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In-Press Preview

In-Press Preview Articles
Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models
Propranolol, a pleiotropic β-adrenergic blocker, was anecdotally reported to reduce cerebral cavernous malformations (CCM) in humans. However, propranolol has neither been rigorously evaluated in...
Published December 10, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144893.
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Concise Communication In-Press Preview Vascular biology

Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models

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Abstract

Propranolol, a pleiotropic β-adrenergic blocker, was anecdotally reported to reduce cerebral cavernous malformations (CCM) in humans. However, propranolol has neither been rigorously evaluated in animal models nor was its mechanism of action in CCM defined. We report that propranolol or its S(-) enantiomer dramatically reduced embryonic venous cavernomas in ccm2 mosaic zebrafish, whereas R-(+)-propranolol, lacking β-antagonism, had no effect. Silencing of β1, but not β2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model as did a β1-selective antagonist, metoprolol. Thus, propranolol ameliorates cavernous malformations by β1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in two chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other β1-selective antagonists may be beneficial in CCM disease.

Authors

Wenqing Li, Robert Shenkar, Matthew R. Detter, Thomas Moore, Christian R. Benavides, Rhonda Lightle, Romuald Girard, Nicholas Hobson, Ying Cao, Yan Li, Erin Griffin, Carol Gallione, Joseph M. Zabramski, Mark H. Ginsberg, Douglas A. Marchuk, Issam A. Awad

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Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+ T cells in vivo
Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and...
Published December 10, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI145254.
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Research In-Press Preview AIDS/HIV Immunology

Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+ T cells in vivo

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Abstract

Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here we show that it is possible to link antigen responsiveness, full proviral sequence, integration site, and T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated Cytomegalovirus (CMV)- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ-integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.

Authors

Francesco R. Simonetti, Hao Zhang, Garshasb P. Soroosh, Jiayi Duan, Kyle Rhodehouse, Alison L. Hill, Subul A. Beg, Kevin McCormick, Hayley E. Raymond, Christopher L. Nobles, John K. Everett, Kyungyoon J. Kwon, Jennifer A. White, Jun Lai, Joseph B. Margolick, Rebecca Hoh, Steven G. Deeks, Frederic D. Bushman, Janet D. Siliciano, Robert F. Siliciano

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The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas
The mechanism by which only some individuals infected with M. tuberculosis (Mtb) develop necrotic granulomas with progressive disease while others form controlled granulomas that contain the...
Published December 10, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI130319.
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Research In-Press Preview Immunology Infectious disease

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas

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The mechanism by which only some individuals infected with M. tuberculosis (Mtb) develop necrotic granulomas with progressive disease while others form controlled granulomas that contain the infection remains poorly defined. Mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human TB granulomas, which are linked to macrophage dysfunction while their congenic counterparts (B6) mice do not. In this study we report that (i) sst1S macrophages developed aberrant, biphasic responses to TNF characterized by super-induction of stress and type I interferon pathways after prolonged TNF stimulation; (ii) the late-stage TNF response was driven via a JNK - IFNβ - PKR circuit; and (iii) induced the integrated stress response (ISR) via PKR-mediated eIF2α phosphorylation and the subsequent hyper-induction of ATF3 and ISR-target genes Chac1, Trib3, Ddit4. The administration of ISRIB, a small molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of Mtb-infected sst1S mice and concomitantly reduced the bacterial burden. Hence induction of the ISR and the locked-in state of escalating stress driven by type I IFN pathway in sst1S macrophages plays a causal role in the development of necrosis in TB granulomas. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel host-directed therapy strategies.

Authors

Bidisha Bhattacharya, Shiqi Xiao, Sujoy Chatterjee, Michael E. Urbanowski, Alvaro A. Ordonez, Elizabeth A. Ihms, Garima Agrahari, Shichun Lun, Robert Berland, Alexander Pichugin, Yuanwei Gao, John H. Connor, Alexander R. Ivanov, Bo-Shiun Yan, Lester Kobzik, Bang-Bon Koo, Sanjay K. Jain, William R. Bishai, Igor Kramnik

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Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models
How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remain largely unknown. Here, we showed that ATP levels were markedly...
Published December 10, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI140242.
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Research In-Press Preview Hematology Stem cells

Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models

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How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remain largely unknown. Here, we showed that ATP levels were markedly increased in the bone marrow niches of mice with acute myeloid leukemia (AML), and LICs preferred to localizing to the endosteal niche with relatively high ATP levels, as indicated by a sensitive ATP indicator. ATP could efficiently induce the influx of ions into LICs in an MLL-AF9-induced murine AML model via the ligand-gated ion channel P2X7. P2x7 deletion led to notably impaired homing and self-renewal capacities of LICs and contributed to an ~5-fold decrease in the number of functional LICs but had no effect on normal hematopoiesis. ATP-P2X7 signaling enhanced the calcium flux-mediated phosphorylation of CREB, which further transactivated the Phgdh expression to maintain serine metabolism and LIC fates. P2X7-knockdown resulted in a markedly extended survival of recipients transplanted with either human AML cell lines or primary leukemia cells. Blockade of ATP-P2X7 signaling could efficiently inhibit leukemogenesis. Here, we provide a unique perspective for understanding how ATP-P2X7 signaling sustains the LIC activities, which may benefit the development of specific strategies for targeting LICs or other types of cancer stem cells

Authors

Xiaoxiao He, Jiangbo Wang, Xiaona Yang, Xiuze Zhang, Dan Huang, Xie Li, Yejun Zou, Chiqi Chen, Zhuo Yu, Li Xie, Yaping Zhang, Ligen Liu, Shangang Li, Yuzheng Zhao, Hongfang Shao, Ye Yu, Junke Zheng

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Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer
The development of ascites correlates with advanced-stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development....
Published December 9, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI140315.
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Research In-Press Preview Cell biology Vascular biology

Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer

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The development of ascites correlates with advanced-stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided the first evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and reactive oxygen species (ROS), which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p-VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Lastly, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taken together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p-VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.

Authors

Shibo Zhang, Bingfan Xie, Lijie Wang, Hua Yang, Haopei Zhang, Yuming Chen, Feng Wang, Changqing Liu, Huanhuan He

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Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury
Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI137047.
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Research In-Press Preview Immunology Pulmonology

Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury

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Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While natural killer (NK) cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in two different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.

Authors

Daniel R. Calabrese, Emily Aminian, Benat Mallavia, Fengchun Liu, Simon J. Cleary, Oscar A. Aguilar, Ping Wang, Jonathan Hoover, Jonathan P. Singer, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel T. Dugger, Mary Nakamura, Lewis L. Lanier, Mark R. Looney, John R. Greenland

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Battle for supremacy: nucleic acid interactions between viruses and cells
Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144227.
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Review In-Press Preview

Battle for supremacy: nucleic acid interactions between viruses and cells

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Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response to infection with SARS-CoV-2 that may reflect differences in host genetics and/or immune response. It is known that the human epigenome is influenced by ethnicity, age, lifestyle, and environmental factors, including previous viral infections. This review will examine the influence of viruses on the host epigenome. We will describe general lessons and methodologies that can be used to understand how the virus evades the host immune response. We will consider how variation in the epigenome may contribute to heterogeneity in the response to SARS-CoV-2 and may identify a precision medicine approach to treatment.

Authors

Elizabeth J. Hennessy, Garret A. FitzGerald

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ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation
Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI139333.
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Research In-Press Preview Oncology

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation

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Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance immune checkpoint blockade (ICB) therapy. However, the molecular mechanism involved is not clearly elucidated. Here we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA and activation of the cGAS/STING pathway. Genetic depletion of ATM in murine cancer cells significantly delayed tumor growth in syngeneic mouse hosts in a T-cell dependent manner. Furthermore, chemical inhibition of ATM significantly potentiated anti-PD1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating TFAM, which led to mitochondrial DNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits for ICB therapy. Our study therefore provides strong evidence that ATM may serve both as a therapeutic target and a biomarker to enable ICB therapy

Authors

Mengjie Hu, Min Zhou, Xuhui Bao, Dong Pan, Meng Jiao, Xinjian Liu, Fang Li, Chuan-Yuan Li

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Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency
Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy and malignancy. Somatic reversion refers to the...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI142434.
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Research In-Press Preview Immunology Infectious disease

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency

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Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to bi-allelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterised by severe bacterial, viral and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic and cellular features of three patients with bi-allelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared to typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further non-redundant functions of DOCK8 in human lymphocyte biology. Lastly, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.

Authors

Bethany A. Pillay, Mathieu Fusaro, Paul E. Gray, Aaron Luke Statham, Leslie Burnett, Liliana Bezrodnik, Alisa Kane, Winnie W. Y. Tong, Chrystelle Abdo, Sarah Winter, Samuel Chevalier, Romain Levy, Cécile Masson, Yohann Schmitt, Christine Bole-Feysot, Marion Malphettes, Elizabeth Macintyre, Jean-Pierre de Villartay, John B. Ziegler, Joanne M. Smart, Jane Peake, Asghar Aghamohammadi, Lennart Hammarström, Hassan Abolhassani, Capucine Picard, Alain Fischer, Sylvain Latour, Benedicte Neven, Stuart Tangye, Cindy S. Ma

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Biomarkers of inflammation and repair in kidney disease progression
Introduction: Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision-making, more accurate information regarding risk of long-term...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI139927.
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Clinical Medicine In-Press Preview Inflammation Nephrology

Biomarkers of inflammation and repair in kidney disease progression

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Introduction: Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision-making, more accurate information regarding risk of long-term progression to kidney failure is required. Methods: We enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein-1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression. Results: Higher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis. Conclusions: Biomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression. Funding: National Institutes of Health grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01HL085757, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, R01DK093771, K01DK120783, P30DK079310, P30DK114809.

Authors

Jeremy Puthumana, Heather Thiessen-Philbrook, Leyuan Xu, Steven G. Coca, Amit X. Garg, Jonathan Himmelfarb, Pavan K. Bhatraju, Talat Alp Ikizler, Edward Siew, Lorraine B. Ware, Kathleen D. Liu, Alan S. Go, James S. Kaufman, Paul L. Kimmel, Vernon M. Chinchilli, Lloyd Cantley, Chirag R. Parikh

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Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice
Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no cure. Using conditional knockout mice, we found that ablation of the genomic organizer Special AT-rich sequence-binding...
Published December 3, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI135711.
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Research In-Press Preview Hematology

Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice

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Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no cure. Using conditional knockout mice, we found that ablation of the genomic organizer Special AT-rich sequence-binding protein-1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T-cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T-cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T-cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition), restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with Mycosis fungoides/Sézary syndrome, a set of incurable diseases.

Authors

Carly M. Harro, Jairo Perez-Sanz, Tara Lee Costich, Kyle K. Payne, Carmen M. Anadon Galindo, Ricardo A. Chaurio, Subir Biswas, Gunjan Mandal, Kristen E. Rigolizzo, Kimberly B. Sprenger, Jessica A. Mine, Louise Showe, Xiaoqing Yu, Kebin Liu, Paulo C. Rodriguez, Javier Pinilla-Ibarz, Lubomir Sokol, Jose R. Conejo-Garcia

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Generating evidence for therapeutic effects: the need for well-conducted randomized trials
In this viewpoint, Robert Califf, former commissioner of the U.S. Food and Drug Administration, and colleagues reflect on how to approach questions about which patient treatments and strategies...
Published December 3, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI146391.
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Viewpoint In-Press Preview

Generating evidence for therapeutic effects: the need for well-conducted randomized trials

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In this viewpoint, Robert Califf, former commissioner of the U.S. Food and Drug Administration, and colleagues reflect on how to approach questions about which patient treatments and strategies work, particularly in light of the tremendous pressure on the government and biomedical research enterprise to quickly develop safe, effective therapies during the SARS-CoV-2 pandemic.

Authors

Robert M. Califf, Lesley H. Curtis, Robert A. Harrington, Adrian F. Hernandez, Eric D. Peterson

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The use of observational research to inform clinical practice
Randomized controlled trials are the preferred design for the analysis of health-related interventions. In this Viewpoint, Nigel Paneth and Michael Joyner discuss circumstances when randomized...
Published December 3, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI146392.
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Viewpoint In-Press Preview

The use of observational research to inform clinical practice

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Randomized controlled trials are the preferred design for the analysis of health-related interventions. In this Viewpoint, Nigel Paneth and Michael Joyner discuss circumstances when randomized controlled trials might not be feasible and the criteria that should be used when considering applying observational data medicine.

Authors

Nigel Paneth, Michael Joyner

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TREM-1 orchestrates Angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm
The triggering receptor expressed on myeloid cells-1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our...
Published December 1, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI142468.
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Research In-Press Preview Inflammation Vascular biology

TREM-1 orchestrates Angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm

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The triggering receptor expressed on myeloid cells-1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of Angiotensin (Ang) II-induced AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalizes with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2 and Mmp9 mRNA expression, and led to a decreased macrophage content, due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L up-regulation and promoted pro-inflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII Receptor Type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared to patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in human.

Authors

Marie Vandestienne, Yujiao Zhang, Icia Santos-Zas, Rida Al-Rifai, Jeremie Joffre, Andreas Giraud, Ludivine Laurans, Bruno Esposito, Florence Pinet, Patrick Bruneval, Juliette Raffort, Fabien Lareyre, Jose Vilar, Amir Boufenzer, Lea Guyonnet, Coralie L. Guerin, Eric Clauser, Jean-Sébastien Silvestre, Sylvie Lang, Laurie Soulat-Dufour, Alain Tedgui, Ziad Mallat, Soraya Taleb, Alexandre Boissonnas, Marc Derive, Giulia Chinetti, Hafid Ait-Oufella

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The vascular landscape of human cancer
Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anti-cancer target. However, only a fraction of cancer patients benefits from angiogenesis...
Published December 1, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI136655.
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Research In-Press Preview Angiogenesis Oncology

The vascular landscape of human cancer

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Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anti-cancer target. However, only a fraction of cancer patients benefits from angiogenesis inhibitors. Whether anti-angiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric – the Endothelial Index (EI) – to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypo-vascular tumors, enabling the classification of human tumors into six vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular hub genes. EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Our studies thus provide an unbiased picture of human tumor vasculature which may enable more precise deployment of anti-angiogenesis therapy.

Authors

Benjamin M. Kahn, Alfredo Lucas, Rohan Alur, Maximilian D. Wengyn, Gregory W. Schwartz, Jinyang Li, Kathryn Sun, H. Carlo Maurer, Kenneth P. Olive, Robert B. Faryabi, Ben Stanger

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Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model
Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGEL2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The...
Published November 24, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144450.
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Research In-Press Preview Neuroscience

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model

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Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGEL2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We ask whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin can alleviate the disabilities of social behavior. We used Magel2 knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We find that the activation of vasopressin neurons and its projections in the lateral septum are inappropriate to perform a social habituation/discrimination task. Mechanistically, the lack of vasopressin impedes the deactivation of somatostatin neurons in the lateral septum, which predicts social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identifies vasopressin in the lateral septum as a key factor in the pathophysiology.

Authors

Amélie M. Borie, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarmenien, Freddy Jeanneteau

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Myeloid cell-targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell-mediated immunity
The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in circulation of...
Published November 24, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI137001.
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Research In-Press Preview Immunology Oncology

Myeloid cell-targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell-mediated immunity

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Abstract

The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in circulation of HNSCC patients undergoing radiotherapy. Here, we analyzed tumor-containing lymph nodes biopsies collected from these patients. After two-weeks of radiotherapy, we found an increase in tumor-associated macrophages (TAMs) with activated STAT3, while CD8 T-cells were reduced as detected using multiplex IHC. Gene expression profiling indicated upregulation of M2 macrophage-related genes (CD163, CD206), immunosuppressive mediators (ARG1, LIF, TGFB1) and Th2 cytokines (IL4, IL5) in irradiated tumors. We next validated STAT3 as a potential target in human HNSCC-associated TAMs, using UM-SCC1 xenotransplants in humanized mice. Local injections of myeloid cell-targeted STAT3 antisense oligonucleotide (CpG-STAT3ASO) activated human DCs/macrophages, promoted CD8 T-cell recruitment and thereby arrested UM-SCC1 tumor growth. Furthermore, CpG-STAT3ASO synergized with tumor irradiation against syngeneic HPV+ mEERL and HPV– MOC2 HNSCC tumors in mice, triggering tumor regression and/or extending animal survival. The antitumor immune responses were CD8+ and CD4+ T-cell-dependent and associated with the activation of antigen-presenting cells (DCs/M1 macrophages) and increased CD8+ to regulatory T-cell ratio. Our observations suggest that targeted inhibition of STAT3 in tumor-associated myeloid cells augments the efficacy of radiotherapy against HNSCC.

Authors

Dayson Moreira, Sagus Sampath, Haejung Won, Seok Voon White, Yu-Lin Su, Marice Alcantara, Chongkai Wang, Peter P. Lee, Ellie Maghami, Erminia Massarelli, Marcin Kortylewski

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Does common cold coronavirus infection protect against severe SARS-CoV2 disease?
The coronavirus disease 2019 (COVID 19) pandemic continues to cause morbidity and mortality. Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause for COVID...
Published November 20, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144807.
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Does common cold coronavirus infection protect against severe SARS-CoV2 disease?

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Abstract

The coronavirus disease 2019 (COVID 19) pandemic continues to cause morbidity and mortality. Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause for COVID 19, some have questioned whether exposure to seasonal common cold coronaviruses (CCCs) could provide tangible protection against SARS-CoV-2 infection or disease. In this issue of the JCI, Sager, et al. examined SARS-CoV-2 infections and outcomes from patients previously tested for CCC as part of a comprehensive respiratory panel using PCR and were segregated into negative (CCC–) or positive (CCC+) exposure. No differences were seen between groups in terms of susceptibility to SARS-CoV-2 infection. However, hospitalized patients with a documented history of CCC+ infection had lower rates of ICU admissions and higher rates of survival than hospitalized CCC– patients. While these findings are associative and not causative, they highlight evidence suggesting that previous CCC+ infection may influence the disease course of SARS-CoV-2 infection.

Authors

David K. Meyerholz, Stanley Perlman

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SARS-CoV-2 B cell receptor signatures in risk populations
Many individuals possess B cells capable of recognizing epitopes on the spike glycoprotein of SARS-CoV-2. In this issue of the JCI, Paschold and Simnica et al. interrogated the frequency of...
Published November 20, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144685.
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Commentary In-Press Preview

SARS-CoV-2 B cell receptor signatures in risk populations

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Abstract

Many individuals possess B cells capable of recognizing epitopes on the spike glycoprotein of SARS-CoV-2. In this issue of the JCI, Paschold and Simnica et al. interrogated the frequency of SARS-CoV-2–specific B cell receptor rearrangements in healthy subjects based on age and cancer status. The authors found that, while SARS-CoV-2–specific antibody signatures can be identified in the repertoires of young, healthy individuals, such sequences are less frequent in elderly subjects or cancer patients. Overall, this study sheds light on B cell repertoire restrictions that might lead to an unfavorable clinical course of COVID-19 infection in risk populations.

Authors

Andrew I. Flyak

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The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury
ABSTRACTIndividuals harboring the loss-of-function (LOF) proprotein convertase subtilising/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein (LDL)...
Published November 19, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI128650.
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Research In-Press Preview Hepatology Vascular biology

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

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Abstract

ABSTRACTIndividuals harboring the loss-of-function (LOF) proprotein convertase subtilising/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein (LDL) cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of pro-PCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes where it would be expected to contribute to ER storage disease (ERSD); a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9Q152H variation. We report that PCSK9Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than to induce them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress-driven conditions of the liver. In summary, we have uncovered a co-chaperone function for PCSK9Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.

Authors

Paul F. Lebeau, Hanny Wassef, Jae Hyun Byun, Khrystyna Platko, Brandon Ason, Simon Jackson, Joshua Dobroff, Susan Shetterly, William G. Richards, Ali A. Al-Hashimi, Kevin D. Won, Majambu Mbikay, Annik Prat, An Tang, Guillaume Paré, Renata Pasqualini, Nabil G. Seidah, Wadih Arap, Michel Chretien, Richard C. Austin

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