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Issue published November 2, 2020 Previous issue | Next issue

  • Volume 130, Issue 11
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On the cover: Inhibiting mitophagy improves macrophage bacterial clearance

Macrophage-mediated bacterial clearance and inflammatory functions play critical roles in controlling sepsis. The role of mitochondria, specifically that of mitophagy, in macrophage activation and function remains unclear. In this issue, Patoli, Mignotte, et al. demonstrate that LPS exposure leads to inhibition of mitophagy in murine macrophages. The work further reveals that mitophagy inhibition enhances bacterial clearance and improves survival in a mouse model. The findings provide a rationale for therapeutic exploration of mitophagy pathways in sepsis. The cover image represents metabolic reprogramming associated with the inhibition of mitophagy. M1 macrophages were stained with JC-1 dye to indicate mitochondria with low (green) or high (red) membrane potential, revealing the effects of LPS exposure. Image credit: Charles Thomas.

Viewpoints
Immune pathogenesis of COVID-19–related multisystem inflammatory syndrome in children
Anne H. Rowley, … , Stanford T. Shulman, Moshe Arditi
Anne H. Rowley, … , Stanford T. Shulman, Moshe Arditi
Published September 1, 2020
Citation Information: J Clin Invest. 2020;130(11):5619-5621. https://doi.org/10.1172/JCI143840.
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Immune pathogenesis of COVID-19–related multisystem inflammatory syndrome in children

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Authors

Anne H. Rowley, Stanford T. Shulman, Moshe Arditi

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Drugs of unproven benefit for COVID-19: a pharma perspective on ethical allocation of available therapies
Arthur L. Caplan, … , Karla Childers, Aran Maree
Arthur L. Caplan, … , Karla Childers, Aran Maree
Published September 15, 2020
Citation Information: J Clin Invest. 2020;130(11):5622-5623. https://doi.org/10.1172/JCI144186.
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Drugs of unproven benefit for COVID-19: a pharma perspective on ethical allocation of available therapies

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Authors

Arthur L. Caplan, Joanne Waldstreicher, Karla Childers, Aran Maree

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Reflections of a Black woman physician-scientist
Rotonya M. Carr
Rotonya M. Carr
Published September 24, 2020
Citation Information: J Clin Invest. 2020;130(11):5624-5625. https://doi.org/10.1172/JCI144525.
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Reflections of a Black woman physician-scientist

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Authors

Rotonya M. Carr

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Toward realizing diversity in academic medicine
John M. Carethers
John M. Carethers
Published September 29, 2020
Citation Information: J Clin Invest. 2020;130(11):5626-5628. https://doi.org/10.1172/JCI144527.
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Toward realizing diversity in academic medicine

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Authors

John M. Carethers

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Review Series
Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy
Stephen M. Hatfield, Michail V. Sitkovsky
Stephen M. Hatfield, Michail V. Sitkovsky
Published September 1, 2020
Citation Information: J Clin Invest. 2020;130(11):5629-5637. https://doi.org/10.1172/JCI137554.
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Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy

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Hypoxia/HIF-1α– and extracellular adenosine/A2 adenosine receptor–mediated immunosuppression protects tissues from collateral damage by antipathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting antitumor immune cells in hypoxic and extracellular adenosine–rich tumors that are the most resistant to current therapies. Here, we explain a potentially novel, antiimmunosuppressive reasoning to justify strategies using respiratory hyperoxia and oxygenation agents in cancer treatment. Earlier attempts to use oxygenation of tumors as a monotherapy or to improve radiotherapy have failed because oxygenation protocols were not combined with immunotherapies of cancer. In contrast, the proposal for therapeutic use of antihypoxic oxygenation described here was motivated by the need to prevent the hypoxia/HIF-1α–driven accumulation of extracellular adenosine to (a) unleash antitumor immune cells from inhibition by intracellular cAMP and (b) prevent immunosuppressive transcription of cAMP response element– and hypoxia response element–containing immunosuppressive gene products (e.g., TGF-β). Use of oxygenation agents together with inhibitors of the A2A adenosine receptor may be required to enable the most effective cancer immunotherapy. The emerging outcomes of clinical trials of cancer patients refractory to all other treatments provide support for the molecular and immunological mechanism–based approach to cancer immunotherapy described here.

Authors

Stephen M. Hatfield, Michail V. Sitkovsky

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Hypoxia-inducible factor signaling in pulmonary hypertension
Soni Savai Pullamsetti, … , Werner Seeger, Rajkumar Savai
Soni Savai Pullamsetti, … , Werner Seeger, Rajkumar Savai
Published September 3, 2020
Citation Information: J Clin Invest. 2020;130(11):5638-5651. https://doi.org/10.1172/JCI137558.
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Hypoxia-inducible factor signaling in pulmonary hypertension

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Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.

Authors

Soni Savai Pullamsetti, Argen Mamazhakypov, Norbert Weissmann, Werner Seeger, Rajkumar Savai

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Review
Stem cell therapy for muscular dystrophies
Stefano Biressi, … , Antonio Filareto, Thomas A. Rando
Stefano Biressi, … , Antonio Filareto, Thomas A. Rando
Published September 18, 2020
Citation Information: J Clin Invest. 2020;130(11):5652-5664. https://doi.org/10.1172/JCI142031.
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Stem cell therapy for muscular dystrophies

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Muscular dystrophies are a heterogeneous group of genetic diseases, characterized by progressive degeneration of skeletal and cardiac muscle. Despite the intense investigation of different therapeutic options, a definitive treatment has not been developed for this debilitating class of pathologies. Cell-based therapies in muscular dystrophies have been pursued experimentally for the last three decades. Several cell types with different characteristics and tissues of origin, including myogenic stem and progenitor cells, stromal cells, and pluripotent stem cells, have been investigated over the years and have recently entered in the clinical arena with mixed results. In this Review, we do a roundup of the past attempts and describe the updated status of cell-based therapies aimed at counteracting the skeletal and cardiac myopathy present in dystrophic patients. We present current challenges, summarize recent progress, and make recommendations for future research and clinical trials.

Authors

Stefano Biressi, Antonio Filareto, Thomas A. Rando

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Commentaries
Nonsuppressible HIV-1 viremia: a reflection of how the reservoir persists
Janet D. Siliciano, Robert F. Siliciano
Janet D. Siliciano, Robert F. Siliciano
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5665-5667. https://doi.org/10.1172/JCI141497.
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Nonsuppressible HIV-1 viremia: a reflection of how the reservoir persists

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Antiretroviral therapy (ART) generally reduces plasma HIV to undetectable levels, although virus persists in latently infected CD4+ T cells. In some individuals, viremia remains detectable despite adherence to ART and the absence of drug resistance mutations. In this issue of the JCI, Halvas et al. describe HIV RNA sequences from plasma of 8 donors with persistent viremia. Residual viremia was dominated by identical HIV-1 RNA sequences that remained relatively constant over 4 years. Plasma virus matched replication-competent virus cultured from CD4+ T cells. Integration site analysis confirmed the presence of large clones of infected cells. These results indicate that nonsuppressible viremia can be due to expanded clones of infected CD4+ T cells carrying replication-competent virus. The individuals described here represent extreme examples of a phenomenon that is seen in all infected individuals and that is a major barrier to curing HIV infection, the in vivo proliferation of latently infected cells.

Authors

Janet D. Siliciano, Robert F. Siliciano

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Oncogene-induced DNA damage: cyclic AMP steps into the ring
James A. Fagin, John H. Petrini
James A. Fagin, John H. Petrini
Published September 28, 2020
Citation Information: J Clin Invest. 2020;130(11):5668-5670. https://doi.org/10.1172/JCI142237.
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Oncogene-induced DNA damage: cyclic AMP steps into the ring

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Growth hormone–secreting (GH-secreting) pituitary tumors are driven by oncogenes that induce cAMP signaling. In this issue of the JCI, Ben-Shlomo et al. performed a whole-exome study of pituitary adenomas. GH-secreting tumors had a high frequency of whole chromosome or chromosome arm copy number alterations and were associated with an increase in the tumor protein p53 and the cyclin-dependent kinase inhibitor p21WAF1/CIP1, which are findings consistent with induction of a response to DNA damage. Further, treatment of mouse pituitary cells with cAMP pathway agonists in vitro and in vivo elicited biomarkers of DNA replication stress or double-strand breaks. The findings of Ben Shlomo et al. indicate that oncoproteins that drive constitutively high cAMP signaling pathway output in susceptible cell types can elicit DNA replication stress and may promote genomic instability.

Authors

James A. Fagin, John H. Petrini

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Getting to the point in point-of-care diagnostics for tuberculosis
Elisa H. Ignatius, … , Keira A. Cohen, William R. Bishai
Elisa H. Ignatius, … , Keira A. Cohen, William R. Bishai
Published September 28, 2020
Citation Information: J Clin Invest. 2020;130(11):5671-5673. https://doi.org/10.1172/JCI142497.
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Getting to the point in point-of-care diagnostics for tuberculosis

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Tuberculosis (TB) continues to affect over 10 million people per year worldwide. Despite advances in diagnosis, smear microscopy insufficiently detects pulmonary disease, with test result reporting taking longer than a day. While urine assays to detect the lipopolysaccharide lipoarabinomannan (LAM), present in mycobacterial cell walls, can provide results within minutes, the currently available assay has low sensitivity and its application is limited to patients with HIV suspected of having TB. In this issue of the JCI, Broger and Nicol et al. investigated 3 rapid urine tests in 372 ambulatory HIV-negative individuals suspected of having TB in South Africa and Peru. FujiLAM emerged as a rapid test to confirm TB diagnosis in the HIV-seronegative population. This study shows that FujiLAM has considerable potential to reshape the TB diagnostics landscape, making diagnosis and treatment in one office visit a reality for TB.

Authors

Elisa H. Ignatius, Keira A. Cohen, William R. Bishai

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Complement and coagulation: key triggers of COVID-19–induced multiorgan pathology
Berhane Ghebrehiwet, Ellinor I. Peerschke
Berhane Ghebrehiwet, Ellinor I. Peerschke
Published September 14, 2020
Citation Information: J Clin Invest. 2020;130(11):5674-5676. https://doi.org/10.1172/JCI142780.
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Complement and coagulation: key triggers of COVID-19–induced multiorgan pathology

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In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have been up to the task of deciphering the mechanisms by which SARS–CoV-2 induces the multisystem and multiorgan inflammatory responses that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros and Mitsios et al. is one such team who report that the complement system plays a substantial role in creating the hyperinflammation and thrombotic microangiopathy that appear to contribute to the severity of COVID-19. In support of the hypothesis that the complement system along with neutrophils and platelets contributes to COVID-19, the authors present empirical evidence showing that treatment with the complement inhibitor compstatin Cp40 inhibited the expression of tissue factor in neutrophils. These results confirm that the complement axis plays a critical role and suggest that targeted therapy using complement inhibitors is a potential therapeutic option to treat COVID-19–induced inflammation.

Authors

Berhane Ghebrehiwet, Ellinor I. Peerschke

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Stathmin-2: adding another piece to the puzzle of TDP-43 proteinopathies and neurodegeneration
Jonathan D. Glass
Jonathan D. Glass
Published October 19, 2020
Citation Information: J Clin Invest. 2020;130(11):5677-5680. https://doi.org/10.1172/JCI142854.
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Stathmin-2: adding another piece to the puzzle of TDP-43 proteinopathies and neurodegeneration

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Cytoplasmic aggregated proteins are a common neuropathological feature of neurodegenerative diseases. Cytoplasmic mislocalization and aggregation of TAR-DNA binding protein 43 (TDP-43) is found in the majority of patients with amyotrophic lateral sclerosis (ALS) and in approximately 50% of patients dying of frontotemporal lobar degeneration (FTLD). In this issue of the JCI, Prudencio, Humphrey, Pickles, and colleagues investigated the relationship of TDP-43 pathology with the loss of stathmin-2 (STMN2), an essential protein for axonal growth and maintenance. Comparing genetic, cellular, and neuropathological data from patients with TDP-43 proteinopathies (ALS, ALS–frontotemporal dementia [ALS-FTD], and FTLD-TDP-43 [FTLD-TDP]) with data from patients with non-TDP–related neurodegenerations, they demonstrate a direct relationship between TDP-43 pathology and STMN2 reduction. Loss of the normal transcription suppressor function of TDP-43 allowed transcription of an early termination cryptic axon, resulting in truncated, nonfunctional mRNA. The authors suggest that measurement of truncated STMN2 mRNA could be a biomarker for discerning TDP proteinopathies from other pathologies.

Authors

Jonathan D. Glass

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Is multisystem inflammatory syndrome in children on the Kawasaki syndrome spectrum?
Rae S.M. Yeung, Polly J. Ferguson
Rae S.M. Yeung, Polly J. Ferguson
Published July 30, 2020
Citation Information: J Clin Invest. 2020;130(11):5681-5684. https://doi.org/10.1172/JCI141718.
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Is multisystem inflammatory syndrome in children on the Kawasaki syndrome spectrum?

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An alarming increase in children presenting with fever, hyperinflammation, and multiorgan dysfunction frequently requiring intensive care has been observed after severe acute respiratory syndrome coronavirus 2 infection. The illness resembles Kawasaki disease (KD), with coronary dilatation and aneurysm occurring in some. However, the cardiovascular manifestations were typically on the severe end of the KD spectrum, with cardiogenic shock a common presentation together with other features. This led to defining a unique syndrome named multisystem inflammatory syndrome in children (MIS-C). In this issue of the JCI, Lee and Day-Lewis et al. and Diorio et al. explored the clinical profiles associated with coronavirus disease 2019 in children. We posit that while splitting MIS-C into a separate disease may aid clinical management decisions, lumping it into the KD pot may better serve to understand pathobiology.

Authors

Rae S.M. Yeung, Polly J. Ferguson

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Proteins for increased surface expression of the α6β4 nicotinic acetylcholine receptor: nothing but good news?
Stephen Grant, Henry A. Lester
Stephen Grant, Henry A. Lester
Published October 19, 2020
Citation Information: J Clin Invest. 2020;130(11):5685-5687. https://doi.org/10.1172/JCI143197.
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Proteins for increased surface expression of the α6β4 nicotinic acetylcholine receptor: nothing but good news?

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Useful animal models of disease in neuroscience can make accurate predictions about a therapeutic outcome, a feature known as predictive validity. In this issue of the JCI, Knowland et al. provide an improved model to assess nicotinic acetylcholine receptor (nAChR) ligands for treating chronic pain. The authors identify two proteins, the voltage-dependent calcium channel auxiliary subunit BARP and the unfolded protein response sensor IRE1α, that are required for robust heterologous expression of α6β4, an nAChR subtype in dorsal root ganglia (DRG). This nAChR is a candidate for the analgesic effects of nicotine as well as the frog toxin epibatidine. Now researchers can efficiently screen for α6β4 nAChR–selective agonists using heterologous expression systems. Candidates that emerge will enable researchers to test the predictive validity of mouse models for chronic pain in the nAChR context. If all these steps work, one can envision a class of non-opioid nAChR-targeted analgesics for chronic pain.

Authors

Stephen Grant, Henry A. Lester

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Research Articles
Arginase impedes the resolution of colitis by altering the microbiome and metabolome
Julia Baier, … , Christian Bogdan, Jochen Mattner
Julia Baier, … , Christian Bogdan, Jochen Mattner
Published July 28, 2020
Citation Information: J Clin Invest. 2020;130(11):e126923. https://doi.org/10.1172/JCI126923.
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Arginase impedes the resolution of colitis by altering the microbiome and metabolome

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Arginase 1 (Arg1), which converts l-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4/IL-13– and intestinal microbiota–dependent manner. Tie2-Cre Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing (Arg1fl/fl) littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells, and an accumulation of intraluminal polyamines that promote epithelial healing. The proresolving effect of Arg1 deletion was reduced by an l-arginine–free diet, but rescued by simultaneous deletion of other l-arginine–metabolizing enzymes, such as Arg2 or Nos2, demonstrating that protection from colitis requires l-arginine. Fecal microbiota transfers from Tie2-Cre Arg1fl/fl mice into WT recipients ameliorated intestinal inflammation, while transfers from WT littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of l-arginine as well as altered intestinal microbiota and metabolic products accounts for the accelerated resolution from colitis in the absence of Arg1. Consequently, l-arginine metabolism may serve as a target for clinical intervention in IBD patients.

Authors

Julia Baier, Maximilian Gänsbauer, Claudia Giessler, Harald Arnold, Mercedes Muske, Ulrike Schleicher, Sören Lukassen, Arif Ekici, Manfred Rauh, Christoph Daniel, Arndt Hartmann, Benjamin Schmid, Philipp Tripal, Katja Dettmer, Peter J. Oefner, Raja Atreya, Stefan Wirtz, Christian Bogdan, Jochen Mattner

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Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
Mercedes Prudencio, … , Pietro Fratta, Leonard Petrucelli
Mercedes Prudencio, … , Pietro Fratta, Leonard Petrucelli
Published August 13, 2020
Citation Information: J Clin Invest. 2020;130(11):e139741. https://doi.org/10.1172/JCI139741.
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Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

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No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell–derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Authors

Mercedes Prudencio, Jack Humphrey, Sarah Pickles, Anna-Leigh Brown, Sarah E. Hill, Jennifer M. Kachergus, J. Shi, Michael G. Heckman, Matthew R. Spiegel, Casey Cook, Yuping Song, Mei Yue, Lillian M. Daughrity, Yari Carlomagno, Karen Jansen-West, Cristhoper Fernandez de Castro, Michael DeTure, Shunsuke Koga, Ying-Chih Wang, Prasanth Sivakumar, Cristian Bodo, Ana Candalija, Kevin Talbot, Bhuvaneish T. Selvaraj, Karen Burr, Siddharthan Chandran, Jia Newcombe, Tammaryn Lashley, Isabel Hubbard, Demetra Catalano, Duyang Kim, Nadia Propp, Samantha Fennessey, NYGC ALS Consortium, Delphine Fagegaltier, Hemali Phatnani, Maria Secrier, Elizabeth M.C. Fisher, Björn Oskarsson, Marka van Blitterswijk, Rosa Rademakers, Neil R. Graff-Radford, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs, E. Aubrey Thompson, Towfique Raj, Michael Ward, Dennis W. Dickson, Tania F. Gendron, Pietro Fratta, Leonard Petrucelli

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X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity
Jenny C. Link, … , Arthur P. Arnold, Karen Reue
Jenny C. Link, … , Arthur P. Arnold, Karen Reue
Published July 23, 2020
Citation Information: J Clin Invest. 2020;130(11):5688-5702. https://doi.org/10.1172/JCI140223.
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X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity

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Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads. We identified the genomic dosage of Kdm5c, an X chromosome gene that escapes X chromosome inactivation, as a determinant of the X chromosome effect on adiposity. Modulating Kdm5c gene dosage in XX female mice to levels that are normally present in males resulted in reduced body weight, fat content, and food intake to a degree similar to that seen with altering the entire X chromosome dosage. In cultured preadipocytes, the levels of KDM5C histone demethylase influenced chromatin accessibility (ATAC-Seq), gene expression (RNA-Seq), and adipocyte differentiation. Both in vitro and in vivo, Kdm5c dosage influenced gene expression involved in extracellular matrix remodeling, which is critical for adipocyte differentiation and adipose tissue expansion. In humans, adipose tissue KDM5C mRNA levels and KDM5C genetic variants were associated with body mass. These studies demonstrate that the sex-dependent dosage of Kdm5c contributes to male/female differences in adipocyte biology and highlight X-escape genes as a critical component of female physiology.

Authors

Jenny C. Link, Carrie B. Wiese, Xuqi Chen, Rozeta Avetisyan, Emilio Ronquillo, Feiyang Ma, Xiuqing Guo, Jie Yao, Matthew Allison, Yii-Der Ida Chen, Jerome I. Rotter, Julia S. El -Sayed Moustafa, Kerrin S. Small, Shigeki Iwase, Matteo Pellegrini, Laurent Vergnes, Arthur P. Arnold, Karen Reue

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Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217
Jason J. Northey, … , Laurie E. Littlepage, Valerie M. Weaver
Jason J. Northey, … , Laurie E. Littlepage, Valerie M. Weaver
Published July 28, 2020
Citation Information: J Clin Invest. 2020;130(11):5721-5737. https://doi.org/10.1172/JCI129249.
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Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217

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Women with dense breasts have an increased lifetime risk of malignancy that has been attributed to a higher epithelial density. Quantitative proteomics, collagen analysis, and mechanical measurements in normal tissue revealed that stroma in the high-density breast contains more oriented, fibrillar collagen that is stiffer and correlates with higher epithelial cell density. microRNA (miR) profiling of breast tissue identified miR-203 as a matrix stiffness–repressed transcript that is downregulated by collagen density and reduced in the breast epithelium of women with high mammographic density. Culture studies demonstrated that ZNF217 mediates a matrix stiffness– and collagen density–induced increase in Akt activity and mammary epithelial cell proliferation. Manipulation of the epithelium in a mouse model of mammographic density supported a causal relationship between stromal stiffness, reduced miR-203, higher levels of the murine homolog Zfp217, and increased Akt activity and mammary epithelial proliferation. ZNF217 was also increased in the normal breast epithelium of women with high mammographic density, correlated positively with epithelial proliferation and density, and inversely with miR-203. The findings identify ZNF217 as a potential target toward which preexisting therapies, such as the Akt inhibitor triciribine, could be used as a chemopreventive agent to reduce cancer risk in women with high mammographic density.

Authors

Jason J. Northey, Alexander S. Barrett, Irene Acerbi, Mary-Kate Hayward, Stephanie Talamantes, Ivory S. Dean, Janna K. Mouw, Suzanne M. Ponik, Jonathon N. Lakins, Po-Jui Huang, Junmin Wu, Quanming Shi, Susan Samson, Patricia J. Keely, Rita A. Mukhtar, Jan T. Liphardt, John A. Shepherd, E. Shelley Hwang, Yunn-Yi Chen, Kirk C. Hansen, Laurie E. Littlepage, Valerie M. Weaver

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DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas
Anat Ben-Shlomo, … , Artak Labadzhyan, Shlomo Melmed
Anat Ben-Shlomo, … , Artak Labadzhyan, Shlomo Melmed
Published July 16, 2020
Citation Information: J Clin Invest. 2020;130(11):5738-5755. https://doi.org/10.1172/JCI138540.
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DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas

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Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole-exome sequencing of 159 prospectively resected pituitary adenomas showed that somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNAs correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed that both cAMP and Fanconi anemia DNA damage repair pathways were affected by SCNAs in growth hormone–secreting (GH-secreting) somatotroph adenomas. As somatotroph differentiation and GH secretion are dependent on cAMP activation and we previously showed DNA damage, aneuploidy, and senescence in somatotroph adenomas, we studied links between cAMP signaling and DNA damage. Stimulation of cAMP in C57BL/6 mouse primary pituitary cultures using forskolin or a long-acting GH-releasing hormone (GHRH) analog increased GH production and DNA damage measured by H2AX phosphorylation and a comet assay. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. We conclude that cAMP, which induces somatotroph proliferation and GH secretion, may concomitantly induce DNA damage, potentially linking hormone hypersecretion to SCNA and genome instability. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment.

Authors

Anat Ben-Shlomo, Nan Deng, Evelyn Ding, Masaaki Yamamoto, Adam Mamelak, Vera Chesnokova, Artak Labadzhyan, Shlomo Melmed

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Diagnostic accuracy of 3 urine lipoarabinomannan tuberculosis assays in HIV-negative outpatients
Tobias Broger, … , Samuel G. Schumacher, Claudia M. Denkinger
Tobias Broger, … , Samuel G. Schumacher, Claudia M. Denkinger
Published July 21, 2020
Citation Information: J Clin Invest. 2020;130(11):5756-5764. https://doi.org/10.1172/JCI140461.
View: Text | PDF Clinical Research and Public Health

Diagnostic accuracy of 3 urine lipoarabinomannan tuberculosis assays in HIV-negative outpatients

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BACKGROUND Inadequate tuberculosis (TB) diagnostics are a major hurdle in the reduction of disease burden, and accurate point-of-care tests (POCTs) are urgently needed. We assessed the diagnostic accuracy of Fujifilm SILVAMP TB lipoarabinomannan (FujiLAM) POCT for TB diagnosis in HIV-negative outpatients and compared it with Alere Determine TB LAM Ag (AlereLAM) POCT and a laboratory-based ultrasensitive electrochemiluminescence LAM research assay (EclLAM).METHODS In this multicenter diagnostic test accuracy study, we recruited HIV-negative adults with symptoms suggestive of pulmonary TB presenting to outpatient health care centers in Peru and South Africa. Urine samples were tested using FujiLAM, AlereLAM, and EclLAM, and the diagnostic accuracy was assessed against a microbiological reference standard (MRS) and a composite reference standard.RESULTS Three hundred seventy-two HIV-negative participants were included and the prevalence of microbiologically confirmed TB was 30%. Compared with the MRS, the sensitivities of AlereLAM, FujiLAM, and EclLAM were 10.8% (95% confidence interval [CI] 6.3%–18.0%), 53.2% (95% CI 43.9%–62.1%), and 66.7% (95% CI 57.5%–74.7%), respectively. The specificities of AlereLAM, FujiLAM, and EclLAM were 92.3% (95% CI 88.5%–95.0%), 98.9% (95% CI 96.7%–99.6%), and 98.1% (95% CI 95.6%–99.2%), respectively. Positive likelihood ratios of AlereLAM, FujiLAM, and EclLAM were 1.4, 46.2, and 34.8, respectively, and positive predictive values were 37.5%, 95.2%, and 93.7%, respectively.CONCLUSION Compared with AlereLAM, FujiLAM detected 5 times more patients with TB in HIV-negative participants, had a high positive predictive value, and has the potential to improve rapid diagnosis of TB at the point-of-care. EclLAM demonstrated that additional sensitivity gains are possible, which highlights LAM’s potential as a biomarker. Additional research is required to assess FujiLAM’s performance in prospective cohorts, its cost-effectiveness, and its impact in real-world clinical settings.FUNDING Global Health Innovative Technology Fund, the UK Department for International Development, the Dutch Ministry of Foreign Affairs, the Bill and Melinda Gates Foundation, the Australian Department of Foreign Affairs and Trade, the German Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, and the NIH and National Institute of Allergy and Infectious Diseases.

Authors

Tobias Broger, Mark P. Nicol, George B. Sigal, Eduardo Gotuzzo, Alexandra J. Zimmer, Shireen Surtie, Tatiana Caceres-Nakiche, Anna Mantsoki, Elena Ivanova Reipold, Rita Székely, Michael Tsionsky, Judith van Heerden, Tatiana Plisova, Kinuyo Chikamatsu, Todd L. Lowary, Abraham Pinter, Satoshi Mitarai, Emmanuel Moreau, Samuel G. Schumacher, Claudia M. Denkinger

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The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis
Anne Müller, … , Klaus Schulze-Osthoff, Daniela Kramer
Anne Müller, … , Klaus Schulze-Osthoff, Daniela Kramer
Published July 23, 2020
Citation Information: J Clin Invest. 2020;130(11):5765-5781. https://doi.org/10.1172/JCI134217.
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The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis

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Psoriasis is a frequent, inflammatory skin disease characterized by keratinocyte hyperproliferation and a disease-related infiltration of immune cells. Here, we identified a novel proinflammatory signaling pathway driven by cyclin-dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid target for psoriasis therapy. Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby triggering a methylation-induced activation of STAT3. Subsequently, active STAT3 resulted in the induction of IκBζ, which is a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis-related proinflammatory gene expression by suppressing IκBζ induction in keratinocytes. Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to fully prevent the development of psoriasis in various mouse models by suppressing STAT3-mediated IκBζ expression. Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin lesions. Thus, this study not only identifies a novel psoriasis-relevant proinflammatory pathway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option for patients with psoriasis.

Authors

Anne Müller, Antje Dickmanns, Claudia Resch, Knut Schäkel, Stephan Hailfinger, Matthias Dobbelstein, Klaus Schulze-Osthoff, Daniela Kramer

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Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma
Byoung-San Moon, … , Min Yu, Wange Lu
Byoung-San Moon, … , Min Yu, Wange Lu
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5782-5799. https://doi.org/10.1172/JCI127916.
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Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma

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Glioblastoma multiforme (GBM) heterogeneity causes a greater number of deaths than any other brain tumor, despite the availability of alkylating chemotherapy. GBM stem-like cells (GSCs) contribute to GBM complexity and chemoresistance, but it remains challenging to identify and target GSCs or factors that control their activity. Here, we identified a specific GSC subset and show that activity of these cells is positively regulated by stabilization of methyl CpG binding domain 3 (MBD3) protein. MBD3 binds to CK1A and to BTRCP E3 ubiquitin ligase, triggering MBD3 degradation, suggesting that modulating this circuit could antagonize GBM recurrence. Accordingly, xenograft mice treated with the CK1A activator pyrvinium pamoate (Pyr-Pam) showed enhanced MBD3 degradation in cells expressing high levels of O6-methylguanine-DNA methyltransferase (MGMT) and in GSCs, overcoming temozolomide chemoresistance. Pyr-Pam blocked recruitment of MBD3 and the repressive nucleosome remodeling and deacetylase (NuRD) complex to neurogenesis-associated gene loci and increased acetyl–histone H3 activity and GSC differentiation. We conclude that CK1A/BTRCP/MBD3/NuRD signaling modulates GSC activation and malignancy, and that targeting this signaling could suppress GSC proliferation and GBM recurrence.

Authors

Byoung-San Moon, Mingyang Cai, Grace Lee, Tong Zhao, Xiaofeng Song, Steven L. Giannotta, Frank J. Attenello, Min Yu, Wange Lu

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Landscape of coordinated immune responses to H1N1 challenge in humans
Zainab Rahil, … , Garry P. Nolan, David R. McIlwain
Zainab Rahil, … , Garry P. Nolan, David R. McIlwain
Published October 12, 2020
Citation Information: J Clin Invest. 2020;130(11):5800-5816. https://doi.org/10.1172/JCI137265.
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Landscape of coordinated immune responses to H1N1 challenge in humans

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Influenza is a significant cause of morbidity and mortality worldwide. Here we show changes in the abundance and activation states of more than 50 immune cell subsets in 35 individuals over 11 time points during human A/California/2009 (H1N1) virus challenge monitored using mass cytometry along with other clinical assessments. Peak change in monocyte, B cell, and T cell subset frequencies coincided with peak virus shedding, followed by marked activation of T and NK cells. Results led to the identification of CD38 as a critical regulator of plasmacytoid dendritic cell function in response to influenza virus. Machine learning using study-derived clinical parameters and single-cell data effectively classified and predicted susceptibility to infection. The coordinated immune cell dynamics defined in this study provide a framework for identifying novel correlates of protection in the evaluation of future influenza therapeutics.

Authors

Zainab Rahil, Rebecca Leylek, Christian M. Schürch, Han Chen, Zach Bjornson-Hooper, Shannon R. Christensen, Pier Federico Gherardini, Salil S. Bhate, Matthew H. Spitzer, Gabriela K. Fragiadakis, Nilanjan Mukherjee, Nelson Kim, Sizun Jiang, Jennifer Yo, Brice Gaudilliere, Melton Affrime, Bonnie Bock, Scott E. Hensley, Juliana Idoyaga, Nima Aghaeepour, Kenneth Kim, Garry P. Nolan, David R. McIlwain

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Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency
Enrica E.K. Tan, … , Woei Kang Liew, John E. Connolly
Enrica E.K. Tan, … , Woei Kang Liew, John E. Connolly
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(11):5817-5832. https://doi.org/10.1172/JCI98882.
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Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency

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Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient’s stimulated leukocytes, in her induced pluripotent stem cell–derived macrophages, and in murine bone marrow–derived macrophages containing the L34P mutation. The patient’s hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.

Authors

Enrica E.K. Tan, Richard A. Hopkins, Chrissie K. Lim, Saumya S. Jamuar, Christina Ong, Koh C. Thoon, Mark J.A. Koh, Eun Mong Shin, Derrick W.Q. Lian, Madhushanee Weerasooriya, Christopher Z.W. Lee, Andreas Alvin Pumomo Soetedjo, Chang Siang Lim, Veonice B. Au, Edmond Chua, Hui Yin Lee, Leigh Ann Jones, Sharmy S. James, Nivashini Kaliaperumal, Jeffery Kwok, Ee Shien Tan, Biju Thomas, Lynn Xue Wu, Lena Ho, Anna Marie Fairhurst, Florent Ginhoux, Adrian K.K. Teo, Yong Liang Zhang, Kok Huar Ong, Weimiao Yu, Byrappa Venkatesh, Vinay Tergaonkar, Bruno Reversade, Keh Chuang Chin, Ah Moy Tan, Woei Kang Liew, John E. Connolly

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Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma
Jason Yongsheng Chan, … , Bin Tean Teh, Khee Chee Soo
Jason Yongsheng Chan, … , Bin Tean Teh, Khee Chee Soo
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5833-5846. https://doi.org/10.1172/JCI139080.
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Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma

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Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non–UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15+), macrophages (CD68+), cytotoxic T cells (CD8+), Tregs (FOXP3+), and PD-L1+ cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.

Authors

Jason Yongsheng Chan, Jing Quan Lim, Joe Yeong, Vinod Ravi, Peiyong Guan, Arnoud Boot, Timothy Kwang Yong Tay, Sathiyamoorthy Selvarajan, Nur Diyana Md Nasir, Jie Hua Loh, Choon Kiat Ong, Dachuan Huang, Jing Tan, Zhimei Li, Cedric Chuan-Young Ng, Thuan Tong Tan, Mikio Masuzawa, Ken Wing-Kin Sung, Mohamad Farid, Richard Hong Hui Quek, Ngian Chye Tan, Melissa Ching Ching Teo, Steven George Rozen, Patrick Tan, Andrew Futreal, Bin Tean Teh, Khee Chee Soo

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HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus
Elias K. Halvas, … , Stephen H. Hughes, John W. Mellors
Elias K. Halvas, … , Stephen H. Hughes, John W. Mellors
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5847-5857. https://doi.org/10.1172/JCI138099.
View: Text | PDF Clinical Research and Public Health

HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus

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BACKGROUND HIV-1 viremia that is not suppressed by combination antiretroviral therapy (ART) is generally attributed to incomplete medication adherence and/or drug resistance. We evaluated individuals referred by clinicians for nonsuppressible viremia (plasma HIV-1 RNA above 40 copies/mL) despite reported adherence to ART and the absence of drug resistance to the current ART regimen.METHODS Samples were collected from at least 2 time points from 8 donors who had nonsuppressible viremia for more than 6 months. Single templates of HIV-1 RNA obtained from plasma and viral outgrowth of cultured cells and from proviral DNA were amplified by PCR and sequenced for evidence of clones of cells that produced infectious viruses. Clones were confirmed by host-proviral integration site analysis.RESULTS HIV-1 genomic RNA with identical sequences were identified in plasma samples from all 8 donors. The identical viral RNA sequences did not change over time and did not evolve resistance to the ART regimen. In 4 of the donors, viral RNA sequences obtained from plasma matched those sequences from viral outgrowth cultures, indicating that the viruses were replication competent. Integration sites for infectious proviruses from those 4 donors were mapped to the introns of the MATR3, ZNF268, ZNF721/ABCA11P, and ABCA11P genes. The sizes of the clones were estimated to be from 50 million to 350 million cells.CONCLUSION These findings show that clones of HIV-1–infected cells producing virus can cause failure of ART to suppress viremia. The mechanisms involved in clonal expansion and persistence need to be defined to effectively target viremia and the HIV-1 reservoir.FUNDING National Cancer Institute, NIH; Howard Hughes Medical Research Fellows Program, Howard Hughes Medical Institute; Bill and Melinda Gates Foundation; Office of AIDS Research; American Cancer Society; National Cancer Institute through a Leidos subcontract; National Institute for Allergy and Infectious Diseases, NIH, to the I4C Martin Delaney Collaboratory; University of Rochester Center for AIDS Research and University of Rochester HIV/AIDS Clinical Trials Unit.

Authors

Elias K. Halvas, Kevin W. Joseph, Leah D. Brandt, Shuang Guo, Michele D. Sobolewski, Jana L. Jacobs, Camille Tumiotto, John K. Bui, Joshua C. Cyktor, Brandon F. Keele, Gene D. Morse, Michael J. Bale, Wei Shao, Mary F. Kearney, John M. Coffin, Jason W. Rausch, Xiaolin Wu, Stephen H. Hughes, John W. Mellors

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Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis
Danish Patoli, … , Laurent Lagrost, Charles Thomas
Danish Patoli, … , Laurent Lagrost, Charles Thomas
Published August 6, 2020
Citation Information: J Clin Invest. 2020;130(11):5858-5874. https://doi.org/10.1172/JCI130996.
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Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis

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Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis, but its contribution to macrophage functions and host defense remains to be delineated. Here, we showed that lipopolysaccharide (LPS) in combination with IFN-γ inhibited PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggered classical macrophage activation in a mitochondrial ROS–dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation, which favored bactericidal clearance and led to a better survival rate. Reciprocally, mitochondrial uncouplers that promote mitophagy reversed LPS/IFN-γ–mediated activation of macrophages and led to immunoparalysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy was inhibited in blood monocytes of patients with sepsis as compared with nonseptic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.

Authors

Danish Patoli, Franck Mignotte, Valérie Deckert, Alois Dusuel, Adélie Dumont, Aurélie Rieu, Antoine Jalil, Kevin Van Dongen, Thibaut Bourgeois, Thomas Gautier, Charlène Magnani, Naig Le Guern, Stéphane Mandard, Jean Bastin, Fatima Djouadi, Christine Schaeffer, Nina Guillaumot, Michel Narce, Maxime Nguyen, Julien Guy, Auguste Dargent, Jean-Pierre Quenot, Mickaël Rialland, David Masson, Johan Auwerx, Laurent Lagrost, Charles Thomas

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Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma
Evon Poon, … , Charles Y. Lin, Louis Chesler
Evon Poon, … , Charles Y. Lin, Louis Chesler
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5875-5892. https://doi.org/10.1172/JCI134132.
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Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

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The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.

Authors

Evon Poon, Tong Liang, Yann Jamin, Susanne Walz, Colin Kwok, Anne Hakkert, Karen Barker, Zuzanna Urban, Khin Thway, Rhamy Zeid, Albert Hallsworth, Gary Box, Marli E. Ebus, Marco P. Licciardello, Yordan Sbirkov, Glori Lazaro, Elizabeth Calton, Barbara M. Costa, Melanie Valenti, Alexis De Haven Brandon, Hannah Webber, Nicolas Tardif, Gilberto S. Almeida, Rossitza Christova, Gunther Boysen, Mark W. Richards, Giuseppe Barone, Anthony Ford, Richard Bayliss, Paul A. Clarke, Johann De Bono, Nathanael S. Gray, Julian Blagg, Simon P. Robinson, Suzanne A. Eccles, Daniella Zheleva, James E. Bradner, Jan Molenaar, Igor Vivanco, Martin Eilers, Paul Workman, Charles Y. Lin, Louis Chesler

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DCAF1 regulates Treg senescence via the ROS axis during immunological aging
Zengli Guo, … , Jenny P.-Y. Ting, Yisong Y. Wan
Zengli Guo, … , Jenny P.-Y. Ting, Yisong Y. Wan
Published July 30, 2020
Citation Information: J Clin Invest. 2020;130(11):5893-5908. https://doi.org/10.1172/JCI136466.
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DCAF1 regulates Treg senescence via the ROS axis during immunological aging

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As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.

Authors

Zengli Guo, Gang Wang, Bing Wu, Wei-Chun Chou, Liang Cheng, Chenlin Zhou, Jitong Lou, Di Wu, Lishan Su, Junnian Zheng, Jenny P.-Y. Ting, Yisong Y. Wan

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Complement activation on endothelium initiates antibody-mediated acute lung injury
Simon J. Cleary, … , James C. Zimring, Mark R. Looney
Simon J. Cleary, … , James C. Zimring, Mark R. Looney
Published July 30, 2020
Citation Information: J Clin Invest. 2020;130(11):5909-5923. https://doi.org/10.1172/JCI138136.
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Complement activation on endothelium initiates antibody-mediated acute lung injury

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Antibodies targeting human leukocyte antigen (HLA)/major histocompatibility complex (MHC) proteins limit successful transplantation and transfusion, and their presence in blood products can cause lethal transfusion-related acute lung injury (TRALI). It is unclear which cell types are bound by these anti-leukocyte antibodies to initiate an immunologic cascade resulting in lung injury. We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. Only the removal of endothelial MHC I reduced lung injury and mortality, related mechanistically to absent endothelial complement fixation and lung platelet retention. Restoration of endothelial MHC I rendered MHC I–deficient mice susceptible to lung injury. Neutrophil responses, including neutrophil extracellular trap (NET) release, were intact in endothelial MHC I–deficient mice, whereas complement depletion reduced both lung injury and NETs. Human pulmonary endothelial cells showed high HLA class I expression, and posttransfusion complement activation was increased in clinical TRALI. These results indicate that the critical source of antigen for anti-leukocyte antibodies is in fact the endothelium, which reframes our understanding of TRALI as a rapid-onset vasculitis. Inhibition of complement activation may have multiple beneficial effects of reducing endothelial injury, platelet retention, and NET release in conditions where antibodies trigger these pathogenic responses.

Authors

Simon J. Cleary, Nicholas Kwaan, Jennifer J. Tian, Daniel R. Calabrese, Beñat Mallavia, Mélia Magnen, John R. Greenland, Anatoly Urisman, Jonathan P. Singer, Steven R. Hays, Jasleen Kukreja, Ariel M. Hay, Heather L. Howie, Pearl Toy, Clifford A. Lowell, Craig N. Morrell, James C. Zimring, Mark R. Looney

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ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming
Fei Li, … , Yu Chen, Dong Gao
Fei Li, … , Yu Chen, Dong Gao
Published July 23, 2020
Citation Information: J Clin Invest. 2020;130(11):5924-5941. https://doi.org/10.1172/JCI137967.
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ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

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Although cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early-stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer proluminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we found that ERG was highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibited those cells’ normal plasticity to transdifferentiate into a basal lineage, and ERG superseded PTEN loss, which favored basal differentiation. ERG KO disrupted prostate cell luminal differentiation, whereas AR KO had no such effects. Trp63 is a known master regulator of the prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG bound and inhibited the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG, in its fundamental role in lineage differentiation in prostate cancer initiation, orchestrated chromatin interactions and regulated prostate cell lineage toward a proluminal program.

Authors

Fei Li, Qiuyue Yuan, Wei Di, Xinyi Xia, Zhuang Liu, Ninghui Mao, Lin Li, Chunfeng Li, Juan He, Yunguang Li, Wangxin Guo, Xiaoyu Zhang, Yiqin Zhu, Rebiguli Aji, Shangqian Wang, Xinyuan Tong, Hongbin Ji, Ping Chi, Brett Carver, Yong Wang, Yu Chen, Dong Gao

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Distinct clinical and immunological features of SARS–CoV-2–induced multisystem inflammatory syndrome in children
Pui Y. Lee, … , Jane W. Newburger, Mary Beth F. Son
Pui Y. Lee, … , Jane W. Newburger, Mary Beth F. Son
Published July 23, 2020
Citation Information: J Clin Invest. 2020;130(11):5942-5950. https://doi.org/10.1172/JCI141113.
View: Text | PDF Clinical Research and Public Health

Distinct clinical and immunological features of SARS–CoV-2–induced multisystem inflammatory syndrome in children

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Abstract

BACKGROUND Pediatric SARS–CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODS We retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTS Twenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS–CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSION MIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDING This work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children’s Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

Authors

Pui Y. Lee, Megan Day-Lewis, Lauren A. Henderson, Kevin G. Friedman, Jeffrey Lo, Jordan E. Roberts, Mindy S. Lo, Craig D. Platt, Janet Chou, Kacie J. Hoyt, Annette L. Baker, Tina M. Banzon, Margaret H. Chang, Ezra Cohen, Sarah D. de Ferranti, Audrey Dionne, Saddiq Habiballah, Olha Halyabar, Jonathan S. Hausmann, Melissa M. Hazen, Erin Janssen, Esra Meidan, Ryan W. Nelson, Alan A. Nguyen, Robert P. Sundel, Fatma Dedeoglu, Peter A. Nigrovic, Jane W. Newburger, Mary Beth F. Son

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Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors
Lulu Wang, … , Xuetong Shen, Guang Peng
Lulu Wang, … , Xuetong Shen, Guang Peng
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5951-5966. https://doi.org/10.1172/JCI130445.
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Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors

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Abstract

ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A’s targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell–intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.

Authors

Lulu Wang, Lin Yang, Chen Wang, Wei Zhao, Zhenlin Ju, Wei Zhang, Jianfeng Shen, Yang Peng, Clemens An, Yen T. Luu, Shumei Song, Timothy A. Yap, Jaffer A. Ajani, Gordon B. Mills, Xuetong Shen, Guang Peng

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Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2
Caroline Diorio, … , David T. Teachey, Hamid Bassiri
Caroline Diorio, … , David T. Teachey, Hamid Bassiri
Published July 30, 2020
Citation Information: J Clin Invest. 2020;130(11):5967-5975. https://doi.org/10.1172/JCI140970.
View: Text | PDF Clinical Research and Public Health

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2

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BACKGROUND Initial reports from the severe acute respiratory coronavirus 2 (SARS–CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODS We prospectively enrolled hospitalized patients with evidence of SARS–CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTS Twenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSION Pediatric patients with SARS–CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDING Financial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex’s Lemonade Stand Foundation for Childhood Cancer; Children’s Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

Authors

Caroline Diorio, Sarah E. Henrickson, Laura A. Vella, Kevin O. McNerney, Julie Chase, Chakkapong Burudpakdee, Jessica H. Lee, Cristina Jasen, Fran Balamuth, David M. Barrett, Brenda L. Banwell, Kathrin M. Bernt, Allison M. Blatz, Kathleen Chiotos, Brian T. Fisher, Julie C. Fitzgerald, Jeffrey S. Gerber, Kandace Gollomp, Christopher Gray, Stephan A. Grupp, Rebecca M. Harris, Todd J. Kilbaugh, Audrey R. Odom John, Michele Lambert, Emily J. Liebling, Michele E. Paessler, Whitney Petrosa, Charles Phillips, Anne F. Reilly, Neil D. Romberg, Alix Seif, Deborah A. Sesok-Pizzini, Kathleen E. Sullivan, Julie Vardaro, Edward M. Behrens, David T. Teachey, Hamid Bassiri

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mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer
Gal Cafri, … , Paul F. Robbins, Steven A. Rosenberg
Gal Cafri, … , Paul F. Robbins, Steven A. Rosenberg
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5976-5988. https://doi.org/10.1172/JCI134915.
View: Text | PDF Clinical Research and Public Health

mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer

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Abstract

BACKGROUND Therapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODS We recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients’ tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTS The vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSION This vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATION Phase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDING Center for Clinical Research, NCI, NIH.

Authors

Gal Cafri, Jared J. Gartner, Tal Zaks, Kristen Hopson, Noam Levin, Biman C. Paria, Maria R. Parkhurst, Rami Yossef, Frank J. Lowery, Mohammad S. Jafferji, Todd D. Prickett, Stephanie L. Goff, Christine T. McGowan, Samantha Seitter, Mackenzie L. Shindorf, Anup Parikh, Praveen D. Chatani, Paul F. Robbins, Steven A. Rosenberg

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Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal
Noé Rodríguez-Rodríguez, … , Florencia Rosetti, José C. Crispín
Noé Rodríguez-Rodríguez, … , Florencia Rosetti, José C. Crispín
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(11):5989-6004. https://doi.org/10.1172/JCI129479.
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Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal

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How T cells integrate environmental cues into signals that limit the magnitude and length of immune responses is poorly understood. Here, we provide data that demonstrate that B55β, a regulatory subunit of protein phosphatase 2A, represents a molecular link between cytokine concentration and apoptosis in activated CD8+ T cells. Through the modulation of AKT, B55β induced the expression of the proapoptotic molecule Hrk in response to cytokine withdrawal. Accordingly, B55β and Hrk were both required for in vivo and in vitro contraction of activated CD8+ lymphocytes. We show that this process plays a role during clonal contraction, establishment of immune memory, and preservation of peripheral tolerance. This regulatory pathway may represent an unexplored opportunity to end unwanted immune responses or to promote immune memory.

Authors

Noé Rodríguez-Rodríguez, Iris K. Madera-Salcedo, J. Alejandro Cisneros-Segura, H. Benjamín García-González, Sokratis A. Apostolidis, Abril Saint-Martin, Marcela Esquivel-Velázquez, Tran Nguyen, Dámaris P. Romero-Rodríguez, George C. Tsokos, Jorge Alcocer-Varela, Florencia Rosetti, José C. Crispín

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Preventing neuronal edema increases network excitability after traumatic brain injury
Punam A. Sawant-Pokam, … , Nick O. McKean, K.C. Brennan
Punam A. Sawant-Pokam, … , Nick O. McKean, K.C. Brennan
Published October 12, 2020
Citation Information: J Clin Invest. 2020;130(11):6005-6020. https://doi.org/10.1172/JCI134793.
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Preventing neuronal edema increases network excitability after traumatic brain injury

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Edema is an important target for clinical intervention after traumatic brain injury (TBI). We used in vivo cellular resolution imaging and electrophysiological recording to examine the ionic mechanisms underlying neuronal edema and their effects on neuronal and network excitability after controlled cortical impact (CCI) in mice. Unexpectedly, we found that neuronal edema 48 hours after CCI was associated with reduced cellular and network excitability, concurrent with an increase in the expression ratio of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2. Treatment with the CCC blocker bumetanide prevented neuronal swelling via a reversal in the NKCC1/KCC2 expression ratio, identifying altered chloride flux as the mechanism of neuronal edema. Importantly, bumetanide treatment was associated with increased neuronal and network excitability after injury, including increased susceptibility to spreading depolarizations (SDs) and seizures, known agents of clinical worsening after TBI. Treatment with mannitol, a first-line edema treatment in clinical practice, was also associated with increased susceptibility to SDs and seizures after CCI, showing that neuronal volume reduction, regardless of mechanism, was associated with an excitability increase. Finally, we observed an increase in excitability when neuronal edema normalized by 1 week after CCI. We conclude that neuronal swelling may exert protective effects against damaging excitability in the aftermath of TBI and that treatment of edema has the potential to reverse these effects.

Authors

Punam A. Sawant-Pokam, Tyler J. Vail, Cameron S. Metcalf, Jamie L. Maguire, Thomas O. McKean, Nick O. McKean, K.C. Brennan

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Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities
Chiara F. Magnani, … , Alessandro Rambaldi, Andrea Biondi
Chiara F. Magnani, … , Alessandro Rambaldi, Andrea Biondi
Published August 11, 2020
Citation Information: J Clin Invest. 2020;130(11):6021-6033. https://doi.org/10.1172/JCI138473.
View: Text | PDF Clinical Research and Public Health

Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities

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BACKGROUND Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability.METHODS We report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells.RESULTS The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD–). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion.CONCLUSION SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.TRIAL REGISTRATION ClinicalTrials.gov NCT03389035.FUNDING This study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).

Authors

Chiara F. Magnani, Giuseppe Gaipa, Federico Lussana, Daniela Belotti, Giuseppe Gritti, Sara Napolitano, Giada Matera, Benedetta Cabiati, Chiara Buracchi, Gianmaria Borleri, Grazia Fazio, Silvia Zaninelli, Sarah Tettamanti, Stefania Cesana, Valentina Colombo, Michele Quaroni, Giovanni Cazzaniga, Attilio Rovelli, Ettore Biagi, Stefania Galimberti, Andrea Calabria, Fabrizio Benedicenti, Eugenio Montini, Silvia Ferrari, Martino Introna, Adriana Balduzzi, Maria Grazia Valsecchi, Giuseppe Dastoli, Alessandro Rambaldi, Andrea Biondi

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Metabolic effects of air pollution exposure and reversibility
Sanjay Rajagopalan, … , Kasper D. Hansen, Shyam Biswal
Sanjay Rajagopalan, … , Kasper D. Hansen, Shyam Biswal
Published August 11, 2020
Citation Information: J Clin Invest. 2020;130(11):6034-6040. https://doi.org/10.1172/JCI137315.
View: Text | PDF Concise Communication

Metabolic effects of air pollution exposure and reversibility

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Air pollution involving particulate matter smaller than 2.5 μm in size (PM2.5) is the world’s leading environmental risk factor contributing to mortality through cardiometabolic pathways. In this study, we modeled early life exposure using chow-fed C57BL/6J male mice that were exposed to real-world inhaled, concentrated PM2.5 (~10 times ambient levels/~60–120 μg/m3) or filtered air over a 14-week period. We investigated the effects of PM2.5 on phenotype, the transcriptome, and chromatin accessibility and compared these with the effects of a prototypical high-fat diet (HFD) as well as cessation of exposure on phenotype reversibility. Exposure to PM2.5 impaired glucose and insulin tolerance and reduced energy expenditure and 18FDG-PET uptake in brown adipose tissue. Multiple differentially expressed gene clusters in pathways involving metabolism and circadian rhythm were noted in insulin-responsive tissues. Although the magnitude of transcriptional change detected with PM2.5 exposure was lower than that observed with a HFD, the degree of alteration in chromatin accessibility after PM2.5 exposure was significant. The novel chromatin remodeler SMARCA5 (SWI/SNF complex) was regulated in response to PM2.5 exposure, the cessation of which was associated with a reversal of insulin resistance and restoration of chromatin accessibility and nucleosome positioning near transcription start sites, as well as a reversal of exposure-induced changes in the transcriptome, including SMARCA5. These changes indicate pliable epigenetic control mechanisms following cessation of exposure.

Authors

Sanjay Rajagopalan, Bongsoo Park, Rengasamy Palanivel, Vinesh Vinayachandran, Jeffrey A. Deiuliis, Roopesh Singh Gangwar, Lopa Das, Jinhu Yin, Youngshim Choi, Sadeer Al-Kindi, Mukesh K. Jain, Kasper D. Hansen, Shyam Biswal

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Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme
Corey Smith, … , David Walker, Rajiv Khanna
Corey Smith, … , David Walker, Rajiv Khanna
Published August 11, 2020
Citation Information: J Clin Invest. 2020;130(11):6041-6053. https://doi.org/10.1172/JCI138649.
View: Text | PDF Clinical Research and Public Health

Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme

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Abstract

BACKGROUND The recent failure of checkpoint-blockade therapies for glioblastoma multiforme (GBM) in late-phase clinical trials has directed interest toward adoptive cellular therapies (ACTs). In this open-label, first-in-human trial, we have assessed the safety and therapeutic potential of cytomegalovirus-specific (CMV-specific) ACT in an adjuvant setting for patients with primary GBM, with an ultimate goal to prevent or delay recurrence and prolong overall survival.METHODS Twenty-eight patients with primary GBM were recruited to this prospective study, 25 of whom were treated with in vitro–expanded autologous CMV-specific T cells. Participants were monitored for safety, progression-free survival, overall survival (OS), and immune reconstitution.RESULTS No participants showed evidence of ACT-related toxicities. Of 25 evaluable participants, 10 were alive at the completion of follow-up, while 5 were disease free. Reconstitution of CMV-specific T cell immunity was evident and CMV-specific ACT may trigger a bystander effect leading to additional T cell responses to nonviral tumor-associated antigens through epitope spreading. Long-term follow-up of participants treated before recurrence showed significantly improved OS when compared with those who progressed before ACT (median 23 months, range 7–65 vs. median 14 months, range 5–19; P = 0.018). Gene expression analysis of the ACT products indicated that a favorable T cell gene signature was associated with improved long-term survival.CONCLUSION Data presented in this study demonstrate that CMV-specific ACT can be safely used as an adjuvant therapy for primary GBM and, if offered before recurrence, this therapy may improve OS of GBM patients.TRIAL REGISTRATION anzctr.org.au: ACTRN12615000656538.FUNDING Philanthropic funding and the National Health and Medical Research Council (Australia).

Authors

Corey Smith, Katie E. Lineburg, J. Paulo Martins, George R. Ambalathingal, Michelle A. Neller, Beth Morrison, Katherine K. Matthews, Sweera Rehan, Pauline Crooks, Archana Panikkar, Leone Beagley, Laetitia Le Texier, Sriganesh Srihari, David Walker, Rajiv Khanna

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Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure
Bo Zhou, … , Kevin D. O’Brien, Rong Tian
Bo Zhou, … , Kevin D. O’Brien, Rong Tian
Published August 13, 2020
Citation Information: J Clin Invest. 2020;130(11):6054-6063. https://doi.org/10.1172/JCI138538.
View: Text | PDF Clinical Research and Public Health

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

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BACKGROUND While mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level.METHODS We compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage–associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor.RESULTS We demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.CONCLUSION These findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF.TRIAL REGISTRATION ClinicalTrials.gov NCT03727646.FUNDING This study was funded by the NIH, the University of Washington, and the American Heart Association.

Authors

Bo Zhou, Dennis Ding-Hwa Wang, Yanhua Qiu, Sophia Airhart, Yaxin Liu, April Stempien-Otero, Kevin D. O’Brien, Rong Tian

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BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation
Julia Volz, … , Markus Sauer, Bernhard Nieswandt
Julia Volz, … , Markus Sauer, Bernhard Nieswandt
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(11):6064-6079. https://doi.org/10.1172/JCI136457.
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BIN2 orchestrates platelet calcium signaling in thrombosis and thrombo-inflammation

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Abstract

Store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx in platelets. The Ca2+ sensor stromal interaction molecule 1 (STIM1) triggers SOCE by forming punctate structures with the Ca2+ channel Orai1 and the inositol trisphosphate receptor (IP3R), thereby linking the endo-/sarcoplasmic reticulum to the plasma membrane. Here, we identified the BAR domain superfamily member bridging integrator 2 (BIN2) as an interaction partner of STIM1 and IP3R in platelets. Deletion of platelet BIN2 (Bin2fl/fl,Pf4-Cre mice) resulted in reduced Ca2+ store release and Ca2+ influx in response to all tested platelet agonists. These defects were a consequence of impaired IP3R function in combination with defective STIM1-mediated SOC channel activation, while Ca2+ store content and agonist-induced IP3 production were unaltered. This severely defective Ca2+ signaling translated into impaired thrombus formation under flow and a protection of Bin2fl/fl,Pf4-Cre mice in models of arterial thrombosis and stroke. Our results establish BIN2 as a central regulator of platelet activation in thrombosis and thrombo-inflammatory disease settings.

Authors

Julia Volz, Charly Kusch, Sarah Beck, Michael Popp, Timo Vögtle, Mara Meub, Inga Scheller, Hannah S. Heil, Julia Preu, Michael K. Schuhmann, Katherina Hemmen, Thomas Premsler, Albert Sickmann, Katrin G. Heinze, David Stegner, Guido Stoll, Attila Braun, Markus Sauer, Bernhard Nieswandt

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Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
Sonja C. Schriever, … , Matthias H. Tschöp, Paul T. Pfluger
Sonja C. Schriever, … , Matthias H. Tschöp, Paul T. Pfluger
Published August 11, 2020
Citation Information: J Clin Invest. 2020;130(11):6093-6108. https://doi.org/10.1172/JCI136363.
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Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

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Abstract

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron–specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.

Authors

Sonja C. Schriever, Dhiraj G. Kabra, Katrin Pfuhlmann, Peter Baumann, Emily V. Baumgart, Joachim Nagler, Fabian Seebacher, Luke Harrison, Martin Irmler, Stephanie Kullmann, Felipe Corrêa-da-Silva, Florian Giesert, Ruchi Jain, Hannah Schug, Julien Castel, Sarah Martinez, Moya Wu, Hans-Ulrich Häring, Martin Hrabe de Angelis, Johannes Beckers, Timo D. Müller, Kerstin Stemmer, Wolfgang Wurst, Jan Rozman, Ruben Nogueiras, Meri De Angelis, Jeffery D. Molkentin, Natalie Krahmer, Chun-Xia Yi, Mathias V. Schmidt, Serge Luquet, Martin Heni, Matthias H. Tschöp, Paul T. Pfluger

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Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance
Vanessa Gauttier, … , Bernard Vanhove, Nicolas Poirier
Vanessa Gauttier, … , Bernard Vanhove, Nicolas Poirier
Published October 19, 2020
Citation Information: J Clin Invest. 2020;130(11):6109-6123. https://doi.org/10.1172/JCI135528.
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Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance

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Abstract

T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.

Authors

Vanessa Gauttier, Sabrina Pengam, Justine Durand, Kevin Biteau, Caroline Mary, Aurore Morello, Mélanie Néel, Georgia Porto, Géraldine Teppaz, Virginie Thepenier, Richard Danger, Nicolas Vince, Emmanuelle Wilhelm, Isabelle Girault, Riad Abes, Catherine Ruiz, Charlène Trilleaud, Kerry Ralph, E. Sergio Trombetta, Alexandra Garcia, Virginie Vignard, Bernard Martinet, Alexandre Glémain, Sarah Bruneau, Fabienne Haspot, Safa Dehmani, Pierre Duplouye, Masayuki Miyasaka, Nathalie Labarrière, David Laplaud, Stéphanie Le Bas-Bernardet, Christophe Blanquart, Véronique Catros, Pierre-Antoine Gouraud, Isabelle Archambeaud, Hélène Aublé, Sylvie Metairie, Jean-François Mosnier, Dominique Costantini, Gilles Blancho, Sophie Conchon, Bernard Vanhove, Nicolas Poirier

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EBV-induced gene 3 augments IL-23Rα protein expression through a chaperone calnexin
Izuru Mizoguchi, … , Kouji Matsushima, Takayuki Yoshimoto
Izuru Mizoguchi, … , Kouji Matsushima, Takayuki Yoshimoto
Published August 18, 2020
Citation Information: J Clin Invest. 2020;130(11):6124-6140. https://doi.org/10.1172/JCI122732.
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EBV-induced gene 3 augments IL-23Rα protein expression through a chaperone calnexin

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Epstein-Barr virus–induced gene 3 (EBI3) is a subunit common to IL-27, IL-35, and IL-39. Here, we explore an intracellular role of EBI3 that is independent of its function in cytokines. EBI3-deficient naive CD4+ T cells had reduced IFN-γ production and failed to induce T cell–dependent colitis in mice. Similarly reduced IFN-γ production was observed in vitro in EBI3-deficient CD4+ T cells differentiated under pathogenic Th17 polarizing conditions with IL-23. This is because the induction of expression of one of the IL-23 receptor (IL-23R) subunits, IL-23Rα, but not another IL-23R subunit, IL-12Rβ1, was selectively decreased at the protein level, but not the mRNA level. EBI3 augmented IL-23Rα expression via binding to the chaperone molecule calnexin and to IL-23Rα in a peptide-dependent manner, but not a glycan-dependent manner. Indeed, EBI3 failed to augment IL-23Rα expression in the absence of endogenous calnexin. Moreover, EBI3 poorly augmented the expression of G149R, an IL-23Rα variant that protects against the development of human colitis, because binding of EBI3 to the variant was reduced. Taken together with the result that EBI3 expression is inducible in T cells, the present results suggest that EBI3 plays a critical role in augmenting IL-23Rα protein expression via calnexin under inflammatory conditions.

Authors

Izuru Mizoguchi, Mio Ohashi, Hideaki Hasegawa, Yukino Chiba, Naoko Orii, Shinya Inoue, Chiaki Kawana, Mingli Xu, Katsuko Sudo, Koji Fujita, Masahiko Kuroda, Shin-ichi Hashimoto, Kouji Matsushima, Takayuki Yoshimoto

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Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population
Sabra L. Klein, … , Arturo Casadevall, Aaron A.R. Tobian
Sabra L. Klein, … , Arturo Casadevall, Aaron A.R. Tobian
Published August 7, 2020
Citation Information: J Clin Invest. 2020;130(11):6141-6150. https://doi.org/10.1172/JCI142004.
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Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population

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Abstract

Convalescent plasma is a leading treatment for coronavirus disease 2019 (COVID-19), but there is a paucity of data identifying its therapeutic efficacy. Among 126 potential convalescent plasma donors, the humoral immune response was evaluated using a severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) virus neutralization assay with Vero-E6-TMPRSS2 cells; a commercial IgG and IgA ELISA to detect the spike (S) protein S1 domain (EUROIMMUN); IgA, IgG, and IgM indirect ELISAs to detect the full-length S protein or S receptor–binding domain (S-RBD); and an IgG avidity assay. We used multiple linear regression and predictive models to assess the correlations between antibody responses and demographic and clinical characteristics. IgG titers were greater than either IgM or IgA titers for S1, full-length S, and S-RBD in the overall population. Of the 126 plasma samples, 101 (80%) had detectable neutralizing antibody (nAb) titers. Using nAb titers as the reference, the IgG ELISAs confirmed 95%–98% of the nAb-positive samples, but 20%–32% of the nAb-negative samples were still IgG ELISA positive. Male sex, older age, and hospitalization for COVID-19 were associated with increased antibody responses across the serological assays. There was substantial heterogeneity in the antibody response among potential convalescent plasma donors, but sex, age, and hospitalization emerged as factors that can be used to identify individuals with a high likelihood of having strong antiviral antibody responses.

Authors

Sabra L. Klein, Andrew Pekosz, Han-Sol Park, Rebecca L. Ursin, Janna R. Shapiro, Sarah E. Benner, Kirsten Littlefield, Swetha Kumar, Harnish Mukesh Naik, Michael J. Betenbaugh, Ruchee Shrestha, Annie A. Wu, Robert M. Hughes, Imani Burgess, Patricio Caturegli, Oliver Laeyendecker, Thomas C. Quinn, David Sullivan, Shmuel Shoham, Andrew D. Redd, Evan M. Bloch, Arturo Casadevall, Aaron A.R. Tobian

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Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis
Panagiotis Skendros, … , John D. Lambris, Konstantinos Ritis
Panagiotis Skendros, … , John D. Lambris, Konstantinos Ritis
Published August 6, 2020
Citation Information: J Clin Invest. 2020;130(11):6151-6157. https://doi.org/10.1172/JCI141374.
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Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis

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Abstract

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.

Authors

Panagiotis Skendros, Alexandros Mitsios, Akrivi Chrysanthopoulou, Dimitrios C. Mastellos, Simeon Metallidis, Petros Rafailidis, Maria Ntinopoulou, Eleni Sertaridou, Victoria Tsironidou, Christina Tsigalou, Maria Tektonidou, Theocharis Konstantinidis, Charalampos Papagoras, Ioannis Mitroulis, Georgios Germanidis, John D. Lambris, Konstantinos Ritis

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Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties
Daniel Knowland, … , Anindya Bhattacharya, David S. Bredt
Daniel Knowland, … , Anindya Bhattacharya, David S. Bredt
Published October 19, 2020
Citation Information: J Clin Invest. 2020;130(11):6158-6170. https://doi.org/10.1172/JCI140311.
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Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties

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Abstract

The α6β4 nicotinic acetylcholine receptor (nAChR) is enriched in dorsal root ganglia neurons and is an attractive non-opioid therapeutic target for pain. However, difficulty expressing human α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human α6β4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted α6β4 surface expression while IRE1α, an unfolded protein response sensor, enhanced α6β4 receptor assembly. Effects on α6β4 involve BARP’s N-terminal region and IRE1α’s splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on α6β4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of α6β4 in pain. These results identify roles for IRE1α and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive α6β4 receptor.

Authors

Daniel Knowland, Shenyan Gu, William A. Eckert III, G. Brent Dawe, Jose A. Matta, James Limberis, Alan D. Wickenden, Anindya Bhattacharya, David S. Bredt

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HTLV-1 targets human placental trophoblasts in seropositive pregnant women
Kenta Tezuka, … , Kiyonori Miura, Isao Hamaguchi
Kenta Tezuka, … , Kiyonori Miura, Isao Hamaguchi
Published October 19, 2020
Citation Information: J Clin Invest. 2020;130(11):6171-6186. https://doi.org/10.1172/JCI135525.
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HTLV-1 targets human placental trophoblasts in seropositive pregnant women

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Abstract

Human T cell leukemia virus type 1 (HTLV-1) is mainly transmitted vertically through breast milk. The rate of mother-to-child transmission (MTCT) through formula feeding, although significantly lower than through breastfeeding, is approximately 2.4%–3.6%, suggesting the possibility of alternative transmission routes. MTCT of HTLV-1 might occur through the uterus, birth canal, or placental tissues; the latter is known as transplacental transmission. Here, we found that HTLV-1 proviral DNA was present in the placental villous tissues of the fetuses of nearly half of pregnant carriers and in a small number of cord blood samples. An RNA ISH assay showed that HTLV-1–expressing cells were present in nearly all subjects with HTLV-1–positive placental villous tissues, and their frequency was significantly higher in subjects with HTLV-1–positive cord blood samples. Furthermore, placental villous trophoblasts expressed HTLV-1 receptors and showed increased susceptibility to HTLV-1 infection. In addition, HTLV-1–infected trophoblasts expressed high levels of viral antigens and promoted the de novo infection of target T cells in a humanized mouse model. In summary, during pregnancy of HTLV-1 carriers, HTLV-1 was highly expressed in placental villous tissues, and villous trophoblasts showed high HTLV-1 sensitivity, suggesting that MTCT of HTLV-1 occurs through the placenta.

Authors

Kenta Tezuka, Naoki Fuchi, Kazu Okuma, Takashi Tsukiyama, Shoko Miura, Yuri Hasegawa, Ai Nagata, Nahoko Komatsu, Hiroo Hasegawa, Daisuke Sasaki, Eita Sasaki, Takuo Mizukami, Madoka Kuramitsu, Sahoko Matsuoka, Katsunori Yanagihara, Kiyonori Miura, Isao Hamaguchi

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Retraction
Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2
Jia Wang, … , Maode Wang, Ichiro Nakano
Jia Wang, … , Maode Wang, Ichiro Nakano
Published October 12, 2020
Citation Information: J Clin Invest. 2020;130(11):6187-6187. https://doi.org/10.1172/JCI144618.
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Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

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Abstract

Authors

Jia Wang, Peng Cheng, Marat S. Pavlyukov, Hai Yu, Zhuo Zhang, Sung-Hak Kim, Mutsuko Minata, Ahmed Mohyeldin, Wanfu Xie, Dongquan Chen, Violaine Goidts, Brendan Frett, Wenhao Hu, Hongyu Li, Yong Jae Shin, Yeri Lee, Do-Hyun Nam, Harley I. Kornblum, Maode Wang, Ichiro Nakano

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Corrigenda
BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome
Cynthia J. Sieben, … , Darren J. Baker, Jan M. van Deursen
Cynthia J. Sieben, … , Darren J. Baker, Jan M. van Deursen
Published November 2, 2020
Citation Information: J Clin Invest. 2020;130(11):6188-6188. https://doi.org/10.1172/JCI144781.
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BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome

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Abstract

Authors

Cynthia J. Sieben, Karthik B. Jeganathan, Grace G. Nelson, Ines Sturmlechner, Cheng Zhang, Willemijn H. van Deursen, Bjorn Bakker, Floris Foijer, Hu Li, Darren J. Baker, Jan M. van Deursen

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Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction
Hilaire C. Lam, … , Stefan W. Ryter, Augustine M.K. Choi
Hilaire C. Lam, … , Stefan W. Ryter, Augustine M.K. Choi
Published November 2, 2020
Citation Information: J Clin Invest. 2020;130(11):6189-6189. https://doi.org/10.1172/JCI143863.
View: Text | PDF | Amended Article

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

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Abstract

Authors

Hilaire C. Lam, Suzanne M. Cloonan, Abhiram R. Bhashyam, Jeffery A. Haspel, Anju Singh, J. Fah Sathirapongsasuti, Morgan Cervo, Hongwei Yao, Anna L. Chung, Kenji Mizumura, Chang Hyeok An, Bin Shan, Jonathan M. Franks, Kathleen J. Haley, Caroline A. Owen, Yohannes Tesfaigzi, George R. Washko, John Quackenbush, Edwin K. Silverman, Irfan Rahman, Hong Pyo Kim, Ashfaq Mahmood, Shyam S. Biswal, Stefan W. Ryter, Augustine M.K. Choi

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