from different primary sites have differing prognoses.
- Published
- 2024
- Full Text
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17. Knife Fight : And Other Struggles
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David Nickle and David Nickle
- Abstract
Stories of the mysterious and macabre from “Canada's answer to Stephen King” (Helen Marshall, author of Gifts for the One Who Comes After). In this follow-up to his award-winning debut collection, Monstrous Affections, David Nickle stretches the boundaries of horror into a sphere of “uncertainty, of helplessness, of traditions and change.... The stories are sui generis in presentation, veering from the discombobulating nightmare that is ‘Basements'to the squid-laden eco-satire ‘Wylde's Kingdom'to the sci-fi love of ‘Love Means Forever.'When it comes to this book, only two things are certain; the stories never travel where you expect, and David Nickle is a monumental talent” (Publishers Weekly, starred review). “Don't make the mistake of overlooking the talent based on preconceptions of what horror might be—read one of these stories and see if you aren't hooked.... Believe the hype. David Nickle is very good.” —The Globe and Mail “Anyone even vaguely interested in horror or weird fiction owes it to themselves to give David Nickle a look, and Knife Fight and Other Struggles is a great place to start.” —The Winnipeg Free Press “Knife Fight and Other Struggles is a remarkable collection that drops some hi-fidelity weirdness on the scene. Nickle's prose has gorgeous lines of symmetry and a steel spine.” —Laird Barron, Shirley Jackson Award–winning author “Dynamic imagination, masterful writing of both the everyday and the nightmare, characters that breathe, and a dark sense of humor make [Knife Fight and Other Struggles] a keeper.” —Jeffrey Ford, World Fantasy Award–winning author
- Published
- 2020
18. The 'Geisters
- Author
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David Nickle and David Nickle
- Abstract
From the award-winning “heir to the mantle of Stephen King”: A supernatural entity draws a woman into a terrifying nightmare (The National Post). Some little girls have imaginary friends. Ann LeSage had the Insect. A violent poltergeist that tore a murderous path through her family, it wasn't imaginary—and it definitely wasn't a friend. Now Ann is all grown up—and so is the Insect. And Ann's upcoming marriage to a mysterious young lawyer is about to open up a whole new world to both of them, rife with secrets and laced with traps. Soon, Ann will find herself in a perverse battle against a group of men who want to wrest control of the Insect from her. What they don't know is, if you play with the Insect, you're sure to get stung... “Few writers do psychosexual horror as well as Toronto's David Nickle, and with The'Geisters he's back with another tale of voluptuous terror and the supernatural.” —Toronto Star “This is a book that buzzes in your ears, climbs your crawling skin with multiple barbed feet, feeling with exquisitely sensitive antennae for the next new and terrible revelation.” —The National Post “[The'Geisters] doesn't just explore the attractiveness of terror—it embodies it in a narrative that demands (excites even as it repels) your attention. It's a(nother) strong novel by one of the best, most interesting horror writers working today.” —Bookgasm
- Published
- 2020
19. Monstrous Affections : Stories
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David Nickle and David Nickle
- Abstract
“Rich characters and a love of unique twists top off a captivating and sometimes gruesome collection of nightmares” from the award-winning author of Volk (Corey Redekop, author of Husk). Winner of the Black Quill Reader's Choice Award, Monstrous Affections heralded the appearance of a thrilling new writer on the horror scene, praised by the National Post as “a worthy heir to the mantle of Stephen King.” David Nickle's debut collection features “13 terrifying tales of rural settings, complex and reticent characters and unexpected twists that question the fundamentals of reality. All are delivered with a certain grace, creating a sparse yet poetic tour of the horrors that exist just out of sight. Standout stories include ‘Janie and the Wind,'where a battered, abandoned woman does what she needs to survive; ‘Other People's Kids,'a disturbing examination of the razor-thin moment dividing childhood from maturity and the hand holding that razor; and ‘The Pit Heads,'a phenomenal story about the cold remnants of a Canadian mining town and the true cost of beauty. This ambitious collection firmly establishes Nickle as a writer to watch” (Publishers Weekly, starred review). “Brilliant... You'd think that you were reading a book full of what you had always expected a horror story to be, but Nickle takes a left turn and blindsides you with tales that are not of the norm, but are all the more horrific because of the surprise twists, darkness and raw emotion.” —January Magazine, “Best Books of 2009” “David Nickle writes'em damned weird and damned good and damned dark. He is bourbon-rough, poetic and vivid. Don't miss this one.” —Cory Doctorow, New York Times–bestselling author
- Published
- 2020
20. Rasputin's Bastards
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David Nickle and David Nickle
- Abstract
“Part BioShock, part X-Files, part Sopranos—and 100%, uncut Nickle... a glorious, chaotic delight” from the Bram Stoker Award–winning author of Volk (Peter Watts, author of Blindsight). Post–Cold War, a group of Russians bred from childhood to be psychic spies are called from around the globe to achieve their true purpose: world domination. But some of them have flourished in the lives they have carved out for themselves—often in nefarious ways—and they will not give up their freedom without a fight, even as a new generation of telepathic children, the beautiful dreamers, are coming into power... In Rasputin's Bastards, David Nickle—the acclaimed author of Eutopia, Monstrous Affections, and Volk—offers readers “an enormous tale, bewilderingly complex, but with lots of twists and turns that reward close attention. It is grotesque, violent, and exciting, with a supernatural tinge that is his hallmark” (Cory Doctorow, BoingBoing). “This novel is supernatural eeriness at its best, with intriguing characters, no clear heroes, and a dark passion at its heart. Horror aficionados and fans of Stephen King's larger novels should appreciate this macabre look at the aftermath of the Cold War.” —Library Journal “Stiffly compelling. Once you're done, there's no question: the hours spent enfolded in Nickle's imagination are well spent. You won't ever feel the desire to ask for them back.” —January Magazine “A journey from the depths of the sea, the heart of Mother Russia, to the darkest corners of the soul.” —K. E. Bergdoll, The Crow's Caw
- Published
- 2020
21. Eutopia : A Novel of Terrible Optimism
- Author
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David Nickle and David Nickle
- Abstract
This debut horror novel by the author of acclaimed short story collection Monstrous Affections “establishes him as a worthy heir to the mantle of Stephen King” (National Post). Set in 1911, Eutopia “mixes utopian vision, rustic Americana, and pure creepiness.... Nickle blends Little House on the Prairie with distillates of Rosemary's Baby and The X-Files to create a chilling survival-of-the-fittest story” (Publishers Weekly). Situated on the edge of the woods and mountains of northern Idaho, the tiny settlement of Eliada is an industrialist's attempt to create heaven on earth. But its secrets are soon to be unveiled, as Jason Thistledown, the sole survivor of a mysterious plague in Montana, and Andrew Waggoner, a black doctor nearly lynched by the KKK, delve beneath the façade of the utopian mill town. What they discover is science warped by ideology—and an unearthly monster that preys on the faith of its own true believers... “A story of piano-wire suspense, grotesque horrors, and, above all, visceral insight into the race politics of American horror, and how they are bound up with the American project itself.” —Cory Doctorow, Boing Boing Praise for David Nickle “His stories are dark, wildly imaginative, and deeply compassionate—even when they're laced with righteous anger.” —Nathan Ballingrud, author of Wounds “David Nickle is Canada's answer to Stephen King. His writing charms even as it slices like a blade between the ribs: sharp, subtle, and never less than devastating.” —Helen Marshall, author of Gifts for the One Who Comes After
- Published
- 2020
22. Volk : A Novel of Radiant Abomination
- Author
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David Nickle and David Nickle
- Abstract
The sequel to Eutopia is “a nailbiter... that is spooky as hell, a critical and sharp demolition of Lovecraft's own romanticization of eugenics” (Cory Doctorow, Boing Boing). In Eutopia, an orphaned farm boy and a black physician came face to face with monsters both human—American eugenicists—and inhuman—a parasite called the Juke. Volk is “another dive into the horrific... a dazzling horror novel that's unafraid to ask questions and leave some of them unanswered” (Publishers Weekly, starred review). At the dawn of the twentieth century, Dr. Andrew Waggoner and Jason Thistledown made it out of the Idaho town of Eliada alive—but so did the Juke... Now, in 1931 Europe, there are those who seek to resurrect the philosophy of the founders of Eliada. Deep in the Bavarian mountains, research has begun on the creature whose seductive poison can be used in the Nazis'quest for a master race. Still struggling with the aftershocks of their encounters with the Juke, Dr. Waggoner has become the head of a secret society in Paris dedicated to the monster's destruction, while Thistledown is a veteran World War I pilot. Drawn back together to fight the evil that is brewing, they will be forced to confront the diabolical plans of those who will stop at nothing to reshape humanity—and the one being capable of destroying it completely... “The most intellectually provocative horror novel of the twenty-first century.” —Toronto Star “[Volk] cements David Nickle's reputation as one of the leaders of his generation of writers.” —John Langan, award-winning author of The Fisherman
- Published
- 2020
23. A phase I/II study of GB1275, a first-in-class oral CD11b modulator, alone, and combined with pembrolizumab in specified advanced solid tumors or with chemotherapy in metastatic pancreatic cancer (KEYNOTE-A36)
- Author
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Jakob Dupont, Wungki Park, Johanna C. Bendell, Laura L. Carter, Lei Zhou, Eileen M. O'Reilly, Anna Galkin, Jack Shiansong Li, Drew W. Rasco, Beatrice Ferguson, Andrea Wang-Gillam, Wells A. Messersmith, David Nickle, and Marya F. Chaney
- Subjects
Cancer Research ,Chemotherapy ,biology ,business.industry ,medicine.medical_treatment ,Pembrolizumab ,Tumor site ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Phase i ii ,Oncology ,Integrin alpha M ,law ,030220 oncology & carcinogenesis ,Metastatic pancreatic cancer ,medicine ,Cancer research ,biology.protein ,Suppressor ,business ,030215 immunology - Abstract
3085 Background: GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) at the tumor site, repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. When combined with an anti-PD-1 antibody or chemotherapy, these immunomodulatory effects translated into potent anti-tumor effects and prolonged survival in orthotopic PDAC models [Panni RZ, et al. Sci Transl Med. 2019 Jul 3;11(499)]. This ongoing first-in-human study consists of dose escalation of GB1275 monotherapy (Regimen A), GB1275 + pembrolizumab (Regimen B), and GB1275 + nab-paclitaxel + gemcitabine (Regimen C), followed by Phase 2 expansion in newly diagnosed metastatic pancreatic, MSS colorectal, and PD-L1-positive gastric/GEJ cancers. Here we report interim results of the dose escalation portion of the trial. Methods: The dose escalation phase is based on a standard oncology phase 1, 3+3 design. Cohorts of 3 to 6 patients (pts) with histologically confirmed locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, prostate, or breast cancer were sequentially assigned to ascending dose levels of GB1275 taken orally twice daily (BID) in 1 of 3 regimens: Regimen A was initiated first; Regimen B commenced after completion of the first two cohorts of Regimen A, and Regimen C will be initiated when Regimen A is completed. Dose escalation was based on assessment of safety including dose-limiting toxicity (DLT). Serial blood and tumor samples were collected for pharmacokinetic (PK) and biomarker analyses. Results: As of January 21, 2020, 13 pts were treated, with 3 each in Regimen A (GB1275 100mg, 200 mg and 400 mg BID) dose levels and 4 in Regimen B with GB1275 100 mg BID + pembrolizumab. No DLTs have been reported. GB1275 treatment-related adverse events were reported in 5 pts; all were Grade 1 in severity. Preliminary PK analyses showed a mean elimination half-life of ~7 hours. Reduction in peripheral MDSCs was observed in the majority of pts with serial samples. Biomarker analysis in serial tumor tissue is ongoing. Conclusions: Preliminary data show minimal treatment-related toxicities with the studied regimens. PK data support BID dosing. Dose escalation is ongoing. Updated data will be presented. Clinical trial information: NCT04060342 .
- Published
- 2020
- Full Text
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24. Volk : A Novel of Radiant Abomination
- Author
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David Nickle and David Nickle
- Abstract
The Bram Stoker Award–winning author “triumphantly returns to the world of Eutopia” in this “dazzling horror novel” of Nazis and demonic forces (Publishers Weekly, starred review). At the dawn of the twentieth century, orphaned farm boy Jason Thistledown and black physician Andrew Waggoner came face to face with monsters both human and inhuman. Alongside American eugenicists seeking to perfect the human race through breeding and culls, there was a parasitic entity named Juke that lived off people's hopes, dreams, and faith, as it consumed humanity from within. Now the year is 1931, and the past that haunts Andrew and Jason is about to bring them together again. Andrew, now living in Paris, continues his tireless work to destroy the elusive Juke. Jason, a veteran pilot of WWI, is embarking on a new career flying mail across North Africa, hoping to forget his encounter with it. But in a remote valley in the Bavarian Alps, Germanic students of those same American eugenicists are desperately trying to uncover the secret of the Juke... and the promise of the Übermensch.
- Published
- 2017
25. Virologic Resistance Analysis From a Phase 2 Study of MK-5172 Combined With Pegylated Interferon/Ribavirin in Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Infection
- Author
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Christopher Gilbert, Niloufar Mobashery, Peggy M. T. Hwang, Richard J. O. Barnard, Mark J. DiNubile, David Nickle, Stephanie Curry, Stuart Black, Anita Y. M. Howe, Luzelena Caro, William Newhard, Rong Liu, and Steven W. Ludmerer
- Subjects
Cyclopropanes ,Microbiology (medical) ,medicine.medical_specialty ,Genotype ,Hepatitis C virus ,Population ,Phases of clinical research ,medicine.disease_cause ,Gastroenterology ,chemistry.chemical_compound ,Pegylated interferon ,Quinoxalines ,Internal medicine ,Drug Resistance, Viral ,Ribavirin ,medicine ,Humans ,education ,Sulfonamides ,education.field_of_study ,business.industry ,Amides ,Hepatitis C ,Infectious Diseases ,chemistry ,Grazoprevir ,Carbamates ,Interferons ,business ,Pegylated Interferon Alfa ,medicine.drug - Abstract
BACKGROUND Virologic failure following treatment of hepatitis C virus (HCV) genotype 1 with direct-acting antiviral agents is often accompanied by the emergence of resistant variants. MK-5172 is an investigational once-daily protease inhibitor. We analyzed variants in treatment-naive noncirrhotic patients with virologic failure on MK-5172 (100-800 mg/day) plus pegylated interferon alfa/ribavirin (peg-IFN/RBV) during a phase 2 trial. METHODS Population and selective clonal sequencing were performed at baseline and at virologic failure in the 4 MK-5172 dosing arms. MK-5172 activity was determined using a mutant replicon assay. RESULTS Six of 266 (2.3%) MK-5172 recipients satisfied prespecified criteria for virologic failure, all with genotype 1a infection. Five patients with virologic failure were in the MK-5172 100-mg arm, including 4 patients with low plasma MK-5172 levels documented during triple therapy. Variants associated with >4-fold loss of potency were detected in 3 of the 4 patients with genotype 1a breakthrough while on MK-5172. The fifth patient had undetectable HCV-RNA levels at the end of triple therapy but subsequently broke through during the peg-IFN/RBV tail 16 weeks after completion of MK-5172. Three patients had D168 variants at virologic failure, including 2 with the D168A variant associated with a 95-fold loss of potency. The sole apparent relapse was actually a genotype 3a reinfection in the MK-5172 200-mg group. CONCLUSIONS Virologic failure occurred uncommonly (6/266 [2.3%]) in MK-5172/peg-IFN/RBV recipients. The most prevalent treatment-emergent variants were detected at the D168 locus. D168A variants conferring approximately 2-log reduction in MK-5172 susceptibility emerged in 2 of the 4 evaluable patients with genotype 1a breakthrough. Clinical Trials Registration. NCT01353911.
- Published
- 2014
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26. New Canadian Noir : The Exile Book of Anthology Series, Number Ten
- Author
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Claude Lalumière, David Nickle, Claude Lalumière, and David Nickle
- Subjects
- Canadian fiction--21st century, Noir fiction
- Abstract
Old vines and older grudges tangle in the Okanagan Valley. An elderly widow, eking out a living collecting detritus, seeks to avenge the murder of her friend. A love-weary security guard clashes with bounty hunters. An ursine meth-cooker faces even stranger creatures on the frozen tundra of Nunavut. As the dead walk and the living despair, a private detective unravels a bizarre mystery. In The Exile Book of New Canadian Noir, the whole spectrum of the noir esthetic is explored: from its hardboiled home in crime fiction to its grim forays into horror, fantasy, and surrealism; from the dystopian shadows it casts in science fiction to the mixture of desire and corruption it brings to erotica; from the blood-spattered romance of the frontier to the stark nihilism of literary realism.
- Published
- 2015
27. Knife Fight : And Other Struggles
- Author
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David Nickle and David Nickle
- Abstract
A collection of genre-bending horror stories from the Bram Stoker Award–winning author is “sui generis in presentation... [by] a monumental talent” (Publishers Weekly, starred review). A young man at loose ends finds he cannot look away from his new lover's alien gaze. A young woman out of time seeks her old lover in the cold spaces between the stars. The fleeing worshippers of an ancient and jealous deity seek solace in an unsuspecting New World congregation. In a suburban nursery, a demon with a grudge and a lonely exorcist face off for what could be the last time. And when a knife-wielding big city mayor faces an unexpected challenger... it turns into a struggle that threatens to consume everything. In Knife Fight: And Other Struggles, David Nickle follows his award-winning debut collection Monstrous Affections with a new set of dark tales that stretch the limits of space, time, and genre.
- Published
- 2014
28. The 'Geisters
- Author
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David Nickle and David Nickle
- Abstract
A young woman's personal demon becomes a coveted poltergeist in this horror novel “full of powerful imagery” by the Bram Stoker Award–winning author (Publishers Weekly). When Ann LeSage was a little girl, she had an invisible friend—a poltergeist that spoke to her with flying knives and howling winds. She called it the Insect. Eventually, with some professional help, Ann learned to contain it. But the nightmare never truly ended. As Ann grew into young woman, the Insect grew with her. It became more than terrifying. It became a thing of murder. Now, as she embarks on a new life married to successful young lawyer, Michael Voors, Ann believes that she finally has the Insect completely under control. But there are others vying to take that control away from her. They may not know exactly what they're dealing with, but they know they want it. They are the'Geisters. And in pursuing their own perverse dream, they risk spawning the most terrible nightmare of all.
- Published
- 2013
29. Eutopia : A Novel of Terrible Optimism
- Author
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David Nickle and David Nickle
- Abstract
The year is 1911. In Cold Spring Harbour, New York, the newly formed Eugenics Records Office is sending its agents to catalogue the infirm, the insane, and the criminal—with an eye to a cull, for the betterment of all. Near Cracked Wheel, Montana, a terrible illness leaves Jason Thistledown an orphan, stranded in his dead mother's cabin until the spring thaw shows him the true meaning of devastation—and the barest thread of hope. At the edge of the utopian mill town of Eliada, Idaho, Doctor Andrew Waggoner faces a Klansman's noose and glimpses wonder in the twisting face of the patient known only as Mister Juke. And deep in a mountain lake overlooking that town, something stirs, and thinks, in its way: Things are looking up. Eutopia follows Jason and Andrew as together and alone, they delve into the secrets of Eliada—industrialist Garrison Harper's attempt to incubate a perfect community on the edge of the dark woods and mountains of northern Idaho. What they find reveals the true, terrible cost of perfection—the cruelty of the surgeon's knife—the folly of the cull—and a monstrous pact with beings that use perfection as a weapon, and faith as a trap.
- Published
- 2012
30. Rasputin's Bastards
- Author
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David Nickle and David Nickle
- Abstract
They were the beautiful dreamers. From a hidden city deep in the Ural mountains, they walked the world as the coldest of Cold Warriors, under the command of the Kremlin and under the power of their own expansive minds. They slipped into the minds of Russia's enemies with diabolical ease, and drove their human puppets to murder, and worse. They moved as Gods. And as Gods, they might have remade the world. But like the mad holy man Rasputin, who destroyed Russia through his own powerful influence... in the end, the psychic spies for the Motherland were only in it for themselves. It is the 1990s. The Cold War is long finished. In a remote Labrador fishing village, an old woman known only as Babushka foresees her ending through the harbour ice, in the giant eye of a dying kraken–and vows to have none of it. Beaten insensible and cast adrift in a life raft, ex-KGB agent Alexei Kilodovich is dragged to the deck of a ship full of criminals, and with them he will embark on a journey that will change everything he knows about himself. And from a suite in an unseen hotel in the heart of Manhattan, an old warrior named Kolyokov sets out with an open heart, to gather together the youngest members of his immense, and immensely talented, family. They are more beautiful, and more terrible, than any who came before them. They are Rasputin's bastards. And they will remake the world.
- Published
- 2012
31. Systems biology approach for new target and biomarker identification
- Author
-
I-Ming, Wang, David J, Stone, David, Nickle, Andrey, Loboda, Oscar, Puig, and Christopher, Roberts
- Subjects
Aging ,Systems Biology ,Drug Discovery ,Genetics ,Animals ,Humans ,Gene Regulatory Networks ,Prognosis ,Polymorphism, Single Nucleotide ,Biomarkers - Abstract
The pharmaceutical industry is spending increasingly large amounts of money on the discovery and development of novel medicines, but this investment is not adequately paying off in an increased rate of newly approved drugs by the FDA. The post-genomic era has provided a wealth of novel approaches for generating large, high-dimensional genetic and transcriptomic data sets from large cohorts of preclinical species as well as normal and diseased individuals. This systems biology approach to understanding disease-related biology is revolutionizing our understanding of the cellular pathways and gene networks underlying the onset of disease, and the mechanisms of pharmacological treatments that ameliorate disease phenotypes. In this article, we review a number of approaches being used by pharmaceutical and biotechnology companies, e.g., high-throughput DNA genotyping, sequencing, and genome-wide gene expression profiling, to enable drug discovery and development through the identification of new drug targets and biomarkers of disease progression, drug pharmacodynamics, and predictive markers for selecting the patients most likely to respond to therapy.
- Published
- 2012
32. 2 The Genetics of HIV-1
- Author
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Jon P. Anderson, Matthew Rain, Daniel Shriner, Allen G. Rodrigo, Yang Wang, David Nickle, Gerald H. Learn, Willscott E. Naugler, and James I. Mullins
- Published
- 2002
- Full Text
- View/download PDF
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