Aqueous proteins help predict the response of patients with neovascular age-related macular degeneration to anti-VEGF therapy
Conclusion Aqueous biomarkers could help identify patients with nvAMD who may not require or benefit from long-term treatment with anti-VEGF therapy. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Xuan Cao, Jaron Castillo Sanchez, Aumreetam Dinabandhu, Chuanyu Guo, Tapan P. Patel, Zhiyong Yang, Ming-Wen Hu, Lijun Chen, Yuefan Wang, Danyal Malik, Kathleen Jee, Yassine J. Daoud, James T. Handa, Hui Zhang, Jiang Qian, Silvia Montaner, Akrit Sodhi Source Type: research

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice
Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5% to 10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal and...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Daniella Rastelli, Ariel Robinson, Valentina N. Lagomarsino, Lynley T. Matthews, Rafla Hassan, Kristina Perez, William Dan, Peter D. Yim, Madison Mixer, Aleksandra Prochera, Amy Shepherd, Liang Sun, Kathryn Hall, Sarah Ballou, Anthony Lembo, Judy Nee, Mee Source Type: research

β3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity
The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared with that of other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-Adrenergic receptor downregulation also occurs after high-fat diet feeding, concurrent with catecholamine res...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Joseph M. Valentine, Maryam Ahmadian, Omer Keinan, Mohammad Abu-Odeh, Peng Zhao, Xin Zhou, Mark P. Keller, Hui Gao, Ruth T. Yu, Christopher Liddle, Michael Downes, Jin Zhang, Aldons J. Lusis, Alan D. Attie, Ronald M. Evans, Mikael Rydén, Alan R. Saltiel Source Type: research

Concerns about the interpretation of subgroup analysis. Reply.
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Shilong Li, Pei Wang, Li Li Source Type: research

Concerns about the interpretation of subgroup analysis
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Arthur M. Albuquerque, Carolina B. Santolia, Ashish Verma Source Type: research

Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma
CONCLUSIONS These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.FUNDING NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGr Source Type: research

Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells
Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/β (TCRα/β) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Brinda Monian, Ang A. Tu, Bert Ruiter, Duncan M. Morgan, Patrick M. Petrossian, Neal P. Smith, Todd M. Gierahn, Julia H. Ginder, Wayne G. Shreffler, J. Christopher Love Source Type: research

Using autoantibody signatures to define cancer risk in dermatomyositis
Dermatomyositis is an idiopathic inflammatory myopathy with a highly heterogeneous disease course. Although there is a known increase in cancer risk surrounding the time of dermatomyositis diagnosis, the mechanisms driving this increased risk are not well understood. Further, there are no current standardized cancer screening guidelines for dermatomyositis patients. In this issue of the JCI, Fiorentino, Mecoli, et al. discovered additional autoantibodies in patients with dermatomyositis and anti–TIF1-γ autoantibodies, a known risk factor for malignancy. They observed a decreased cancer risk with an increasing n...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Jessica L. Turnier, J. Michelle Kahlenberg Source Type: research

Interpreting success or failure of peanut oral immunotherapy
Peanut oral immunotherapy (OIT) was recently approved by the US FDA. However, not all patients respond to OIT, and there is a high likelihood of regaining sensitization to peanuts after cessation of treatment. It is important, therefore, to identify biomarkers that impact and predict OIT outcomes. In this issue of the JCI, Monian, Tu, and colleagues describe distinct subsets of peanut-reactive CD4+ Th cell phenotypes and gene signatures with relevance to OIT outcomes using single-cell RNA-Seq and paired T cell receptor (TCR) α/β sequencing. The insights obtained will inform the development of therapeutics that t...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Shijie Cao, Cathryn R. Nagler Source Type: research

Immune responses to CCAR1 and other dermatomyositis autoantigens are associated with attenuated cancer emergence
BACKGROUND The temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-γ (TIF1-γ). Nevertheless, many patients with anti–TIF1-γ antibodies never develop cancer. We investigated whether additional autoantibodies are found in anti–TIF1-γ–positive patients without cancer.METHODS Using a proteomic approach, we defined 10 previously undescribed autoantibody specificities in 5 index anti–TIF1-γ–positive DM patients without cancer. These were subsequently examined...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: David F. Fiorentino, Christopher A. Mecoli, Matthew C. Rosen, Lorinda S. Chung, Lisa Christopher-Stine, Antony Rosen, Livia Casciola-Rosen Source Type: research

Positive and negative selection shape the human naive B cell repertoire
Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II–restricted sel...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Jeff W. Chen, Jean-Nicolas Schickel, Nikolaos Tsakiris, Joel Sng, Florent Arbogast, Delphine Bouis, Daniele Parisi, Ruchi Gera, Joshua M. Boeckers, Fabien R. Delmotte, Margaret Veselits, Catharina Schuetz, Eva-Maria Jacobsen, Carsten Posovszky, Ansgar S. Source Type: research

The role of itaconate in host defense and inflammation
Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because ...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Christian G. Peace, Luke A.J. O’Neill Source Type: research

Sensing of RNA stress by mTORC1 drives autoinflammation
Loss-of-function mutations in SKIV2L underlie trichohepatoenteric syndrome (THES2), a rare inborn error of immunity characterized by diarrhea, skin lesions, brittle hair, and immunodeficiency. SKIV2L is part of a multiprotein complex required for exosome-mediated RNA surveillance through RNA decay. In this issue of the JCI, Yang et al. delineate a mechanism underlying autoinflammatory skin disease in Skiv2l-deficient mice. Thus, a lack of SKIV2L activates mTORC1 signaling in keratinocytes and T cells, impeding skin barrier integrity and T cell homeostasis. Interestingly, treatment with the mTOR inhibitor rapamycin improves...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Min Ae Lee-Kirsch Source Type: research

SARS-CoV-2–specific memory B cells can persist in the elderly who have lost detectable neutralizing antibodies
Memory B cells (MBCs) can provide a recall response able to supplement waning antibodies (Abs) with an affinity-matured response better able to neutralize variant viruses. We studied a cohort of elderly care home residents and younger staff (median age of 87 years and 56 years, respectively), who had survived COVID-19 outbreaks with only mild or asymptomatic infection. The cohort was selected because of its high proportion of individuals who had lost neutralizing antibodies (nAbs), thus allowing us to specifically investigate the reserve immunity from SARS-CoV-2–specific MBCs in this setting. Class-switched spike and...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Anna Jeffery-Smith, Alice R. Burton, Sabela Lens, Chloe Rees-Spear, Jessica Davies, Monika Patel, Robin Gopal, Luke Muir, Felicity Aiano, Katie J. Doores, J. Yimmy Chow, Shamez N. Ladhani, Maria Zambon, Laura E. McCoy, Mala K. Maini Source Type: research

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies
Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be ...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: George Robinson, Ines Pineda-Torra, Coziana Ciurtin, Elizabeth C. Jury Source Type: research

If these myocytes could talk, they would speak the language of metabolites
Cardiac wound healing following ischemic injury requires a well-described spatiotemporal progression of events involving multiple cell types and cell-cell interactions. While cellular crosstalk among immune cell, endothelial cell, and fibroblast populations is known to regulate these progressive phases, the role of cardiac myocytes in controlling the wound-healing program is unclear. In this issue of the JCI, Li et al. describe a mechanism of cellular crosstalk between cardiac myocytes and fibroblasts that disrupts nonmyocyte cell function and worsens wound healing outcomes following myocardial infarction (MI). This tour d...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Logan R.J. Bailey, Jennifer Davis Source Type: research

Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynur...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Frank L. van de Veerdonk, Giorgia Renga, Marilena Pariano, Marina M. Bellet, Giuseppe Servillo, Francesca Fallarino, Antonella De Luca, Rossana G. Iannitti, Danilo Piobbico, Marco Gargaro, Giorgia Manni, Fiorella D’Onofrio, Claudia Stincardini, Luigi Sf Source Type: research

Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease
Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA–mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a ...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Kun Yang, Jie Han, Mayumi Asada, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, Tracey Wright, Christian A. Wysocki, M. Teresa de la Morena, Luis A. Garza, Nan Yan Source Type: research

Fighting in a wasteland: deleterious metabolites and antitumor immunity
As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture. The TME is not a metabolic vacuum, only consuming essential nutrients and never producing by-products. Rather, the by-products of depleted nutrients, “toxic” metabolites in the...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: McLane J. Watson, Greg M. Delgoffe Source Type: research

RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis
In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its recep...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H.-F. Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Ali Source Type: research

B cell receptor isotypes differentially associate with cell signaling, kinetics, and outcome in chronic lymphocytic leukemia
In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events. Since both IgM and IgD carry the same antigen-binding domains, the divergent actions of the receptors are attributed to differences in immunoglobulin (Ig) structure or the outcome of signal transduction. We ...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Andrea N. Mazzarello, Eva Gentner-Göbel, Marcus Dühren-von Minden, Tatyana N. Tarasenko, Antonella Nicolò, Gerardo Ferrer, Stefano Vergani, Yun Liu, Davide Bagnara, Kanti R. Rai, Jan A. Burger, Peter J. McGuire, Palash C. Maity, Hassan Jumaa, Nicholas Source Type: research

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Yuki Sato, Akiko Oguchi, Yuji Fukushima, Kyoko Masuda, Naoya Toriu, Keisuke Taniguchi, Takahisa Yoshikawa, Xiaotong Cui, Makiko Kondo, Takeshi Hosoi, Shota Komidori, Yoko Shimizu, Harumi Fujita, Li Jiang, Yingyi Kong, Takashi Yamanashi, Jun Seita, Takuya Source Type: research

Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1
T cell polyfunctionality is a hallmark of protective immunity against pathogens and cancer, yet the molecular mechanism governing it remains mostly elusive. We found that canonical Wnt agonists inhibited human memory CD8+ T cell differentiation while simultaneously promoting the generation of highly polyfunctional cells. Downstream effects of Wnt activation persisted after removal of the drug, and T cells remained polyfunctional following subsequent cell division, indicating the effect is epigenetically regulated. Wnt activation induced a gene expression pattern that is enriched with stem cell–specific gene signature...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Bo-Yi Sung, Yi-Hsin Lin, Qiongman Kong, Pali D. Shah, Joan Glick Bieler, Scott Palmer, Kent J. Weinhold, Hong-Ru Chang, Hailiang Huang, Robin K. Avery, Jonathan Schneck, Yen-Ling Chiu Source Type: research

Alzheimer’s disease and progressive supranuclear palsy share similar transcriptomic changes in distinct brain regions
Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer’s disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from 231 temporal cortex and 224 cerebellum samples from patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identified a striking correlation in the directionality and magnitude of gene expression changes between these 2 neurodegenerative proteinopathies. Further, the transcriptomic changes in AD and PSP brains ware highly conserved between the tempor...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Xue Wang, Mariet Allen, Özkan İş, Joseph S. Reddy, Frederick Q. Tutor-New, Monica Castanedes Casey, Minerva M. Carrasquillo, Stephanie R. Oatman, Yuhao Min, Yan W. Asmann, Cory Funk, Thuy Nguyen, Charlotte C.G. Ho, Kimberly G. Malphrus, Nicholas T. Sey Source Type: research

Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair
Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis...
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Shen Li, Tomohiro Yokota, Ping Wang, Johanna ten Hoeve, Feiyang Ma, Thuc M. Le, Evan R. Abt, Yonggang Zhou, Rimao Wu, Maxine Nanthavongdouangsy, Abraham Rodriguez, Yijie Wang, Yen-Ju Lin, Hayato Muranaka, Mark Sharpley, Demetrios T. Braddock, Vicky E. Mac Source Type: research

In vivo imaging of the human eye using a 2-photon-excited fluorescence scanning laser ophthalmoscope
Conclusion Our work establishes a TPE instrument and measurement method for noninvasive metabolic assessment of the human retina. This approach opens the possibility for monitoring eye diseases in the earliest stages before structural damage to the retina occurs.Funding NIH, Research to Prevent Blindness, Foundation for Polish Science, European Regional Development Fund, Polish National Agency for Academic Exchange, and Polish Ministry of Science and Higher Education. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 19, 2022 Category: Biomedical Science Authors: Jakub Boguslawski, Grazyna Palczewska, Slawomir Tomczewski, Jadwiga Milkiewicz, Piotr Kasprzycki, Dorota Stachowiak, Katarzyna Komar, Marcin J. Marzejon, Bartosz L. Sikorski, Arkadiusz Hudzikowski, Aleksander Głuszek, Zbigniew Łaszczych, Karol Karnowski Source Type: research

Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Hui-Hua Li, Monte S. Willis, Pamela Lockyer, Nathaniel Miller, Holly McDonough, David J. Glass, Cam Patterson Source Type: research

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Lauren Herl Martens, Jiasheng Zhang, Sami J. Barmada, Ping Zhou, Sherry Kamiya, Binggui Sun, Sang-Won Min, Li Gan, Steven Finkbeiner, Eric J. Huang, Robert V. Farese Jr Source Type: research

15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation
Altered redox biology challenges all cells, with compensatory responses often determining a cell’s fate. When 15 lipoxygenase 1 (15LO1), a lipid-peroxidizing enzyme abundant in asthmatic human airway epithelial cells (HAECs), binds phosphatidylethanolamine-binding protein 1 (PEBP1), hydroperoxy-phospholipids, which drive ferroptotic cell death, are generated. Peroxidases, including glutathione peroxidase 4 (GPX4), metabolize hydroperoxy-phospholipids to hydroxy derivatives to prevent ferroptotic death, but consume reduced glutathione (GSH). The cystine transporter SLC7A11 critically restores/maintains intracellular G...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Tadao Nagasaki, Alexander J. Schuyler, Jinming Zhao, Svetlana N. Samovich, Kazuhiro Yamada, Yanhan Deng, Scott P. Ginebaugh, Stephanie A. Christenson, Prescott G. Woodruff, John V. Fahy, John B. Trudeau, Detcho Stoyanovsky, Anuradha Ray, Yulia Y. Tyurina, Source Type: research

Addressing dyslipidemic risk beyond LDL-cholesterol
Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced choles...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Alan R. Tall, David G. Thomas, Ainara G. Gonzalez-Cabodevilla, Ira J. Goldberg Source Type: research

Long-term corneal recovery by simultaneous delivery of hPSC-derived corneal endothelial precursors and nicotinamide
Human pluripotent stem cells (hPSCs) hold great promise for the treatment of various human diseases. However, their therapeutic benefits and mechanisms for treating corneal endothelial dysfunction remain undefined. Here, we developed a therapeutic regimen consisting of the combination of hPSC-derived corneal endothelial precursors (CEPs) with nicotinamide (NAM) for effective treatment of corneal endothelial dysfunction. In rabbit and nonhuman primate models, intracameral injection of CEPs and NAM achieved long-term recovery of corneal clarity and thickness, similar with the therapeutic outcome of cultured human corneal end...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Zongyi Li, Haoyun Duan, Yanni Jia, Can Zhao, Wenjing Li, Xin Wang, Yajie Gong, Chunxiao Dong, Bochao Ma, Shengqian Dou, Bin Zhang, Dongfang Li, Yihai Cao, Lixin Xie, Qingjun Zhou, Weiyun Shi Source Type: research

RTS,S: the first malaria vaccine
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Fidel Zavala Source Type: research

Indoxyl sulfate in uremia: an old idea with updated concepts
Patients with end-stage kidney disease (ESKD) have increased vascular disease. While protein-bound molecules that escape hemodialysis may contribute to uremic toxicity, specific contributing toxins remain ambiguous. In this issue of the JCI, Arinze et al. explore the role of tryptophan metabolites in chronic kidney disease–associated (CKD-associated) peripheral arterial disease. The authors used mouse and zebrafish models to show that circulating indoxyl sulfate (IS) blocked endothelial Wnt signaling, which impaired angiogenesis. Plasma levels of IS and other tryptophan metabolites correlated with adverse peripheral ...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Anders H. Berg, Sanjeev Kumar, S. Ananth Karumanchi Source Type: research

The role of 15 lipoxygenase 1 in asthma comes into focus
IL-4– and IL-13–driven epithelial cell expression of 15 lipoxygenase 1 (15LO1) is a consistent feature of eosinophil-dominated asthma known as type 2–high (T2-high) asthma. The abundant soluble products of arachidonic acid (AA) metabolized by 15LO1 reflect a high level of enzymatic activity in asthma and chronic rhinosinusitis. However, the precise role of 15LO1 and its products in disease pathogenesis remains enigmatic. In this issue of the JCI, Nagasaki and colleagues demonstrate a role for 15LO1 in controlling redox balance and epithelial homeostasis in T2-high asthma by metabolizing AA that is esterif...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Joshua A. Boyce Source Type: research

Moving toward genome-editing therapies for cardiovascular diseases
The rapid invention of genome-editing technologies over the past decade, which has already been transformative for biomedical research, has raised the tantalizing prospect of an entirely new therapeutic modality. Whereas the treatment of chronic cardiovascular diseases has heretofore entailed the use of chronic therapies that typically must be taken repeatedly and frequently for the remainder of the lifetime, genome editing will enable the development of “one-and-done” therapies with durable effects. This Review summarizes the variety of available genome-editing approaches, including nuclease editing, base edit...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Kiran Musunuru Source Type: research

Clinical development of metabolic inhibitors for oncology
Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each a...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Kathryn M. Lemberg, Sadakatali S. Gori, Takashi Tsukamoto, Rana Rais, Barbara S. Slusher Source Type: research

Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease
Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remains elusive. Here, we show that the dietary tryptophan-derived uremic solutes including indoxyl sulfate (IS) and kynurenine (Kyn) at concentrations corresponding to those in CKD patients suppress β-catenin in several cell types, including microvascular endothelial cells (ECs), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated β-ca...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Nkiruka V. Arinze, Wenqing Yin, Saran Lotfollahzadeh, Marc Arthur Napoleon, Sean Richards, Joshua A. Walker, Mostafa Belghasem, Jonathan D. Ravid, Mohamed Hassan Kamel, Stephen A. Whelan, Norman Lee, Jeffrey J. Siracuse, Stephan Anderson, Alik Farber, Dav Source Type: research

A molecular target of vascular calcification in chronic kidney disease
Vascular calcification (VC) causes cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), particularly those with end-stage kidney disease (ESKD) on maintenance dialysis treatment. Although many mechanisms have been proposed, their detailed effects remain incompletely understood. In this issue of the JCI, Li et al. examined the molecular mechanism of the protective role of SIRT6 in VC in patients with CKD. Using in vitro and animal models of CKD, the authors demonstrated that SIRT6 prevents VC by suppressing the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Mechanis...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Mohamed G. Atta Source Type: research

Response to Kunos et al. and Lotersztajn and Mallat
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton Source Type: research

Does CB-1 in hepatic stellate cells contribute to liver fibrosis?
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Sophie Lotersztajn, Ariane Mallat Source Type: research

Do endocannabinoids acting via hepatic CB-1 contribute to NAFLD and hepatic insulin resistance?
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: George Kunos, Tony Jourdan, Joseph Tam Source Type: research

SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease
Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of the Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD). However, the exact role and molecular mechanism of SIRT6 in VC in patients with CKD remain unclear. Here, we demonstrated that SIRT6 was markedly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of patients with CKD with VC. SIRT6-transgenic (SIRT6-Tg) mi...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Wenxin Li, Weijing Feng, Xiaoyan Su, Dongling Luo, Zhibing Li, Yongqiao Zhou, Yongjun Zhu, Mengbi Zhang, Jie Chen, Baohua Liu, Hui Huang Source Type: research

Early peanut introduction wins over the HLA-DQA1*01:02 allele in the interplay between environment and genetics
The rising incidence of food allergy in children underscores the importance of environmental exposures; however, genetic factors play a major role. How the environment and genetics interact to cause food allergy remains unclear. The landmark Learning Early About Peanut Allergy (LEAP) clinical trial established that early peanut introduction protects high-risk infants, consistent with the tolerizing effects of gut exposure. In this issue of the JCI, Kanchan et al. leveraged the LEAP trial data to examine molecular genetic mechanisms of early sensitization. A previously identified HLA risk allele for peanut allergy (DQA1*01:...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Monali Manohar, Kari Christine Nadeau, Maya Kasowski Source Type: research

HLA alleles and sustained peanut consumption promote IgG4 responses in subjects protected from peanut allergy
We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded Ig...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Kanika Kanchan, Stepan Grinek, Henry T. Bahnson, Ingo Ruczinski, Gautam Shankar, David Larson, George Du Toit, Kathleen C. Barnes, Hugh A. Sampson, Mayte Suarez-Farinas, Gideon Lack, Gerald T. Nepom, Karen Cerosaletti, Rasika A. Mathias Source Type: research

Targeting memory T cell metabolism to improve immunity
Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or ...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Mauro Corrado, Erika L. Pearce Source Type: research

Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B
Efficient sarcolemmal repair is required for muscle cell survival, with deficits in this process leading to muscle degeneration. Lack of the sarcolemmal protein dysferlin impairs sarcolemmal repair by reducing secretion of the enzyme acid sphingomyelinase (ASM), and causes limb girdle muscular dystrophy 2B (LGMD2B). The large size of the dysferlin gene poses a challenge for LGMD2B gene therapy efforts aimed at restoring dysferlin expression in skeletal muscle fibers. Here, we present an alternative gene therapy approach targeting reduced ASM secretion, the consequence of dysferlin deficit. We showed that the bulk endocytic...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Daniel C. Bittel, Sen Chandra Sreetama, Goutam Chandra, Robin Ziegler, Kanneboyina Nagaraju, Jack H. Van der Meulen, Jyoti K. Jaiswal Source Type: research

The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses
T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murin...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Samantha A. Chalmers, Rajalakshmy Ayilam Ramachandran, Sayra J. Garcia, Evan Der, Leal Herlitz, Jeanette Ampudia, Dalena Chu, Nicole Jordan, Ting Zhang, Ioannis Parodis, Iva Gunnarsson, Huihua Ding, Nan Shen, Michelle Petri, Chi Chiu Mok, Ramesh Saxena, K Source Type: research

Anti-HIV antibody development up to 1 year after antiretroviral therapy initiation in acute HIV infection
We report here that Env-specific plasma antibody (Ab) levels and Ab-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with Ab levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific Ab levels and ADCC activity on ART than did those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses that were detectable 1 year after ART initiation, even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center (GC...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Julie L. Mitchell, Justin Pollara, Kenneth Dietze, R. Whitney Edwards, Junsuke Nohara, Kombo F. N’guessan, Michelle Zemil, Supranee Buranapraditkun, Hiroshi Takata, Yifan Li, Roshell Muir, Eugene Kroon, Suteeraporn Pinyakorn, Shalini Jha, Sopark Manasna Source Type: research

Kidney VISTA prevents IFN-γ/IL-9 axis–mediated tubulointerstitial fibrosis after acute glomerular injury
Severe glomerular injury ultimately leads to tubulointerstitial fibrosis that determines patient outcome, but the immunological molecules connecting these processes remain undetermined. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir–/–) kidney suffered more damage than those in WT kidneys. When interstitial immune ...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Min-Gang Kim, Donghwan Yun, Chae Lin Kang, Minki Hong, Juhyeon Hwang, Kyung Chul Moon, Chang Wook Jeong, Cheol Kwak, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Dong-Sup Lee, Seung Seok Han Source Type: research

Gasdermin D inhibition confers antineutrophil-mediated cardioprotection in acute myocardial infarction
Acute myocardial infarction (AMI) induces blood leukocytosis, which correlates inversely with patient survival. The molecular mechanisms leading to leukocytosis in the infarcted heart remain poorly understood. Using an AMI mouse model, we identified gasdermin D (GSDMD) in activated leukocytes early in AMI. We demonstrated that GSDMD is required for enhanced early mobilization of neutrophils to the infarcted heart. Loss of GSDMD resulted in attenuated IL-1β release from neutrophils and subsequent decreased neutrophils and monocytes in the infarcted heart. Knockout of GSDMD in mice significantly reduced infarct size, im...
Source: Journal of Clinical Investigation - January 10, 2022 Category: Biomedical Science Authors: Kai Jiang, Zizhuo Tu, Kun Chen, Yue Xu, Feng Chen, Sheng Xu, Tingting Shi, Jie Qian, Lan Shen, John Hwa, Dandan Wang, Yaozu Xiang Source Type: research