tbuckley/cabot-search huggingface dataset:
Atrial Functional Mitral Regurgitation Subtypes Undergoing Transcatheter Edge-to-Edge Repair
Authors: Philipp von Stein, Jennifer von Stein, Christopher Hohmann, Hendrik Wienemann, Henning Guthoff, Maria I Körber, Stephan Baldus, Roman Pfister, Rebecca T Hahn, Christos Iliadis
Journal: JACC. Cardiovascular imaging (2024)

Two subtypes of atrial functional mitral regurgitation (AFMR) have been described, one is characterized by Carpentier type I and the other by Carpentier type IIIb leaflet motion.
Next-generation CAR T cell therapies for glioblastoma
Authors: Joshua D. Bernstock, Jakob V. E. Gerstl, Pablo A. Valdés, Gregory K. Friedman, E. Chiocca
Journal: Science Translational Medicine (2024)

Interim results from two phase 1 trials demonstrate progress in the use of chimeric antigen receptor (CAR) T cell therapy for recurrent glioblastoma (GBM).
Inhibiting endothelial <i>Rhoj</i> blocks profibrotic vascular intussusception and angiocrine factors to sustain lung regeneration
Authors: Jie Ma, Liyin Zhang, Xu Zhang, Lanlan Zhang, Hua Zhang, Yulei Zhu, Xingming Huang, Ting Zhang, Xiangdong Tang, Yuan Wang, Lu Chen, Qiang Pu, Liming Yang, Zhongwei Cao, Bi-Sen Ding
Journal: Science Translational Medicine (2024)

Lung regeneration after fibrosis requires formation of functional new vasculature, which is essential for gas exchange and cellular cross-talk with other lung cells. It remains unknown how the lung vasculature can be regenerated without fibrosis. Here, we tested the role of N6-methyladenosine (m6A) modification of forkhead box protein O1 ( Foxo1 ) mRNA in lung regeneration after pneumonectomy (PNX) in mice, a model for lung regrowth after surgical resection. Endothelial cell (EC)–specific knockout of methyltransferase-like 3 ( Mettl3 ) and Foxo1 caused nonproductive intussusceptive angiogenesis (IA), which impaired regeneration and enhanced fibrosis. This nonproductive IA was characterized by enhanced endothelial proliferation and increased vascular splitting with increased numbers of pillar ECs. Endothelial-selective knockout of Mettl3 in mice stimulated nonproductive IA and up-regulation of profibrotic factors after PNX, promoting regeneration to fibrotic transition. EC-specific mutation of m6A modification sites in the Foxo1 gene in mice revealed that endothelial Mettl3 modified A504 and A2035 sites in the Foxo1 mRNA to maintain pro-regenerative endothelial glycolysis, ensuring productive IA and lung regeneration without fibrosis. Suppression of Mettl3-Foxo1 signaling stimulated a subset of hyperglycolytic and hyperproliferative 6-phosphofructo-2-kinase/fructose-2 , 6-biphosphatase 3 ( Pfkfb3 ) + , Ras homolog family member J ( Rhoj ) + , and platelet-derived growth factor subunit B ( Pdgfb ) + ECs in both human and mouse lungs with fibrosis. Inhibiting this Pfkfb3 + Rhoj + Pdgfb + EC subset normalized IA, alleviated fibrosis, and restored regeneration in bleomycin (BLM)–injured mouse lungs. We found that m6A modification of Foxo1 in the mouse vasculature promoted lung regeneration over fibrosis after PNX and BLM injury.
An autoimmune transcriptional circuit drives FOXP3 <sup>+</sup> regulatory T cell dysfunction
Authors: Tomokazu S. Sumida, Matthew R. Lincoln, Liang He, Yongjin Park, Mineto Ota, Akiko Oguchi, Raku Son, Alice Yi, Helen A. Stillwell, Greta A. Leissa, Keishi Fujio, Yasuhiro Murakawa, Alexander M. Kulminski, Charles B. Epstein, Bradley E. Bernstein, Manolis Kellis, David A. Hafler
Journal: Science Translational Medicine (2024)

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4 + FOXP3 + regulatory T cells (T regs ) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T regs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1 , which led to destabilization of forkhead box P3 (FOXP3) and T reg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T regs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and T reg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T regs in autoimmune diseases.
Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer
Authors: Loretah Chibaya, Kelly D. DeMarco, Christina F. Lusi, Griffin I. Kane, Meghan L. Brassil, Chaitanya N. Parikh, Katherine C. Murphy, Shreya R. Chowdhury, Junhui Li, Boyang Ma, Tiana E. Naylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R. Pitarresi, Lihua Julie Zhu, Katherine A. Fitzgerald, Prabhani U. Atukorale, Marcus Ruscetti
Journal: Science Translational Medicine (2024)

Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell–driven and type I interferon–mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8 + T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon–driven innate and adaptive immune response with durable antitumor efficacy against PDAC.
Activation and antitumor immunity of CD8 <sup>+</sup> T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid
Authors: Ying Liu, Feng Wang, Dongxue Peng, Dan Zhang, Luping Liu, Jun Wei, Jian Yuan, Luyao Zhao, Huimin Jiang, Tingting Zhang, Yunxuan Li, Chenxi Zhao, Shuhua He, Jie Wu, Yechao Yan, Peitao Zhang, Chunyi Guo, Jiaming Zhang, Xia Li, Huan Gao, Ke Li
Journal: Science Translational Medicine (2024)

CD8 + T cell activation leads to the rapid proliferation and differentiation of effector T cells (T effs ), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8 + T effs , the mechanisms that regulate CD8 + T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8 + T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8 + T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8 + T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8 + T cells by directly binding to GLUT10’s intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8 + T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti–programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8 + T cells and identify that TME accumulated lactic acid inhibits CD8 + T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8 + T cell–mediated antitumor effects.
Advancing rectal cancer therapy: mFOLFIRINOX reduces metastasis and improves survival outcomes. Letter to the Editor regarding ‘Total neoadjuvant therapy with mFOLFIRINOX versus preoperativechemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial’ by Conroy T et al.
Authors: Q.T.H. Shubhra, Q. Cai
Journal: Annals of Oncology (2024)
Prevalence and impact of persistent symptoms following SARS-CoV-2 infection among healthcare workers: a cross-sectional survey in the SIREN cohort
Authors: Sarah Foulkes, Josie Evans, Claire Neill, Jennifer Bishop, Jameel Khawam, Jasmin Islam, Ana Atti, Colin S Brown, Susan Hopkins, Lesley Price, Victoria Hall
Journal: Journal of Infection (2024)

Following SARS-CoV-2 infection, some patients experience a range of long-lasting symptoms, with a specific burden on their lives and ability to work.
Author Correction: Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial
Authors: Bram De Laere, Alessio Crippa, Andrea Discacciati, Berit Larsson, Maria Persson, Susanne Johansson, Sanne D’hondt, Rebecka Bergström, Venkatesh Chellappa, Markus Mayrhofer, Mahsan Banijamali, Anastasijia Kotsalaynen, Céline Schelstraete, Jan Pieter Vanwelkenhuyzen, Marie Hjälm-Eriksson, Linn Pettersson, Anders Ullén, Nicolaas Lumen, Gunilla Enblad, Camilla Thellenberg Karlsson, Elin Jänes, Johan Sandzén, Peter Schatteman, Maria Nyre Vigmostad, Martha Olsson, Christophe Ghysel, Brieuc Sautois, Wendy De Roock, Siska Van Bruwaene, Mats Anden, Ingrida Verbiene, Daan De Maeseneer, Els Everaert, Jochen Darras, Bjørg Y. Aksnessether, Daisy Luyten, Michiel Strijbos, Ashkan Mortezavi, Jan Oldenburg, Piet Ost, Martin Eklund, Henrik Grönberg, Johan Lindberg
Journal: Nature Medicine (2024)
Efficacy rigor of neoadjuvant therapy: The role and synthesis of tumor subtype analysis. Letter to the Editor regarding “Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial.” by Conroy T et al.
Authors: H Li, Y Gui, Z Luo
Journal: Annals of Oncology (2024)
Interpretation of long-term overall survival from the PRODIGE 23 study. Letter to the Editor regarding “Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial”, by T. Conroy et al.
Authors: R Moretto, G Vetere, M Di Maio
Journal: Annals of Oncology (2024)
Plasma proteins, circulating metabolites mediate causal inference studies on the effect of gut bacteria on the risk of osteoporosis development
Authors: Baoxin Zhang, Wanxiong He, Zhiwei Pei, Qingwen Guo, Jianzhong Wang, Mingqi Sun, Xiaolong Yang, Jirigala Ariben, Siqin Li, Wei Feng, Chenyang Meng, Zhenqun Zhao, Chao Sun, Xiaoxin Hu, Rui Bai, Xing Wang, Ting Hao
Journal: Ageing Research Reviews (2024)

The role of gut bacteria in preventing and delaying osteoporosis has been studied. However, the causal relationship between gut bacteria, plasma proteins, circulating metabolites and osteoporosis (OP) risk has not been fully revealed.
Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells
Authors: Yingying Wang, Youping Zhang, Hao Luo, Wei Wei, Wanting Liu, Weiwei Wang, Yunzhao Wu, Cheng Peng, Yanjie Ji, Jianfang Zhang, Chujiao Zhu, Wenhui Bai, Li Xia, Hu Lei, Hanzhang Xu, Leimiao Yin, Wei Weng, Li Yang, Ligen Liu, Aiwu Zhou, Yueyue Wei, Qi Zhu, Weiliang Zhu, Yongqing Yang, Zhijian Xu, Yingli Wu
Journal: Acta Pharmaceutica Sinica B (2024)

Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation in vitro and in vivo. Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.
Effects of reducing sedentary behaviour by increasing physical activity, on cognitive function, brain function and structure across the lifespan: a systematic review and meta-analysis
Authors: Natan Feter, Tomasz S Ligeza, Neha Bashir, Ramiya J Shanmugam, Bryan Montero Herrera, Tamara Aldabbagh, Anne-Farah Usman, Ayumi Yonezawa, Shane McCarthy, Danielle Herrera, Denise Vargas, Emaad M Mir, Talha Syed, Sanam Desai, Hector Shi, William Kim, Natalie Puhar, Kushi Gowda, Olivia Nowak, Jin Kuang, Flor Quiroz, Eduardo L Caputo, Qian Yu, JJ Pionke, Liye Zou, Lauren B Raine, Gabriele Gratton, Monica Fabiani, David R Lubans, Pedro C Hallal, Dominika M Pindus
Journal: British Journal of Sports Medicine (2024)

To examine the acute and chronic effects of reducing prolonged sedentary time (ST) with physical activity (PA) on cognitive and brain health. Systematic review and meta-analysis. PubMed, Scopus, CINAHL, PsycINFO, SPORTDiscus, Web of Science, and ProQuest Dissertation and Theses. Randomised controlled trials (RCTs) published from inception to 17 June 2024, with healthy participants without cognitive impairment or neurological conditions that affect cognitive functioning, aged ≥4 years, testing acute and chronic effects of reducing ST and/or prolonged ST by reallocating ST to PA on cognitive function, brain function, and structure. We included 25 RCTs (n=1289) investigating acute (21 studies) and chronic (4 studies) effects on cognitive function (acute: n=20, chronic: n=4) and brain function (acute: n=7, chronic: n=1); there were no studies on brain structure. Acutely interrupting continuous ST with either multiple or a single PA bout improved cognitive function measured from 3 hours to three consecutive days based on 91 effect sizes (g=0.17, 95% CI: 0.05 to 0.29, p=0.005, I 2=45.5%). When comparing single versus multiple PA bouts, only multiple PA bouts yielded a positive effect on cognitive function based on 72 effect sizes (g=0.20, 95% CI: 0.06 to 0.35, p=0.006; I 2=48.8%). Chronic studies reported null findings on cognitive function (n=4), with some evidence of improved neural efficiency of the hippocampus (n=1). Interrupting ST with PA acutely improves cognitive function. The evidence from chronic studies remains inconclusive. PROSPERO CRD42020200998.
Serum from patients with idiopathic inflammatory myopathy induces skeletal muscle weakness
Authors: Cecilia Leijding, Suchada Kaewin, Kristofer M Andreasson, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Eveline Van Gompel, Maryam Dastmalchi, Stefano Gastaldello, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson
Journal: Annals of the Rheumatic Diseases (2024)
IOC consensus statement on elite youth athletes competing at the Olympic Games: essentials to a healthy, safe and sustainable paradigm
Authors: Michael F Bergeron, Jean Côté, Sean P Cumming, Rosemary Purcell, Neil Armstrong, Luca Basilico, Kirsty Burrows, Jean-Benoit Charrin, Allyson Felix, Heike Groesswang, Yasunobu Iwasaki, Mininder S Kocher, Magali Martowicz, Kit McConnell, Jane Moran, Christine Holm Moseid, Margo Mountjoy, Torbjørn Soligard, Evgenia Tetelbaum, Ansgar Thiel, Tine Vertommen, Gloria Viseras, Richard Budgett, Lars Engebretsen, Uğur Erdener
Journal: British Journal of Sports Medicine (2024)

With the pronounced ongoing growth of global youth sports, opportunities for and participation of youth athletes on the world sports stage, including the Olympic Games, are expected to escalate. Yet, adolescence is a vulnerable period of development and inherently dynamic, with non-linear and asynchronous progression of physical, physiological, psychological and social attributes. These non-concurrent changes within and between individuals are accompanied by irregular and unpredictable threats and impediments. Likewise, the evident age-based criteria and conventional path for those youth athletes deemed eligible candidates for the Olympic Games are not well or consistently defined. Furthermore, the unstructured and largely varying policies and practices across the sporting International Federations specific to youth participation underscore the need to establish a contemporary universal paradigm that would enable elite youth athletes to navigate an individualised healthy pathway to personal, athletic and sport success. First, we reviewed and summarised key challenges facing elite youth athletes and the relevant evidence fundamental to facilitating and supporting central aspects of health and well-being, while empowering safe, sustainable and positive engagement during athletic and personal advancement and competition. Second, we developed and present a modern elite youth athlete model that emphasises a child-centred, practical framework with corresponding guidelines and recommendations to protect health and well-being while safely and favourably managing international sport competition. Our proposed evidence-informed paradigm will enable and support individualised pathways for healthy, well-rounded and sustainable positive engagement while achieving sport success for youth contending or aiming to compete at world-class international sporting events.
Proton-Activated Chloride Channel Increases Endplate Porosity and Pain in a Mouse Spinal Degeneration Model
Authors: Peng Xue, Weixin Zhang, Mengxi Shen, Junhua Yang, Jiachen Chu, Shenyu Wang, Mei Wan, Junying Zheng, Zhaozhu Qiu, Xu Cao
Journal: Journal of Clinical Investigation (2024)

Chronic low back pain (LBP) can severely affect daily physical activity. Aberrant osteoclast-mediated resorption leads to porous endplates, which allow the sensory innervation that causes LBP. Here, we report that expression of the proton-activated chloride (PAC) channel was induced during osteoclast differentiation in the porous endplates via a RANKL/NFATc1 signaling pathway. Extracellular acidosis evoked robust PAC currents in osteoclasts. An acidic environment of porous endplates and elevated PAC activation-enhanced osteoclast fusion provoked LBP. Furthermore, we found that genetic knockout of the PAC gene Pacc1 significantly reduced endplate porosity and spinal pain in a mouse LBP model, but it did not affect bone development or homeostasis of bone mass in adult mice. Moreover, both the osteoclast bone-resorptive compartment environment and PAC traffic from the plasma membrane to endosomes to form an intracellular organelle Cl channel had a low pH of approximately 5.0. The low pH environment activated the PAC channel to increase sialyltransferase St3gal1 expression and sialylation of TLR2 in the initiation of osteoclast fusion. Aberrant osteoclast-mediated resorption is also found in most skeletal disorders, including osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, heterotopic ossification, and enthesopathy. Thus, elevated Pacc1 expression and PAC activity could be a potential therapeutic target for the treatment of LBP and osteoclast-associated pain.
Deep multiomic profiling reveals molecular signatures that underpin preschool wheeze and asthma
Authors: Matthew Macowan, Céline Pattaroni, Katie Bonner, Roxanne Chatzis, Carmel Daunt, Mindy Gore, Adnan Custovic, Michael D. Shields, Ultan F. Power, Jonathan Grigg, Graham Roberts, Peter Ghazal, Jürgen Schwarze, Steve Turner, Andrew Bush, Sejal Saglani, Clare M. Lloyd, Benjamin J. Marsland
Journal: Journal of Allergy and Clinical Immunology (2024)

Wheezing in childhood is prevalent, with over one-half of all children experiencing at least 1 episode by age 6. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear. This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multiomic profiling. Unsupervised, group-agnostic integrative multiomic factor analysis was performed using host/bacterial (meta)transcriptomic and bacterial shotgun metagenomic datasets from bronchial brush samples paired with metabolomic/lipidomic data from bronchoalveolar lavage samples acquired from children 1-17 years old. Two multiomic factors were identified: one characterizing preschool-aged recurrent wheeze and another capturing an inferred trajectory from health to wheeze and school-aged asthma. Recurrent wheeze was driven by type 1-immune signatures, coupled with upregulation of immune-related and neutrophil-associated lipids and metabolites. Comparatively, progression toward asthma from ages 1 to 18 was dominated by changes related to airway epithelial cell gene expression, type 2-immune responses, and constituents of the airway microbiome, such as increased Haemophilus influenzae. These factors highlighted distinctions between an inflammation-related phenotype in preschool wheeze, and the predominance of airway epithelial-related changes linked with the inferred trajectory toward asthma. These findings provide insights into the differential mechanisms driving the progression from wheeze to asthma and may inform targeted therapeutic strategies.
North American Expert Consensus on the Post-procedural Care of Patients After Per-oral Endoscopic Myotomy Using a Delphi Process
Authors: Dennis Yang, Abdul Mohammed, Rena Yadlapati, Andrew Y Wang, Thurarshen Jeyalingam, Peter V Draganov, Ernesto Robalino Gonzaga, Muhammad K Hasan, Alexander Schlachterman, Ming-Ming Xu, Ahmed Saeed, Aziz Aadam, Reem Z Sharaiha, Ryan Law, Louis M Wong Kee Song, Monica Saumoy, John E Pandolfino, Makoto Nishimura, Michel Kahaleh, Joo Ha Hwang, Robert Bechara, Vani Ja Konda, John M DeWitt, Prashant Kedia, Nikhil A Kumta, Irteza Inayat, Stavros N Stavropoulos, Vivek Kumbhari, Uzma D Siddiqui, Salmaan Jawaid, Sherif Andrawes, Mouen Khashab, Joseph R Triggs, Neil Sharma, Mohamed Othman, Amrita Sethi, Alexandra J Baumann, Cyrus Priraka, Christy M Dunst, Mihir S Wagh, Mohammad Al-Haddad, C Prakash Gayawali, Sergey Kantsevoy, B Joseph Elmunzer
Journal: Clinical Gastroenterology and Hepatology (2024)