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Issue published October 24, 2022

  • Volume 7, Issue 20
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  • Research Articles
  • Technical Advances
  • Corrigendums
Gene therapy with a synthetic AAV vector improves audiovestibular phenotypes in Pjvk mutant mice

Lu et al. report that delivery of the PJVK transgene using a synthetic AAV2/Anc80L65 vector promotes audiovestibular restoration in a model of nonsyndromic deafness caused by Pjvk mutations. The cover image shows a scanning electron micrograph of hair cell bundles from a WT mouse.

Technical Advances
Cell-free DNA topology depends on its subcellular and cellular origins in cancer
Ethan Z. Malkin, … , Mark D. Minden, Scott V. Bratman
Ethan Z. Malkin, … , Mark D. Minden, Scott V. Bratman
Published September 20, 2022
Citation Information: JCI Insight. 2022;7(20):e159590. https://doi.org/10.1172/jci.insight.159590.
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Cell-free DNA topology depends on its subcellular and cellular origins in cancer

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Abstract

Cancer cells release large quantities of cell-free DNA (cfDNA) into the surrounding tissue and circulation. As cfDNA is a common source of biomarkers for liquid biopsy and has been implicated as a functional mediator for intercellular communication, fundamental characterization of cfDNA topology has widespread biological and clinical ramifications. Whether the topology of cfDNA is such that it exists predominantly in membrane-bound extracellular vesicles (EVs) or in nonvesicular DNA-protein complexes remains poorly understood. Here, we employed a DNA-targeted approach to comprehensively assess total cfDNA topology in cancer. Using preclinical models and patient samples, we demonstrate that nuclear cfDNA is predominantly associated with nucleosomal particles and not EVs, while a substantial subset of mitochondrial cfDNA is membrane protected and disproportionately derived from nontumor cells. In addition, discrimination between membrane-protected and accessible mitochondrial cfDNA added diagnostic and prognostic value in a cohort of head and neck cancer patients. Our results support a revised model for cfDNA topology in cancer. Due to its abundance, nuclear cfDNA within nucleosomal particles is the most compelling liquid biopsy substrate, while EV-bound and accessible mitochondrial cfDNA represent distinct reservoirs of potential cancer biomarkers whose structural conformations may also influence their extracellular stability and propensity for uptake by recipient cells.

Authors

Ethan Z. Malkin, Steven De Michino, Meghan Lambie, Rita Gill, Zhen Zhao, Ariana Rostami, Andrea Arruda, Mark D. Minden, Scott V. Bratman

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Resident macrophage subpopulations occupy distinct microenvironments in the kidney
Matthew D. Cheung, … , Anupam Agarwal, James F. George
Matthew D. Cheung, … , Anupam Agarwal, James F. George
Published September 6, 2022
Citation Information: JCI Insight. 2022;7(20):e161078. https://doi.org/10.1172/jci.insight.161078.
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Resident macrophage subpopulations occupy distinct microenvironments in the kidney

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Abstract

The kidney contains a population of resident macrophages from birth that expands as it grows and forms a contiguous network throughout the tissue. Kidney-resident macrophages (KRMs) are important in homeostasis and the response to acute kidney injury. While the kidney contains many microenvironments, it is unknown whether KRMs are a heterogeneous population differentiated by function and location. We combined single-cell RNA-Seq (scRNA-Seq), spatial transcriptomics, flow cytometry, and immunofluorescence imaging to localize, characterize, and validate KRM populations during quiescence and following 19 minutes of bilateral ischemic kidney injury. scRNA-Seq and spatial transcriptomics revealed 7 distinct KRM subpopulations, which are organized into zones corresponding to regions of the nephron. Each subpopulation was identifiable by a unique transcriptomic signature, suggesting distinct functions. Specific protein markers were identified for 2 clusters, allowing analysis by flow cytometry or immunofluorescence imaging. Following injury, the original localization of each subpopulation was lost, either from changing locations or transcriptomic signatures. The original spatial distribution of KRMs was not fully restored for at least 28 days after injury. The change in KRM localization confirmed a long-hypothesized dysregulation of the local immune system following acute injury and may explain the increased risk for chronic kidney disease.

Authors

Matthew D. Cheung, Elise N. Erman, Kyle H. Moore, Jeremie M.P. Lever, Zhang Li, Jennifer R. LaFontaine, Gelare Ghajar-Rahimi, Shanrun Liu, Zhengqin Yang, Rafay Karim, Bradley K. Yoder, Anupam Agarwal, James F. George

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Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice
Achim Buck, … , Reinhold G. Erben, Axel Walch
Achim Buck, … , Reinhold G. Erben, Axel Walch
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e162138. https://doi.org/10.1172/jci.insight.162138.
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Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice

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Abstract

Patients with the renal phosphate–wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic hormone FGF23. The mineralization defect in patients with XLH and Hyp mice is caused by a combination of hypophosphatemia and local accumulation of mineralization-inhibiting molecules in bone. However, the mechanism by which PHEX deficiency regulates bone cell metabolism remains elusive. Here, we used spatial metabolomics by employing matrix-assisted laser desorption/ionization (MALDI) Fourier-transform ion cyclotron resonance mass spectrometry imaging (MSI) of undecalcified bone cryosections to characterize in situ metabolic changes in bones of Hyp mice in a holistic, unbiased manner. We found complex changes in Hyp bone metabolism, including perturbations in pentose phosphate, purine, pyrimidine, and phospholipid metabolism. Importantly, our study identified an upregulation of several biochemical pathways involved in intra- and extracellular production of the mineralization inhibitor pyrophosphate in the bone matrix of Hyp mice. Our data emphasize the utility of MSI–based spatial metabolomics in bone research and provide holistic in situ insights as to how Phex deficiency–induced changes in biochemical pathways in bone cells are linked to impaired bone mineralization.

Authors

Achim Buck, Verena M. Prade, Thomas Kunzke, Reinhold G. Erben, Axel Walch

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Research Articles
Macrophage TGF-β signaling is critical for wound healing with heterotopic ossification after trauma
Nicole K. Patel, … , Amanda K. Huber, Benjamin Levi
Nicole K. Patel, … , Amanda K. Huber, Benjamin Levi
Published September 13, 2022
Citation Information: JCI Insight. 2022;7(20):e144925. https://doi.org/10.1172/jci.insight.144925.
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Macrophage TGF-β signaling is critical for wound healing with heterotopic ossification after trauma

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Abstract

Transforming growth factor–β1 (TGF-β1) plays a central role in normal and aberrant wound healing, but the precise mechanism in the local environment remains elusive. Here, using a mouse model of aberrant wound healing resulting in heterotopic ossification (HO) after traumatic injury, we find autocrine TGF-β1 signaling in macrophages, and not mesenchymal stem/progenitor cells, is critical in HO formation. In-depth single-cell transcriptomic and epigenomic analyses in combination with immunostaining of cells from the injury site demonstrated increased TGF-β1 signaling in early infiltrating macrophages, with open chromatin regions in TGF-β1–stimulated genes at binding sites specific for transcription factors of activated TGF-β1 (SMAD2/3). Genetic deletion of TGF-β1 receptor type 1 (Tgfbr1; Alk5), in macrophages, resulted in increased HO, with a trend toward decreased tendinous HO. To bypass the effect seen by altering the receptor, we administered a systemic treatment with TGF-β1/3 ligand trap TGF-βRII-Fc, which resulted in decreased HO formation and a delay in macrophage infiltration to the injury site. Overall, our data support the role of the TGF-β1/ALK5 signaling pathway in HO.

Authors

Nicole K. Patel, Johanna H. Nunez, Michael Sorkin, Simone Marini, Chase A. Pagani, Amy L. Strong, Charles D. Hwang, Shuli Li, Karthik R. Padmanabhan, Ravi Kumar, Alec C. Bancroft, Joey A. Greenstein, Reagan Nelson, Husain A. Rasheed, Nicholas Livingston, Kaetlin Vasquez, Amanda K. Huber, Benjamin Levi

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Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis
Yusuke Isshiki, … , Chiaki Nakaseko, Atsushi Iwama
Yusuke Isshiki, … , Chiaki Nakaseko, Atsushi Iwama
Published September 21, 2022
Citation Information: JCI Insight. 2022;7(20):e151482. https://doi.org/10.1172/jci.insight.151482.
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Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis

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Abstract

POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. Because the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. Herein, we performed single-cell RNA-Seq of BM plasma cells from patients with POEMS syndrome and identified POEMS clones that had Ig λ light chain (IGL) sequences (IGLV1-36, -40, -44, and -47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller than in patients with multiple myeloma (MM) and patients with monoclonal gammopathy of undetermined significance (MGUS). Single-cell transcriptomes revealed that POEMS clones were CD19+, CD138+, and MHC class IIlo, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM clones, accounting for their small size. VEGF mRNA was not upregulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

Authors

Yusuke Isshiki, Motohiko Oshima, Naoya Mimura, Kensuke Kayamori, Yurie Miyamoto-Nagai, Masahide Seki, Yaeko Nakajima-Takagi, Takashi Kanamori, Eisuke Iwamoto, Tomoya Muto, Shokichi Tsukamoto, Yusuke Takeda, Chikako Ohwada, Sonoko Misawa, Jun-ichiro Ikeda, Masashi Sanada, Satoshi Kuwabara, Yutaka Suzuki, Emiko Sakaida, Chiaki Nakaseko, Atsushi Iwama

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Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in Pjvk-mutant mice
Ying-Chang Lu, … , Chen-Chi Wu, Yen-Fu Cheng
Ying-Chang Lu, … , Chen-Chi Wu, Yen-Fu Cheng
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e152941. https://doi.org/10.1172/jci.insight.152941.
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Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in Pjvk-mutant mice

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Abstract

Recessive PJVK mutations that cause a deficiency of pejvakin, a protein expressed in both sensory hair cells and first-order neurons of the inner ear, are an important cause of hereditary hearing impairment. Patients with PJVK mutations garner limited benefits from cochlear implantation; thus, alternative biological therapies may be required to address this clinical difficulty. The synthetic adeno-associated viral vector Anc80L65, with its wide tropism and high transduction efficiency in various inner ear cells, may provide a solution. We delivered the PJVK transgene to the inner ear of Pjvk mutant mice using the synthetic Anc80L65 vector. We observed robust exogenous pejvakin expression in the hair cells and neurons of the cochlea and vestibular organs. Subsequent morphologic and audiologic studies demonstrated significant restoration of spiral ganglion neuron density and hair cells in the cochlea, along with partial recovery of sensorineural hearing impairment. In addition, we observed a recovery of vestibular ganglion neurons and balance function to WT levels. Our study demonstrates the utility of Anc80L65-mediated gene delivery in Pjvk mutant mice and provides insights into the potential of gene therapy for PJVK-related inner ear deficits.

Authors

Ying-Chang Lu, Yi-Hsiu Tsai, Yen-Huei Chan, Chin-Ju Hu, Chun-Ying Huang, Ru Xiao, Chuan-Jen Hsu, Luk H. Vandenberghe, Chen-Chi Wu, Yen-Fu Cheng

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Single-cell transcriptomics reveals skewed cellular communication and phenotypic shift in pulmonary artery remodeling
Slaven Crnkovic, … , Leigh M. Marsh, Grazyna Kwapiszewska
Slaven Crnkovic, … , Leigh M. Marsh, Grazyna Kwapiszewska
Published September 13, 2022
Citation Information: JCI Insight. 2022;7(20):e153471. https://doi.org/10.1172/jci.insight.153471.
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Single-cell transcriptomics reveals skewed cellular communication and phenotypic shift in pulmonary artery remodeling

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Abstract

A central feature of progressive vascular remodeling is altered smooth muscle cell (SMC) homeostasis; however, the understanding of how different cell populations contribute to this process is limited. Here, we utilized single-cell RNA sequencing to provide insight into cellular composition changes within isolated pulmonary arteries (PAs) from pulmonary arterial hypertension and donor lungs. Our results revealed that remodeling skewed the balanced communication network between immune and structural cells, in particular SMCs. Comparative analysis with murine PAs showed that human PAs harbored heterogeneous SMC populations with an abundant intermediary cluster displaying a gradient transition between SMCs and adventitial fibroblasts. Transcriptionally distinct SMC populations were enriched in specific biological processes and could be differentiated into 4 major clusters: oxygen sensing (enriched in pericytes), contractile, synthetic, and fibroblast-like. End-stage remodeling was associated with phenotypic shift of preexisting SMC populations and accumulation of synthetic SMCs in neointima. Distinctly regulated genes in clusters built nonredundant regulatory hubs encompassing stress response and differentiation regulators. The current study provides a blueprint of cellular and molecular changes on a single-cell level that are defining the pathological vascular remodeling process.

Authors

Slaven Crnkovic, Francesco Valzano, Elisabeth Fließer, Jürgen Gindlhuber, Helene Thekkekara Puthenparampil, Maria Basil, Mike P. Morley, Jeremy Katzen, Elisabeth Gschwandtner, Walter Klepetko, Edward Cantu, Heimo Wolinski, Horst Olschewski, Jörg Lindenmann, You-Yang Zhao, Edward E. Morrisey, Leigh M. Marsh, Grazyna Kwapiszewska

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Distinct patterns of responses in endothelial cells and smooth muscle cells following vascular injury
Xili Ding, … , Yubo Fan, Song Li
Xili Ding, … , Yubo Fan, Song Li
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e153769. https://doi.org/10.1172/jci.insight.153769.
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Distinct patterns of responses in endothelial cells and smooth muscle cells following vascular injury

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Vascular smooth muscle cells (SMCs) are heterogeneous, and their differential responses to vascular injury are not well understood. To address this question, we performed single-cell analysis of vascular cells to a ligation injury in mouse carotid arteries after 3 days. While endothelial cells had a homogeneous activation of mesenchymal genes, less than 30% of SMCs responded to the injury and generated 2 distinct clusters — i.e., proinflammatory SMCs and stress-responsive SMCs. Proinflammatory SMCs were enriched with high levels of inflammatory markers such as vascular cell adhesion molecule-1 while stress-responsive SMCs overexpressed heat shock proteins. Trajectory analysis suggested that proinflammatory SMCs were potentially derived from a specific subpopulation of SMCs. Ligand-receptor pair analysis showed that the interaction between macrophages and proinflammatory SMCs was the major cell-cell communication among all cell types in the injured arteries. In vitro coculture demonstrated that VCAM1+ SMCs had a stronger chemotactic effect on macrophage recruitment than VCAM1– SMCs. Consistently, the number of VCAM1+ SMCs significantly increased in injured arteries and atherosclerotic lesions of ApoE–/– mice and human arteries. These findings provide insights at the single-cell level on the distinct patterns of endothelial cells and SMC responses to vascular injury.

Authors

Xili Ding, Qin An, Weikang Zhao, Yang Song, Xiaokai Tang, Jing Wang, Chih-Chiang Chang, Gexin Zhao, Tzung Hsiai, Guoping Fan, Yubo Fan, Song Li

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Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency
Chynna N. Broxton, … , Vernon E. Anderson, Marni J. Falk
Chynna N. Broxton, … , Vernon E. Anderson, Marni J. Falk
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e156222. https://doi.org/10.1172/jci.insight.156222.
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Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency

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Abstract

Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.

Authors

Chynna N. Broxton, Prabhjot Kaur, Manuela Lavorato, Smruthi Ganesh, Rui Xiao, Neal D. Mathew, Eiko Nakamaru-Ogiso, Vernon E. Anderson, Marni J. Falk

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Successful prednisolone or calcimimetic treatment of acquired hypocalciuric hypercalcemia caused by biased allosteric CaSR autoantibodies
Noriko Makita, … , Masaomi Nangaku, Taroh Iiri
Noriko Makita, … , Masaomi Nangaku, Taroh Iiri
Published September 13, 2022
Citation Information: JCI Insight. 2022;7(20):e156742. https://doi.org/10.1172/jci.insight.156742.
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Successful prednisolone or calcimimetic treatment of acquired hypocalciuric hypercalcemia caused by biased allosteric CaSR autoantibodies

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Abstract

Biased agonism is a frontier field in GPCR research. Acquired hypocalciuric hypercalcemia (AHH) is a rare disease caused by calcium-sensing receptor (CaSR) autoantibodies, to date, showing either simple blocking or biased properties (i.e., stimulatory or blocking effects on different downstream signaling pathways). This emphasizes the importance of the Gi/o (pertussis toxin–sensitive G proteins, whose βγ subunits activate multiple signals, including ERK1/2) in regulating parathyroid hormone secretion. We here describe 3 patients with symptomatic AHH who shared characteristics with the 2 cases we previously reported as follows: (a) elderly (74–87 years at diagnosis), (b) male, (c) unexpectedly showed no other autoimmune diseases, (d) showed spontaneously fluctuating Ca levels from approximately normal to near fatally high ranges, (e) acute exacerbations could be successfully treated with prednisolone and/or calcimimetics, (f) the presence of CaSR autoantibodies that operated as biased allosteric modulators of CaSR, and (g) were likely to be conformational (i.e., recognizing and, thereby, stabilizing a unique active conformation of CaSR that activates Gq/11, activating phosphatidylinositol turnover, but not Gi/o). Our observations with these prominent commonalities may provide new insights into the phenotype and characteristics of AHH and the mechanisms by which the biased agonism of GPCRs operate.

Authors

Noriko Makita, Junichiro Sato, Katsunori Manaka, Kimiko Akahane, Takahiro Ito, Hajime Yamazaki, Akira Mizoguchi, Yusuke Hikima, Hirofumi Horikoshi, Masaomi Nangaku, Taroh Iiri

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PRC2 loss drives MPNST metastasis and matrix remodeling
Qierra R. Brockman, … , Christopher S. Stipp, Rebecca D. Dodd
Qierra R. Brockman, … , Christopher S. Stipp, Rebecca D. Dodd
Published September 6, 2022
Citation Information: JCI Insight. 2022;7(20):e157502. https://doi.org/10.1172/jci.insight.157502.
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PRC2 loss drives MPNST metastasis and matrix remodeling

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Abstract

The histone methyltransferase PRC2 plays a complex role in cancer. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with frequent loss-of-function mutations in PRC2 that are associated with poor outcome. Here, we identify a critical role for PRC2 loss in driving MPNST metastasis. PRC2-dependent metastatic phenotypes included increased collagen-dependent invasion, upregulation of matrix-remodeling enzymes, and elevated lung metastasis in orthotopic mouse models. Furthermore, clinical sample analysis determined that PRC2 loss correlated with metastatic disease, increased fibrosis, and decreased survival in patients with MPNSTs. These results may have broad implications for PRC2 function across multiple cancers and provide a strong rationale for investigating potential therapies targeting ECM-remodeling enzymes and tumor fibrosis to improve outcomes in patients with MPNSTs.

Authors

Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew P. Voigt, Alexandra L. Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher S. Stipp, Rebecca D. Dodd

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Early-life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats
Linda Tsan, … , Scott E. Kanoski, Lindsey A. Schier
Linda Tsan, … , Scott E. Kanoski, Lindsey A. Schier
Published September 13, 2022
Citation Information: JCI Insight. 2022;7(20):e157714. https://doi.org/10.1172/jci.insight.157714.
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Early-life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats

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Abstract

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region–specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling–related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.

Authors

Linda Tsan, Sandrine Chometton, Anna M.R. Hayes, Molly E. Klug, Yanning Zuo, Shan Sun, Lana Bridi, Rae Lan, Anthony A. Fodor, Emily E. Noble, Xia Yang, Scott E. Kanoski, Lindsey A. Schier

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NOX4 inhibition promotes the remodeling of dystrophic muscle
David W. Hammers
David W. Hammers
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e158316. https://doi.org/10.1172/jci.insight.158316.
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NOX4 inhibition promotes the remodeling of dystrophic muscle

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Abstract

The muscular dystrophies (MDs) are genetic muscle diseases that result in progressive muscle degeneration followed by the fibrotic replacement of affected muscles as regenerative processes fail. Therapeutics that specifically address the fibrosis and failed regeneration associated with MDs represent a major unmet clinical need for MD patients, particularly those with advanced-stage disease progression. The current study investigated targeting NAD(P)H oxidase 4 (NOX4) as a potential strategy to reduce fibrosis and promote regeneration in disease-burdened muscle that models Duchenne muscular dystrophy (DMD). NOX4 was elevated in the muscles of dystrophic mice and DMD patients, localizing primarily to interstitial cells located between muscle fibers. Genetic and pharmacological targeting of NOX4 significantly reduced fibrosis in dystrophic respiratory and limb muscles. Mechanistically, NOX4 targeting decreased the number of fibrosis-depositing cells (myofibroblasts) and restored the number of muscle-specific stem cells (satellite cells) localized to their physiological niche, thereby rejuvenating muscle regeneration. Furthermore, acute inhibition of NOX4 was sufficient to induce apoptotic clearing of myofibroblasts within dystrophic muscle. These data indicate that targeting NOX4 is an effective strategy to promote the beneficial remodeling of disease-burdened muscle representative of DMD and, potentially, other MDs and muscle pathologies.

Authors

David W. Hammers

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Intraperitoneal injection of class A TLR9 agonist enhances anti–PD-1 immunotherapy in colorectal peritoneal metastases
Ting Jiang, … , Timothy R. Billiar, Meihong Deng
Ting Jiang, … , Timothy R. Billiar, Meihong Deng
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e160063. https://doi.org/10.1172/jci.insight.160063.
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Intraperitoneal injection of class A TLR9 agonist enhances anti–PD-1 immunotherapy in colorectal peritoneal metastases

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Peritoneal metastases are associated with a low response rate to immune checkpoint blockade (ICB) therapy. The numbers of peritoneal resident macrophages (PRMs) are reversely correlated with the response rate to ICB therapy. We have previously shown that TLR9 in fibroblastic reticular cells (FRCs) plays a critical role in regulating peritoneal immune cell recruitment. However, the role of TLR9 in FRCs in regulating PRMs is unclear. Here, we demonstrated that the class A TLR9 agonist, ODN1585, markedly enhanced the efficacy of anti–PD-1 therapy in mouse models of colorectal peritoneal metastases. ODN1585 injected i.p. reduced the numbers of Tim4+ PRMs and enhanced CD8+ T cell antitumor immunity. Mechanistically, treatment of ODN1585 suppressed the expression of genes required for retinoid metabolism in FRCs, and this was associated with reduced expression of the PRM lineage–defining transcription factor GATA6. Selective deletion of TLR9 in FRCs diminished the benefit of ODN1585 in anti–PD-1 therapy in reducing peritoneal metastases. The crosstalk between PRMs and FRCs may be utilized to develop new strategies to improve the efficacy of ICB therapy for peritoneal metastases.

Authors

Ting Jiang, Hongji Zhang, Yiming Li, Preethi Jayakumar, Hong Liao, Hai Huang, Timothy R. Billiar, Meihong Deng

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Transcriptome and DNA methylome analyses reveal underlying mechanisms for the racial disparity in uterine fibroids
Emmanuel N. Paul, … , Hui Shen, Jose M. Teixeira
Emmanuel N. Paul, … , Hui Shen, Jose M. Teixeira
Published September 6, 2022
Citation Information: JCI Insight. 2022;7(20):e160274. https://doi.org/10.1172/jci.insight.160274.
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Transcriptome and DNA methylome analyses reveal underlying mechanisms for the racial disparity in uterine fibroids

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Uterine fibroids (leiomyomas) affect Black women disproportionately compared with women of other races and ethnicities in terms of prevalence, incidence, and severity of symptoms. The causes of this racial disparity are essentially unknown. We hypothesized that myometria of Black women are more susceptible to developing fibroids, and we examined the transcriptomic and DNA methylation profiles of myometria and fibroids from Black and White women for comparison. Myometrial samples cluster by race in both their transcriptome and DNA methylation profiles, whereas fibroid samples only cluster by race in the latter. More differentially expressed genes (DEGs) were detected in the Black and White myometrial sample comparison than in the fibroid comparison. Leiomyoma gene set expression analysis identified 4 clusters of DEGs, including a cluster of 24 genes with higher expression in myometrial samples from Black women. One of the DEGs in this group, von Willibrands factor (VWF), was significantly hypomethylated in both myometrial samples from Black women and in all fibroids at 2 CpG probes that are near a putative enhancer site and that are correlated with VWF expression levels. These results suggest that the molecular basis for the disparity in fibroid disease between Black and White women could be found in the myometria before fibroid development and not in the fibroids themselves.

Authors

Emmanuel N. Paul, Joshua A. Grey, Tyler J. Carpenter, Zachary B. Madaj, Kin H. Lau, Scott A. Givan, Gregory W. Burns, Ronald L. Chandler, Ganesa R. Wegienka, Hui Shen, Jose M. Teixeira

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A single-cell mass cytometry platform to map the effects of preclinical drugs on cartilage homeostasis
Neety Sahu, … , Fiorella Carla Grandi, Nidhi Bhutani
Neety Sahu, … , Fiorella Carla Grandi, Nidhi Bhutani
Published October 4, 2022
Citation Information: JCI Insight. 2022;7(20):e160702. https://doi.org/10.1172/jci.insight.160702.
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A single-cell mass cytometry platform to map the effects of preclinical drugs on cartilage homeostasis

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Abstract

No disease-modifying drug exists for osteoarthritis (OA). Despite success in animal models, candidate drugs continue to fail in clinical trials owing to the unmapped interpatient heterogeneity and disease complexity. We used a single-cell platform based on cytometry by time-of-flight (cyTOF) to precisely outline the effects of candidate drugs on human OA chondrocytes. OA chondrocytes harvested from patients undergoing total knee arthroplasty were treated with 2 drugs, an NF-κB pathway inhibitor, BMS-345541, and a chondroinductive small molecule, kartogenin, that showed preclinical success in animal models for OA. cyTOF conducted with 30 metal isotope–labeled antibodies parsed the effects of the drugs on inflammatory, senescent, and chondroprogenitor cell populations. The NF-κB pathway inhibition decreased the expression of p–NF-κB, HIF2A, and inducible NOS in multiple chondrocyte clusters and significantly depleted 4 p16ink4a-expressing senescent populations, including NOTCH1+STRO1+ chondroprogenitor cells. While kartogenin also affected select p16ink4a-expressing senescent clusters, there was a less discernible effect on chondroprogenitor cell populations. Overall, BMS-345541 elicited a uniform drug response in all patients, while only a few responded to kartogenin. These studies demonstrate that a single-cell cyTOF-based drug screening platform can provide insights into patient response assessment and patient stratification.

Authors

Neety Sahu, Fiorella Carla Grandi, Nidhi Bhutani

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Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis
Amee Sonigra, … , Kim Campbell, Ranjeny Thomas
Amee Sonigra, … , Kim Campbell, Ranjeny Thomas
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e160964. https://doi.org/10.1172/jci.insight.160964.
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Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis

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BACKGROUND Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under “sub-immunogenic” conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol.METHODS A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71–specific (Cit-Vim–specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate.RESULTS DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim–specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181–treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim–specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSION The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATION Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDING Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287.

Authors

Amee Sonigra, Hendrik J. Nel, Pascale Wehr, Nishta Ramnoruth, Swati Patel, Karin A. van Schie, Maxwell W. Bladen, Ahmed M. Mehdi, Joanne Tesiram, Meghna Talekar, Jamie Rossjohn, Hugh H. Reid, Frederik E. Stuurman, Helen Roberts, Phillip Vecchio, Ian Gourley, Mark Rigby, Stephane Becart, Rene E.M. Toes, Hans Ulrich Scherer, Kim-Anh Lê Cao, Kim Campbell, Ranjeny Thomas

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Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study
Donghai Wen, … , Eugene P. Rhee, the CKD Biomarkers Consortium and CRIC Study Investigators
Donghai Wen, … , Eugene P. Rhee, the CKD Biomarkers Consortium and CRIC Study Investigators
Published September 1, 2022
Citation Information: JCI Insight. 2022;7(20):e161696. https://doi.org/10.1172/jci.insight.161696.
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Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

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BACKGROUND Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODS We examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTS In CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSION Our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDING This study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

Authors

Donghai Wen, Zihe Zheng, Aditya Surapaneni, Bing Yu, Linda Zhou, Wen Zhou, Dawei Xie, Haochang Shou, Julian Avila-Pacheco, Sahir Kalim, Jiang He, Chi-Yuan Hsu, Afshin Parsa, Panduranga Rao, James Sondheimer, Raymond Townsend, Sushrut S. Waikar, Casey M. Rebholz, Michelle R. Denburg, Paul L. Kimmel, Ramachandran S. Vasan, Clary B. Clish, Josef Coresh, Harold I. Feldman, Morgan E. Grams, Eugene P. Rhee, the CKD Biomarkers Consortium and CRIC Study Investigators

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Benefits of global mutant huntingtin lowering diminish over time in a Huntington’s disease mouse model
Deanna M. Marchionini, … , David Howland, Scott O. Zeitlin
Deanna M. Marchionini, … , David Howland, Scott O. Zeitlin
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e161769. https://doi.org/10.1172/jci.insight.161769.
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Benefits of global mutant huntingtin lowering diminish over time in a Huntington’s disease mouse model

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We have developed an inducible Huntington’s disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow-up revealed that the benefits, in all mHtt-lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12 months of age, and late mHtt lowering did not ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefits in humans.

Authors

Deanna M. Marchionini, Jeh-Ping Liu, Alberto Ambesi-Impiombato, Kimberly Kerker, Kim Cirillo, Mukesh Bansal, Rich Mushlin, Daniela Brunner, Sylvie Ramboz, Mei Kwan, Kirsten Kuhlbrodt, Karsten Tillack, Finn Peters, Leena Rauhala, John Obenauer, Jonathan R. Greene, Christopher Hartl, Vinod Khetarpal, Brenda Lager, Jim Rosinski, Jeff Aaronson, Morshed Alam, Ethan Signer, Ignacio Muñoz-Sanjuán, David Howland, Scott O. Zeitlin

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Insulin increases sensory nerve density and reflex bronchoconstriction in obese mice
Gina N. Calco, … , Allison D. Fryer, Zhenying Nie
Gina N. Calco, … , Allison D. Fryer, Zhenying Nie
Published September 15, 2022
Citation Information: JCI Insight. 2022;7(20):e161898. https://doi.org/10.1172/jci.insight.161898.
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Insulin increases sensory nerve density and reflex bronchoconstriction in obese mice

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Obesity-induced asthma responds poorly to all current pharmacological interventions, including steroids, suggesting that classic, eosinophilic inflammation is not a mechanism. Since insulin resistance and hyperinsulinemia are common in obese individuals and associated with increased risk of asthma, we used diet-induced obese mice to study how insulin induces airway hyperreactivity. Inhaled 5-HT or methacholine induced dose-dependent bronchoconstriction that was significantly potentiated in obese mice. Cutting the vagus nerves eliminated bronchoconstriction in both obese and nonobese animals, indicating that it was mediated by a neural reflex. There was significantly greater density of airway sensory nerves in obese compared with nonobese mice. Deleting insulin receptors on sensory nerves prevented the increase in sensory nerve density and prevented airway hyperreactivity in obese mice with hyperinsulinemia. Our data demonstrate that high levels of insulin drives obesity-induced airway hyperreactivity by increasing sensory innervation of the airways. Therefore, pharmacological interventions to control metabolic syndrome and limit reflex-mediated bronchoconstriction may be a more effective approach to reduce asthma exacerbations in obese and patients with asthma.

Authors

Gina N. Calco, Jessica N. Maung, David B. Jacoby, Allison D. Fryer, Zhenying Nie

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SARS-CoV-2 reinfections during the Delta and Omicron waves
C. Paul Morris, … , Eili Y. Klein, Heba H. Mostafa
C. Paul Morris, … , Eili Y. Klein, Heba H. Mostafa
Published September 1, 2022
Citation Information: JCI Insight. 2022;7(20):e162007. https://doi.org/10.1172/jci.insight.162007.
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SARS-CoV-2 reinfections during the Delta and Omicron waves

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BACKGROUND Increased SARS-CoV-2 reinfection rates have been reported recently, with some locations basing reinfection on a second positive PCR test at least 90 days after initial infection. In this study, we used Johns Hopkins SARS-CoV-2 genomic surveillance data to evaluate the frequency of sequencing-validated, confirmed, and inferred reinfections between March 2020 and July 2022.METHODS Patients who had 2 or more positive SARS-CoV-2 tests in our system, with samples sequenced as a part of our surveillance efforts, were identified as the cohort for our study. SARS-CoV-2 genomes of patients’ initial and later samples were compared.RESULTS A total of 755 patients (920 samples) had a positive test at least 90 days after the initial test, with a median time between tests of 377 days. Sequencing was attempted on 231 samples and was successful in 127. Rates of successful sequencing spiked during the Omicron surge; there was a higher median number of days from initial infection in these cases compared with those with failed sequences. A total of 122 (98%) patients showed evidence of reinfection; 45 of these patients had sequence-validated reinfection and 77 had inferred reinfections (later sequencing showed a clade that was not circulating when the patient was initially infected). Of the 45 patients with sequence-validated reinfections, 43 (96%) had reinfections that were caused by the Omicron variant, 41 (91%) were symptomatic, 32 (71%) were vaccinated prior to the second infection, 6 (13%) were immunosuppressed, and only 2 (4%) were hospitalized.CONCLUSION Sequence-validated reinfections increased with the Omicron surge but were generally associated with mild infections.FUNDING Funding was provided by the Johns Hopkins Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C), CDC (75D30121C11061), Johns Hopkins University President’s Fund Research Response, Johns Hopkins Department of Pathology, and the Maryland Department of Health.

Authors

C. Paul Morris, Raghda E. Eldesouki, Amary Fall, David C. Gaston, Julie M. Norton, Nicholas D. Gallagher, Chun Huai Luo, Omar Abdullah, Eili Y. Klein, Heba H. Mostafa

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Longitudinal associations of insulin resistance with change in bone mineral density in midlife women
Albert Shieh, … , Preethi Srikanthan, Arun S. Karlamangla
Albert Shieh, … , Preethi Srikanthan, Arun S. Karlamangla
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e162085. https://doi.org/10.1172/jci.insight.162085.
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Longitudinal associations of insulin resistance with change in bone mineral density in midlife women

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BACKGROUND The effects of insulin resistance on bone mineral density (BMD) are unclear.METHODS In Study of Women’s Health Across the Nation (SWAN) participants, we used multivariable regression to test average insulin resistance (homeostatic model assessment of insulin resistance, HOMA-IR) and rate of change in insulin resistance as predictors of rate of change in lumbar spine (LS) and femoral neck (FN) BMD in 3 stages: premenopause (n = 861), menopause transition (MT) (n = 571), and postmenopause (n = 693). Models controlled for age, average BW, change in BW, cigarette use, race and ethnicity, and study site.RESULTS The relation between HOMA-IR and BMD decline was biphasic. When average log2HOMA-IR was less than 1.5, greater HOMA-IR was associated with slower BMD decline; i.e., each doubling of average HOMA-IR in premenopause was associated with a 0.0032 (P = 0.01, LS) and 0.0041 (P = 0.004, FN) g/cm2 per year slower BMD loss. When greater than or equal to 1.5, average log2HOMA-IR was not associated with BMD change. In women in whom HOMA-IR decreased in premenopause, the association between the HOMA-IR change rate and BMD change rate was positive; i.e, slower HOMA-IR decline was associated with slower BMD loss. In women in whom insulin resistance increased in premenopause, the association was negative; i.e, faster HOMA-IR rise was associated with faster BMD decline. Associations of average HOMA-IR and HOMA-IR change rate with BMD change rate were similar in postmenopause, but weaker during the MT.CONCLUSION When it decreases, insulin resistance is associated with BMD preservation; when it increases, insulin resistance is associated with BMD loss.FUNDING The SWAN has grant support from the NIH of the Department of Health and Human Services (DHHS) through the NIH National Institute on Aging (NIA), National Institute of Nursing Research (NINR), and Office of Research on Women’s Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, and U19AG063720).

Authors

Albert Shieh, Gail A. Greendale, Jane A. Cauley, Preethi Srikanthan, Arun S. Karlamangla

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Subtype C HIV-1 reservoirs throughout the body in ART-suppressed individuals
Zhou Liu, … , John T. West, Charles Wood
Zhou Liu, … , John T. West, Charles Wood
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e162604. https://doi.org/10.1172/jci.insight.162604.
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Subtype C HIV-1 reservoirs throughout the body in ART-suppressed individuals

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Abstract

Subtype B HIV-1 reservoirs have been intensively investigated, but reservoirs in other subtypes and how they respond to antiretroviral therapy (ART) is substantially less established. To characterize subtype C HIV-1 reservoirs, we implemented postmortem frozen, as well as formalin fixed paraffin embedded (FFPE) tissue sampling of central nervous system (CNS) and peripheral tissues. HIV-1 LTR, gag, envelope (env) DNA and RNA was quantified using genomic DNA and RNA extracted from frozen tissues. RNAscope was used to localize subtype C HIV-1 DNA and RNA in FFPE tissue. Despite uniform viral load suppression in our cohort, PCR results showed that subtype C HIV-1 proviral copies vary both in magnitude and tissue distribution, with detection primarily in secondary lymphoid tissues. Interestingly, the appendix harbored proviruses in all subjects. Unlike subtype B, subtype C provirus was rarely detectable in the CNS, and there was no detectable HIV-1 RNA. HIV-1 RNA was detected in peripheral lymphoid tissues of 6 out of 8 ART-suppressed cases. In addition to active HIV-1 expression in lymphoid tissues, RNAscope revealed HIV RNA detection in CD4-expressing cells in the appendix, suggesting that this tissue was a previously unreported potential treatment-resistant reservoir for subtype C HIV-1.

Authors

Zhou Liu, Peter Julius, Guobin Kang, John T. West, Charles Wood

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Corrigendums
Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy
Margaret M. Lowe, … , Scott L. Hansen, Michael D. Rosenblum
Margaret M. Lowe, … , Scott L. Hansen, Michael D. Rosenblum
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e165502. https://doi.org/10.1172/jci.insight.165502.
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Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy

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Authors

Margaret M. Lowe, Haley B. Naik, Sean Clancy, Mariela Pauli, Kathleen M. Smith, Yingtao Bi, Robert Dunstan, Johann E. Gudjonsson, Maia Paul, Hobart Harris, Esther Kim, Uk Sok Shin, Richard Ahn, Wilson Liao, Scott L. Hansen, Michael D. Rosenblum

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Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis
Magdalena B. Flak, … , Jesmond Dalli, Costantino Pitzalis
Magdalena B. Flak, … , Jesmond Dalli, Costantino Pitzalis
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e165600. https://doi.org/10.1172/jci.insight.165600.
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Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis

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Authors

Magdalena B. Flak, Romain A. Colas, Estefanía Muñoz-Atienza, Michael A. Curtis, Jesmond Dalli, Costantino Pitzalis

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PPT1 inhibition enhances the antitumor activity of anti–PD-1 antibody in melanoma
Gaurav Sharma, … , Dmitry I. Gabrilovich, Ravi K. Amaravadi
Gaurav Sharma, … , Dmitry I. Gabrilovich, Ravi K. Amaravadi
Published October 24, 2022
Citation Information: JCI Insight. 2022;7(20):e165688. https://doi.org/10.1172/jci.insight.165688.
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PPT1 inhibition enhances the antitumor activity of anti–PD-1 antibody in melanoma

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Authors

Gaurav Sharma, Rani Ojha, Estela Noguera-Ortega, Vito W. Rebecca, John Attanasio, Shujing Liu, Shengfu Piao, Jennifer J. Lee, Michael C. Nicastri, Sandra L. Harper, Amruta Ronghe, Vaibhav Jain, Jeffrey D. Winkler, David W. Speicher, Jerome Mastio, Phyllis A. Gimotty, Xiaowei Xu, E. John Wherry, Dmitry I. Gabrilovich, Ravi K. Amaravadi

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