tbuckley/cabot-search huggingface dataset:
Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation
Authors: Tomoyoshi Tamura, Changde Cheng, Ana B. Villaseñor-Altamirano, Kohei Yamada, Kohei Ikeda, Kei Hayashida, Jaivardhan A. Menon, Xi Dawn Chen, Hattie Chung, Jack Varon, Jiani Chen, Jiyoung Choi, Aidan M. Cullen, Jingyu Guo, Xi Lin, Benjamin A. Olenchock, Mayra A. Pinilla-Vera, Reshmi Manandhar, Muhammad Dawood Amir Sheikh, Peter C. Hou, Patrick R. Lawler, William M. Oldham, Raghu R. Seethala, Rebecca M. Baron, Erin A. Bohula, David A. Morrow, Richard S. Blumberg, Fei Chen, Louis T. Merriam, Alexandra J. Weissman, Michael B. Brenner, Xiang Chen, Fumito Ichinose, Edy Y. Kim, H. S. Sohn, T. Rolland, B. R. Weil
Journal: Science Translational Medicine (2024)

Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post–cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells ( Cd1d −/− ), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. Cd1d −/− mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.
<i>Glp1r-Lepr</i> coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist
Authors: Joseph Polex-Wolf, Kristine Deibler, Wouter Frederik Johan Hogendorf, Sarah Bau, Tine Glendorf, Carsten Enggaard Stidsen, Christian Wenzel Tornøe, Dong Tiantang, Sofia Lundh, Charles Pyke, Abigail J. Tomlinson, Stace Kernodle, Irwin Jack Magrisso, Kilian W. Conde-Frieboes, Martin G. Myers, Lotte Bjerre Knudsen, Randy J. Seeley
Journal: Science Translational Medicine (2024)

Glucagon-like peptide-1 (GLP-1) and leptin signal recent feeding and long-term energy stores, respectively, and play complementary roles in the modulation of energy balance. Previous work using single-cell techniques in mice revealed the existence of a population of leptin receptor ( Lepr )–containing dorsomedial hypothalamus (DMH) neurons marked by the expression of GLP-1 receptor ( Glp1r ; LepR Glp1r neurons) that play important roles in the control of feeding and body weight by leptin. Here, we demonstrate the existence of a population of LepR Glp1r neurons in the DMHs of nonhuman primates (NHPs), suggesting the potential translational relevance of these neurons. Consequently, we developed a GLP-1R/LepR dual agonist and demonstrated the physiological activity of both components in vivo using leptin-deficient and Lepr- deficient murine models. We further found roles for LepR Glp1r neurons in mediating the dual agonist’s efficacy on food intake and body weight loss. Ablating Lepr in Glp1r -expressing neurons (Lepr Glp1r KO mice) abrogated the suppression of food intake by the dual agonist. Furthermore, reactivation of Glp1r expression in Lepr neurons on an otherwise Glp1r -null background (Glp1r Lepr Re mice) was sufficient to permit the suppression of food intake and body weight by the dual agonist. Hence, LepR Glp1r neurons represent targets for a GLP-1R/LepR dual agonist that potently reduces food intake and body weight.
RANKL treatment restores thymic function and improves T cell–mediated immune responses in aged mice
Authors: Jérémy C. Santamaria, Jessica Chevallier, Léa Dutour, Amandine Picart, Camille Kergaravat, Agata Cieslak, Mourad Amrane, Renaud Vincentelli, Denis Puthier, Emmanuel Clave, Arnauld Sergé, Martine Cohen-Solal, Antoine Toubert, Magali Irla
Journal: Science Translational Medicine (2024)

Age-related thymic involution, leading to reduced T cell production, is one of the major causes of immunosenescence. This results in an increased susceptibility to cancers, infections, and autoimmunity and in reduced vaccine efficacy. Here, we identified that the receptor activator of nuclear factor κB (RANK)-RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.
Lessons from the Use of Monoclonal Antibodies to SARS-CoV-2 Spike Protein During the COVID-19 Pandemic
Authors: Arturo Casadevall, Daniele Focosi
Journal: Annual Review of Medicine (2024)

Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein were deployed during the COVID-19 pandemic. While all of the clinically authorized mAbs were eventually defeated by SARS-CoV-2 variants, they were highly effective in preventing disease progression when given early in the course of the disease. The experience with mAbs to SARS-CoV-2 offers important lessons for the use of mAbs in future infectious disease emergencies, such as choosing mAbs that target conserved epitopes and designing cocktails to reduce the emergence of escape variants. Planning for future use must include the creation of infusion centers and the development of strategies to minimize the emergence of escape variants.
New Therapeutic Options for BRCA Mutant Patients
Authors: Anthony Ghanem, Susan M. Domchek
Journal: Annual Review of Medicine (2024)

Pathogenic variants in BRCA1 and BRCA2 are associated with significantly elevated lifetime risks of breast, ovarian, pancreatic, and prostate cancer. These genes are critical in double-strand break repair through homologous recombination. An understanding of the biology of BRCA1 and BRCA2 led to the development of targeted therapeutics, specifically poly(ADP-ribose) polymerase (PARP) inhibitors, which are approved by the US Food and Drug Administration for multiple BRCA1/2 -associated cancers. Here, we discuss the development of PARP inhibitors, mechanisms of resistance, and the potential utility of these drugs beyond canonical BRCA1/2 tumors, and we describe novel agents under study.
YAP1 induces bladder cancer progression and promotes immune evasion through IL-6/ STAT3 pathway and CXCL deregulation
Authors: Pritam Sadhukhan, Mingxiao Feng, Emily Illingworth, Ido Sloma, Akira Ooki, Andres Matoso, David Sidransky, Burles A Johnson, Luigi Marchionni, Fenna Cm Sillé, Woonyoung Choi, David McConkey, Mohammad Hoque
Journal: Journal of Clinical Investigation (2024)

The Hippo signaling pathway plays a key role in tumorigenesis in different cancer types. We investigated the role of the Hippo effector YAP1 in the tumor immune microenvironment (TIME) of urothelial carcinoma of the bladder (UCB) and evaluated the efficacy of immunotherapy in the context of YAP1 signaling. We performed numerous in vitro and in vivo experiments to determine the role of YAP1 using genetic and pharmacological attenuation of YAP1 activity. Briefly, RNA sequencing was carried out with mouse and human cell lines to identify novel YAP1-regulated downstream targets unbiasedly. We then experimentally confirmed that YAP1 regulates the TIME through the IL-6/STAT3 signaling pathway and varied C-X-C motif chemokine regulation. We analyzed several human sample sets to explore the TIME status in the context of YAP1 expression. Our data indicate that YAP1 attenuation decreases M2 macrophages and myeloid-derived suppressor cells in the TIME compared with YAP1-expressing cells. In summary, this study provides insights into YAP1 signaling as a driver for cancer stemness and an inducer of immunosuppressive TIME. Moreover, the therapeutic efficacy of YAP1 attenuation indicates that combined blockade of YAP1 and immune checkpoints may yield clinical value for treating patients with UCB.
Surfactant protein B deficiency: the RespiRare cohort
Authors: Manon Fleury, Céline Delestrain, Léa Roditis, Caroline Perisson, Marie-Catherine Renoux, Caroline Thumerelle, Ralph Epaud, Camille Fletcher, Nouha Jedidi, Aurore Coulomb L'Hermine, Harriet Corvol, Hubert Ducou le Pointe, Pascale Fanen, Chiara Sileo, Camille Louvrier, Alix de Becdelievre, Marie Legendre, Nadia Nathan
Journal: Thorax (2024)

Childhood interstitial lung diseases (chILD) are rare and usually severe disorders. Among them, very rare cases of surfactant protein (SP)-B deficiencies have been reported so far and are usually associated with fatal forms of chILD. The RespiRare network allows the collection of precise phenotypic and genotypic information. This study that reports a series of 11 SP-B-deficient patients underscores two key observations: patients with severe loss-of-function variants associated with SP-B complete deficiency presented symptoms at birth and died at a median age of 1 month; and extremely rare cases of hypomorphic variants with partially preserved SP-B function may allow survival.
Validation Requirements for AI-based Intervention-Evaluation in Aging and Longevity Research and Practice
Authors: Georg Fuellen, Anton Kulaga, Sebastian Lobentanzer, Maximilian Unfried, Roberto A Avelar, Daniel Palmer, Brian K Kennedy
Journal: Ageing Research Reviews (2024)

The field of aging and longevity research is overwhelmed by vast amounts of data, calling for the use of Artificial Intelligence (AI), including Large Language Models (LLMs), for the evaluation of geroprotective interventions. Such evaluations should be correct, useful, comprehensive, explainable, and they should consider causality, interdisciplinarity, adherence to standards, longitudinal data and known aging biology. In particular, comprehensive analyses should go beyond comparing data based on canonical biomedical databases, suggesting the use of AI to interpret changes in biomarkers and outcomes. Our requirements motivate the use of LLMs with Knowledge Graphs and dedicated workflows employing, e.g., Retrieval-Augmented Generation. While naive trust in the responses of AI tools can cause harm, adding our requirements to LLM queries can improve response quality, calling for benchmarking efforts and justifying the informed use of LLMs for advice on longevity interventions.
Inhibiting IP6K1 confers atheroprotection by elevating circulating apolipoprotein A-I
Authors: Xiaoqi Liu, Zixuan Zhang, Tim Aguirre, Megan L Shipton, Lin Fu, Jimin Du, David Furkert, Ji Qi, Alfred C Chin, Andrew M Riley, Tong Liu, Xu Zhang, Barry V L Potter, Dorothea Fiedler, Yi Zhu, Chenglai Fu
Journal: Metabolism (2024)
Advanced MicroRNA delivery for lung inflammatory therapy: surfactant protein A controls cellular internalisation and degradation of extracellular vesicles
Authors: Miji Kim, Sujeong Park, Nayoung Lee, Dohyun Kim, Dongwoo Kim, Yang Jin, Seon-Jin Lee, Jung Joo Hong, Heedoo Lee
Journal: Thorax (2024)

Introduction Alveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular vesicles (EVs) have emerged as a promising drug delivery platform due to their minimal cytotoxicity. However, precise targeting of specific cell types and the rapid lysosomal degradation of EVs within recipient cells remain persistent challenges. Method In this study, we explored the biological significance of SP-A-EVs as novel drug delivery systems for combating lung inflammation. We first verified that respiratory EVs express SP-A receptor (SP-R210), facilitating the conjugation of SP-A with EVs. The delivery efficiency, cellular internalisation pathways and therapeutic effects were evaluated using an in vivo mouse model. Results SP-A-EVs were robustly internalised into AMs both in vitro and in vivo. Furthermore, our investigation revealed that the toll-like receptor 4-mediated endocytosis pathway was employed for the uptake of SP-A-EVs, significantly delaying their degradation compared with natural EVs, which primarily followed the conventional lysosomal degradation pathway within AMs. In a functional study, we successfully loaded anti-inflammatory microRNA ( let-7b ) into SP-A-EVs, leading to the suppression of AM activation and the alleviation of lung inflammation induced by lipopolysaccharide. Conclusion These findings underscore the potential of SP-A-EVs as highly effective drug delivery systems for targeted therapeutics in lung-related disorders, capitalising on the strong affinity between AMs and SP-A and the modulation of cellular internalisation.
Photothrombolytics: A light-driven technology for the targeted lysis of thrombi
Authors: Brianna M Vickerman, Basanta Acharya, Caylie A McGlade, Haifeng Yin, Tomohiro Kawano, Lauren Haar, Nigel Mackman, Rani S Sellers, Xianming Tan, Aadra P Bhatt, David S Lawrence
Journal: Journal of Controlled Release (2024)
Exploring the potential of plasma and adipose mesenchymal stem cell-derived extracellular vesicles as novel platforms for neuroinflammation therapy
Authors: Rummenigge Oliveira Silva, Mohamed Haddad, Hermine Counil, Charlotte Zaouter, Shunmoogum A Patten, Tamas Fulop, Charles Ramassamy
Journal: Journal of Controlled Release (2024)

Persistent reactive oxygen species (ROS) and neuroinflammation contribute to the onset and progression of neurodegenerative diseases, underscoring the need for targeted therapeutic strategies to mitigate these effects. Extracellular vesicles (EVs) show promise in drug delivery due to their biocompatibility, ability to cross biological barriers, and and specific interactions with cell and tissue receptors. In this study, we demonstrated that human plasma-derived EVs (pEVs) exhibit higher brain-targeting specificity, while adipose-derived mesenchymal stem cells EVs (ADMSC-EVs) offer regenerative and immunomodulatory properties. We further investigated the potential of these EVs as therapeutic carriers for brain-targeted drug delivery, using Donepezil (DNZ) as the model drug. DNZ, a cholinesterase inhibitor commonly used for Alzheimer's disease (AD), also has neuroprotective and anti-inflammatory properties. The size of EVs used ranged from 50 to 300 nm with a surface charge below -30 mV. Both formulations showed rapid cellular internalization, without toxicity, and the ability to cross the blood-brain barrier (BBB) in a zebrafish model. The have analyzed the anti-inflammatory and antioxidant actions of pEVs-DNZ and ADMSC-EVs-DNZ in the presence of lipopolysaccharide (LPS). ADMSC-EVs significantly reduced the inflammatory mediators released by HMC3 microglial cells while treatment with pEVs-DNZ and ADMSC-EVs-DNZ lowered both phagocytic activity and ROS levels in these cells. In vivo experiments using zebrafish larvae revealed that both EV formulations reduced microglial proliferation and exhibited antioxidant effects. Overall, this study highlights the potential of EVs loaded with DNZ as a novel approach for treating neuroinflammation underlying various neurodegenerative diseases.
TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV
Authors: Giuseppina Grieco, Sandro Montefusco, Edoardo Nusco, Antonella Capuozzo, Francesca Cervellini, Elena Polishchuk, Martha Bishop, Antonio Miele, Luciano D’Apolito, Claudia La Vecchia, Miriam Aurilia, Michela Schiavo, Leopoldo Staiano, Marcella Cesana, Rebecca Oberman, Anna V. Lynch, Patricia Musolino, Francesco Trepiccione, Yulia Grishchuk, Diego Luis Medina
Journal: Journal of the American Society of Nephrology (2024)

Loss-of-function mutations in the lysosomal channel transient receptor potential cation channel (TRPML-1) cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood. A cross-sectional review of medical records from 21 patients with MLIV (ages 3–43 years) was conducted to assess kidney function impairment. In addition, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo kidney filtration measurements. Of the 21 patients with MLIV, only adults were diagnosed with stage 2–3 CKD. Laboratory abnormalities included lower eGFR and higher levels BUN/creatine in blood and proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor–mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. In addition, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the proinflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, adeno-associated viral–mediated TRPML-1 gene delivery reversed key pathological phenotypes in MLIV mice, underscoring TRPML-1's critical role in kidney function. Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV.
Treatment duration of adjuvant immune checkpoint inhibitors in hepatocellular carcinoma patients at high risk of recurrence after resection: A prospective, multicentric cohort study
Authors: Jia-Yong Su, Shao-Ping Liu, Xiao-Ling Xu, Jun-Jie Ou, Po-Hua Ye, Bin-Tong Zhao, Jia-Song Chen, Qiu-Mei Luo, Jin-Rong Liu, Fei-Min Tang, Jian-Rong Li, Da-Long Yang, Zhu-Jian Deng, Li-Xin Pan, Yao-Jie Li, Le Li, Zhen-Ming Qin, Xiu-Mei Liang, Yi-Li Ma, Liang Ma, Jian-Hong Zhong
Journal: Liver Cancer (2024)

Introduction: Adjuvant immune checkpoint inhibitors (ICIs) may improve recurrence-free survival (RFS) in patients with hepatocellular carcinoma (HCC). This study evaluated the effects of adjuvant ICI treatment duration on RFS and overall survival (OS) among patients with HCC at high risk of recurrence. Methods: The RFS and OS of patients from three centers who received either adjuvant ICI therapy or active surveillance after curative hepatic resection between January 1, 2019 and December 31, 2023 were analyzed. Further analysis was performed to evaluate the effects of ICI treatment duration on RFS and OS. Results: A total of 1271 patients were included, of whom 1032 (81.2%) received active surveillance and 239 (18.8%) received adjuvant ICI therapy. The median RFS in the adjuvant therapy cohort was 22.6 months (95% CI 18.3–26.9), significantly higher than the RFS of 19.1 months (95% CI 16.4–21.4) in the active surveillance cohort (HR 0.79; 95% CI 0.66–0.95; p = 0.019). The median OS was not reached for either group, but OS tended to be better in the adjuvant therapy cohort than in the active surveillance group (HR 0.72, 95%CI 0.54–0.94; p = 0.010). Similar results were obtained after propensity score matching. Among patients who received adjuvant ICI therapy, those who received it for longer than 6 months had slightly higher RFS (HR 0.66; 95% CI 0.42–1.04; p = 0.071) and OS (HR 0.59; 95% CI 0.30–1.17; p = 0.128) than those who received it for up to 6 months. Conclusions: Adjuvant ICI therapy significantly improves the prognosis of patients with HCC at high risk of recurrence after curative resection. Six months of adjuvant ICI treatment may be insufficient.
Greenspace Morphology and Preterm Birth: A State-Wide Study in Georgia, United States (2001–2016)
Authors: Huaqing Wang, Xucheng Huang, Hua Hao, Howard H. Chang
Journal: Environmental Health Perspectives (2024)

Residential greenness is linked to birth outcomes. However, the role of greenspace morphology remains poorly understood. Additionally, evidence is lacking regarding whether these relationships vary by subpopulation.
Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma
Authors: Jia Ming Nickolas Teo, Zhulin Chen, Weixin Chen, Rachael Julia Yuenyinn Tan, Qi Cao, Yingming Chu, Delin Ma, Liting Chen, Huajian Yu, Ka-Hei Lam, Terence Kin Wah Lee, Svetoslav Chakarov, Burkhard Becher, Ning Zhang, Zhao Li, Stephanie Ma, Ruidong Xue, Guang Sheng Ling
Journal: The Journal of Experimental Medicine (2024)

Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs affect metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) more than viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development.