10 results on '"James W. Keith"'
Search Results
2. Supplemental Tables 1 and 2 from Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression
- Author
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Richard J. Wong, Eric Pamer, Johanna A. Joyce, Efsevia Vakiani, Ziv Gil, Nora Katabi, Hikmat A. Al-Ahmadie, James W. Keith, Andrea R. Marcadis, Ingrid M. Leiner, Oakley C. Olson, Sei-Young Lee, William McNamara, Shizhi He, Yi Zhou, Anna Lyubchik, Sylvie Deborde, Chun-Hao Chen, Huizhong Xiong, and Richard L. Bakst
- Abstract
Tables contain information on the list of candidate genes screened from murine macrophages and clinical data on human pancreatic samples. This file contains 2 tables (Supplemental Tables 1 and 2).
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- 2023
3. Figs S10-S11 from Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression
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Richard J. Wong, Eric Pamer, Johanna A. Joyce, Efsevia Vakiani, Ziv Gil, Nora Katabi, Hikmat A. Al-Ahmadie, James W. Keith, Andrea R. Marcadis, Ingrid M. Leiner, Oakley C. Olson, Sei-Young Lee, William McNamara, Shizhi He, Yi Zhou, Anna Lyubchik, Sylvie Deborde, Chun-Hao Chen, Huizhong Xiong, and Richard L. Bakst
- Abstract
Analysis of human prostate cancer and adenoid cystic carcinoma specimens demonstrates macrophage infiltration around the majority of invaded nerves. This file contains two supplemental figures (S10-S11).
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- 2023
4. Data from Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression
- Author
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Richard J. Wong, Eric Pamer, Johanna A. Joyce, Efsevia Vakiani, Ziv Gil, Nora Katabi, Hikmat A. Al-Ahmadie, James W. Keith, Andrea R. Marcadis, Ingrid M. Leiner, Oakley C. Olson, Sei-Young Lee, William McNamara, Shizhi He, Yi Zhou, Anna Lyubchik, Sylvie Deborde, Chun-Hao Chen, Huizhong Xiong, and Richard L. Bakst
- Abstract
Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B–mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2–CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B–producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400–14. ©2017 AACR.
- Published
- 2023
5. Antibiotic degradation by commensal microbes shields pathogens
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Eric G. Pamer, James W. Keith, Tobias M. Hohl, Mytrang H. Do, Mergim Gjonbalaj, and Simone Becattini
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Antibiotics ,Drug Resistance ,Gut flora ,medicine.disease_cause ,Mice ,Ampicillin ,Ampicillin/administration & dosage/metabolism/pharmacology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Anti-Bacterial Agents/administration & dosage/metabolism/pharmacology ,Hydrolysis ,Bacterial ,Bacterial Infections ,Anti-Bacterial Agents ,3. Good health ,Intestines ,Beta-Lactamases/metabolism ,Infectious Diseases ,Horizontal gene transfer ,Clostridium difficile/drug effects/growth & development ,Listeria monocytogenes/drug effects ,medicine.drug ,medicine.drug_class ,Immunology ,Microbiology ,beta-Lactamases ,03 medical and health sciences ,Antibiotic resistance ,Listeria monocytogenes ,Drug Resistance, Bacterial ,Escherichia coli ,medicine ,Animals ,Gene ,030304 developmental biology ,Escherichia coli/enzymology/growth & development/metabolism ,Microbial Viability ,Clostridioides difficile ,030306 microbiology ,Microbial Viability/drug effects ,Intestines/microbiology ,biology.organism_classification ,Commensalism ,Enzyme ,chemistry ,Microbial Interactions ,Parasitology ,Bacteria - Abstract
The complex bacterial populations that constitute the gut microbiota can harbor antibiotic resistance genes (ARGs), including those encoding β-lactamase enzymes (BLA), which degrade commonly prescribed antibiotics such as ampicillin. The prevalence of such genes in commensal bacteria has been increased in recent years by the wide use of antibiotics in human populations and in livestock. While transfer of ARGs between bacterial species has well-established dramatic public health implications, these genes can also function in trans within bacterial consortia, where antibiotic-resistant bacteria can provide antibiotic-sensitive neighbors with leaky protection from drugs, as shown both in vitro and in vivo, in models of lung and subcutaneous coinfection. However, whether the expression of ARGs by harmless commensal bacterial species can destroy antibiotics in the intestinal lumen and shield antibiotic-sensitive pathogens is unknown. To address this question, we colonized germfree or wild-type mice with a model intestinal commensal strain of Escherichia coli that produces either functional or defective BLA. Mice were subsequently infected with Listeria monocytogenes or Clostridioides difficile, followed by treatment with oral ampicillin. The production of functional BLA by commensal E. coli markedly reduced clearance of these pathogens and enhanced systemic dissemination during ampicillin treatment. Pathogen resistance was independent of ARG acquisition via horizontal gene transfer but instead relied on antibiotic degradation in the intestinal lumen by BLA. We conclude that commensal bacteria that have acquired ARGs can mediate shielding of pathogens from the bactericidal effects of antibiotics.
- Published
- 2019
6. Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression
- Author
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Ziv Gil, James W. Keith, Eric G. Pamer, Chun-Hao Chen, Ingrid Leiner, Yi Zhou, William F. McNamara, Efsevia Vakiani, Shizhi He, Johanna A. Joyce, Oakley C. Olson, Anna Lyubchik, Andrea R Marcadis, Hikmat Al-Ahmadie, Richard L. Bakst, Sei Young Lee, Huizhong Xiong, Richard J. Wong, Sylvie Deborde, and Nora Katabi
- Subjects
0301 basic medicine ,Cancer Research ,Receptors, CCR2 ,Transplantation, Heterologous ,Perineural invasion ,Mice, Nude ,CCL2 ,Biology ,CCL7 ,Article ,Monocytes ,Cathepsin B ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Animals ,Humans ,Neoplasm Invasiveness ,Peripheral Nerves ,Chemokine CCL2 ,Mice, Knockout ,Cathepsin ,Tumor microenvironment ,Macrophages ,Neoplasms, Experimental ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Transplantation ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,Schwann Cells - Abstract
Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B–mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2–CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B–producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400–14. ©2017 AACR.
- Published
- 2017
7. Impact of Antibiotic-Resistant Bacteria on Immune Activation and Clostridioides difficile Infection in the Mouse Intestine
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Ingrid Leiner, Eric G. Pamer, Matthew T. Sorbara, James W. Keith, Jonathan Kevin Sia, Mergim Gjonbalaj, Ruth Seok, Simone Becattini, Qiwen Dong, and Eric R. Littmann
- Subjects
medicine.drug_class ,Immunology ,Antibiotics ,Virulence ,Colonisation resistance ,Gut flora ,Microbiology ,Mice ,Antibiotic resistance ,Drug Resistance, Bacterial ,Enterobacter cloacae ,medicine ,Animals ,Colonization ,Colitis ,Proteus mirabilis ,biology ,Enterobacteriaceae Infections ,Bacterial Infections ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Anti-Bacterial Agents ,Disease Models, Animal ,Klebsiella pneumoniae ,Infectious Diseases ,Clostridium Infections ,Microbial Interactions ,Parasitology ,Enterococcus faecium - Abstract
Antibiotic treatment of patients undergoing complex medical treatments can deplete commensal bacterial strains from the intestinal microbiota, thereby reducing colonization resistance against a wide range of antibiotic-resistant pathogens. Loss of colonization resistance can lead to marked expansion of vancomycin-resistant Enterococcus faecium (VRE), Klebsiella pneumoniae, and Escherichia coli in the intestinal lumen, predisposing patients to bloodstream invasion and sepsis. The impact of intestinal domination by these antibiotic-resistant pathogens on mucosal immune defenses and epithelial and mucin-mediated barrier integrity is unclear. We used a mouse model to study the impact of intestinal domination by antibiotic-resistant bacterial species and strains on the colonic mucosa. Intestinal colonization with K. pneumoniae, Proteus mirabilis, or Enterobacter cloacae promoted greater recruitment of neutrophils to the colonic mucosa. To test the hypothesis that the residual microbiota influences the severity of colitis caused by infection with Clostridioides difficile, we coinfected mice that were colonized with ampicillin-resistant bacteria with a virulent strain of C. difficile and monitored colonization and pathogenesis. Despite the compositional differences in the gut microbiota, the severity of C. difficile infection (CDI) and mortality did not differ significantly between mice colonized with different ampicillin-resistant bacterial species. Our results suggest that the virulence mechanisms enabling CDI and epithelial destruction outweigh the relatively minor impact of less-virulent antibiotic-resistant intestinal bacteria on the outcome of CDI.
- Published
- 2019
8. Innate Lymphocyte/Ly6C hi Monocyte Crosstalk Promotes Klebsiella Pneumoniae Clearance
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James W. Keith, Dane Samilo, Eric G. Pamer, Ingrid Leiner, Rebecca A. Carter, and Huizhong Xiong
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0301 basic medicine ,Lymphocyte ,Inflammation ,Biology ,Monocytes ,Article ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Lymphocytes ,Lung ,Pathogen ,Innate immune system ,Tumor Necrosis Factor-alpha ,Monocyte ,Interleukin-17 ,Innate lymphoid cell ,Klebsiella Infections ,respiratory tract diseases ,Klebsiella pneumoniae ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Tumor necrosis factor alpha ,Interleukin 17 ,medicine.symptom ,030215 immunology - Abstract
Increasing antibiotic resistance among bacterial pathogens has rendered some infections untreatable with available antibiotics. Klebsiella pneumoniae, a bacterial pathogen that has acquired high-level antibiotic resistance, is a common cause of pulmonary infections. Optimal clearance of K. pneumoniae from the host lung requires TNF and IL-17A. Herein we demonstrate that inflammatory monocytes are rapidly recruited to the lungs of K. pneumoniae infected mice, and produce TNF, which markedly increases the frequency of IL-17-producing innate lymphoid cells. While pulmonary clearance of K. pneumoniae is preserved in neutrophil-depleted mice, monocyte depletion or TNF deficiency impairs IL-17A–dependent resolution of pneumonia. Monocyte-mediated bacterial uptake and killing is enhanced by ILC production of IL-17A, indicating that innate lymphocytes engage in a positive feedback loop with monocytes that promotes clearance of pneumonia. Innate immune defense against a highly antibiotic-resistant bacterial pathogen depends on crosstalk between inflammatory monocytes and innate lymphocytes that is mediated by TNF and IL-17A.
- Published
- 2016
9. Hepatitis B Virus–Specific and Global T-Cell Dysfunction in Chronic Hepatitis B
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Jang-June Park, David K. Wong, Abdus S. Wahed, William M. Lee, Jordan J. Feld, Norah Terrault, Mandana Khalili, Richard K. Sterling, Kris V. Kowdley, Natalie Bzowej, Daryl T. Lau, W. Ray Kim, Coleman Smith, Robert L. Carithers, Keith W. Torrey, James W. Keith, Danielle L. Levine, Daniel Traum, Suzanne Ho, Mary E. Valiga, Geoffrey S. Johnson, Edward Doo, Anna S.F. Lok, Kyong-Mi Chang, Raymond T. Chung, Lewis R. Roberts, Adrian M. Di Bisceglie, Mauricio Lisker-Melman, Harry L.A. Janssen, Joshua Juan, Colina Yim, Jenny Heathcote, Robert Perrillo, Son Do, Steven-Huy B. Han, Tram T. Tran, Stewart L. Cooper, Robert J. Fontana, Naoky Tsai, Michael W. Fried, Keyur Patel, Donna Evon, Margaret Shuhart, Chia C. Wang, Marc G. Ghany, T. Jake Liang, Steven Belle, Yona Cloonan, and David Kleiner
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0301 basic medicine ,Hepatitis B virus ,HBsAg ,Hepatology ,Gastroenterology ,FOXP3 ,Hepatitis B ,Biology ,medicine.disease_cause ,medicine.disease ,Virology ,03 medical and health sciences ,030104 developmental biology ,HBeAg ,Interferon ,CTLA-4 ,Immunology ,medicine ,Cytotoxic T cell ,medicine.drug - Abstract
Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health−supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3 + CD127 − regulatory T cells and CD4 + T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg) + than HBeAg − patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg + than HBeAg − patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell−based immune signatures for clinical phenotypes. These findings suggest additional T-cell−independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.
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- 2016
10. LINEAR HABITATS AND THE NESTED CLADE ANALYSIS: AN EMPIRICAL EVALUATION OF GEOGRAPHIC VERSUS RIVER DISTANCES USING AN OZARK CRAYFISH (DECAPODA: CAMBARIDAE)
- Author
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Fetzner, Crandall, James W., Keith A., Fetzner and Shaw, K.
- Published
- 2003
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