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Review

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Through the layers: how macrophages drive atherosclerosis across the vessel wall
Leah I. Susser, Katey J. Rayner
Leah I. Susser, Katey J. Rayner
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e157011. https://doi.org/10.1172/JCI157011.
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Through the layers: how macrophages drive atherosclerosis across the vessel wall

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Abstract

Cardiovascular disease (CVD) accounts for almost half of all deaths related to non-communicable disease worldwide, making it the single largest global cause of mortality. Although the risk factors for coronary artery disease — the most common cause of CVD — are well known and include hypertension, high cholesterol, age, and genetics, CVDs are now recognized as chronic inflammatory conditions. Arterial blockages, known as atherosclerosis, develop due to excess cholesterol accumulating within the arterial wall, creating a perpetually inflammatory state. The normally quiescent intimal layer of the vessel wall becomes laden with inflammatory cells, which alters the surrounding endothelial, smooth muscle, and extracellular matrix components to propagate disease. Macrophages, which can be either tissue resident or monocyte derived, are a key player in atherosclerotic disease progression and regression, and the understanding of their functions and origins continues to evolve with the use of deep phenotyping methodologies. This Review outlines how macrophages interact with each layer of the developing atherosclerotic plaque and discusses new concepts that are challenging our previous views on how macrophages function and our evolving understanding of the contribution of macrophages to disease.

Authors

Leah I. Susser, Katey J. Rayner

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CRISPR/Cas therapeutic strategies for autosomal dominant disorders
Salvatore Marco Caruso, … , Bruna Lopes da Costa, Stephen H. Tsang
Salvatore Marco Caruso, … , Bruna Lopes da Costa, Stephen H. Tsang
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e158287. https://doi.org/10.1172/JCI158287.
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CRISPR/Cas therapeutic strategies for autosomal dominant disorders

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Abstract

Autosomal dominant disorders present unique challenges, as therapeutics must often distinguish between healthy and diseased alleles while maintaining high efficiency, specificity, and safety. For this task, CRISPR/Cas remains particularly promising. Various CRISPR/Cas systems, like homology-directed repair, base editors, and prime editors, have been demonstrated to selectively edit mutant alleles either by incorporating these mutations into sgRNA sequences (near the protospacer-adjacent motif [“near the PAM”]) or by targeting a novel PAM generated by the mutation (“in the PAM”). However, these probability-based designs are not always assured, necessitating generalized, mutation-agnostic strategies like ablate-and-replace and single-nucleotide polymorphism editing. Here, we detail recent advancements in CRISPR therapeutics to treat a wide range of autosomal dominant disorders and discuss how they are altering the landscape for future therapies.

Authors

Salvatore Marco Caruso, Peter M.J. Quinn, Bruna Lopes da Costa, Stephen H. Tsang

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Messenger RNA vaccines for cancer immunotherapy: progress promotes promise
Amanda L. Huff, … , Elizabeth M. Jaffee, Neeha Zaidi
Amanda L. Huff, … , Elizabeth M. Jaffee, Neeha Zaidi
Published March 15, 2022
Citation Information: J Clin Invest. 2022;132(6):e156211. https://doi.org/10.1172/JCI156211.
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Messenger RNA vaccines for cancer immunotherapy: progress promotes promise

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Abstract

The COVID-19 pandemic has elevated mRNA vaccines to global recognition due to their unprecedented success rate in protecting against a deadly virus. This international success is underscored by the remarkable versatility, favorable immunogenicity, and overall safety of the mRNA platform in diverse populations. Although mRNA vaccines have been studied in preclinical models and patients with cancer for almost three decades, development has been slow. The recent technological advances responsible for the COVID-19 vaccines have potential implications for successfully adapting this vaccine platform for cancer therapeutics. Here we discuss the lessons learned along with the chemical, biologic, and immunologic adaptations needed to optimize mRNA technology to successfully treat cancers.

Authors

Amanda L. Huff, Elizabeth M. Jaffee, Neeha Zaidi

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The changing role of natural killer cells in cancer metastasis
Isaac S. Chan, Andrew J. Ewald
Isaac S. Chan, Andrew J. Ewald
Published March 15, 2022
Citation Information: J Clin Invest. 2022;132(6):e143762. https://doi.org/10.1172/JCI143762.
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The changing role of natural killer cells in cancer metastasis

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Abstract

Natural killer (NK) cells are innate immune cells that are critical to the body’s antitumor and antimetastatic defense. As such, novel therapies are being developed to utilize NK cells as part of a next generation of immunotherapies to treat patients with metastatic disease. Therefore, it is essential for us to examine how metastatic cancer cells and NK cells interact with each other throughout the metastatic cascade. In this Review, we highlight the recent body of work that has begun to answer these questions. We explore how the unique biology of cancer cells at each stage of metastasis alters fundamental NK cell biology, including how cancer cells can evade immunosurveillance and co-opt NK cells into cells that promote metastasis. We also discuss the translational potential of this knowledge.

Authors

Isaac S. Chan, Andrew J. Ewald

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Fungal microbiome in inflammatory bowel disease: a critical assessment
David M. Underhill, Jonathan Braun
David M. Underhill, Jonathan Braun
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(5):e155786. https://doi.org/10.1172/JCI155786.
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Fungal microbiome in inflammatory bowel disease: a critical assessment

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Abstract

The gut microbiome is at the center of inflammatory bowel disease (IBD) pathogenesis and disease activity. While this has mainly been studied in the context of the bacterial microbiome, recent advances have provided tools for the study of host genetics and metagenomics of host-fungal interaction. Through these tools, strong evidence has emerged linking certain fungal taxa, such as Candida and Malassezia, with cellular and molecular pathways of IBD disease biology. Mouse models and human fecal microbial transplant also suggest that some disease-participatory bacteria and fungi may act not via the host directly, but via their fungal-bacterial ecologic interactions. We hope that these insights, and the study design and multi-omics strategies used to develop them, will facilitate the inclusion of the fungal community in basic and translational IBD research.

Authors

David M. Underhill, Jonathan Braun

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β-Catenin signaling in hepatocellular carcinoma
Chuanrui Xu, … , Diego F. Calvisi, Xin Chen
Chuanrui Xu, … , Diego F. Calvisi, Xin Chen
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e154515. https://doi.org/10.1172/JCI154515.
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β-Catenin signaling in hepatocellular carcinoma

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Abstract

Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.

Authors

Chuanrui Xu, Zhong Xu, Yi Zhang, Matthias Evert, Diego F. Calvisi, Xin Chen

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Colorectal cancer: the facts in the case of the microbiota
Slater L. Clay, … , Diogo Fonseca-Pereira, Wendy S. Garrett
Slater L. Clay, … , Diogo Fonseca-Pereira, Wendy S. Garrett
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e155101. https://doi.org/10.1172/JCI155101.
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Colorectal cancer: the facts in the case of the microbiota

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Abstract

The importance of the microbiota in the development of colorectal cancer (CRC) is increasingly evident, but identifying specific microbial features that influence CRC initiation and progression remains a central task for investigators. Studies determining the microbial mechanisms that directly contribute to CRC development or progression are revealing bacterial factors such as toxins that contribute to colorectal carcinogenesis. However, even when investigators have identified bacteria that express toxins, questions remain about the host determinants of a toxin’s cancer-potentiating effects. For other cancer-correlating bacteria that lack toxins, the challenge is to define cancer-relevant virulence factors. Herein, we evaluate three CRC-correlating bacteria, colibactin-producing Escherichia coli, enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum, for their virulence features relevant to CRC. We also consider the beneficial bioactivity of gut microbes by highlighting a microbial metabolite that may enhance CRC antitumor immunity. In doing so, we aim to elucidate unique and shared mechanisms underlying the microbiota’s contributions to CRC and to accelerate investigation from target validation to CRC therapeutic discovery.

Authors

Slater L. Clay, Diogo Fonseca-Pereira, Wendy S. Garrett

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Cellular senescence and the skeleton: pathophysiology and therapeutic implications
Sundeep Khosla, … , Joshua N. Farr, David G. Monroe
Sundeep Khosla, … , Joshua N. Farr, David G. Monroe
Published February 1, 2022
Citation Information: J Clin Invest. 2022;132(3):e154888. https://doi.org/10.1172/JCI154888.
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Cellular senescence and the skeleton: pathophysiology and therapeutic implications

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Abstract

Cellular senescence is a fundamental aging mechanism that is currently the focus of considerable interest as a pathway that could be targeted to ameliorate aging across multiple tissues, including the skeleton. There is now substantial evidence that senescent cells accumulate in the bone microenvironment with aging and that targeting these cells prevents age-related bone loss, at least in mice. Cellular senescence also plays important roles in mediating the skeletal fragility associated with diabetes mellitus, radiation, and chemotherapy. As such, there are ongoing efforts to develop “senolytic” drugs that kill senescent cells by targeting key survival mechanisms in these cells without affecting normal cells. Because senescent cells accumulate across tissues with aging, senolytics offer the attractive possibility of treating multiple age-related comorbidities simultaneously.

Authors

Sundeep Khosla, Joshua N. Farr, David G. Monroe

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Health inequity drives disease biology to create disparities in prostate cancer outcomes
William G. Nelson, … , Tamara L. Lotan, Angelo M. De Marzo
William G. Nelson, … , Tamara L. Lotan, Angelo M. De Marzo
Published February 1, 2022
Citation Information: J Clin Invest. 2022;132(3):e155031. https://doi.org/10.1172/JCI155031.
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Health inequity drives disease biology to create disparities in prostate cancer outcomes

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Abstract

Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis. Studies of inherited susceptibility highlight the contributions of genes involved in prostate cell and tissue repair (BRCA1/2, ATM) and regeneration (HOXB13 and MYC). Social determinants of health appear to accentuate these genetic influences by fueling prostate inflammation and associated cell and genome damage. Molecular characterization of the prostate cancers that arise in Black versus White men further implicates this inflammatory microenvironment in disease behavior. Yet, when Black and White men with similar grade and stage of prostate cancer are treated equally, they exhibit equivalent outcomes. The central role of prostate inflammation in prostate cancer development and progression augments the impact of the social determinants of health on disease pathogenesis. And, when coupled with poorer access to high-quality treatment, these inequities result in a disparate burden of prostate cancer on African American men.

Authors

William G. Nelson, Otis W. Brawley, William B. Isaacs, Elizabeth A. Platz, Srinivasan Yegnasubramanian, Karen S. Sfanos, Tamara L. Lotan, Angelo M. De Marzo

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Circadian rhythms and renal pathophysiology
Rajesh Mohandas, … , Yogesh Scindia, Michelle L. Gumz
Rajesh Mohandas, … , Yogesh Scindia, Michelle L. Gumz
Published February 1, 2022
Citation Information: J Clin Invest. 2022;132(3):e148277. https://doi.org/10.1172/JCI148277.
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Circadian rhythms and renal pathophysiology

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Abstract

The reality of life in modern times is that our internal circadian rhythms are often out of alignment with the light/dark cycle of the external environment. This is known as circadian disruption, and a wealth of epidemiological evidence shows that it is associated with an increased risk for cardiovascular disease. Cardiovascular disease remains the top cause of death in the United States, and kidney disease in particular is a tremendous public health burden that contributes to cardiovascular deaths. There is an urgent need for new treatments for kidney disease; circadian rhythm–based therapies may be of potential benefit. The goal of this Review is to summarize the existing data that demonstrate a connection between circadian rhythm disruption and renal impairment in humans. Specifically, we will focus on chronic kidney disease, lupus nephritis, hypertension, and aging. Importantly, the relationship between circadian dysfunction and pathophysiology is thought to be bidirectional. Here we discuss the gaps in our knowledge of the mechanisms underlying circadian dysfunction in diseases of the kidney. Finally, we provide a brief overview of potential circadian rhythm–based interventions that could provide benefit in renal disease.

Authors

Rajesh Mohandas, Lauren G. Douma, Yogesh Scindia, Michelle L. Gumz

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