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Article ; Online: TAM family kinases as therapeutic targets at the interface of cancer and immunity.

DeRyckere, Deborah / Huelse, Justus M / Earp, H Shelton / Graham, Douglas K

2023 Volume 20, Issue 11, Page(s) 755–779

Abstract: Novel treatment approaches are needed to overcome innate and acquired mechanisms of resistance to current anticancer therapies in cancer cells and the tumour immune microenvironment. The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) ... ...

Abstract	Novel treatment approaches are needed to overcome innate and acquired mechanisms of resistance to current anticancer therapies in cancer cells and the tumour immune microenvironment. The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) are potential therapeutic targets in a wide range of cancers. In cancer cells, TAM RTKs activate signalling pathways that promote cell survival, metastasis and resistance to a variety of chemotherapeutic agents and targeted therapies. TAM RTKs also function in innate immune cells, contributing to various mechanisms that suppress antitumour immunity and promote resistance to immune-checkpoint inhibitors. Therefore, TAM antagonists provide an unprecedented opportunity for both direct and immune-mediated therapeutic activity provided by inhibition of a single target, and are likely to be particularly effective when used in combination with other cancer therapies. To exploit this potential, a variety of agents have been designed to selectively target TAM RTKs, many of which have now entered clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians, including an overview of the rationale for therapeutic targeting of TAM RTKs in cancer cells and the tumour immune microenvironment, a description of the current preclinical and clinical experience with TAM inhibitors, and a perspective on strategies for continued development of TAM-targeted agents for oncology applications.
MeSH term(s)	Humans ; Axl Receptor Tyrosine Kinase ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/metabolism ; Neoplasms/drug therapy ; c-Mer Tyrosine Kinase/genetics ; c-Mer Tyrosine Kinase/metabolism ; Tumor Microenvironment
Chemical Substances	Axl Receptor Tyrosine Kinase ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1)
Language	English
Publishing date	2023-09-04
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-023-00813-7
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Article: Targeting MERTK and AXL in

Yan, Dan / Earp, H Shelton / DeRyckere, Deborah / Graham, Douglas K

Cancers

2021 Volume 13, Issue 22

Abstract: MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and ... ...

Abstract	MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations.
Language	English
Publishing date	2021-11-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13225639
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Article ; Online: Discovery and characterization of a functional scFv for CCR2 inhibition via an extracellular loop.

Jasiewicz, Natalie E / Brown, Adam D / Deci, Michael / Matysiak, Silvina / Earp, H Shelton / Nguyen, Juliane

International journal of pharmaceutics

2022 Volume 632, Page(s) 122547

Abstract: The chemokine receptor CCR2 plays a key role in cellular migration and inflammatory processes. While tremendous progress has been made in elucidating CCR2 function and inhibition, the majority of approaches target its N-terminal domain and less is known ... ...

Abstract	The chemokine receptor CCR2 plays a key role in cellular migration and inflammatory processes. While tremendous progress has been made in elucidating CCR2 function and inhibition, the majority of approaches target its N-terminal domain and less is known about the function of the remaining extracellular loops and their potential as targets. Here, we used phage display to identify an antibody-derived scFv (single chain variable fragment) clone that specifically targets the second extracellular epitope of CCR2 (ECL2) for inhibition. Using in silico molecular docking, we identified six potential primary binding conformations of the novel scFv to the specified CCR2 epitope. In silico molecular dynamic analysis was used to determine conformational stability and identify protein-protein interactions. Umbrella sampling of a range of configurations with incrementally increasing separation of scFv and target generated by force pulling simulations was used to calculate binding energies. Downstream characterization by ELISA showed high binding affinity of the ECL2-scFv to CCR2. Furthermore, we showed that blocking the second extracellular loop inhibits macrophage migration and polarized macrophages towards M1 inflammatory cytokine production as potently as lipopolysaccharide (LPS). These studies highlight the applicability of epitope-specific targeting, emphasize the importance of in silico predictive modeling, and warrant further investigation into the role of the remaining epitopes of CCR2.
MeSH term(s)	Molecular Docking Simulation ; Single-Chain Antibodies/chemistry ; Epitopes ; Molecular Dynamics Simulation ; Molecular Conformation
Chemical Substances	Single-Chain Antibodies ; Epitopes
Language	English
Publishing date	2022-12-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2022.122547
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Article: Beyond growth signaling: apoptotic sensor MERTK activates AKT by a novel mechanism.

Zhang, Yanqiong / Earp, H Shelton / Liu, Pengda

Molecular & cellular oncology

2019 Volume 6, Issue 4, Page(s) 1611161

Abstract: Canonically the oncogenic kinase AKT is activated by growth signals. Our work suggests apoptotic materials, abundant in tumors, also contribute to AKT activation by stimulating MERTK that in turn phosphorylates Y26 in the AKT PH domain. pY26 reverses ... ...

Abstract	Canonically the oncogenic kinase AKT is activated by growth signals. Our work suggests apoptotic materials, abundant in tumors, also contribute to AKT activation by stimulating MERTK that in turn phosphorylates Y26 in the AKT PH domain. pY26 reverses binding of an AKT endogenous, WW-domain containing inhibitor, SAV1, allowing AKT responsiveness to classic growth signals. This novel mechanism may contribute to drug resistance.
Language	English
Publishing date	2019-05-07
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2019.1611161
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Article ; Online: Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors.

Kong, Deyu / Tian, Qiang / Chen, Zhilong / Zheng, Hongchao / Stashko, Michael A / Yan, Dan / Earp, H Shelton / Frye, Stephen V / DeRyckere, Deborah / Kireev, Dmitri / Graham, Douglas K / Wang, Xiaodong

Journal of medicinal chemistry

2024 Volume 67, Issue 7, Page(s) 5866–5882

Abstract: MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide ... ...

Abstract	MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound
MeSH term(s)	Humans ; c-Mer Tyrosine Kinase/metabolism ; Axl Receptor Tyrosine Kinase ; Proto-Oncogene Proteins/metabolism ; Carcinoma, Non-Small-Cell Lung ; Lung Neoplasms/drug therapy ; Cell Line, Tumor
Chemical Substances	c-Mer Tyrosine Kinase (EC 2.7.10.1) ; Axl Receptor Tyrosine Kinase ; Proto-Oncogene Proteins ; MERTK protein, human (EC 2.7.10.1)
Language	English
Publishing date	2024-03-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.4c00148
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Article ; Online: TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.

Chouhan, Surbhi / Sawant, Mithila / Weimholt, Cody / Luo, Jingqin / Sprung, Robert W / Terrado, Mailyn / Mueller, David M / Earp, H Shelton / Mahajan, Nupam P

Autophagy

2022 Volume 19, Issue 3, Page(s) 1000–1025

Abstract: The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by ... ...

Abstract	The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (
MeSH term(s)	Humans ; Male ; Mice ; Animals ; Phosphorylation ; Autophagy ; Protein-Tyrosine Kinases/metabolism ; Prostatic Neoplasms ; Mice, Transgenic ; Mitochondria/metabolism ; Tyrosine ; Adenosine Triphosphate/metabolism
Chemical Substances	3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Tyrosine (42HK56048U) ; Adenosine Triphosphate (8L70Q75FXE) ; TNK2 protein, human (EC 2.7.10.2)
Language	English
Publishing date	2022-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2022.2103961
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Article ; Online: A cryptic transactivation domain of EZH2 binds AR and AR's splice variant, promoting oncogene activation and tumorous transformation.

Wang, Jun / Park, Kwang-Su / Yu, Xufen / Gong, Weida / Earp, H Shelton / Wang, Gang Greg / Jin, Jian / Cai, Ling

Nucleic acids research

2022 Volume 50, Issue 19, Page(s) 10929–10946

Abstract: Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin/gene regulators involved in the development and/or progression of prostate cancer, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate ... ...

Abstract	Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin/gene regulators involved in the development and/or progression of prostate cancer, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate tumorigenicity, EZH2 establishes non-canonical biochemical interaction with AR for mediating oncogene activation, in addition to its canonical role as a transcriptional repressor and enzymatic subunit of Polycomb Repressive Complex 2 (PRC2). However, the molecular basis underlying non-canonical activities of EZH2 in prostate cancer remains elusive, and a therapeutic strategy for targeting EZH2:AR-mediated oncogene activation is also lacking. Here, we report that a cryptic transactivation domain of EZH2 (EZH2TAD) binds both AR and AR spliced variant 7 (AR-V7), a constitutively active AR variant enriched in CRPC, mediating assembly and/or recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding. Such non-canonical targets of EZH2:AR/AR-V7:(co-)activators are enriched for the clinically relevant oncogenes. We also show that EZH2TAD is required for the chromatin recruitment of EZH2 to oncogenes, for EZH2-mediated oncogene activation and for CRPC growth in vitro and in vivo. To completely block EZH2's multifaceted oncogenic activities in prostate cancer, we employed MS177, a recently developed proteolysis-targeting chimera (PROTAC) of EZH2. Strikingly, MS177 achieved on-target depletion of both EZH2's canonical (EZH2:PRC2) and non-canonical (EZH2TAD:AR/AR-V7:co-activators) complexes in prostate cancer cells, eliciting far more potent antitumor effects than the catalytic inhibitors of EZH2. Overall, this study reports a previously unappreciated requirement for EZH2TAD for mediating EZH2's non-canonical (co-)activator recruitment and gene activation functions in prostate cancer and suggests EZH2-targeting PROTACs as a potentially attractive therapeutic for the treatment of aggressive prostate cancer that rely on the circuits wired by EZH2 and AR.
MeSH term(s)	Humans ; Male ; Cell Line, Tumor ; Chromatin/genetics ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Gene Expression Regulation, Neoplastic ; Oncogenes ; Polycomb Repressive Complex 2/genetics ; Polycomb Repressive Complex 2/metabolism ; Prostatic Neoplasms, Castration-Resistant/pathology ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Transcriptional Activation ; Protein Isoforms
Chemical Substances	Chromatin ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; EZH2 protein, human (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; Receptors, Androgen ; Protein Isoforms
Language	English
Publishing date	2022-10-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac861
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Article ; Online: Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment.

Cruz Cruz, Joselyn / Allison, Kristen C / Page, Lauren S / Jenkins, Alexis J / Wang, Xiaodong / Earp, H Shelton / Frye, Stephen V / Graham, Douglas K / Verneris, Michael R / Lee-Sherick, Alisa B

Frontiers in immunology

2023 Volume 14, Page(s) 1146721

Abstract: Background: Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process ... ...

Abstract	Background: Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the immunosuppressive leukemia microenvironment and that this was driven by aberrant phosphatidylserine expression from cell turnover and cell membrane dysregulation. Methods: Since MerTK is the prototypic efferocytosis receptor, we assessed whether the MerTK inhibitor MRX2843, which is currently in clinical trials, would reverse immune evasion and enhance immune-mediated clearance of leukemia cells. Results: We found that inhibition of MerTK decreased leukemia-associated macrophage expression of M2 markers PD-L1, PD-L2, Tim-3, CD163 and Arginase-1 compared to vehicle-treated controls. Additionally, MerTK inhibition led to M1 macrophage repolarization including elevated CD86 and HLA-DR expression, and increased production of T cell activating cytokines, including IFN-β, IL-18, and IL-1β through activation of NF-κB. Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1 Discussion: These results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML.
MeSH term(s)	Humans ; c-Mer Tyrosine Kinase/metabolism ; Hepatitis A Virus Cellular Receptor 2/metabolism ; Macrophages ; Leukemia/metabolism ; Immunosuppression Therapy ; Tumor Microenvironment
Chemical Substances	c-Mer Tyrosine Kinase (EC 2.7.10.1) ; Hepatitis A Virus Cellular Receptor 2
Language	English
Publishing date	2023-03-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1146721
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Article: Inherited predisposition to breast cancer in the Carolina Breast Cancer Study.

Walsh, Tom / Gulsuner, Suleyman / Lee, Ming K / Troester, Melissa A / Olshan, Andrew F / Earp, H Shelton / Perou, Charles M / King, Mary-Claire

NPJ breast cancer

2021 Volume 7, Issue 1, Page(s) 6

Abstract: The Carolina Breast Cancer Study (CBCS) phases I-II was a case-control study of biological and social risk factors for invasive breast cancer that enrolled cases and controls between 1993 and 1999. Case selection was population-based and stratified by ... ...

Abstract	The Carolina Breast Cancer Study (CBCS) phases I-II was a case-control study of biological and social risk factors for invasive breast cancer that enrolled cases and controls between 1993 and 1999. Case selection was population-based and stratified by ancestry and age at diagnosis. Controls were matched to cases by age, self-identified race, and neighborhood of residence. Sequencing genomic DNA from 1370 cases and 1635 controls yielded odds ratios (with 95% confidence limits) for breast cancer of all subtypes of 26.7 (3.59, 189.1) for BRCA1, 8.8 (3.44, 22.48) for BRCA2, and 9.0 (2.06, 39.60) for PALB2; and for triple-negative breast cancer (TNBC) of 55.0 (7.01, 431.4) for BRCA1, 12.1 (4.18, 35.12) for BRCA2, and 10.8 (1.97, 59.11) for PALB2. Overall, 5.6% of patients carried a pathogenic variant in BRCA1, BRCA2, PALB2, or TP53, the four most highly penetrant breast cancer genes. Analysis of cases by tumor subtype revealed the expected association of TNBC versus other tumor subtypes with BRCA1, and suggested a significant association between TNBC versus other tumor subtypes with BRCA2 or PALB2 among African-American (AA) patients [2.95 (1.18, 7.37)], but not among European-American (EA) patients [0.62 (0.18, 2.09)]. AA patients with pathogenic variants in BRCA2 or PALB2 were 11 times more likely to be diagnosed with TNBC versus another tumor subtype than were EA patients with pathogenic variants in either of these genes (P = 0.001). If this pattern is confirmed in other comparisons of similarly ascertained AA and EA breast cancer patients, it could in part explain the higher prevalence of TNBC among AA breast cancer patients.
Language	English
Publishing date	2021-01-21
Publishing country	United States
Document type	Journal Article
ISSN	2374-4677
ISSN	2374-4677
DOI	10.1038/s41523-020-00214-4
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Article ; Online: Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response.

Ubil, Eric / Caskey, Laura / Holtzhausen, Alisha / Hunter, Debra / Story, Charlotte / Earp, H Shelton

The Journal of clinical investigation

2018 Volume 128, Issue 6, Page(s) 2356–2369

Abstract: Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor ... ...

Abstract	Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor cells with CRISPR-based deletion of Pros1 failed to inhibit M1 polarization. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice. In addition, several other murine and human tumor cell lines suppressed macrophage M1 cytokine expression induced by IFN-γ and LPS. Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival. TAM activation can also inhibit TLR-mediated M1 polarization. Treatment with resiquimod, a TLR7/8 agonist, did not improve survival in mice bearing Pros1-secreting tumors but doubled survival for Pros1-deleted tumors. The tumor-derived Pros1 immune suppressive system, like PD-L1, was cytokine responsive, with IFN-γ inducing Pros1 transcription and secretion. Inhibition of Pros1/TAM interaction represents a potential novel strategy to block tumor-derived immune suppression.
MeSH term(s)	Animals ; B7-H1 Antigen/genetics ; B7-H1 Antigen/immunology ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Cytokines/genetics ; Cytokines/immunology ; Humans ; Imidazoles/pharmacology ; Macrophages/immunology ; Macrophages/pathology ; Membrane Glycoproteins/agonists ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; Mice ; Mice, Knockout ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/pathology ; Toll-Like Receptor 7/agonists ; Toll-Like Receptor 7/genetics ; Toll-Like Receptor 7/immunology ; Toll-Like Receptor 8/agonists ; Toll-Like Receptor 8/genetics ; Toll-Like Receptor 8/immunology
Chemical Substances	B7-H1 Antigen ; Carrier Proteins ; Cd274 protein, mouse ; Cytokines ; Imidazoles ; Membrane Glycoproteins ; Pros1 protein, mouse ; TLR8 protein, mouse ; Tlr7 protein, mouse ; Toll-Like Receptor 7 ; Toll-Like Receptor 8 ; resiquimod (V3DMU7PVXF)
Language	English
Publishing date	2018-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI97354
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