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1. Distinct blood transcriptomic signature of treatment in latent tuberculosis infected individuals at risk of developing active disease

Author

Burel, Julie G, Singhania, Akul, Dubelko, Paige, Muller, Julius, Tanner, Rachel, Parizotto, Eneida, Dedicoat, Martin, Fletcher, Thomas E, Dunbar, James, Cunningham, Adam F, Lindestam Arlehamn, Cecilia S, Catanzaro, Donald G, Catanzaro, Antonino, Rodwell, Timothy, McShane, Helen, O'Shea, Matthew K, and Peters, Bjoern

Subjects
Biomedical and Clinical Sciences, Immunology, Tuberculosis, Rare Diseases, Infectious Diseases, Clinical Research, Genetics, Infection, Good Health and Well Being, Adult, Case-Control Studies, England, Female, Gene Expression Profiling, Humans, Latent Tuberculosis, Longitudinal Studies, Male, Middle Aged, Mycobacterium tuberculosis, State Medicine, Tissue Array Analysis, Transcriptome, Latent tuberculosis, Blood transcriptomics, Prophylaxis treatment, Medical and Health Sciences, Microbiology, Clinical sciences, Medical microbiology
Abstract

Although only a small fraction will ever develop the active form of tuberculosis (ATB) disease, chemoprophylaxis treatment in latent TB infected (LTBI) individuals is an effective strategy to control pathogen transmission. Characterizing immune responses in LTBI upon chemoprophylactic treatment is important to facilitate treatment monitoring, and thus improve TB control strategies. Here, we studied changes in the blood transcriptome in a cohort of 42 LTBI and 8 ATB participants who received anti-TB therapy. Based on the expression of previously published gene signatures of progression to ATB, we stratified the LTBI cohort in two groups and examined if individuals deemed to be at elevated risk of developing ATB before treatment (LTBI-Risk) differed from others (LTBI-Other). We found that LTBI-Risk and LTBI-Other groups were associated with two distinct transcriptomic treatment signatures, with the LTBI-Risk signature resembling that of treated ATB patients. Notably, overlapping genes between LTBI-Risk and ATB treatment signatures were associated with risk of progression to ATB and interferon (IFN) signaling, and were selectively downregulated upon treatment in the LTBI-Risk but not the LTBI-Other group. Our results suggest that transcriptomic reprogramming following treatment of LTBI is heterogeneous and can be used to distinguish LTBI-Risk individuals from the LTBI cohort at large.

Published
2021

2. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition

Author

Gallo, David, Young, Jordan T. F., Fourtounis, Jimmy, Martino, Giovanni, Álvarez-Quilón, Alejandro, Bernier, Cynthia, Duffy, Nicole M., Papp, Robert, Roulston, Anne, Stocco, Rino, Szychowski, Janek, Veloso, Artur, Alam, Hunain, Baruah, Prasamit S., Fortin, Alexanne Bonneau, Bowlan, Julian, Chaudhary, Natasha, Desjardins, Jessica, Dietrich, Evelyne, Fournier, Sara, Fugère-Desjardins, Chloe, Goullet de Rugy, Theo, Leclaire, Marie-Eve, Liu, Bingcan, Bhaskaran, Vivek, Mamane, Yael, Melo, Henrique, Nicolas, Olivier, Singhania, Akul, Szilard, Rachel K., Tkáč, Ján, Yin, Shou Yun, Morris, Stephen J., Zinda, Michael, Marshall, C. Gary, and Durocher, Daniel

Published
2022
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3. Distinct blood transcriptomic signature of treatment in latent tuberculosis infected individuals at risk of developing active disease

Author

Burel, Julie G., Singhania, Akul, Dubelko, Paige, Muller, Julius, Tanner, Rachel, Parizotto, Eneida, Dedicoat, Martin, Fletcher, Thomas E., Dunbar, James, Cunningham, Adam F., Lindestam Arlehamn, Cecilia S., Catanzaro, Donald G., Catanzaro, Antonino, Rodwell, Timothy, McShane, Helen, O'Shea, Matthew K., and Peters, Bjoern

Published
2021
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5. Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis

Author

Moreira-Teixeira, Lúcia, Tabone, Olivier, Graham, Christine M., Singhania, Akul, Stavropoulos, Evangelos, Redford, Paul S., Chakravarty, Probir, Priestnall, Simon L., Suarez-Bonnet, Alejandro, Herbert, Eleanor, Mayer-Barber, Katrin D., Sher, Alan, Fonseca, Kaori L., Sousa, Jeremy, Cá, Baltazar, Verma, Raman, Haldar, Pranabashis, Saraiva, Margarida, and O’Garra, Anne

Published
2020
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6. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Author

Adcock, I.M., Ahmed, H., Auffray, C., Bakke, P., Bansal, A.T., Baribaud, F., Bates, S., Bel, E.H., Bigler, J., Bisgaard, H., Boedigheimer, M.J., Bønnelykke, K., Brandsma, J., Brinkman, P., Bucchioni, E., Burg, D., Bush, A., Caruso, M., Chaiboonchoe, A., Chanez, P., Chung, F.K., Compton, C.H., Corfield, J., D'Amico, A., Dahlen, S.E., De Meulder, B., Djukanovic, R., Erpenbeck, V.J., Erzen, D., Fichtner, K., Fitch, N., Fleming, L.J., Formaggio, E., Fowler, S.J., Frey, U., Gahlemann, M., Geiser, T., Goss, V., Guo, Y., Hashimoto, S., Haughney, J., Hedlin, G., Hekking, P.W., Higenbottam, T., Hohlfeld, J.M., Holweg, C., Horváth, I., James, A.J., Knowles, R., Knox, A.J., Krug, N., Lefaudeux, D., Loza, M.J., Manta, A., Matthews, J.G., Mazein, A., Meiser, A., Middelveld, R.J.M., Miralpeix, M., Montuschi, P., Mores, N., Murray, C.S., Musial, J., Myles, D., Pahus, L., Pandis, I., Pavlidis, S., Postle, A., Powel, P., Praticò, G., Rao, N., Riley, J., Roberts, A., Roberts, G., Rowe, A., Sandström, T., Schofield, J.P.R., Seibold, W., Selby, A., Shaw, D.E., Sigmund, R., Singer, F., Skipp, P.J., Sousa, A.R., Sterk, P.J., Sun, K., Thornton, B., van Aalderen, W.M., van Geest, M., Vestbo, J., Vissing, N.H., Wagener, A.H., Wagers, S.S., Weiszhart, Z., Wheelock, C.E., Wilson, S.J., Jevnikar, Zala, Östling, Jörgen, Ax, Elisabeth, Calvén, Jenny, Thörn, Kristofer, Israelsson, Elisabeth, Öberg, Lisa, Singhania, Akul, Lau, Laurie C.K., Wilson, Susan J., Ward, Jonathan A., Chauhan, Anoop, Sousa, Ana R., De Meulder, Bertrand, Loza, Matthew J., Baribaud, Frédéric, Sterk, Peter J., Chung, Kian Fan, Sun, Kai, Guo, Yike, Adcock, Ian M., Payne, Debbie, Dahlen, Barbro, Chanez, Pascal, Shaw, Dominick E., Krug, Norbert, Hohlfeld, Jens M., Sandström, Thomas, Djukanovic, Ratko, James, Anna, Hinks, Timothy S.C., Howarth, Peter H., Vaarala, Outi, van Geest, Marleen, and Olsson, Henric

Published
2019
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7. Vitamin D Metabolites Inhibit Hepatitis C Virus and Modulate Cellular Gene Expression

Author

Gutierrez, Julio A, Jones, Krysten A, Flores, Roxana, Singhania, Akul, Woelk, Christopher H, Schooley, Robert T, and Wyles, David L

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Emerging Infectious Diseases, Hepatitis, Nutrition, Liver Disease, Chronic Liver Disease and Cirrhosis, Genetics, Digestive Diseases, Biotechnology, Infectious Diseases, Hepatitis - C, Good Health and Well Being, Hepatitis C Virus, Interferon, Ribavirin therapy
Abstract

Background and aimsPrevious studies suggest that low serum 25-hydroxyvitamin D [25(OH) D] levels are associated with reduced responsiveness to interferon and ribavirin therapy. We investigated the impact of vitamin D metabolites on HCV and cellular gene expression in cultured hepatoma cells.MethodsHCV Replicon cell lines stably expressing luciferase reporter constructs (genotype 1b and 2a replicon) or JC1-Luc2a were incubated in the presence of vitamin D2, vitamin D3 or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Presence of HCV was quantified by a luciferase reporter assay and immunoblot of the Core protein. Synergy of interferon-alpha A/D (IFN-α) and 1,25(OH)2D3 was evaluated using the Chou-Talalay method. Cellular gene expression by microarray analysis using Illumina Bead Chips and real-time quantitative PCR.ResultsVitamin D2, D3 and 1,25(OH)2D3 each demonstrated anti-HCV activity at low micro molar concentrations. In vitro conversion from D3 to 25(OH)D3 was shown by LC/MS/MS. Combination indices of 1,25(OH)2D3 and IFN-α demonstrated a synergistic effect (0.23-0.46) and significantly reduced core expression by immunoblot. Differentially expressed genes were identified between Huh7.5.1 cells in the presence and absence of 1,25(OH)2D3 and HCV. Genes involved with classical effects of vitamin D metabolism and excretion were activated, along with genes linked to autophagy such as G-protein coupled receptor 37 (GPR37) and Hypoxia-inducible factor 1-alpha (HIF1a). Additionally, additive effects of 1,25(OH)2D3 and IFN-α were seen on mRNA expression of chemokine motif ligand 20 (CCL20).ConclusionsThis study shows that vitamin D reduces HCV protein production in cell culture synergistically with IFN-α. Vitamin D also activates gene expression independently and additively with IFN-α and this may explain its ability to aid in the clearance of HCV in vivo.

Published
2014

8. Differential gene expression in HIV-infected individuals following ART

Author

Massanella, Marta, Singhania, Akul, Beliakova-Bethell, Nadejda, Pier, Rose, Lada, Steven M, White, Cory H, Pérez-Santiago, Josué, Blanco, Julià, Richman, Douglas D, Little, Susan J, and Woelk, Christopher H

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Lymphoma, HIV/AIDS, Hematology, Biotechnology, Rare Diseases, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Infection, Antiretroviral Therapy, Highly Active, Gene Expression Profiling, HIV Infections, Humans, Male, Microarray Analysis, Real-Time Polymerase Chain Reaction, Antiretroviral therapy, Droplet digital PCR, Gene expression, HIV, Microarray, Paired analysis, Microbiology, Pharmacology and Pharmaceutical Sciences, Virology, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

Previous studies of the effect of ART on gene expression in HIV-infected individuals have identified small numbers of modulated genes. Since these studies were underpowered or cross-sectional in design, a paired analysis of peripheral blood mononuclear cells (PBMCs), isolated before and after ART, from a robust number of HIV-infected patients (N=32) was performed. Gene expression was assayed by microarray and 4157 differentially expressed genes (DEGs) were identified following ART using multivariate permutation tests. Pathways and gene ontology (GO) terms over-represented for DEGs reflected the transition from a period of active virus replication before ART to one of viral suppression (e.g., repression of JAK-STAT signaling) and possible prolonged drug exposure (e.g., oxidative phosphorylation pathway) following ART. CMYC was the DEG whose product made the greatest number of interactions at the protein level in protein interaction networks (PINs), which has implications for the increased incidence of Hodgkin's lymphoma (HL) in HIV-infected patients. The differential expression of multiple genes was confirmed by RT-qPCR including well-known drug metabolism genes (e.g., ALOX12 and CYP2S1). Targets not confirmed by RT-qPCR (i.e., GSTM2 and RPL5) were significantly confirmed by droplet digital (ddPCR), which may represent a superior method when confirming DEGs with low fold changes. In conclusion, a paired design revealed that the number of genes modulated following ART was an order of magnitude higher than previously recognized.

Published
2013

9. Gene expression in human fungal pathogen Coccidioides immitis changes as arthroconidia differentiate into spherules and mature

Author

Viriyakosol, Suganya, Singhania, Akul, Fierer, Joshua, Goldberg, Jonathan, Kirkland, Theo N, and Woelk, Christopher H

Abstract

Abstract Background Coccidioides immitis is a dimorphic fungus that causes disease in mammals, including human beings. It grows as a mycelium containing arthroconidia in the soil and in the host arthroconidia differentiates into a unique structure called a spherule. We used a custom open reading frame oligonucleotide microarray to compare the transcriptome of C. immitis mycelia with early (day 2) and late stage (day 8) spherules grown in vitro. All hybridizations were done in quadruplicate and stringent criteria were used to identify significantly differentially expressed genes. Results 22% of C. immitis genes were differentially expressed in either day 2 or day 8 spherules compared to mycelia, and about 12% of genes were differentially expressed comparing the two spherule time points. Oxireductases, including an extracellular superoxide dismutase, were upregulated in spherules and they may be important for defense against oxidative stress. Many signal transduction molecules, including pleckstrin domain proteins, protein kinases and transcription factors were downregulated in day 2 spherules. Several genes involved in sulfur metabolism were downregulated in day 8 spherules compared to day 2 spherules. Transcription of amylase and α (1,3) glucan synthase was upregulated in spherules; these genes have been found to be important for differentiation to yeast in Histoplasma. There were two homologs of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD); transcription of one was up- and the other downregulated. We tested the effect of a 4-HPPD inhibitor, nitisinone, on mycelial and spherule growth and found that it inhibited mycelial but not spherule growth. Conclusions Transcription of many genes was differentially expressed in the process of arthroconidia to spherule conversion and spherule maturation, as would be expected given the magnitude of the morphologic change. The transcription profile of early stage (day 2) spherules was different than late stage (day 8) endosporulating spherules. In addition, very few genes that are important for spore to yeast conversion in other dimorphic fungi are differentially expressed in C. immitis mycelia and spherules suggesting that dimorphic fungi may have evolved different mechanisms to differentiate from mycelia to tissue invasive forms.

Published
2013

10. Factors regulated by interferon gamma and hypoxia-inducible factor 1A contribute to responses that protect mice from Coccidioides immitis infection

Author

Woelk, Christopher H, Zhang, Jin X, Walls, Lorraine, Viriyakosol, Suganya, Singhania, Akul, Kirkland, Theo N, and Fierer, Joshua

Abstract

Abstract Background Coccidioidomycosis results from airborne infections caused by either Coccidioides immitis or C. posadasii. Both are pathogenic fungi that live in desert soil in the New World and can infect normal hosts, but most infections are self-limited. Disseminated infections occur in approximately 5% of cases and may prove fatal. Mouse models of the disease have identified strains that are resistant (e.g. DBA/2) or susceptible (e.g. C57BL/6) to these pathogens. However, the genetic and immunological basis for this difference has not been fully characterized. Results Microarray technology was used to identify genes that were differentially expressed in lung tissue between resistant DBA/2 and sensitive C57BL/6 mice after infection with C. immitis. Differentially expressed genes were mapped onto biological pathways, gene ontologies, and protein interaction networks, which revealed that innate immune responses mediated by Type II interferon (i.e., IFNG) and the signal transducer and activator of transcription 1 (STAT1) contribute to the resistant phenotype. In addition, upregulation of hypoxia inducible factor 1A (HIF1A), possibly as part of a larger inflammatory response mediated by tumor necrosis factor alpha (TNFA), may also contribute to resistance. Microarray gene expression was confirmed by real-time quantitative PCR for a subset of 12 genes, which revealed that IFNG HIF1A and TNFA, among others, were significantly differentially expressed between the two strains at day 14 post-infection. Conclusion These results confirm the finding that DBA/2 mice express more Type II interferon and interferon stimulated genes than genetically susceptible strains and suggest that differential expression of HIF1A may also play a role in protection.

Published
2012

13. Single-cell profiling reveals distinct subsets of CD14+ monocytes drive blood immune signatures of active tuberculosis

Author

Hillman, Hannah, primary, Khan, Nabeela, additional, Singhania, Akul, additional, Dubelko, Paige, additional, Soldevila, Ferran, additional, Tippalagama, Rashmi, additional, DeSilva, Aruna D., additional, Gunasena, Bandu, additional, Perera, Judy, additional, Scriba, Thomas J., additional, Ontong, Cynthia, additional, Fisher, Michelle, additional, Luabeya, Angelique, additional, Taplitz, Randy, additional, Seumois, Gregory, additional, Vijayanand, Pandurangan, additional, Hedrick, Catherine C., additional, Peters, Bjoern, additional, and Burel, Julie G., additional

Published
2023
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16. Profiling the myeloid compartment of PBMC in active tuberculosis reveals substantial changes in CD14+ cells and upregulation of CD16 in pro-inflammatory dendritic cells

Author

Burel, Julie G, primary, Hillman, Hannah, additional, Khan, Nabeela, additional, Singhania, Akul, additional, Dubelko, Paige, additional, Casals, Ferran Soldevilla, additional, Tippalagama, Rashmi, additional, deSilva, Aruna D, additional, Scriba, Thomas J, additional, Taplitz, Randy, additional, Seumois, Gregory, additional, Vijayanand, Pandurangan, additional, Hedrick, Catherine C, additional, Sette, Alessandro, additional, and Peters, Bjoern, additional

Published
2022
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17. CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

Author

Singhania, Akul, primary, Dubelko, Paige, additional, Kuan, Rebecca, additional, Chronister, William D., additional, Muskat, Kaylin, additional, Das, Jyotirmoy, additional, Phillips, Elizabeth J., additional, Mallal, Simon A., additional, Seumois, Grégory, additional, Vijayanand, Pandurangan, additional, Sette, Alessandro, additional, Lerm, Maria, additional, Peters, Bjoern, additional, and Lindestam Arlehamn, Cecilia, additional

Published
2021
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19. Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis

Author

Tabone, Olivier, primary, Verma, Raman, additional, Singhania, Akul, additional, Chakravarty, Probir, additional, Branchett, William J., additional, Graham, Christine M., additional, Lee, Jo, additional, Trang, Tran, additional, Reynier, Frederic, additional, Leissner, Philippe, additional, Kaiser, Karine, additional, Rodrigue, Marc, additional, Woltmann, Gerrit, additional, Haldar, Pranabashis, additional, and O’Garra, Anne, additional

Published
2021
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22. HLA-DR Marks Recently Divided Antigen-Specific Effector CD4 T Cells in Active Tuberculosis Patients

Author

Tippalagama, Rashmi, primary, Singhania, Akul, additional, Dubelko, Paige, additional, Lindestam Arlehamn, Cecilia S., additional, Crinklaw, Austin, additional, Pomaznoy, Mikhail, additional, Seumois, Gregory, additional, deSilva, Aruna D., additional, Premawansa, Sunil, additional, Vidanagama, Dhammika, additional, Gunasena, Bandu, additional, Goonawardhana, N. D. Suraj, additional, Ariyaratne, Dinuka, additional, Scriba, Thomas J., additional, Gilman, Robert H., additional, Saito, Mayuko, additional, Taplitz, Randy, additional, Vijayanand, Pandurangan, additional, Sette, Alessandro, additional, Peters, Bjoern, additional, and Burel, Julie G., additional

Published
2021
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23. CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

Author

Singhania, Akul, Dubelko, Paige, Kuan, Rebecca, Chronister, William D., Muskat, Kaylin, Das, Jyotirmoy, Phillips, Elizabeth J., Mallal, Simon A., Seumois, Gregory, Vijayanand, Pandurangan, Sette, Alessandro, Lerm, Maria, Peters, Bjoern, Arlehamn, Cecilia Lindestam, Singhania, Akul, Dubelko, Paige, Kuan, Rebecca, Chronister, William D., Muskat, Kaylin, Das, Jyotirmoy, Phillips, Elizabeth J., Mallal, Simon A., Seumois, Gregory, Vijayanand, Pandurangan, Sette, Alessandro, Lerm, Maria, Peters, Bjoern, and Arlehamn, Cecilia Lindestam

Abstract

Background: The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Methods: We investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool. Findings: Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* (CXCR3+CCR6+) and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. Interpretation: The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies. (C) 2021 The Author(s). Published by Elsevier B.V., Funding Agencies|NIH, USAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI118626, S10 RR027366, S10 OD016262]

Published
2021
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24. CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

Author

Gallo, David, primary, Young, Jordan T.F., additional, Fourtounis, Jimmy, additional, Martino, Giovanni, additional, Álvarez-Quilón, Alejandro, additional, Bernier, Cynthia, additional, Duffy, Nicole M., additional, Papp, Robert, additional, Roulston, Anne, additional, Stocco, Rino, additional, Szychowski, Janek, additional, Veloso, Artur, additional, Alam, Hunain, additional, Baruah, Prasamit S., additional, Fortin, Alexanne Bonneau, additional, Bowlan, Julian, additional, Chaudhary, Natasha, additional, Desjardins, Jessica, additional, Dietrich, Evelyne, additional, Fournier, Sara, additional, Fugère-Desjardins, Chloe, additional, de Rugy, Theo Goullet, additional, Leclaire, Marie-Eve, additional, Liu, Bingcan, additional, Melo, Henrique, additional, Nicolas, Olivier, additional, Singhania, Akul, additional, Szilard, Rachel K., additional, Tkáč, Ján, additional, Yin, Shou Yun, additional, Morris, Stephen J., additional, Zinda, Michael, additional, Gary Marshall, C., additional, and Durocher, Daniel, additional

Published
2021
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25. Blood Transcriptional Phenotypes of Progressive Latent M. tuberculosis Infection Inform Novel Signatures That Improve Prediction of Tuberculosis Risk

Author

Richardson, Matthew, primary, Verma, Raman, additional, Singhania, Akul, additional, Tabone, Olivier, additional, Das, Mrinal, additional, Rodrigue, Marc, additional, Leissner, Philippe, additional, Woltmann, Gerrit, additional, Cooper, Andrea, additional, O’Garra, Anne, additional, and Haldar, Pranabashis, additional

Published
2021
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29. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Author

Jevnikar, Zala, Ostling, Jorgen, Calven, Jenny, Thorn, Kristofer, Israelsson, Elisabeth, Oberg, Lisa, Singhania, Akul, Lau, Laurie C. K., Wilson, Susan J., Ward, Jonathan A., Chauhan, Anoop, Sousa, Ana R., De Meulder, Bertrand, Loza, Matthew J., Baribaud, Frederic, Sterk, Peter J., Chung, Kian Fan, Sun, Kai, Guo, Yike, Adcock, Ian M., Payne, Debbie, Dahlen, Barbro, Chanez, Pascal, Shaw, Dominick E., Krug, Norbert, Hohlfeld, Jens M., Sandström, Thomas, Djukanovic, Ratko, James, Anna, Hinks, Timothy S. C., Howarth, Peter H., Vaarala, Outi, van Geest, Marleen, Olsson, Henric, Jevnikar, Zala, Ostling, Jorgen, Calven, Jenny, Thorn, Kristofer, Israelsson, Elisabeth, Oberg, Lisa, Singhania, Akul, Lau, Laurie C. K., Wilson, Susan J., Ward, Jonathan A., Chauhan, Anoop, Sousa, Ana R., De Meulder, Bertrand, Loza, Matthew J., Baribaud, Frederic, Sterk, Peter J., Chung, Kian Fan, Sun, Kai, Guo, Yike, Adcock, Ian M., Payne, Debbie, Dahlen, Barbro, Chanez, Pascal, Shaw, Dominick E., Krug, Norbert, Hohlfeld, Jens M., Sandström, Thomas, Djukanovic, Ratko, James, Anna, Hinks, Timothy S. C., Howarth, Peter H., Vaarala, Outi, van Geest, Marleen, and Olsson, Henric

Abstract

Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammati

Published
2019
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30. LSC - 2019 - Novel cellular effects of ultrafine particulate matter from an underground railway station uncovered through RNAseq

Author

Loxham, Matthew, primary, Woo, Jeongmin, additional, Singhania, Akul, additional, Smithers, Natalie, additional, Yeomans, Alison, additional, Packham, Graham, additional, Crainic, Alina, additional, Cook, Richard, additional, Cassee, Flemming, additional, Woelk, Christopher, additional, and Davies, Donna, additional

Published
2019
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31. Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases

Author

Singhania, Akul, primary, Graham, Christine M., additional, Gabryšová, Leona, additional, Moreira-Teixeira, Lúcia, additional, Stavropoulos, Evangelos, additional, Pitt, Jonathan M., additional, Chakravarty, Probir, additional, Warnatsch, Annika, additional, Branchett, William J., additional, Conejero, Laura, additional, Lin, Jing-Wen, additional, Davidson, Sophia, additional, Wilson, Mark S., additional, Bancroft, Gregory, additional, Langhorne, Jean, additional, Frickel, Eva, additional, Sesay, Abdul K., additional, Priestnall, Simon L., additional, Herbert, Eleanor, additional, Ioannou, Marianna, additional, Wang, Qian, additional, Humphreys, Ian R., additional, Dodd, Jonathan, additional, Openshaw, Peter J. M., additional, Mayer-Barber, Katrin D., additional, Jankovic, Dragana, additional, Sher, Alan, additional, Lloyd, Clare M., additional, Baldwin, Nicole, additional, Chaussabel, Damien, additional, Papayannopoulos, Venizelos, additional, Wack, Andreas, additional, Banchereau, Jacques F., additional, Pascual, Virginia M., additional, and O’Garra, Anne, additional

Published
2019
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33. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Author

Jevnikar, Zala, primary, Östling, Jörgen, additional, Ax, Elisabeth, additional, Calvén, Jenny, additional, Thörn, Kristofer, additional, Israelsson, Elisabeth, additional, Öberg, Lisa, additional, Singhania, Akul, additional, Lau, Laurie C.K., additional, Wilson, Susan J., additional, Ward, Jonathan A., additional, Chauhan, Anoop, additional, Sousa, Ana R., additional, De Meulder, Bertrand, additional, Loza, Matthew J., additional, Baribaud, Frédéric, additional, Sterk, Peter J., additional, Chung, Kian Fan, additional, Sun, Kai, additional, Guo, Yike, additional, Adcock, Ian M., additional, Payne, Debbie, additional, Dahlen, Barbro, additional, Chanez, Pascal, additional, Shaw, Dominick E., additional, Krug, Norbert, additional, Hohlfeld, Jens M., additional, Sandström, Thomas, additional, Djukanovic, Ratko, additional, James, Anna, additional, Hinks, Timothy S.C., additional, Howarth, Peter H., additional, Vaarala, Outi, additional, van Geest, Marleen, additional, Olsson, Henric, additional, Adcock, I.M., additional, Ahmed, H., additional, Auffray, C., additional, Bakke, P., additional, Bansal, A.T., additional, Baribaud, F., additional, Bates, S., additional, Bel, E.H., additional, Bigler, J., additional, Bisgaard, H., additional, Boedigheimer, M.J., additional, Bønnelykke, K., additional, Brandsma, J., additional, Brinkman, P., additional, Bucchioni, E., additional, Burg, D., additional, Bush, A., additional, Caruso, M., additional, Chaiboonchoe, A., additional, Chanez, P., additional, Chung, F.K., additional, Compton, C.H., additional, Corfield, J., additional, D'Amico, A., additional, Dahlen, S.E., additional, De Meulder, B., additional, Djukanovic, R., additional, Erpenbeck, V.J., additional, Erzen, D., additional, Fichtner, K., additional, Fitch, N., additional, Fleming, L.J., additional, Formaggio, E., additional, Fowler, S.J., additional, Frey, U., additional, Gahlemann, M., additional, Geiser, T., additional, Goss, V., additional, Guo, Y., additional, Hashimoto, S., additional, Haughney, J., additional, Hedlin, G., additional, Hekking, P.W., additional, Higenbottam, T., additional, Hohlfeld, J.M., additional, Holweg, C., additional, Horváth, I., additional, James, A.J., additional, Knowles, R., additional, Knox, A.J., additional, Krug, N., additional, Lefaudeux, D., additional, Loza, M.J., additional, Manta, A., additional, Matthews, J.G., additional, Mazein, A., additional, Meiser, A., additional, Middelveld, R.J.M., additional, Miralpeix, M., additional, Montuschi, P., additional, Mores, N., additional, Murray, C.S., additional, Musial, J., additional, Myles, D., additional, Pahus, L., additional, Pandis, I., additional, Pavlidis, S., additional, Postle, A., additional, Powel, P., additional, Praticò, G., additional, Rao, N., additional, Riley, J., additional, Roberts, A., additional, Roberts, G., additional, Rowe, A., additional, Sandström, T., additional, Schofield, J.P.R., additional, Seibold, W., additional, Selby, A., additional, Shaw, D.E., additional, Sigmund, R., additional, Singer, F., additional, Skipp, P.J., additional, Sousa, A.R., additional, Sterk, P.J., additional, Sun, K., additional, Thornton, B., additional, van Aalderen, W.M., additional, van Geest, M., additional, Vestbo, J., additional, Vissing, N.H., additional, Wagener, A.H., additional, Wagers, S.S., additional, Weiszhart, Z., additional, Wheelock, C.E., additional, and Wilson, S.J., additional

Published
2019
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34. CCNE1amplification is synthetic lethal with PKMYT1 kinase inhibition

Author

Gallo, David, Young, Jordan T. F., Fourtounis, Jimmy, Martino, Giovanni, Álvarez-Quilón, Alejandro, Bernier, Cynthia, Duffy, Nicole M., Papp, Robert, Roulston, Anne, Stocco, Rino, Szychowski, Janek, Veloso, Artur, Alam, Hunain, Baruah, Prasamit S., Fortin, Alexanne Bonneau, Bowlan, Julian, Chaudhary, Natasha, Desjardins, Jessica, Dietrich, Evelyne, Fournier, Sara, Fugère-Desjardins, Chloe, Goullet de Rugy, Theo, Leclaire, Marie-Eve, Liu, Bingcan, Bhaskaran, Vivek, Mamane, Yael, Melo, Henrique, Nicolas, Olivier, Singhania, Akul, Szilard, Rachel K., Tkáč, Ján, Yin, Shou Yun, Morris, Stephen J., Zinda, Michael, Marshall, C. Gary, and Durocher, Daniel

Abstract

Amplification of the CCNE1locus on chromosome 19q12 is prevalent in multiple tumour types, particularly in high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling and resistance to cytotoxic and targeted therapies1–4. To uncover therapeutic targets for tumours with CCNE1amplification, we undertook genome-scale CRISPR–Cas9-based synthetic lethality screens in cellular models of CCNE1amplification. Here we report that increasing CCNE1dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumour regressions when combined with gemcitabine in models of CCNE1amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively in CCNE1-overexpressing cells, promoting early mitosis in cells undergoing DNA synthesis. CCNE1overexpression disrupts CDK1 homeostasis at least in part through an early activation of the MMB–FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

Published
2022
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35. OnPLS-Based Multi-Block Data Integration : A Multivariate Approach to Interrogating Biological Interactions in Asthma

Author

Reinke, Stacey N., Galindo-Prieto, Beatriz, Skotare, Tomas, Broadhurst, David I., Singhania, Akul, Horowitz, Daniel, Djukanovic, Ratko, Hinks, Timothy S. C., Geladi, Paul, Trygg, Johan, Wheelock, Craig E., Reinke, Stacey N., Galindo-Prieto, Beatriz, Skotare, Tomas, Broadhurst, David I., Singhania, Akul, Horowitz, Daniel, Djukanovic, Ratko, Hinks, Timothy S. C., Geladi, Paul, Trygg, Johan, and Wheelock, Craig E.

Abstract

Integration of multiomics data remains a key challenge in fulfilling the potential of comprehensive systems biology. Multiple-block orthogonal projections to latent structures (OnPLS) is a Multi projection method that simultaneously models multiple data matrices, reducing feature space without relying on a priori biological knowledge. In order to improve the interpretability of OnPLS models, the associated multi-block variable influence on orthogonal projections (MB-VIOP) method is used to identify variables with the highest contribution to the model. This study combined OnPLS and MB-VIOP with interactive visualization methods to interrogate an exemplar multiomics study, using a subset of 22 individuals from an asthma cohort. Joint data structure in six data blocks was assessed: transcriptomics; metabolomics; targeted assays for sphingolipids, oxylipins, and fatty acids; and a clinical block including lung function, immune cell differentials, and cytokines. The model identified seven components, two of which had contributions from all blocks (globally joint structure) and five that had contributions from two to five blocks (locally joint structure). Components 1 and 2 were the most informative, identifying differences between healthy controls and asthmatics and a disease sex interaction, respectively. The interactions between features selected by MB-VIOP were visualized using chord plots, yielding putative novel insights into asthma disease pathogenesis, the effects of asthma treatment, and biological roles of uncharacterized genes. For example, the gene ATP6 V1G1, which has been implicated in osteoporosis, correlated with metabolites that are dysregulated by inhaled corticoid steroids (ICS), providing insight into the mechanisms underlying bone density loss in asthma patients taking ICS. These results show the potential for OnPLS, combined with MB-VIOP variable selection and interaction visualization techniques, to generate hypotheses from multiomics studies and in

Published
2018
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36. OnPLS-Based Multi-Block Data Integration: A Multivariate Approach to Interrogating Biological Interactions in Asthma

Author

Reinke, Stacey N., primary, Galindo-Prieto, Beatriz, additional, Skotare, Tomas, additional, Broadhurst, David I., additional, Singhania, Akul, additional, Horowitz, Daniel, additional, Djukanović, Ratko, additional, Hinks, Timothy S.C., additional, Geladi, Paul, additional, Trygg, Johan, additional, and Wheelock, Craig E., additional

Published
2018
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38. A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection

Author

Singhania, Akul, primary, Verma, Raman, additional, Graham, Christine M., additional, Lee, Jo, additional, Tran, Trang, additional, Richardson, Matthew, additional, Lecine, Patrick, additional, Leissner, Philippe, additional, Berry, Matthew P. R., additional, Wilkinson, Robert J., additional, Kaiser, Karine, additional, Rodrigue, Marc, additional, Woltmann, Gerrit, additional, Haldar, Pranabashis, additional, and O’Garra, Anne, additional

Published
2018
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39. Differential expression of an alternative splice variant of IL-12Rβ1 impacts early dissemination in the mouse and associates with disease outcome in both mouse and humans exposed to tuberculosis

Author

Das, Mrinal K., primary, Ray, Aurelie A., additional, Cai, Yi, additional, Singhania, Akul, additional, Graham, Christine M., additional, Liao, Mingfeng, additional, Fountain, Jeffrey J., additional, Pearl, John E., additional, Pareek, Manish, additional, Haldar, Pranab, additional, O’Garra, Anne, additional, Chen, Xinchun, additional, and Cooper, Andrea M., additional

Published
2018
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40. A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection

Author

Singhania, Akul, primary, Verma, Raman, additional, Graham, Christine M., additional, Lee, Jo, additional, Trang, Tran, additional, Richardson, Matthew, additional, Lecine, Patrick, additional, Leissner, Philippe, additional, Berry, Matthew P.R., additional, Wilkinson, Robert J., additional, Kaiser, Karine, additional, Rodrigue, Marc, additional, Woltmann, Gerrit, additional, Haldar, Pranabashis, additional, and O’Garra, Anne, additional

Published
2017
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44. Gender-Dependent Differences in Plasma Matrix Metalloproteinase-8 Elevated in Pulmonary Tuberculosis

Author

Sathyamoorthy, Tarangini, primary, Sandhu, Gurjinder, additional, Tezera, Liku B., additional, Thomas, Richard, additional, Singhania, Akul, additional, Woelk, Christopher H., additional, Dimitrov, Borislav D., additional, Agranoff, Dan, additional, Evans, Carlton A. W., additional, Friedland, Jon S., additional, and Elkington, Paul T., additional

Published
2015
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45. Whole Serum 3D LC-nESI-FTMS Quantitative Proteomics Reveals Sexual Dimorphism in the Milieu Intérieur of Overweight and Obese Adults

Author

Al-Daghri, Nasser M., primary, Al-Attas, Omar S., additional, Johnston, Harvey E., additional, Singhania, Akul, additional, Alokail, Majed S., additional, Alkharfy, Khalid M., additional, Abd-Alrahman, Sherif H., additional, Sabico, Shaun l., additional, Roumeliotis, Theodoros I., additional, Manousopoulou-Garbis, Antigoni, additional, Townsend, Paul A., additional, Woelk, Christopher H., additional, Chrousos, George. P., additional, and Garbis, Spiros D., additional

Published
2014
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46. An In-Depth Comparison of Latent HIV-1 Reactivation in Multiple Cell Model Systems and Resting CD4+ T Cells from Aviremic Patients

Author

Spina, Celsa A., primary, Anderson, Jenny, additional, Archin, Nancie M., additional, Bosque, Alberto, additional, Chan, Jonathan, additional, Famiglietti, Marylinda, additional, Greene, Warner C., additional, Kashuba, Angela, additional, Lewin, Sharon R., additional, Margolis, David M., additional, Mau, Matthew, additional, Ruelas, Debbie, additional, Saleh, Suha, additional, Shirakawa, Kotaro, additional, Siliciano, Robert F., additional, Singhania, Akul, additional, Soto, Paula C., additional, Terry, Valeri H., additional, Verdin, Eric, additional, Woelk, Christopher, additional, Wooden, Stacey, additional, Xing, Sifei, additional, and Planelles, Vicente, additional

Published
2013
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49. Whole Serum 3D LC-nESI-FTMS Quantitative Proteomics Reveals Sexual Dimorphism in the Milieu Intérieurof Overweight and Obese Adults

Author

Al-Daghri, Nasser M., Al-Attas, Omar S., Johnston, Harvey E., Singhania, Akul, Alokail, Majed S., Alkharfy, Khalid M., Abd-Alrahman, Sherif H., Sabico, Shaun l., Roumeliotis, Theodoros I., Manousopoulou-Garbis, Antigoni, Townsend, Paul A., Woelk, Christopher H., Chrousos, George. P., and Garbis, Spiros D.

Abstract

Linking gender-specific differences to the molecular etiology of obesity has been largely based on genomic and transcriptomic evidence lacking endophenotypic insight and is not applicable to the extracellular fluid compartments, or the milieu intérieur, of the human body. To address this need, this study profiled the whole serum proteomes of age-matched nondiabetic overweight and obese females (n= 28) and males (n= 31) using a multiplex design with pooled biological and technical replicates. To bypass basic limitations of immunodepletion-based strategies, subproteome enrichment by size-exclusion chromatography (SuPrE-SEC) followed by iTRAQ 2D-LC-nESI-FTMS analysis was used. The study resulted in the reproducible analysis of 2472 proteins (peptide FDR < 5%, q< 0.05). A total of 248 proteins exhibited significant modulation between men and women (p< 0.05) that mapped to pathways associated with β-estradiol, lipid and prostanoid metabolism, vitamin D function, immunity/inflammation, and the complement and coagulation cascades. This novel endophenotypic signature of gender-specific differences in whole serum confirmed and expanded the results of previous physiologic and pharmacologic studies exploring sexual dimorphism at the genomic and transcriptomic level in tissues and cells. Conclusively, the multifactorial and pleiotropic nature of human obesity exhibits sexual dimorphism in the circulating proteome of importance to clinical study design.

Published
2014
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