1,809 results on '"Gaggar, A"'
Search Results
52. Transcriptional firing represses bactericidal activity in cystic fibrosis airway neutrophils
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Margaroli, Camilla, Moncada-Giraldo, Diego, Gulick, Dalia Arafat, Dobosh, Brian, Giacalone, Vincent D., Forrest, Osric A., Sun, Fangxu, Gu, Chunhui, Gaggar, Amit, Kissick, Haydn, Wu, Ronghu, Gibson, Greg, and Tirouvanziam, Rabindra
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- 2021
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53. Genome-Scale Identification, in Silico Characterization and Interaction Study Between Wheat SNARE and NPSN Gene Families Involved in Vesicular Transport.
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Payal Gaggar, Manish Kumar, and Kunal Mukhopadhyay
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- 2021
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54. The endothelial glycocalyx in critical illness: A pediatric perspective
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Robert P. Richter, Gregory A. Payne, Namasivayam Ambalavanan, Amit Gaggar, and Jillian R. Richter
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Children ,Critical illness ,Endothelial glycocalyx ,Vascular biology ,Biology (General) ,QH301-705.5 - Abstract
The vascular endothelium is the interface between circulating blood and end organs and thus has a critical role in preserving organ function. The endothelium is lined by a glycan-rich glycocalyx that uniquely contributes to endothelial function through its regulation of leukocyte and platelet interactions with the vessel wall, vascular permeability, coagulation, and vasoreactivity. Degradation of the endothelial glycocalyx can thus promote vascular dysfunction, inflammation propagation, and organ injury. The endothelial glycocalyx and its role in vascular pathophysiology has gained increasing attention over the last decade. While studies characterizing vascular glycocalyx injury and its downstream consequences in a host of adult human diseases and in animal models has burgeoned, studies evaluating glycocalyx damage in pediatric diseases are relatively few. As children have unique physiology that differs from adults, significant knowledge gaps remain in our understanding of the causes and effects of endothelial glycocalyx disintegrity in pediatric critical illness. In this narrative literature overview, we offer a unique perspective on the role of the endothelial glycocalyx in pediatric critical illness, drawing from adult and preclinical data in addition to pediatric clinical experience to elucidate how marked derangement of the endothelial surface layer may contribute to aberrant vascular biology in children. By calling attention to this nascent field, we hope to increase research efforts to address important knowledge gaps in pediatric vascular biology that may inform the development of novel therapeutic strategies.
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- 2022
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55. Targeted long-read sequencing reveals clonally expanded HBV-associated chromosomal translocations in patients with chronic hepatitis B
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Nicholas van Buuren, Ricardo Ramirez, Cameron Soulette, Vithika Suri, Dong Han, Lindsey May, Scott Turner, P.C. Parvangada, Ross Martin, Henry L.Y. Chan, Patrick Marcellin, Maria Buti, Nam Bui, Neeru Bhardwaj, Anuj Gaggar, Li Li, Hongmei Mo, and Becket Feierbach
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Integrated HBV DNA ,Chronic HBV ,Chromosomal translocations ,Clonal expansion ,Long-read sequencing ,Targeted sequencing ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: HBV infects over 257 million people worldwide and is associated with the development of hepatocellular carcinoma (HCC). Integration of HBV DNA into the host genome is likely a key driver of HCC oncogenesis. Here, we utilise targeted long-read sequencing to determine the structure of HBV DNA integrations as well as full isoform information of HBV mRNA with more accurate quantification than traditional next generation sequencing platforms. Methods: DNA and RNA were isolated from fresh frozen liver biopsies collected within the GS-US-174-0149 clinical trial. A pan-genotypic panel of biotinylated oligos was developed to enrich for HBV sequences from sheared genomic DNA (∼7 kb) and full-length cDNA libraries from poly-adenylated RNA. Samples were sequenced on the PacBio long-read platform and analysed using a custom bioinformatic pipeline. Results: HBV-targeted long-read DNA sequencing generated high coverage data spanning entire integrations. Strikingly, in 13 of 42 samples (31%) we were able to detect HBV sequences flanked by 2 different chromosomes, indicating a chromosomal translocation associated with HBV integration. Chromosomal translocations were unique to each biopsy sample, suggesting that each originated randomly, and in some cases had evidence of clonal expansion. Using targeted long-read RNA sequencing, we determined that upwards of 95% of all HBV transcripts in patients who are HBeAg-positive originate from cccDNA. In contrast, patients who are HBeAg-negative expressed mostly HBsAg from integrations. Conclusions: Targeted lso-Seq allowed for accurate quantitation of the HBV transcriptome and assignment of transcripts to either cccDNA or integration origins. The existence of multiple unique HBV-associated inter-chromosomal translocations in non-HCC CHB patient liver biopsies suggests a novel mechanism with mutagenic potential that may contribute to progression to HCC. Lay summary: Fresh frozen liver biopsies from patients infected with HBV were subjected to targeted long-read RNA and DNA sequencing. Long-read RNA sequencing captures entire HBV transcripts in a single read, allowing for resolution of overlapping transcripts from the HBV genome. This resolution allowed us to quantify the burden of transcription from integrations vs. cccDNA origin in individual patients. Patients who were HBeAg-positive had a significantly larger fraction of the HBV transcriptome originating from cccDNA compared with those who were HBeAg-negative. Long-read DNA sequencing captured entire integrated HBV sequences including multiple kilobases of flanking host sequence within single reads. This resolution allowed us to describe integration events flanked by 2 different host chromosomes, indicating that integrated HBV DNA are associated with inter-chromosomal translocations. This may lead to significant transcriptional dysregulation and drive progression to HCC.
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- 2022
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56. MicroRNA 219-5p inhibits alveolarization by reducing platelet derived growth factor receptor-alpha
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Amelia Freeman, Luhua Qiao, Nelida Olave, Gabriel Rezonzew, Samuel Gentle, Brian Halloran, Gloria S. Pryhuber, Amit Gaggar, Trent E. Tipple, Namasivayam Ambalavanan, and Charitharth Vivek Lal
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Lung development ,Infant ,Bronchopulmonary dysplasia ,microRNAs ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background MicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Previous genome-wide analysis studies in preterm infants indicate that pathways of miR 219-5p are important in infants with Bronchopulmonary Dysplasia (BPD). Methods Here we report a prospective cohort study of extremely preterm neonates wherein infants diagnosed with severe BPD expressed increased airway miR-219-5p and decreased platelet derived growth factor receptor alpha (PDGFR-α), a target of mir-219-5p and a key regulator of alveolarization, compared to post-conception age-matched term infants. Results miR-219-5p was highly expressed in the pulmonary epithelial lining in lungs of infants with BPD by in situ hybridization of human infant lungs. In both in vitro and in vivo (mouse) models of BPD, miR-219-5p was increased on exposure to hyperoxia compared with the normoxia control, with a complementary decrease of PDGFR-α. To further confirm the target relationship between miR‐219 and PDGFR-α, pulmonary epithelial cells (MLE12) and lung primary fibroblasts were treated with a mimic of miR-219-5p and a locked nucleic acid (LNA) based inhibitor of miR-219-5p. In comparison with the control group, the level of miR‐219 increased significantly after miR‐219 mimic treatment, while the level of PDGFR-α declined markedly. LNA exposure increased PDGFR-α. Moreover, in BPD mouse model, over-expression of miR-219-5p inhibited alveolar development, indicated by larger alveolar spaces accompanied by reduced septation. Conclusions Taken together, our results demonstrate that increased miR-219-5p contributes to the pathogenesis of BPD by targeting and reducing PDGFR-α. The use of specific miRNA antagonists may be a therapeutic strategy for preventing the development of BPD.
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- 2021
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57. The Matrix Reloaded—The Role of the Extracellular Matrix in Cancer
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Hans Raskov, Shruti Gaggar, Asma Tajik, Adile Orhan, and Ismail Gögenur
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extracellular matrix ,composition ,cancer ,desmoplasia ,therapeutical targets ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
As the core component of all organs, the extracellular matrix (ECM) is an interlocking macromolecular meshwork of proteins, glycoproteins, and proteoglycans that provides mechanical support to cells and tissues. In cancer, the ECM can be remodelled in response to environmental cues, and it controls a plethora of cellular functions, including metabolism, cell polarity, migration, and proliferation, to sustain and support oncogenesis. The biophysical and biochemical properties of the ECM, such as its structural arrangement and being a reservoir for bioactive molecules, control several intra- and intercellular signalling pathways and induce cytoskeletal changes that alter cell shapes, behaviour, and viability. Desmoplasia is a major component of solid tumours. The abnormal deposition and composition of the tumour matrix lead to biochemical and biomechanical alterations that determine disease development and resistance to treatment. This review summarises the complex roles of ECM in cancer and highlights the possible therapeutic targets and how to potentially remodel the dysregulated ECM in the future. Furthering our understanding of the ECM in cancer is important as the modification of the ECM will probably become an important tool in the characterisation of individual tumours and personalised treatment options.
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- 2023
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58. PNPLA3 polymorphisms are associated with raised alanine aminotransferase levels in hepatitis C virus genotype 3
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Agrawal, Tanvi, Gaggar, Anuj, Subramanian, Mani, Kottilil, Shyam, Choudhary, Abhijit, Rao, Padaki N., Shah, Sameer, and Trehanpati, Nirupma
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- 2020
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59. An in vivo model for extracellular vesicle–induced emphysema
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Camilla Margaroli, Matthew C. Madison, Liliana Viera, Derek W. Russell, Amit Gaggar, Kristopher R. Genschmer, and J. Edwin Blalock
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Pulmonology ,Medicine - Abstract
Chronic obstructive pulmonary disease (COPD) is a debilitating chronic disease and the third-leading cause of mortality worldwide. It is characterized by airway neutrophilia, promoting tissue injury through release of toxic mediators and proteases. Recently, it has been shown that neutrophil-derived extracellular vesicles (EVs) from lungs of patients with COPD can cause a neutrophil elastase–dependent (NE-dependent) COPD-like disease upon transfer to mouse airways. However, in vivo preclinical models elucidating the impact of EVs on disease are lacking, delaying opportunities for therapeutic testing. Here, we developed an in vivo preclinical mouse model of lung EV–induced COPD. EVs from in vivo LPS-activated mouse neutrophils induced COPD-like disease in naive recipients through an α-1 antitrypsin–resistant, NE-dependent mechanism. Together, these results show a key pathogenic and mechanistic role for neutrophil-derived EVs in a mouse model of COPD. Broadly, the in vivo model described herein could be leveraged to develop targeted therapies for severe lung disease.
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- 2022
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60. Nontypeable Haemophilus influenzae Redox Recycling of Protein Thiols Promotes Resistance to Oxidative Killing and Bacterial Survival in Biofilms in a Smoke-Related Infection Model
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Benjamin C. Hunt, Xin Xu, Amit Gaggar, and W. Edward Swords
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Haemophilus influenzae ,bacteria ,biofilm ,pneumonia ,smoking-related infection ,Microbiology ,QR1-502 - Abstract
ABSTRACT Smoke exposure is a risk factor for community-acquired pneumonia, which is typically caused by host-adapted airway opportunists like nontypeable Haemophilus influenzae (NTHi). Genomic analyses of NTHi revealed homologs of enzymes with predicted roles in reduction of protein thiols, which can have key roles in oxidant resistance. Using a clinical NTHi isolate (NTHi 7P49H1), we generated isogenic mutants in which homologs of glutathione reductase (open reading frame NTHI 0251), thioredoxin-dependent thiol peroxidase (NTHI 0361), thiol peroxidase (NTHI 0907), thioredoxin reductase (NTHI 1327), and glutaredoxin/peroxiredoxin (NTHI 0705) were insertionally inactivated. Bacterial protein analyses revealed that protein oxidation after hydrogen peroxide treatment was elevated in all the mutant strains. Similarly, each of these mutants was less resistant to oxidative killing than the parental strain; these phenotypes were reversed by genetic complementation. Analysis of biofilm communities formed by the parental and mutant strains showed reduction in overall biofilm thickness and density and significant sensitization of bacteria within the biofilm structure to oxidative killing. Experimental respiratory infection of smoke-exposed mice with NTHi 7P49H1 showed significantly increased bacterial counts compared to control mice. Immunofluorescent staining of lung tissues showed NTHi communities on lung mucosae, interspersed with neutrophil extracellular traps; these bacteria had transcript profiles consistent with NTHi biofilms. In contrast, infection with the panel of NTHi mutants showed a significant decrease in bacterial load. Comparable results were observed in bactericidal assays with neutrophil extracellular traps in vitro. Thus, we conclude that thiol-mediated redox homeostasis is a determinant of persistence of NTHi within biofilm communities. IMPORTANCE Chronic bacterial respiratory infections are a significant problem for smoke-exposed individuals, especially those with chronic obstructive pulmonary disease (COPD). These infections often persist despite antibiotic use. Thus, the bacteria remain and contribute to the development of inflammation and other respiratory problems. Respiratory bacteria often form biofilms within the lungs; during growth in a biofilm, their antibiotic and oxidative stress resistance is incredibly heightened. It is well documented that redox homeostasis genes are upregulated during this phase of growth. Many common respiratory pathogens, such as NTHi and Streptococcus pneumoniae, are reliant on scavenging from the host the necessary components they need to maintain these redox systems. This work begins to lay the foundation for exploiting this requirement and thiol redox homeostasis pathways of these bacteria as a therapeutic target for managing chronic respiratory bacterial infections, which are resistant to traditional antibiotic treatments alone.
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- 2022
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61. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study
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Lampertico, Pietro, Buti, Maria, Fung, Scott, Ahn, Sang Hoon, Chuang, Wan-Long, Tak, Won Young, Ramji, Alnoor, Chen, Chi-Yi, Tam, Edward, Bae, Ho, Ma, Xiaoli, Flaherty, John F, Gaggar, Anuj, Lau, Audrey, Liu, Yang, Wu, George, Suri, Vithika, Tan, Susanna K, Subramanian, G Mani, Trinh, Huy, Yoon, Seung-Kew, Agarwal, Kosh, Lim, Young-Suk, and Chan, Henry L Y
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- 2020
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62. Long-term Benefits of Sustained Virologic Response for Patient-Reported Outcomes in Patients With Chronic Hepatitis C Virus Infection
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Younossi, Zobair M., Stepanova, Maria, Racila, Andrei, Afendy, Arian, Lawitz, Eric J., Schwabe, Christian, Ruane, Peter J., Lalezari, Jay, Reddy, K. Rajender, Jacobson, Ira M., Muir, Andrew J., Gaggar, Anuj, Myers, Robert P., Younossi, Issah, and Nader, Fatema
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- 2020
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63. Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis
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Turnbull, Andrew R., Pyle, Chloe J., Patel, Dhiren F., Jackson, Patricia L., Hilliard, Tom N., Regamey, Nicolas, Tan, Hui-Leng, Brown, Sarah, Thursfield, Rebecca, Short, Christopher, Mc Fie, Megan, Alton, Eric W.F.W., Gaggar, Amit, Blalock, J. Edwin, Lloyd, Clare M., Bush, Andrew, Davies, Jane C., and Snelgrove, Robert J.
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- 2020
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64. Ledipasvir-sofosbuvir in Adolescents With Chronic Hepatitis C and Hematological Malignancies Undergoing Chemotherapy
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El-Sayed, Manal Hamdy, Ebeid, Fatma S. Elsayed, Zekri, Abdel-Rahman, Massetto, Benedetta, Kersey, Kathryn, Zhang, Fangqiu, Gaggar, Anuj, Elsayed, Walaa, and El-Haddad, Alaa
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- 2022
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65. Spatial Transcriptomics Resolve an Emphysema-specific Lymphoid Follicle B Cell Signature in COPD
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Rojas-Quintero, Joselyn, primary, Ochsner, Scott A, additional, New, Felicia, additional, Divakar, Prajan, additional, Yang, Chen Xi, additional, Wu, Tianshi David, additional, Robinson, Jerid, additional, Shimoga Chandrashekar, Darshan, additional, Banovich, Nicholas E, additional, Rosas, Ivan O., additional, Sauler, Maor, additional, Kheradmand, Farrah, additional, Gaggar, Amit, additional, Margaroli, Camilla, additional, San Jose Estepar, Raul, additional, McKenna, Neil J, additional, and Polverino, Francesca, additional
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- 2023
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66. Protease-armed, Pathogenic Extracellular Vesicles Link Smoking and Chronic Obstructive Pulmonary Disease
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Madison, Matthew C., primary, Margaroli, Camilla, additional, Genschmer, Kristopher R., additional, Russell, Derek W., additional, Wells, James M., additional, Sari, Ezgi, additional, Soto-Vazquez, Yixel M., additional, Guo, Yuan-Yuan, additional, Mincham, Kyle T., additional, Snelgrove, Robert J., additional, Gaggar, Amit, additional, and Blalock, James E., additional
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- 2023
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67. 155 Normal, but not cystic fibrosis, sputum inhibits pro-inflammatory Orai1 Ca2+ signaling
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Goriounova, A., primary, Wrennall, J., additional, Gaggar, A., additional, and Tarran, R., additional
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- 2023
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68. 172 Epidermal growth factor receptor–inducible nitric oxide synthase signaling axis modulates bacterial killing in cystic fibrosis airway neutrophils
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Soto-Vazquez, Y., primary, Koff, J., additional, Tirouvanziam, R., additional, Gaggar, A., additional, and Margaroli, C., additional
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- 2023
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69. Spatially Resolved Whole Transcriptome Analysis of Histologically-Characterized Tissue Microarray of Patient-Matched Primary and Recurrent Glioblastomas to Identify Underlying Mechanisms of Treatment Resistance
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Lee, K.J., primary, Chkheidze, R., additional, Alrefai, H., additional, Margaroli, C., additional, Gaggar, A., additional, Nguyen, T., additional, Anderson, J.C., additional, Bash, R., additional, Miller, C.R., additional, and Willey, C.D., additional
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- 2023
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70. Differences in airway microbiome and metabolome of single lung transplant recipients
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Nirmal S. Sharma, Grant Vestal, Keith Wille, Kapil N. Patel, Feng Cheng, Srinivas Tipparaju, Sultan Tousif, Mudassir M. Banday, Xin Xu, Landon Wilson, Viswam S. Nair, Casey Morrow, Don Hayes, Andreas Seyfang, Stephen Barnes, Jessy S. Deshane, and Amit Gaggar
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Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Recent studies suggest that alterations in lung microbiome are associated with occurrence of chronic lung diseases and transplant rejection. To investigate the host-microbiome interactions, we characterized the airway microbiome and metabolome of the allograft (transplanted lung) and native lung of single lung transplant recipients. Methods BAL was collected from the allograft and native lungs of SLTs and healthy controls. 16S rRNA microbiome analysis was performed on BAL bacterial pellets and supernatant used for metabolome, cytokines and acetylated proline-glycine-proline (Ac-PGP) measurement by liquid chromatography-high-resolution mass spectrometry. Results In our cohort, the allograft airway microbiome was distinct with a significantly higher bacterial burden and relative abundance of genera Acinetobacter & Pseudomonas. Likewise, the expression of the pro-inflammatory cytokine VEGF and the neutrophil chemoattractant matrikine Ac-PGP in the allograft was significantly higher. Airway metabolome distinguished the native lung from the allografts and an increased concentration of sphingosine-like metabolites that negatively correlated with abundance of bacteria from phyla Proteobacteria. Conclusions Allograft lungs have a distinct microbiome signature, a higher bacterial biomass and an increased Ac-PGP compared to the native lungs in SLTs compared to the native lungs in SLTs. Airway metabolome distinguishes the allografts from native lungs and is associated with distinct microbial communities, suggesting a functional relationship between the local microbiome and metabolome.
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- 2020
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71. Durability of Hepatitis B Surface Antigen Loss With Nucleotide Analogue and Peginterferon Therapy in Patients With Chronic Hepatitis B
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Anna S. Lok, Fabien Zoulim, Geoffrey Dusheiko, Henry L.Y. Chan, Maria Buti, Marc G. Ghany, Anuj Gaggar, Jenny C. Yang, George Wu, John F. Flaherty, G. Mani Subramanian, Stephen Locarnini, and Patrick Marcellin
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
In patients with chronic hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) is considered a functional cure. However, HBsAg loss is uncommon with existing therapies, and predictive factors associated with HBsAg seroreversion are unknown. Using pooled data from three phase 3 clinical trials of patients with CHB treated with nucleos(t)ide analogue (NUC) monotherapy or peginterferon (Peg‐IFN) ± NUC combination therapy, we conducted a retrospective analysis to characterize patients who achieved sustained HBsAg loss, the predictors of HBsAg seroreversion, and the impact of hepatitis B surface antibody (anti‐HBs) seroconversion on durability of HBsAg loss. In these three international trials, 1,381 adults with CHB received either NUC monotherapy for up to 10 years or Peg‐IFN‐containing regimens for up to 1 year. A total of 55 patients had confirmed HBsAg loss, defined as two or more consecutive negative‐qualitative HBsAg results, with a minimum of one repeat result after the end of treatment. Throughout a median of 96 (quartile [Q]1, Q3, 46, 135) weeks follow‐up after HBsAg loss, HBsAg loss was durable in 82% (n = 45) of patients, with 10 patients experiencing HBsAg seroreversion. Anti‐HBs seroconversion was observed during follow‐up in 78% of patients who lost HBsAg and in 60% of those who subsequently seroreverted. In analyzing predictors of HBsAg seroreversion, study treatment was significant, yet anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not. Risk of HBsAg seroreversion was observed to be lower if HBsAg loss was sustained through the off‐treatment week 24 visit (8/10 seroreversions occurred by posttreatment week 24). Conclusion: HBsAg loss after NUC or Peg‐IFN‐containing regimens was durable in 82% of patients with CHB. Anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not significantly associated with durability of HBsAg loss.
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- 2020
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72. MicroRNA 219-5p inhibits alveolarization by reducing platelet derived growth factor receptor-alpha
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Freeman, Amelia, Qiao, Luhua, Olave, Nelida, Rezonzew, Gabriel, Gentle, Samuel, Halloran, Brian, Pryhuber, Gloria S., Gaggar, Amit, Tipple, Trent E., Ambalavanan, Namasivayam, and Lal, Charitharth Vivek
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- 2021
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73. The matrikine acetyl-proline-glycine-proline and clinical features of COPD: findings from SPIROMICS
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J. Michael Wells, Dongqi Xing, Liliana Viera, Robert M. Burkes, Yixin Wu, Surya P. Bhatt, Mark T. Dransfield, David J. Couper, Wanda O’Neal, Eric A. Hoffman, Amit Gaggar, Igor Barjaktarevic, Jeffrey L. Curtis, Wassim W. Labaki, Mei Lan K. Han, Christine M. Freeman, Nirupama Putcha, Thomas Schlange, J. Edwin Blalock, and for the SPIROMICS Investigators,
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COPD ,Acetyl proline-glycine-proline (AcPGP) ,Sputum ,Matrikine ,Inflammation ,Biomarker ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD. Methods Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation. Results The 182 COPD participants in the analysis were 66 ± 8 years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61 ± 1.89 ng/mL (mean ± SD) in sputum and 0.60 ± 1.13 ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV1/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk. Conclusions In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up. Trial registration ClinicalTrials.gov: NCT01969344 (SPIROMICS).
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- 2019
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74. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study
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Gane, Edward, Verdon, Daniel J., Brooks, Anna E., Gaggar, Anuj, Nguyen, Anh Hoa, Subramanian, G. Mani, Schwabe, Christian, and Dunbar, P. Rod
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- 2019
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75. HLA-C and KIR permutations influence chronic obstructive pulmonary disease risk
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Takudzwa Mkorombindo, Thi K. Tran-Nguyen, Kaiyu Yuan, Yingze Zhang, Jianmin Xue, Gerard J. Criner, Young-il Kim, Joseph M. Pilewski, Amit Gaggar, Michael H. Cho, Frank C. Sciurba, and Steven R. Duncan
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Immunology ,Pulmonology ,Medicine - Abstract
A role for hereditary influences in the susceptibility for chronic obstructive pulmonary disease (COPD) is widely recognized. Cytotoxic lymphocytes are implicated in COPD pathogenesis, and functions of these leukocytes are modulated by interactions between their killer cell Ig-like receptors (KIR) and human leukocyte antigen–Class I (HLA–Class I) molecules on target cells. We hypothesized HLA–Class I and KIR inheritance affect risks for COPD. HLA–Class I alleles and KIR genotypes were defined by candidate gene analyses in multiple cohorts of patients with COPD (total n = 392) and control smokers with normal spirometry (total n = 342). Compared with controls, patients with COPD had overrepresentations of HLA-C*07 and activating KIR2DS1, with underrepresentations of HLA-C*12. Particular HLA-KIR permutations were synergistic; e.g., the presence of HLA-C*07 + KIR2DS1 + HLA-C12null versus HLAC*07null + KIR2DS1null + HLA-C12 was associated with COPD, especially among HLA-C1 allotype homozygotes. Cytotoxicity of COPD lymphocytes was more enhanced by KIR stimulation than those of controls and was correlated with lung function. These data show HLA-C and KIR polymorphisms strongly influence COPD susceptibility and highlight the importance of lymphocyte-mediated cytotoxicity in COPD pathogenesis. Findings here also indicate that HLA-KIR typing could stratify at-risk patients and raise possibilities that HLA-KIR axis modulation may have therapeutic potential.
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- 2021
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76. Efficacy of a Probiotic and Herbal Supplement in Models of Lung Inflammation
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Nancy M. Wenger, Luhua Qiao, Teodora Nicola, Zoha Nizami, Xin Xu, Kent A. Willis, Namasivayam Ambalavanan, Amit Gaggar, and Charitharth Vivek Lal
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lung inflammation ,probiotic supplement ,chronic pulmonary disease ,Biology (General) ,QH301-705.5 - Abstract
Background: Gut microbiome dysbiosis is associated with lung disease through the gut-lung axis. Abundant proteobacteria increase MMP-9 and contribute to tissue proteolysis followed by neutrophil recruitment, lung tissue injury, and perpetuation of chronic lung disease. We sought to determine if a scientifically formulated probiotic and herbal supplement could attenuate neutrophilic inflammation and improve lung structure and function in models of lung inflammation. Methods: For in vitro experiments, epithelial cells exposed to proteobacteria were treated with resB—a blend of three probiotic Lactobacillus strains and turmeric, holy basil, and vasaka herbal extracts. For in vivo experimentation, mice exposed to pulmonary proteobacteria-derived lipopolysaccharide were treated by gavage with resB. Results: In vitro, the bacterial and herbal components of resB decreased activity of the MMP-9 pathway. Mice exposed to LPS and pre- and post-treated with resB had decreased neutrophil recruitment and inflammatory biomarkers in bronchoalveolar lavage fluid, serum, and lung tissue compared to untreated mice. Conclusions: This study describes the mechanisms and efficacy of probiotic and herbal blend in pre-clinical models of lung injury and inflammation.
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- 2022
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77. Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection
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Cheng, Xiaoming, Uchida, Takuro, Xia, Yuchen, Umarova, Regina, Liu, Chun-Jen, Chen, Pei-Jer, Gaggar, Anuj, Suri, Vithika, Mucke, Marcus M., Vermehren, Johannes, Zeuzem, Stefan, Teraoka, Yuji, Osawa, Mitsutaka, Aikata, Hiroshi, Tsuji, Keiji, Mori, Nami, Hige, Shuhei, Karino, Yoshiyasu, Imamura, Michio, Chayama, Kazuaki, and Liang, T. Jake
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United States. Food and Drug Administration ,Sofosbuvir -- Health aspects ,Backup software -- Health aspects ,Biological response modifiers -- Health aspects ,Medical research -- Health aspects ,Infection -- Health aspects ,Hepatitis C virus -- Health aspects ,Interferon -- Health aspects ,Comorbidity -- Health aspects ,Hepatitis B -- Health aspects ,Backup software ,Health care industry - Abstract
In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons., Introduction Hepatitis B virus (HBV) and hepatitis C virus (HCV) together infect more than 300 million people worldwide. Due to the shared modes of transmission and epidemiological features, they frequently [...]
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- 2020
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78. Application of smoothed particle hydrodynamics for the simulation and analysis of vibratory finishing process
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Gaggar, Saarang, Vasudevan, Durga, Kumar, Pankaj, and Mitra, Santanu
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- 2020
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79. Therapeutic effect of two strategies directed at disruption of pathogenic neutrophil extracellular vesicles in a murine emphysema model
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Kristopher R. Genschmer, Matthew Madison, Liliana Viera, Camilla Margaroli, Amit Gaggar, J. Edwin Blalock, and Derek W. Russell
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Pulmonary and Respiratory Medicine ,Physiology ,Physiology (medical) ,Cell Biology - Abstract
Protamine sulfate facilitates the removal of neutrophil elastase (NE) from the surface of extracellular vesicles from activated neutrophils. This “free” NE is no longer protected from inhibition by its endogenous anti-protease, α-1-anti-trypsin. This function of protamine sulfate highlights it as a potential therapeutic strategy for COPD, which may attenuate the disease process.
- Published
- 2023
80. Optimisation of the use of APRI and FIB-4 to rule out cirrhosis in patients with chronic hepatitis B: results from the SONIC-B study
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Sonneveld, Milan J, Brouwer, Willem P, Chan, Henry L-Y, Piratvisuth, Teerha, Jia, Ji-Dong, Zeuzem, Stefan, Liaw, Yun-Fan, Hansen, Bettina E, Choi, Hannah, Wat, Cynthia, Pavlovic, Vedran, Gaggar, Anuj, Xie, Qing, Buti, Maria, de Knegt, Robert J, and Janssen, Harry L A
- Published
- 2019
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81. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials
- Author
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Buti, Maria, Wong, David K, Gane, Edward, Flisiak, Robert, Manns, Michael, Kaita, Kelly, Janssen, Harry L A, Op den Brouw, Marjoleine, Jump, Belinda, Kitrinos, Kathryn, Crans, Gerald, Flaherty, John, Gaggar, Anuj, and Marcellin, Patrick
- Published
- 2019
- Full Text
- View/download PDF
82. Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy
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Hans Raskov, Adile Orhan, Shruti Gaggar, and Ismail Gögenur
- Subjects
cancer-associated fibroblasts ,tumor-associated macrophages ,tumor microenvironment ,cancer immunotherapy ,cancer biology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Our understanding of the tumor microenvironment (TME), including the interplay between tumor cells, stromal cells, immune cells, and extracellular matrix components, is mandatory for the innovation of new therapeutic approaches in cancer. The cell-cell communication within the TME plays a pivotal role in the evolution and progression of cancer. Cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) are major cell populations in the stroma of all solid tumors and often exert protumorigenic functions; however, the origin and precise functions of CAF and TAM are still incompletely understood. CAF and TAM hold significant potential as therapeutic targets to improve outcomes in oncology when combined with existing therapies. The regulation of CAF/TAM communication and/or their differentiation could be of high impact for improving the future targeted treatment strategies. Nevertheless, there is much scope for research and innovation in this field with regards to the development of novel drugs. In this review, we elaborate on the current knowledge on CAF and TAM in cancer and cancer immunotherapy. Additionally, by focusing on their heterogenous functions in different stages and types of cancer, we explore their role as potential therapeutic targets and highlight certain aspects of their functions that need further research.
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- 2021
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83. Transcriptional firing represses bactericidal activity in cystic fibrosis airway neutrophils
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Camilla Margaroli, Diego Moncada-Giraldo, Dalia Arafat Gulick, Brian Dobosh, Vincent D. Giacalone, Osric A. Forrest, Fangxu Sun, Chunhui Gu, Amit Gaggar, Haydn Kissick, Ronghu Wu, Greg Gibson, and Rabindra Tirouvanziam
- Subjects
neutrophils ,transcriptional firing ,bacterial clearance ,chronic lung disease ,Medicine (General) ,R5-920 - Abstract
Summary: Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacterial infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of anabolic genes and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Treatment by the RNA polymerase II and III inhibitor α-amanitin restores the expression of key antimicrobial genes and increases the bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the site of inflammation via RNA and protein synthesis, leading to adaptations that affect their canonical functions (i.e., bacterial clearance).
- Published
- 2021
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84. Spatial mapping of SARS-CoV-2 and H1N1 lung injury identifies differential transcriptional signatures
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Camilla Margaroli, Paul Benson, Nirmal S. Sharma, Matthew C. Madison, Sarah W. Robison, Nitin Arora, Kathy Ton, Yan Liang, Liang Zhang, Rakesh P. Patel, and Amit Gaggar
- Subjects
SARS-CoV-2 ,COVID-19 ,H1N1 influenza ,ARDS ,spatial transcriptomics ,Medicine (General) ,R5-920 - Abstract
Summary: Severe SARS-CoV-2 infection often leads to the development of acute respiratory distress syndrome (ARDS), with profound pulmonary patho-histological changes post-mortem. It is not clear whether ARDS from SARS-CoV-2 is similar to that observed in influenza H1N1, another common viral cause of lung injury. Here, we analyze specific ARDS regions of interest utilizing a spatial transcriptomic platform on autopsy-derived lung tissue from patients with SARS-CoV-2 (n = 3), H1N1 (n = 3), and a dual infected individual (n = 1). Enhanced gene signatures in alveolar epithelium, vascular tissue, and lung macrophages identify not only increased regional coagulopathy but also increased extracellular remodeling, alternative macrophage activation, and squamous metaplasia of type II pneumocytes in SARS-CoV-2. Both the H1N1 and dual-infected transcriptome demonstrated an enhanced antiviral response compared to SARS-CoV-2. Our results uncover regional transcriptional changes related to tissue damage/remodeling, altered cellular phenotype, and vascular injury active in SARS-CoV-2 and present therapeutic targets for COVID-19-related ARDS.
- Published
- 2021
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85. A mechanism for matrikine regulation in acute inflammatory lung injury
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Sarah W. Robison, JinDong Li, Liliana Viera, Jonathan P. Blackburn, Rakesh P. Patel, J. Edwin Blalock, Amit Gaggar, and Xin Xu
- Subjects
COVID-19 ,Inflammation ,Medicine - Abstract
Proline-glycine-proline (PGP) and its acetylated form (Ac-PGP) are neutrophil chemoattractants generated by collagen degradation, and they have been shown to play a role in chronic inflammatory disease. However, the mechanism for matrikine regulation in acute inflammation has not been well established. Here, we show that these peptides are actively transported from the lung by the oligopeptide transporter, PEPT2. Following intratracheal instillation of Ac-PGP in a mouse model, there was a rapid decline in concentration of the labeled peptide in the bronchoalveolar lavage (BAL) over time and redistribution to extrapulmonary sites. In vitro knockdown of the PEPT2 transporter in airway epithelia or use of a competitive inhibitor of PEPT2, cefadroxil, significantly reduced uptake of Ac-PGP. Animals that received intratracheal Ac-PGP plus cefadroxil had higher levels of Ac-PGP in BAL and lung tissue. Utilizing an acute LPS-induced lung injury model, we demonstrate that PEPT2 blockade enhanced pulmonary Ac-PGP levels and lung inflammation. We further validated this effect using clinical samples from patients with acute lung injury in coculture with airway epithelia. This is the first study to our knowledge to determine the in vitro and in vivo significance of active matrikine transport as a mechanism of modulating acute inflammation and to demonstrate that it may serve as a potential therapeutic target.
- Published
- 2021
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86. Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Coinfection
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Sulkowski, Mark S, Naggie, Susanna, Lalezari, Jacob, Fessel, Walford Jeffrey, Mounzer, Karam, Shuhart, Margaret, Luetkemeyer, Anne F, Asmuth, David, Gaggar, Anuj, Ni, Liyun, Svarovskaia, Evguenia, Brainard, Diana M, Symonds, William T, Subramanian, G Mani, McHutchison, John G, Rodriguez-Torres, Maribel, and Dieterich, Douglas
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Emerging Infectious Diseases ,Liver Disease ,Clinical Research ,Digestive Diseases ,Hepatitis - C ,Genetics ,Clinical Trials and Supportive Activities ,HIV/AIDS ,Infectious Diseases ,Hepatitis ,Chronic Liver Disease and Cirrhosis ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Administration ,Oral ,Adult ,Aged ,Antiviral Agents ,Coinfection ,Drug Administration Schedule ,Drug Therapy ,Combination ,Female ,Genotype ,HIV Infections ,Hepacivirus ,Hepatitis C ,Humans ,Male ,Middle Aged ,RNA ,Viral ,Ribavirin ,Sofosbuvir ,Treatment Outcome ,Uridine Monophosphate ,Viral Load ,Young Adult ,PHOTON-1 Investigators ,Medical and Health Sciences ,General & Internal Medicine ,Biomedical and clinical sciences ,Health sciences - Abstract
ImportanceTreatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon.ObjectiveTo determine the rates of HCV eradication (sustained virologic response [SVR]) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment.Design, setting, and participantsOpen-label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/μL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/μL. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants.InterventionsTreatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks.Main outcomes and measuresThe primary study outcome was the proportion of patients with SVR (serum HCV
- Published
- 2014
87. Spatial Transcriptomics Resolve an Emphysema-Specific Lymphoid Follicle B Cell Signature in Chronic Obstructive Pulmonary Disease.
- Author
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Rojas-Quintero, Joselyn, Ochsner, Scott A., New, Felicia, Divakar, Prajan, Chen Xi Yang, Wu, Tianshi David, Robinson, Jerid, Chandrashekar, Darshan Shimoga, Banovich, Nicholas E., Rosas, Ivan O., Sauler, Maor, Kheradmand, Farrah, Gaggar, Amit, Margaroli, Camilla, Estepar, Raul San Jose, McKenna, Neil J., and Polverino, Francesca
- Subjects
CHRONIC obstructive pulmonary disease ,B cells ,TRANSCRIPTOMES ,GENE regulatory networks ,GENE expression - Abstract
Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. Objectives: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Methods: Lung sections from 40 patients with COPD and eversmokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. Measurements and Main Results: Overall, 115 LFs from eversmokers andGlobal Initiative for ChronicObstructive LungDisease (GOLD) 1-2 andGOLD3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cellmarker genes in subjects with severe emphysema. High-confidence transcriptional analysis revealed activation of an abnormal B cell activity signature in LFs (q-value= 2.56E-111). LFs frompatients withGOLD 1-2 COPDwith emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs frompatients with GOLD1-2COPD without emphysema showed an antiinflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cellmaturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed toward chronic B cell activation. Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2024
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88. Active transcription in the vascular bed characterizes rapid progression in idiopathic pulmonary fibrosis
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Sharma, Nirmal S., primary, Patel, Kapil, additional, Sari, Ezgi, additional, Shankar, Shruti, additional, Gastanadui, Maria G., additional, Moncada-Giraldo, Diego, additional, Soto-Vazquez, Yixel, additional, Stacks, Delores, additional, Hecker, Louise, additional, Dsouza, Kevin, additional, Banday, Mudassir, additional, O’Neill, Edward, additional, Benson, Paul, additional, Payne, Gregory, additional, Margaroli, Camilla, additional, and Gaggar, Amit, additional
- Published
- 2023
- Full Text
- View/download PDF
89. Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients
- Author
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Ondrej Podlaha, Edward Gane, Maurizia Brunetto, Scott Fung, Wan-Long Chuang, Calvin Q. Pan, Zhaoshi Jiang, Yang Liu, Neeru Bhardwaj, Prasenjit Mukherjee, John Flaherty, Anuj Gaggar, Mani Subramanian, Namiki Izumi, Shalimar, Young-Suk Lim, Patrick Marcellin, Maria Buti, Henry L. Y. Chan, and Kosh Agarwal
- Subjects
Medicine ,Science - Abstract
Abstract Despite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients’ clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to the negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient’s HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.
- Published
- 2019
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90. Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression
- Author
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Edward J. Gane, P. Rod Dunbar, Anna E. Brooks, Fangqiu Zhang, Diana Chen, Jeffrey J. Wallin, Nicholas van Buuren, Priyanka Arora, Simon P. Fletcher, Susanna K. Tan, Jenny C. Yang, Anuj Gaggar, Shyamasundaran Kottilil, and Lydia Tang
- Subjects
Hepatology - Published
- 2023
91. Different‐sized extracellular vesicles derived from stored red blood cells package diverse cargoes and cause distinct cellular effects
- Author
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Joo‐Yeun Oh, Marisa B. Marques, Xin Xu, Jindong Li, Kristopher R. Genschmer, Edward Phillips, Melissa F. Chimento, James Mobley, Amit Gaggar, and Rakesh P. Patel
- Subjects
Immunology ,Immunology and Allergy ,Hematology - Published
- 2023
92. IL-33 mediates Pseudomonas induced airway fibrogenesis and is associated with CLAD
- Author
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Mudassir M Banday, Sangeetha B Rao, Shruthi Shankar, Mudasir A. Khanday, Jon Finan, Edward O'Neill, Antonio Coppolino, Andreas Seyfang, Archit Kumar, Daniel E Rinewalt, Hilary J. Goldberg, Ann Woolley, Hari Reddy Mallidi, Gary Visner, Amit Gaggar, Kapil N Patel, and Nirmal S Sharma
- Subjects
Pulmonary and Respiratory Medicine ,Transplantation ,Surgery ,Cardiology and Cardiovascular Medicine - Published
- 2023
93. Prolyl endopeptidase contributes to early neutrophilic inflammation in acute myocardial transplant rejection
- Author
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Gregory A. Payne, Nirmal S. Sharma, Charitharth V. Lal, Chunyan Song, Lingling Guo, Camilla Margaroli, Liliana Viera, Siva Kumar, Jindong Li, Dongqi Xing, Melanie Bosley, Xin Xu, J. Michael Wells, James F. George, Jose Tallaj, Massoud Leesar, J. Edwin Blalock, and Amit Gaggar
- Subjects
Cardiology ,Transplantation ,Medicine - Abstract
Altered inflammation and tissue remodeling are cardinal features of cardiovascular disease and cardiac transplant rejection. Neutrophils have increasingly been understood to play a critical role in acute rejection and early allograft failure; however, discrete mechanisms that drive this damage remain poorly understood. Herein, we demonstrate that early acute cardiac rejection increases allograft prolyl endopeptidase (PE) in association with de novo production of the neutrophil proinflammatory matrikine proline-glycine-proline (PGP). In a heterotopic murine heart transplant model, PGP production and PE activity were associated with early neutrophil allograft invasion and allograft failure. Pharmacologic inhibition of PE with Z-Pro-prolinal reduced PGP, attenuated early neutrophil graft invasion, and reduced proinflammatory cytokine expression. Importantly, these changes helped preserve allograft rejection-free survival and function. Notably, within 2 independent patient cohorts, both PGP and PE activity were increased among patients with biopsy-proven rejection. The observed induction of PE and matrikine generation provide a link between neutrophilic inflammation and cardiovascular injury, represent a potential target to reduce allogenic immune responses, and uncover a mechanism of cardiovascular disease that has been previously unrecognized to our knowledge.
- Published
- 2021
- Full Text
- View/download PDF
94. Antiviral kinetics of tenofovir alafenamide and tenofovir disoproxil fumarate over 24 weeks in women of childbearing potential with chronic HBV.
- Author
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Calvin Q Pan, Ting-Tsung Chang, Si Hyun Bae, Maurizia Brunetto, Wai-Kay Seto, Carla S Coffin, Susanna K Tan, Shuyuan Mo, John F Flaherty, Anuj Gaggar, Mindie H Nguyen, Mustafa Kemal Çelen, Alexander Thompson, and Edward J Gane
- Subjects
Medicine ,Science - Abstract
Background/purposeUse of tenofovir disoproxil fumarate (TDF) improves patient outcomes in preventing mother-to-child transmission (pMTCT) of the hepatitis B virus (HBV) in mothers with chronic HBV and high viral loads. Given the lack of data for tenofovir alafenamide (TAF) in pMTCT, rates of early viral suppression with TAF and TDF were evaluated in women of childbearing potential (WOCBP) participating in 2 randomized, double-blind, Phase 3 studies in chronic HBV.MethodsIn a patient subset meeting WOCBP criteria and with baseline HBV DNA >200,000 IU/mL, rates of viral suppression with TAF or TDF in achieving the target of HBV DNA ResultsIn 275 of 1298 (21%) patients meeting WOCBP criteria with high viral load, 93% and 96% had HBV DNA ConclusionsIn WOCBP with high VL, no differences were found between TAF and TDF in reducing HBV DNA to levels associated with lower transmission risk. These data support ongoing studies of TAF for pMTCT.
- Published
- 2021
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95. TLR7 Agonist Increases Responses of Hepatitis B Virus–Specific T Cells and Natural Killer Cells in Patients With Chronic Hepatitis B Treated With Nucleos(T)Ide Analogues
- Author
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Boni, Carolina, Vecchi, Andrea, Rossi, Marzia, Laccabue, Diletta, Giuberti, Tiziana, Alfieri, Arianna, Lampertico, Pietro, Grossi, Glenda, Facchetti, Floriana, Brunetto, Maurizia R., Coco, Barbara, Cavallone, Daniela, Mangia, Alessandra, Santoro, Rosanna, Piazzolla, Valeria, Lau, Audrey, Gaggar, Anuj, Subramanian, G. Mani, and Ferrari, Carlo
- Published
- 2018
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96. LCA-Net: Light Convolutional Autoencoder for Image Dehazing.
- Author
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Pavan A, Adithya Bennur, Mohit Gaggar, and Shylaja S. S
- Published
- 2020
97. Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B
- Author
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Publicover, Jean, Gaggar, Anuj, Nishimura, Stephen, Van Horn, Christine M, Goodsell, Amanda, Muench, Marcus O, Reinhardt, R Lee, van Rooijen, Nico, Wakil, Adil E, Peters, Marion, Cyster, Jason G, Erle, David J, Rosenthal, Philip, Cooper, Stewart, and Baron, Jody L
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Digestive Diseases ,Hepatitis - B ,Chronic Liver Disease and Cirrhosis ,Vaccine Related ,Hepatitis ,Infectious Diseases ,Immunization ,Liver Disease ,2.1 Biological and endogenous factors ,Infection ,Inflammatory and immune system ,Good Health and Well Being ,Adult ,Age Factors ,Animals ,Chemokine CXCL13 ,Disease Resistance ,Hepatitis B virus ,Hepatitis B ,Chronic ,Humans ,Immunity ,Innate ,Infant ,Interleukins ,Liver ,Lymphoid Tissue ,Macrophages ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Oligonucleotide Array Sequence Analysis ,Receptors ,CXCR5 ,Spleen ,Transcriptome ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.
- Published
- 2013
98. Complex genetic encoding of the hepatitis B virus on-drug persistence
- Author
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Thai, Hong, Lara, James, Xu, Xiaojun, Kitrinos, Kathryn, Gaggar, Anuj, Chan, Henry Lik Yuen, Xia, Guo-liang, Ganova-Raeva, Lilia, and Khudyakov, Yury
- Published
- 2020
- Full Text
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99. Hepatitis B virus haplotype number at baseline is a predictive marker of functional cure during antiviral therapy for patients with genotypes A and D <scp>HBeAg</scp> ‐positive chronic hepatitis B
- Author
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Josef Wagner, Lilly Yuen, Margaret Littlejohn, Vitina Sozzi, Kathy Jackson, Ross Martin, Thomas Aeschbacher, Vithika Suri, Susanna K. Tan, Becket Feierbach, Anuj Gaggar, Patrick Marcellin, Maria Buti Ferret, Harry L. A. Janssen, Ed Gane, Niamh Meagher, David J. Price, Darren Wong, Alexander T. Thompson, and Peter A. Revill
- Subjects
Hepatology ,Gastroenterology ,Pharmacology (medical) - Abstract
We investigated associations between hepatitis B virus (HBV) genome-length haplotype number (HN) at baseline in subjects with HBeAg-positive chronic hepatitis B (CHB), and the likelihood of achieving functional cure during direct-acting antiviral therapy METHOD: We analysed 86 HBeAg-positive baseline samples from patients with HBV genotypes A and D who were enrolled in a Phase II trial of tenofovir disoproxil fumarate (TDF) to determine if HN was a biomarker of HBsAg loss during therapy. Findings were validated using baseline samples from 181 patients with HBV genotypes A and D from an independent clinical trial utilising TDF or tenofovir alafenamide therapy in HBeAg-positive CHB.In the HBeAg-positive test cohort, patients with genotypes A or D and ≤2 haplotypes had a minimum of 21-fold higher likelihood of achieving HBsAg loss on TDF. Baseline HN (p 0.0001) was a stronger predictor of HBsAg loss on therapy than HBsAg titre (p = 0.03), HBeAg titre (p = 0.0002), or the presence of HBV basal core promoter (A1762T, p = 0.0379 and G1764A, p = 0.0176) or G1896A precore mutations (p = 0.0218). This finding was validated in the independent validation cohort. HN was statistically higher in patients with HBV genotypes B or C infection compared to genotypes A and D.Baseline HN ≤2 predicts which patients with HBV genotypes A or D will more likely progress to functional cure on current direct-acting antiviral therapy, with greater accuracy than current biomarkers including baseline HBsAg and HBeAg titre.
- Published
- 2022
100. Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study
- Author
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Catherine A Chappell, MD, Kimberly K Scarsi, PharmD, Brian J Kirby, PhD, Vithika Suri, MSc, Anuj Gaggar, MD, Debra L Bogen, ProfMD, Ingrid S Macio, PA, Leslie A Meyn, PhD, Katherine E Bunge, MD, Elizabeth E Krans, MD, and Sharon L Hillier, ProfPhD
- Subjects
Medicine (General) ,R5-920 ,Microbiology ,QR1-502 - Abstract
Summary: Background: Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women. Methods: This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir–sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks' gestation and had a 12-week course of oral ledipasvir–sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25–26, 29–30, and 33–34 weeks' gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir–sofosbuvir area under the concentration–time curve of the dosing interval (AUCtau) during pregnancy compared with the reference group by geometric mean ratio. This study is registered with ClinicalTrials.gov, NCT02683005. Findings: From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUCtau ledipasvir 89·3% [90% CI 68·7–116·1]; sofosbuvir 91·1% [78·0–106·3]). Interpretation: Ledipasvir–sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women. Funding: National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women's Health, and Gilead Sciences.
- Published
- 2020
- Full Text
- View/download PDF
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