tbuckley/cabot-search huggingface dataset:
Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota–gut–brain axis
Authors: María R. Aburto, John F. Cryan
Journal: Nature Reviews Gastroenterology & Hepatology (2024)

Crosstalk between gut and brain has long been appreciated in health and disease, and the gut microbiota is a key player in communication between these two distant organs. Yet, the mechanisms through which the microbiota influences development and function of the gut–brain axis remain largely unknown. Barriers present in the gut and brain are specialized cellular interfaces that maintain strict homeostasis of different compartments across this axis. These barriers include the gut epithelial barrier, the blood–brain barrier and the blood–cerebrospinal fluid barrier. Barriers are ideally positioned to receive and communicate gut microbial signals constituting a gateway for gut–microbiota–brain communication. In this Review, we focus on how modulation of these barriers by the gut microbiota can constitute an important channel of communication across the gut–brain axis. Moreover, barrier malfunction upon alterations in gut microbial composition could form the basis of various conditions, including often comorbid neurological and gastrointestinal disorders. Thus, we should focus on unravelling the molecular and cellular basis of this communication and move from simplistic framing as 'leaky gut'. A mechanistic understanding of gut microbiota modulation of barriers, especially during critical windows of development, could be key to understanding the aetiology of gastrointestinal and neurological disorders. The gut microbiota is an important modulator of the gut–brain axis. This Review provides an overview of barrier function across this axis and examines the role of the gut microbiota in communication across and between these specialized gastrointestinal and brain barriers in health and disease.
Targeting de novo lipogenesis to mitigate kidney disease
Authors: Haikuo Li, Benjamin D Humphreys
Journal: Journal of Clinical Investigation (2024)

Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While dysregulated lipid metabolism is one hallmark of CKD, the pathogenesis of cellular lipid accumulation remains unclear. In this issue of the JCI, Mukhi et al. Identify acyl-CoA synthetase short-chain family 2 (ACSS2) as a disease risk gene and demonstrate a role for ACSS2 in de novo lipogenesis (DNL). Notably, genetic or pharmacological inhibition of DNL protected against kidney disease progression in mice. These findings warrant evaluation of DNL inhibition with respect to efficacy and safety in people with CKD.
NKT cells in the antitumor response: the β version?
Authors: Mitchell Kronenberg, Isaac Engel
Journal: Journal of Clinical Investigation (2024)

NKT cells recognize glycolipids presented by CD1d-expressing antigen-presenting cells (APCs) and include type I NKT cells with antitumor function and type II NKT cells, which have been reported to suppress the antitumor response. Some type II NKT cells recognize sulfatide, a glycosphingolipid with a sulfate modification of the sugar. Type I NKT cells recognize different glycosphingolipids. In this issue of the JCI, Nishio and colleagues showed that APCs could process sulfatide antigens, analogous to protein processing for peptide-reactive T cells. Antigen processing in lysosomes removed sulfate to generate a glycosphingolipid that stimulated type I NKT cells and thereby turned an antigen with no antitumor activity into one that not only stimulated type I NKT cells but also stimulated antitumor responses. These findings may extend to the development of glycolipid antigens that could stimulate anticancer responses via antigen processing by APCs.
Left Atrial Imaging Prior to Cardioversion
Authors: Benjamin J.W. Chow, Matthew Cheung, Graeme Prosperi-Porta, Anahita Tavoosi, Pouya Motazedian, Emel Celiker Guler, Yeung Yam, Ian Burwash, Carole Dennie, Gary R. Small, Mehrdad Golian
Journal: JACC. Cardiovascular imaging (2024)
Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression
Authors: Lan Bai, Weiyi Qu, Xu Cheng, Hailong Yang, Yong-Ping Huang, Zhenya Wang, Cuijuan Han, Rui-Feng Tian, Fengjiao Hu, Ling Yang, Song Tian, Han Tian, Zhiwei Cai, Juan Wan, Jingwei Jiang, Jiajun Fu, Junjie Zhou, Yufeng Hu, Tengfei Ma, Xin Zhang, Yan-Xiao Ji, Jingjing Cai, Zhi-Gang She, Yibin Wang, Peng Zhang, Lingli Huang, Hongliang Li, Xiao-Jing Zhang
Journal: Science Translational Medicine (2024)

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε ( SIKE ) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-β–activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.
Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo
Authors: Laura Díez-Alonso, Aïda Falgas, Javier Arroyo-Ródenas, Paola A. Romencín, Alba Martínez, Marina Gómez-Rosel, Belén Blanco, Anaïs Jiménez-Reinoso, Andrea Mayado, Alba Pérez-Pons, Óscar Aguilar-Sopeña, Ángel Ramírez-Fernández, Alejandro Segura-Tudela, Lorena Perez-Amill, Antonio Tapia-Galisteo, Carmen Domínguez-Alonso, Laura Rubio-Pérez, Maria Jara, Francesc Solé, Oana Hangiu, Laura Almagro, Ángela Albitre, Petronila Penela, Laura Sanz, Eduardo Anguita, Antonio Valeri, Almudena García-Ortiz, Paula Río, Manel Juan, Joaquín Martínez-López, Pedro Roda-Navarro, Beatriz Martín-Antonio, Alberto Orfao, Pablo Menéndez, Clara Bueno, Luis Álvarez-Vallina
Journal: Science Translational Medicine (2024)

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell–limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.
Autologous transplantation of P63 <sup>+</sup> lung progenitor cells for chronic obstructive pulmonary disease therapy
Authors: Yujia Wang, Zili Meng, Ming Liu, Yueqing Zhou, Difei Chen, Yu Zhao, Ting Zhang, Nanshan Zhong, Xiaotian Dai, Shiyue Li, Wei Zuo
Journal: Science Translational Medicine (2024)

Adult lung resident stem/progenitor cells, including P63 + progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63 + progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63 + progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0.7 × 10 6 to 5.2 × 10 6 cells per kilogram of body weight. Twenty patients were evaluable at the end of the study (intervention group, n = 17; control group, n = 3). No grade 3 to 5 adverse events (AEs) or serious AEs occurred. Although bronchoscopy-associated AEs were recorded in participants in the intervention group, other AEs were not substantial different between groups. Twenty-four weeks after transplantation, participants in the intervention group displayed improvement in gas transfer capacity [diffusing capacity of the lung for carbon monoxide (DLCO) change from baseline: +18.2%], whereas the control group experienced a decrease (DLCO change from baseline: −17.4%; P = 0.008). Furthermore, participants in the intervention group showed &gt;30-meter increase in walking distance within 6 minutes. Transcriptomic analysis of progenitor cells isolated from responding and nonresponding individuals in the intervention group showed that higher expression of P63 was associated with treatment efficacy. In conclusion, transplantation of cultured P63 + lung progenitor cells was safe and might represent a potential therapeutic strategy for COPD.
Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization
Authors: Jiajia Chen, Daniel J. Laverty, Surabhi Talele, Ashwin Bale, Brett L. Carlson, Kendra A. Porath, Katrina K. Bakken, Danielle M. Burgenske, Paul A. Decker, Rachael A. Vaubel, Jeanette E. Eckel-Passow, Rohit Bhargava, Zhenkun Lou, Petra Hamerlik, Brendan Harley, William F. Elmquist, Zachary D. Nagel, Shiv K. Gupta, Jann N. Sarkaria
Journal: Science Translational Medicine (2024)

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G 0 -G 1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53 -mutant tumors but not in TP53 -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53 -mutant, but not in TP53 -WT, PDXs. In plasmid-based reporter assays, GBM43 ( TP53 -mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53 -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53 -mutant cells to ATM inhibitor–mediated radiosensitization.
Dynamic load modulation predicts right heart tolerance of left ventricular cardiovascular assist in a porcine model of cardiogenic shock
Authors: Kimberly K. Lamberti, Steven P. Keller, Elazer R. Edelman
Journal: Science Translational Medicine (2024)

Ventricular assist devices (VADs) offer mechanical support for patients with cardiogenic shock by unloading the impaired ventricle and increasing cardiac outflow and subsequent tissue perfusion. Their ability to adjust ventricular assistance allows for rapid and safe dynamic changes in cardiac load, which can be used with direct measures of chamber pressures to quantify cardiac pathophysiologic state, predict response to interventions, and unmask vulnerabilities such as limitations of left-sided support efficacy due to intolerance of the right heart. We defined hemodynamic metrics in five pigs with dynamic peripheral transvalvular VAD (pVAD) support to the left ventricle. Metrics were obtained across a spectrum of disease states, including left ventricular ischemia induced by titrated microembolization of a coronary artery and right ventricular strain induced by titrated microembolization of the pulmonary arteries. A sweep of different pVAD speeds confirmed mechanisms of right heart decompensation after left-sided support and revealed intolerance. In contrast to the systemic circulation, pulmonary vascular compliance dominated in the right heart and defined the ability of the right heart to adapt to left-sided pVAD unloading. We developed a clinically accessible metric to measure pulmonary vascular compliance at different pVAD speeds that could predict right heart efficiency and tolerance to left-sided pVAD support. Findings in swine were validated with retrospective hemodynamic data from eight patients on pVAD support. This methodology and metric could be used to track right heart tolerance, predict decompensation before right heart failure, and guide titration of device speed and the need for biventricular support.
Cancer-associated fibroblast–secreted collagen is associated with immune inhibitor receptor LAIR1 in gliomas
Authors: Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Jason Miska, Kathleen McCortney, Alicia Steffens, Jordain Walshon, Daniel Winkowski, Michael Cloney, Matthew Ordon, William Gibson, Hanna Kemeny, Mark Youngblood, Rebecca Du, James Mossner, Pavlos Texakalidis, Annelise Sprau, Matthew Tate, Charles David James, Craig M Horbinski, Nitin R Wadhwani, Maciej S Lesniak, Sandi Lam, Ankita Sati, Manish Aghi, Michael DeCuypere, Amy B Heimberger
Journal: Journal of Clinical Investigation (2024)
An engineered immunomodulatory IgG1 Fc suppresses autoimmune inflammation through pathways shared with i.v. immunoglobulin
Authors: Sunny L Sneed, Brian B Reese, Ana Fs Laureano, Sneha Ratnapriya, Isabella Fraschilla, Kate L Jeffrey, Greg P Coffey, Pamela B Conley, Robert M Anthony
Journal: Journal of Clinical Investigation (2024)

Immunoglobulin G (IgG) antibodies in the form of high-dose intravenous immunoglobulin (IVIG) exert immunomodulatory activity and are used in this capacity to treat inflammatory and autoimmune diseases. Reductionist approaches have revealed that terminal sialylation of the single asparagine-linked (N-linked) glycan at position 297 of the IgG1 Fc bestows antiinflammatory activity, which can be recapitulated by introduction of an F241A point mutation in the IgG1 Fc (FcF241A). Here, we examined the antiinflammatory activity of CHO-K1 cell-produced FcF241A in vivo in models of autoimmune inflammation and found it to be independent of sialylation. Intriguingly, sialylation markedly improved the half-life and bioavailability of FcF241A via impaired interaction with the asialoglycoprotein receptor ASGPR. Further, FcF241A suppressed inflammation through the same molecular pathways as IVIG and sialylated IgG1 Fc and required the C-type lectin SIGN-R1 in vivo. This contrasted with FcAbdeg (efgartigimod), an engineered IgG1 Fc with enhanced neonatal Fc receptor (FcRn) binding, which reduced total serum IgG concentrations, independent of SIGN-R1. When coadministered, FcF241A and FcAbdeg exhibited combinatorial antiinflammatory activity. Together, these results demonstrated that the antiinflammatory activity of FcF241A requires SIGN-R1, similarly to that of high-dose IVIG and sialylated IgG1, and can be used in combination with other antiinflammatory therapeutics that rely on divergent pathways, including FcAbdeg.
Lipid droplets in the endothelium: The missing link between metabolic syndrome and cardiovascular disease?
Authors: Iris Z Jaffe, S Ananth Karumanchi
Journal: Journal of Clinical Investigation (2024)

The physiology of lipid droplets (LDs) has been most extensively characterized in adipocytes, but LDs also accumulate in endothelial cells lining blood vessels in response to changing levels of triglycerides. In recent issues of the JCI, two independent papers highlight a direct role of endothelial LDs in the genesis of hypertension and atherosclerosis in rodent models. Kim et al. demonstrated that accumulation of LDs in the endothelium leads to hypertension, impairs endothelial function, and accelerates atherosclerosis. Boutagy, Gamez-Mendez, et al. knocked out Atgl in the endothelium and confirmed triglyceride accumulation in endothelial cells that was associated with reduced NO synthesis and impaired endothelial-dependent vasodilation. These data suggest that enhancing triglyceride breakdown in the endothelium could provide a treatment target for patients with metabolic syndrome.
Reduced Bik expression drives low-grade airway inflammation and increased risk for COPD in females
Authors: Irina Petrache, David Wh Riches
Journal: Journal of Clinical Investigation (2024)

Chronic low-grade inflammation is increasingly recognized as a subtle yet potent risk factor for a multitude of age-related disorders, including respiratory diseases, cardiovascular conditions, metabolic syndromes, autoimmunity, and cancer. In this issue of the JCI, Mebratu, Jones, and colleagues shed new light on the mechanisms that promote low-grade airway inflammation and how this contributes to the development of chronic obstructive pulmonary disease (COPD). Their finding that Bik deficiency leads to spontaneous emphysema in female mice, but not in males, marks a notable advancement in our understanding of how inflammatory processes can diverge based on biological sex. This finding is of clinical relevance, given the vulnerability of women to developing COPD.
Reversibly Adhesive, Anti‐Swelling, and Antibacterial Hydrogels for Tooth‐Extraction Wound Healing
Authors: Siyu Li, Lunhao Zhi, Qin Chen, Weifeng Zhao, Changsheng Zhao
Journal: Advanced Healthcare Materials (2024)

Oral wound treatment faces challenges due to the complex oral environment, thus, sealing the wound quickly becomes necessary. Although some materials have achieved adhesion and sterilization, how to effectively solve the contradiction between strong adhesion and on-demand removal remains a challenge. Herein, a reversibly adhesive hydrogel is designed by free radical copolymerization of cationic monomer [2-(acryloyloxy) ethyl] trimethylammonium chloride (ATAC), hydrophobic monomer ethylene glycol phenyl ether acrylate (PEA) and N-isopropylacrylamide (NIPAAm). The cationic quaternary ammonium salts provide electrostatic interactions, the hydrophobic groups provide hydrophobic interactions, and the PNIPAAm chain segments provide hydrogen bonding, leading to strong adhesion. Therefore, the hydrogel obtains an adhesion strength of 18.67 KPa to oral mucosa and can seal wounds fast within 10 s. Furthermore, unlike pure PNIPAAm, the hydrogel has a lower critical solution temperature of 40.3 °C due to the contribution of ATAC and PEA, enabling rapid removal with 40 °C water after treatment. In addition, the hydrogel realizes excellent anti-swelling ratio (≈80%) and antibacterial efficiency (over 90%). Animal experiments prove that the hydrogel effectively reduces inflammation infiltration, promotes collagen deposition and vascular regeneration. Thus, hydrogel as a multi-functional dressing has great application prospects in oral wound management.
Inflamed immune phenotype predicts favorable clinical outcomes of immune checkpoint inhibitor therapy across multiple cancer types
Authors: Jeanne Shen, Yoon-La Choi, Taebum Lee, Hyojin Kim, Young Kwang Chae, Ben W Dulken, Stephanie Bogdan, Maggie Huang, George A Fisher, Sehhoon Park, Se-Hoon Lee, Jun-Eul Hwang, Jin-Haeng Chung, Leeseul Kim, Heon Song, Sergio Pereira, Seunghwan Shin, Yoojoo Lim, Chang Ho Ahn, Seulki Kim, Chiyoon Oum, Sukjun Kim, Gahee Park, Sanghoon Song, Wonkyung Jung, Seokhwi Kim, Yung-Jue Bang, Tony S K Mok, Siraj M. Ali, Chan-Young Ock
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The inflamed immune phenotype (IIP), defined by enrichment of tumor-infiltrating lymphocytes (TILs) within intratumoral areas, is a promising tumor-agnostic biomarker of response to immune checkpoint inhibitor (ICI) therapy. However, it is challenging to define the IIP in an objective and reproducible manner during manual histopathologic examination. Here, we investigate artificial intelligence (AI)-based immune phenotypes capable of predicting ICI clinical outcomes in multiple solid tumor types. Methods Lunit SCOPE IO is a deep learning model which determines the immune phenotype of the tumor microenvironment based on TIL analysis. We evaluated the correlation between the IIP and ICI treatment outcomes in terms of objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in a cohort of 1,806 ICI-treated patients representing over 27 solid tumor types retrospectively collected from multiple institutions. Results We observed an overall IIP prevalence of 35.2% and significantly more favorable ORRs (26.3% vs 15.8%), PFS (median 5.3 vs 3.1 months, HR 0.68, 95% CI 0.61 to 0.76), and OS (median 25.3 vs 13.6 months, HR 0.66, 95% CI 0.57 to 0.75) after ICI therapy in IIP compared with non-IIP patients, respectively (p&lt;0.001 for all comparisons). On subgroup analysis, the IIP was generally prognostic of favorable PFS across major patient subgroups, with the exception of the microsatellite unstable/mismatch repair deficient subgroup. Conclusion The AI-based IIP may represent a practical, affordable, clinically actionable, and tumor-agnostic biomarker prognostic of ICI therapy response across diverse tumor types.