Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Issue published October 1, 2024 Previous issue | Next issue

  • Volume 134, Issue 19
Go to section:
  • Editorial
  • 100th Anniversary Viewpoints
  • Viewpoints
  • Review Series Viewpoint
  • Review Series
  • Commentaries
  • Research Letter
  • Research Articles
  • Retraction

On the cover: The first century of JCI and beyond

Editor in Chief Elizabeth M. McNally reflects on the 100th anniversary of the Journal of Clinical Investigation, major breakthroughs in medicine in the last century, and emerging areas of innovation. We also celebrate this milestone with a special collection of 100th Anniversary Viewpoints that highlight important discoveries in medicine and underscore how understanding the molecular basis of disease can transform human health.

Editorial
The first century of JCI and beyond
Elizabeth M. McNally
Elizabeth M. McNally
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e186113. https://doi.org/10.1172/JCI186113.
View: Text | PDF

The first century of JCI and beyond

  • Text
  • PDF
Abstract

Authors

Elizabeth M. McNally

×
100th Anniversary Viewpoints
Toward a better understanding of chronic hepatitis B virus infection
Barbara Rehermann
Barbara Rehermann
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e185568. https://doi.org/10.1172/JCI185568.
View: Text | PDF

Toward a better understanding of chronic hepatitis B virus infection

  • Text
  • PDF
Abstract

Authors

Barbara Rehermann

×

Intertwining clonality and resistance: Staphylococcus aureus in the antibiotic era
Henry F. Chambers, Vance G. Fowler Jr
Henry F. Chambers, Vance G. Fowler Jr
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e185824. https://doi.org/10.1172/JCI185824.
View: Text | PDF

Intertwining clonality and resistance: Staphylococcus aureus in the antibiotic era

  • Text
  • PDF
Abstract

Authors

Henry F. Chambers, Vance G. Fowler Jr

×

The expanding application of antisense oligonucleotides to neurodegenerative diseases
Charlotte J. Sumner, Timothy M. Miller
Charlotte J. Sumner, Timothy M. Miller
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e186116. https://doi.org/10.1172/JCI186116.
View: Text | PDF

The expanding application of antisense oligonucleotides to neurodegenerative diseases

  • Text
  • PDF
Abstract

Authors

Charlotte J. Sumner, Timothy M. Miller

×

The arc of discovery, from the description of cystic fibrosis to effective treatments
Michael J. Welsh
Michael J. Welsh
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e186231. https://doi.org/10.1172/JCI186231.
View: Text | PDF

The arc of discovery, from the description of cystic fibrosis to effective treatments

  • Text
  • PDF
Abstract

Authors

Michael J. Welsh

×
Viewpoints
2024 Lasker Award Recipient Zhijian Chen elucidates how DNA stimulates immunity
Amy B. Heimberger
Amy B. Heimberger
Published September 19, 2024
Citation Information: J Clin Invest. 2024;134(19):e186104. https://doi.org/10.1172/JCI186104.
View: Text | PDF

2024 Lasker Award Recipient Zhijian Chen elucidates how DNA stimulates immunity

  • Text
  • PDF
Abstract

Authors

Amy B. Heimberger

×

Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen awarded Lasker prize for pioneering work on GLP-1
Hossein Ardehali
Hossein Ardehali
Published September 19, 2024
Citation Information: J Clin Invest. 2024;134(19):e186225. https://doi.org/10.1172/JCI186225.
View: Text | PDF

Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen awarded Lasker prize for pioneering work on GLP-1

  • Text
  • PDF
Abstract

Authors

Hossein Ardehali

×
Review Series Viewpoint
The emergence of clonal hematopoiesis as a disease determinant
Kenneth Walsh
Kenneth Walsh
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e180063. https://doi.org/10.1172/JCI180063.
View: Text | PDF

The emergence of clonal hematopoiesis as a disease determinant

  • Text
  • PDF
Abstract

Authors

Kenneth Walsh

×
Review Series
Clonal hematopoiesis and hematological malignancy
William G. Dunn, … , Matthew A. McLoughlin, George S. Vassiliou
William G. Dunn, … , Matthew A. McLoughlin, George S. Vassiliou
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e180065. https://doi.org/10.1172/JCI180065.
View: Text | PDF

Clonal hematopoiesis and hematological malignancy

  • Text
  • PDF
Abstract

Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.

Authors

William G. Dunn, Matthew A. McLoughlin, George S. Vassiliou

×

Clonal hematopoiesis and atherosclerosis
Ohad Oren, … , Aeron M. Small, Peter Libby
Ohad Oren, … , Aeron M. Small, Peter Libby
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e180066. https://doi.org/10.1172/JCI180066.
View: Text | PDF

Clonal hematopoiesis and atherosclerosis

  • Text
  • PDF
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.

Authors

Ohad Oren, Aeron M. Small, Peter Libby

×

Distinct landscape and clinical implications of therapy-related clonal hematopoiesis
Koichi Takahashi, … , Daisuke Nakada, Margaret Goodell
Koichi Takahashi, … , Daisuke Nakada, Margaret Goodell
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e180069. https://doi.org/10.1172/JCI180069.
View: Text | PDF

Distinct landscape and clinical implications of therapy-related clonal hematopoiesis

  • Text
  • PDF
Abstract

Therapy-related clonal hematopoiesis (t-CH) is defined as clonal hematopoiesis detected in individuals previously treated with chemotherapy and/or radiation therapy. With the increased use of genetic analysis in oncological care, the detection of t-CH among cancer patients is becoming increasingly common. t-CH arises through the selective bottleneck imposed by chemotherapies and potentially through direct mutagenesis from chemotherapies, resulting in a distinct mutational landscape enriched with mutations in DNA damage-response pathway genes such as TP53, PPM1D, and CHEK2. Emerging evidence sheds light on the mechanisms of t-CH development and potential strategies to mitigate its emergence. Due to its unique characteristics that predominantly affect cancer patients, t-CH has clinical implications distinct from those of CH in the general population. This Review discusses the potential mechanisms of t-CH development, its mutational landscape, mutant-drug relationships, and its clinical significance. We highlight the distinct nature of t-CH and call for intensified research in this field.

Authors

Koichi Takahashi, Daisuke Nakada, Margaret Goodell

×
Commentaries
Sleepless nights and social plights: medial septum GABAergic hyperactivity in a neuroligin 3–deficient autism model
Claire E. Cho, … , Dahee Jung, Reesha R. Patel
Claire E. Cho, … , Dahee Jung, Reesha R. Patel
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e184795. https://doi.org/10.1172/JCI184795.
View: Text | PDF

Sleepless nights and social plights: medial septum GABAergic hyperactivity in a neuroligin 3–deficient autism model

  • Text
  • PDF
Abstract

Social deficits represent a core symptom domain of autism spectrum disorder (ASD), which is often comorbid with sleep disturbances. In this issue of the JCI, Sun et al. explored a medial septum (MS) circuit linking these behaviors in a neuroligin 3 conditional knockout model of autism. They identified GABAergic neuron hyperactivity following neuroligin 3 deletion in the MS. This hyperactivity resulted in the inhibition of the downstream preoptic area (POA) and hippocampal CA2 region, resulting in sleep loss and social memory deficits, respectively. Inactivating the hyperactive MS GABA neurons or activating the POA or CA2 rescued the behavioral deficits. Together, these findings deepen our understanding of neural circuits underlying social and sleep deficits in ASD.

Authors

Claire E. Cho, Dahee Jung, Reesha R. Patel

×

Ciliary localization of GPR75 promotes fat accumulation in mice
Marcelo Chávez, … , Anushweta Asthana, Peter K. Jackson
Marcelo Chávez, … , Anushweta Asthana, Peter K. Jackson
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e185059. https://doi.org/10.1172/JCI185059.
View: Text | PDF

Ciliary localization of GPR75 promotes fat accumulation in mice

  • Text
  • PDF
Abstract

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands.

Authors

Marcelo Chávez, Anushweta Asthana, Peter K. Jackson

×

IFN-γ and YAP lead epithelial cells astray after severe respiratory infection
Bradley E. Hiller, Joseph P. Mizgerd
Bradley E. Hiller, Joseph P. Mizgerd
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e185072. https://doi.org/10.1172/JCI185072.
View: Text | PDF

IFN-γ and YAP lead epithelial cells astray after severe respiratory infection

  • Text
  • PDF
Abstract

Ineffective recovery from pneumonia can lead to interstitial lung disease characterized by aberrant epithelial cells in fibrotic regions. In this issue of the JCI, Lin et al. define molecular pathways leading to the development and persistence of keratin 5+ (Krt5+) epithelial cells in the alveolar parenchyma when mice struggle to recover from influenza infection. The receptor for IFN-γ on lung epithelium was essential for the formation of aberrant Krt5+ cells and fibrotic lung disease. The transcription factor Yes-associated protein 1 (YAP) was necessary for persistence of these Krt5+ cells, and IFN-γ activated YAP in lung epithelial cells via JAK, focal adhesion kinase (FAK), and Src kinases. These findings establish a targetable pathway underlying some of the pulmonary postacute sequelae of pneumonia.

Authors

Bradley E. Hiller, Joseph P. Mizgerd

×
Research Letter
Mucins protect against Streptococcus pneumoniae virulence by suppressing pneumolysin expression
Jade Bath, … , Victor Nizet, Katharina Ribbeck
Jade Bath, … , Victor Nizet, Katharina Ribbeck
Published August 22, 2024
Citation Information: J Clin Invest. 2024;134(19):e182769. https://doi.org/10.1172/JCI182769.
View: Text | PDF

Mucins protect against Streptococcus pneumoniae virulence by suppressing pneumolysin expression

  • Text
  • PDF
Abstract

Authors

Jade Bath, Elisabet Bjånes, Cengiz Goekeri, Jeff Hsiao, Deniz Uzun, Geraldine Nouailles, Victor Nizet, Katharina Ribbeck

×
Research Articles
Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair
Mingzhu Fu, … , Yulong Zhong, Shanshan Ai
Mingzhu Fu, … , Yulong Zhong, Shanshan Ai
Published August 27, 2024
Citation Information: J Clin Invest. 2024;134(19):e175297. https://doi.org/10.1172/JCI175297.
View: Text | PDF

Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair

  • Text
  • PDF
Abstract

Cardiac mononuclear phagocytic cells (Cardiac MPCs) participate in maintaining homeostasis and orchestrating cardiac responses upon injury. However, the function of specific MPC subtypes and the related cell fate commitment mechanisms remain elusive in regenerative and nonregenerative hearts due to their cellular heterogeneities. Using spatiotemporal single-cell epigenomic analysis of cardiac MPCs in regenerative (P1) and nonregenerative (P10) mouse hearts after injury, we found that P1 hearts accumulate reparative Arg1+ macrophages, while proinflammatory S100a9+Ly6c+ monocytes are uniquely abundant during nonregenerative remodeling. Moreover, blocking chemokine CXCR2 to inhibit the specification of the S100a9+Ly6c+-biased inflammatory fate in P10 hearts resulted in elevated wound repair responses and marked improvements in cardiac function after injury. Single-cell RNA-Seq further confirmed an increased Arg1+ macrophage subpopulation after CXCR2 blockade, which was accomplished by increased expression of wound repair–related genes and reduced expression of proinflammatory genes. Collectively, our findings provide instructive insights into the molecular mechanisms underlying the function and fate specification of heterogeneous MPCs during cardiac repair and identify potential therapeutic targets for myocardial infarction.

Authors

Mingzhu Fu, Shengtao Jia, Longhui Xu, Xin Li, Yufang Lv, Yulong Zhong, Shanshan Ai

×

Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation
Laura P. Kincer, … , Paola Cinque, Sarah B. Joseph
Laura P. Kincer, … , Paola Cinque, Sarah B. Joseph
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e176358. https://doi.org/10.1172/JCI176358.
View: Text | PDF

Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation

  • Text
  • PDF
Abstract

During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.

Authors

Laura P. Kincer, Ameet Dravid, Mattia Trunfio, Andrea Calcagno, Shuntai Zhou, Riccardo Vercesi, Serena Spudich, Magnus Gisslen, Richard W. Price, Paola Cinque, Sarah B. Joseph

×

Autism-associated neuroligin 3 deficiency in medial septum causes social deficits and sleep loss in mice
Haiyan Sun, … , Wei Xie, Shuming An
Haiyan Sun, … , Wei Xie, Shuming An
Published July 26, 2024
Citation Information: J Clin Invest. 2024;134(19):e176770. https://doi.org/10.1172/JCI176770.
View: Text | PDF

Autism-associated neuroligin 3 deficiency in medial septum causes social deficits and sleep loss in mice

  • Text
  • PDF
Abstract

Patients with autism spectrum disorder (ASD) frequently experience sleep disturbance. Genetic mutations in the neuroligin 3 (NLG3) gene are highly correlative with ASD and sleep disturbance. However, the cellular and neural circuit bases of this correlation remain elusive. Here, we found that the conditional knockout of Nlg3 (Nlg3-CKO) in the medial septum (MS) impairs social memory and reduces sleep. Nlg3 CKO in the MS caused hyperactivity of MSGABA neurons during social avoidance and wakefulness. Activation of MSGABA neurons induced social memory deficits and sleep loss in C57BL/6J mice. In contrast, inactivation of these neurons ameliorated social memory deficits and sleep loss in Nlg3-CKO mice. Sleep deprivation led to social memory deficits, while social isolation caused sleep loss, both resulting in a reduction in NLG3 expression and an increase in activity of GABAergic neurons in the MS from C57BL/6J mice. Furthermore, MSGABA-innervated CA2 neurons specifically regulated social memory without impacting sleep, whereas MSGABA-innervating neurons in the preoptic area selectively controlled sleep without affecting social behavior. Together, these findings demonstrate that the hyperactive MSGABA neurons impair social memory and disrupt sleep resulting from Nlg3 CKO in the MS, and achieve the modality specificity through their divergent downstream targets.

Authors

Haiyan Sun, Yu Shen, Pengtao Ni, Xin Liu, Yan Li, Zhentong Qiu, Jiawen Su, Yihan Wang, Miao Wu, Xiangxi Kong, Jun-Li Cao, Wei Xie, Shuming An

×

Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli
Xiuyu Lin, … , Bo Liu, Pengfei Sui
Xiuyu Lin, … , Bo Liu, Pengfei Sui
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e176828. https://doi.org/10.1172/JCI176828.
View: Text | PDF

Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli

  • Text
  • PDF
Abstract

Severe viral pneumonia can induce rapid expansion of KRT5+ basal-like cells in small airways and alveoli; this forms a scar-like structure that persists in the injured alveoli and impedes normal alveolar epithelium regeneration. In this study, we investigated the mechanism by which viral infection induced this remodeling response. Through comparing different lung-injury models, we demonstrated that infection induced strong IFN-γ signal–stimulated dysplastic KRT5+ cell formation. Inactivation of interferon receptor 1 (Ifngr1) reduced dysplastic cell formation, ameliorated lung fibrosis, and improved lung-function recovery. Mechanistically, IFN-γ regulated dysplastic cell formation via the focal adhesion kinase (FAK)/Yes-associated protein 1 (YAP) pathway. Inhibiting FAK/Src diminished IFN-γ–induced YAP nuclear translocation and dysplastic cell formation. Inhibiting YAP during viral infection prevented dysplastic cell formation, whereas inhibiting YAP in persistent KRT5+ cells led to their conversion into distal club cells. Importantly, human dysplastic cells exhibited elevated FAK and YAP activity, and IFN-γ treatment promoted the transformation of human alveolar progenitor cells into dysplastic cells. These findings uncover the role of infection-induced inflammatory response in alveolar remodeling and may provide potential therapeutic avenues for the treatment of alveolar remodeling in patients with severe viral pneumonia.

Authors

Xiuyu Lin, Weicheng Chen, Guilin Yang, Jiazhu Zhang, Huilin Wang, Zeyu Liu, Ying Xi, Tao Ren, Bo Liu, Pengfei Sui

×

Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma
Shashwat Tripathi, … , Amy B. Heimberger, Michael DeCuypere
Shashwat Tripathi, … , Amy B. Heimberger, Michael DeCuypere
Published August 13, 2024
Citation Information: J Clin Invest. 2024;134(19):e177413. https://doi.org/10.1172/JCI177413.
View: Text | PDF

Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma

  • Text
  • PDF
Abstract

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain vasculature. TIM3 expression became upregulated on immune cells in the PA microenvironment, and anti-TIM3 reprogrammed ex vivo immune cells from human PAs to a proinflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven, low-grade gliomas, anti-TIM3 treatment increased median survival over IgG- and anti–PD-1–treated mice. Single-cell RNA-Seq data during the therapeutic window of anti-TIM3 revealed enrichment of the MG-Act population. The therapeutic activity of anti-TIM3 was abrogated in mice on the CX3CR1 MG–KO background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade, MAPK-driven gliomas.

Authors

Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P. Chandler, Roger Stupp, Adam M. Sonabend, Craig M. Horbinski, Rimas V. Lukas, Joanne Xiu, Giselle Lopez, Theodore P. Nicolaides, Valerie Brown, Nitin R. Wadhwani, Sandi K. Lam, Charles David James, Ganesh Rao, Maria G. Castro, Amy B. Heimberger, Michael DeCuypere

×

Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer
Xiaolin Zhu, … , Michiel S. van der Heijden, Felix Y. Feng
Xiaolin Zhu, … , Michiel S. van der Heijden, Felix Y. Feng
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e178604. https://doi.org/10.1172/JCI178604.
View: Text | PDF Clinical Research and Public Health

Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer

  • Text
  • PDF
Abstract

BACKGROUND Androgen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODS To investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTS We confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSION Our findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDING National Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

Authors

Xiaolin Zhu, Tatyanah Farsh, Daniël Vis, Ivan Yu, Haolong Li, Tianyi Liu, Martin Sjöström, Raunak Shrestha, Jeroen Kneppers, Tesa Severson, Meng Zhang, Arian Lundberg, Thaidy Moreno Rodriguez, Alana S. Weinstein, Adam Foye, Niven Mehra, Rahul R. Aggarwal, Andries M. Bergman, Eric J. Small, Nathan A. Lack, Wilbert Zwart, David A. Quigley, Michiel S. van der Heijden, Felix Y. Feng

×

IL-7–dependent and –independent lineages of IL-7R–dependent human T cells
Carlos A. Arango-Franco, … , Jean-Laurent Casanova, Anne Puel
Carlos A. Arango-Franco, … , Jean-Laurent Casanova, Anne Puel
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e180251. https://doi.org/10.1172/JCI180251.
View: Text | PDF

IL-7–dependent and –independent lineages of IL-7R–dependent human T cells

  • Text
  • PDF
Abstract

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T–B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7–independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R–binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7–independent pathway of human T cell development.

Authors

Carlos A. Arango-Franco, Masato Ogishi, Susanne Unger, Ottavia M. Delmonte, Julio César Orrego, Ahmad Yatim, Margarita M. Velasquez-Lopera, Andrés F. Zea-Vera, Jonathan Bohlen, Marwa Chbihi, Antoine Fayand, Juan Pablo Sánchez, Julian Rojas, Yoann Seeleuthner, Tom Le Voyer, Quentin Philippot, Kathryn J. Payne, Adrian Gervais, Lucia V. Erazo-Borrás, Luis A. Correa-Londoño, Axel Cederholm, Alejandro Gallón-Duque, Pedro Goncalves, Jean-Marc Doisne, Liran Horev, Bénédicte Charmeteau-de Muylder, Jesús Á. Álvarez, Diana M. Arboleda, Lizet Pérez-Zapata, Estefanía Vásquez-Echeverri, Marcela Moncada-Vélez, Juan A. López, Yolanda Caicedo, Boaz Palterer, Pablo J. Patiño, Carlos J. Montoya, Matthieu Chaldebas, Peng Zhang, Tina Nguyen, Cindy S. Ma, Mohamed Jeljeli, Juan F. Alzate, Felipe Cabarcas, Taushif Khan, Darawan Rinchai, Jean-Luc Prétet, Bertrand Boisson, Generalized Verrucosis Japanese Consortium, Nico Marr, Ruba Ibrahim, Vered Molho-Pessach, Stéphanie Boisson-Dupuis, Dimitra Kiritsi, João T. Barata, Nils Landegren, Bénédicte Neven, Laurent Abel, Andrea Lisco, Vivien Béziat, Emmanuelle Jouanguy, Jacinta Bustamante, James P. Di Santo, Stuart G. Tangye, Luigi D. Notarangelo, Rémi Cheynier, Ken Natsuga, Andrés A. Arias, José Luis Franco, Klaus Warnatz, Jean-Laurent Casanova, Anne Puel

×

The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression
Ji Hye Jun, … , Steven S. Pullen, Anna Mae Diehl
Ji Hye Jun, … , Steven S. Pullen, Anna Mae Diehl
Published August 27, 2024
Citation Information: J Clin Invest. 2024;134(19):e180310. https://doi.org/10.1172/JCI180310.
View: Text | PDF

The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression

  • Text
  • PDF
Abstract

The burden of senescent hepatocytes correlates with the severity of metabolic dysfunction–associated steatotic liver disease (MASLD), but the mechanisms driving senescence and how it exacerbates MASLD are poorly understood. Hepatocytes experience lipotoxicity and become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine whether the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA-Seq analysis of liver samples from human and murine cohorts with MASLD confirmed that hepatocyte populations in MASLD livers were depleted of Smo+ cells and enriched with senescent cells. When fed a choline-deficient, amino acid–restricted high-fat diet (CDA-HFD) to induce MASLD, Smo– mice had lower antioxidant markers and developed worse DNA damage, senescence, steatohepatitis, and fibrosis than did Smo+ mice. Sera and hepatocyte-conditioned medium from Smo– mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo– hepatocytes with TP reduced senescence and lipotoxicity, whereas inhibiting TP in Smo+ hepatocytes had the opposite effect and exacerbated hepatocyte senescence, steatohepatitis, and fibrosis in CDA-HFD–fed mice. We conclude that inhibition of Hedgehog signaling in hepatocytes promoted MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.

Authors

Ji Hye Jun, Kuo Du, Rajesh Kumar Dutta, Raquel Maeso-Diaz, Seh Hoon Oh, Liuyang Wang, Guannan Gao, Ana Ferreira, Jon Hill, Steven S. Pullen, Anna Mae Diehl

×

Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing
Omid Sadeghi-Alavijeh, … , Adam P. Levine, Daniel P. Gale
Omid Sadeghi-Alavijeh, … , Adam P. Levine, Daniel P. Gale
Published August 27, 2024
Citation Information: J Clin Invest. 2024;134(19):e181467. https://doi.org/10.1172/JCI181467.
View: Text | PDF Clinical Research and Public Health

Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing

  • Text
  • PDF
Abstract

BACKGROUND Cystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.METHODS Using whole-genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.RESULTS In 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK Biobank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations, but suggested this category of variation contributes 3%–9% to the heritability of CyKD across European ancestries.CONCLUSION By providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counseling in the clinic.

Authors

Omid Sadeghi-Alavijeh, Melanie M.Y. Chan, Gabriel T. Doctor, Catalin D. Voinescu, Alexander Stuckey, Athanasios Kousathanas, Alexander T. Ho, Horia C. Stanescu, Detlef Bockenhauer, Richard N. Sandford, Adam P. Levine, Daniel P. Gale

×

Central regulation of feeding and body weight by ciliary GPR75
Yiao Jiang, … , Yu Xun, Zhao Zhang
Yiao Jiang, … , Yu Xun, Zhao Zhang
Published August 13, 2024
Citation Information: J Clin Invest. 2024;134(19):e182121. https://doi.org/10.1172/JCI182121.
View: Text | PDF

Central regulation of feeding and body weight by ciliary GPR75

  • Text
  • PDF
Abstract

Variants of the G protein–coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75-knockout (Gpr75–/–) mice. Gpr75–/– mice displayed reduced food intake under high-fat diet (HFD) feeding, and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag-tagged Gpr75-knockin (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants in individuals with a lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in leptin ob–mutant (Lepob-mutant) mice and adenylate cyclase 3–mutant (Adcy3-mutant) mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake.

Authors

Yiao Jiang, Yu Xun, Zhao Zhang

×
Retraction
Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells
Chia-Lin Chen, … , Joseph H. Jeong, Keigo Machida
Chia-Lin Chen, … , Joseph H. Jeong, Keigo Machida
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e186923. https://doi.org/10.1172/JCI186923.
View: Text | PDF | Amended Article

Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells

  • Text
  • PDF
Abstract

Authors

Chia-Lin Chen, Hidekazu Tsukamoto, Jian-Chang Liu, Claudine Kashiwabara, Douglas Feldman, Linda Sher, Steven Dooley, Samuel W. French, Lopa Mishra, Lydia Petrovic, Joseph H. Jeong, Keigo Machida

×
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts