tbuckley/cabot-search huggingface dataset:
RAS signaling pathway is essential in regulating <scp>PIEZO1</scp>‐mediated hepatic iron overload in dehydrated hereditary stomatocytosis
Authors: Barbara Eleni Rosato, Vanessa D'Onofrio, Roberta Marra, Antonella Nostroso, Federica Maria Esposito, Anthony Iscaro, Vito Alessandro Lasorsa, Mario Capasso, Achille Iolascon, Roberta Russo, Immacolata Andolfo
Journal: American Journal of Hematology (2024)

Abstract PIEZO1 encodes a mechanoreceptor, a cation channel activated by mechanical stimuli. Gain‐of‐function (GoF) variants in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS), or xerocytosis, a pleiotropic syndrome characterized by anemia and iron overload. DHS patients develop hepatic iron overload independent of the degree of anemia and transfusion regimen. PIEZO1‐GoF variants suppress hepcidin expression in both hepatic cellular model and constitutive/macrophage‐specific Piezo1‐GoF mice model. Therefore, PIEZO1‐GoF variants regulate hepcidin expression by a crosstalk between hepatocytes (HCs) and macrophages with a still unknown mechanism. Transcriptomic and proteomics analysis in the human hepatic Hep3B cells engineered for the PIEZO1‐R2456H variant (PIEZO1‐KI) revealed alterations in the actin cytoskeleton regulation, MAPK cascade, and RAS signaling. These changes mainly occur through a novel key regulator, RRAS, whose protein and mRNA levels are regulated by PIEZO1 activation and inhibition. This regulation was further confirmed in C57BL/6 mouse primary HCs treated with Yoda‐1 and/or GsMTx‐4. Indeed, PIEZO1‐KI cells exhibited hyper‐activated RAS‐GTPase activity that is rescued by PIEZO1 inhibition, restoring expression of the hepcidin gene HAMP . A negative correlation between RAS signaling and HAMP regulation was confirmed by inhibiting RAS‐GTPase and MEK1‐2 activity. Conversely, rescued HAMP gene expression requires downregulation of RRAS, confirming negative feedback between RAS‐MAPK and BMP/SMADs pathways in HAMP regulation. We demonstrated that PIEZO1‐GoF variants influence the actin cytoskeleton organization by activating the hepatic RAS signaling system. Understanding the role of RAS signaling in regulating iron metabolism could pave the way for new therapeutic strategies in DHS and other conditions characterized by iron overload.
Photothermal Nano‐Immunotherapy Against Methicillin‐Resistant <i>Staphylococcus aureus</i> (MRSA) Biofilm Infections
Authors: Lei Xu, Baoliang Lu, Kai Xie, Wangyang Fan, Shiyuan Fang, Junchen Zhu, Jiazhao Yang, Bin Xu
Journal: Advanced Healthcare Materials (2024)

Methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections are a prevalent type of biofilm-associated infection with a poor prognosis and antibiotic resistance. The senescence of immune cells in the immune microenvironment contributes to biofilm formation. In this study, Ti₃C₂ MXene-PVA nanosheets loaded with metformin (Met@TiC) are developed for the treatment of MRSA biofilm infections. Nanosheets utilize near-infrared light to induce photothermal effects and provide direct bactericidal activity against biofilm structures. Met, which is known for its anti-inflammatory and anti-senescence properties, modulates immune responses by revitalizing the function of senescent macrophages within the biofilm microenvironment, thereby enhancing their phagocytic and biofilm-eradicating capabilities. The efficacy of this nanoplatform both in vitro and in an MRSA biofilm infection mouse model, demonstrating its potential as a photothermal nanoimmunotherapy for combating MRSA biofilm infections is validated. In summary, the Met@TiC nanoplatform offers a significant alternative to clinical solutions for MRSA biofilm infections.
Ultralow Dose Iron‐Copper Bimetallic Single‐Atom Nanozymes for Efficient Photothermal‐Chemodynamic Antibacterial and Wound Healing
Authors: Yujie Zhai, Shenglin Pei, Xuhui Qin, Lu Zhang, Xijun Liu, Shuangqi Cai, Weiqing Zhang
Journal: Advanced Healthcare Materials (2024)

Abstract The combination of photothermal and chemodynamic therapy (PTT‐CDT) using single‐atom nanozymes (SAzymes) shows great promise in combating pathogenic and drug‐resistant bacteria. However, the photothermal conversion efficiency and catalytic activity of SAzymes with solely metal sites remain inadequate, often requiring high doses for effectiveness. Herein, a bimetallic single‐atomic nanozymes with Fe and Cu active sites (FeCu BSNs) designed is reported for efficient treatment of bacterial infections through hyperthermia‐amplified nanozyme catalysis strategy. The FeCu BSNs demonstrate remarkable peroxidase (POD) activity with a specific activity (SA) of 752.25 U mg −1 , which is 2.3 folds larger than that of Fe SAzymes (323.45 U mg −1 ). Additionally, their photothermal effect achieve a photothermal conversion efficiency up to 56.26%, which is two times higher that of Fe SAzymes (29.69%) and Cu SAzymes (25.55%). These enhancements can be attributed to the hybridization of Fe and Cu sites. The FeCu BSNs‐mediated PTT‐CDT combination therapy demonstrates potent antibacterial effects in both in vitro and in vivo models, attributed to high levels of reactive oxygen species (ROS) generation and hyperthermia. This study effectively validates the application of ultralow‐dose bimetallic single‐atom nanozymes in PTT‐CDT for wound healing, offering a promising approach for enhanced wound recovery.
Artificially Engineered Nanoprobes for Ultrasensitive Magnetic Resonance Imaging
Authors: Xuyan Li, Qingshan Liu, Menglin Wu, Hao Wang, Jiang Yang, Xiaoyu Mu, Xiao‐Dong Zhang
Journal: Advanced Healthcare Materials (2024)

Abstract Magnetic resonance imaging (MRI) is a noninvasive and radiation‐free technique used for soft tissue. However, there are some limitations of the MRI modality, such as low sensitivity and poor image resolution. Artificially engineered magnetic nanoprobes have been extensively explored as a versatile platform for ultrasensitive MRI contrast agents due to their unique physiochemical characteristics and tunable magnetic properties. In this review, the emphasis is on recent progress in MRI nanoprobes with different structures and elements, including gadolinium‐, iron‐, manganese‐based and metal‐free nanoprobes. The key influencing factors and advanced engineering strategies for modulating the relaxation ratio of MRI nanoprobes are systematically condensed. Furthermore, the widespread and noninvasive visualization applications of MRI nanoprobes for real time monitoring of major organs and accurate disease diagnosing, such as cerebrovascular, ischemia, Alzheimer's disease, liver fibrosis, whole‐body tumors, inflammation, as well as multi‐mode imaging applications are summarized. Finally, the challenges and prospects for the future development of MRI nanoprobes are discussed, and promising strategies are specifically emphasized for improving biocompatibility, precisely engineering of optimal size, AI‐driven prediction and design, and multifunctional self‐assembly to enhance diagnostics. This review will provide new inspiration for artificial engineering and nanotechnology‐based molecular probes for medical diagnosis and therapy with ultrasensitive MRI.
Laser‐Assisted Micropatterned 3D Printed Scaffolds with Customizable Surface Topography and Porosity for Modulation of Cell Function
Authors: Lucia Aboal‐Castro, Yago Radziunas‐Salinas, Maria Pita‐Vilar, Bastian Carnero, Antonios G. Mikos, Carmen Alvarez‐Lorenzo, Maria Teresa Flores‐Arias, Luis Diaz‐Gomez
Journal: Advanced Healthcare Materials (2024)

Abstract The dynamic interaction between cells and their substrate is a cornerstone of biomaterial‐based tissue regeneration focused on unraveling the complex factors that govern this crucial relationship. A key challenge is translating physical cues from 2D to 3D due to limitations in current biofabrication techniques. In response, this study introduces an innovative approach that combines additive and subtractive manufacturing for precise surface patterning of 3D printed scaffolds. Using poly(𝜀‐caprolactone) as the scaffold material, polymeric fibers are 3D printed and subsequently laser‐engraved with femtosecond laser to precisely create controlled microtopographies, including microgrooves (10 and 80 µm in width) and micropits (25 µm in diameter). Testing shows that the process does not compromise the mechanical properties of the fibers, which is critical for structural applications in tissue engineering. Human mesenchymal stem cells are used to investigate the effects of these topographical features on cell behavior. The 10 µm wide microgrooves notably enhance cell attachment, with cells aligning in elongated forms along the grooves, while micropits and unpatterned surfaces promote polygonal cell shapes. This combined approach demonstrates that precisely engineered microtopographies on 3D printed scaffolds can better mimic the natural extracellular matrix, improving cellular responses and offering a promising strategy for advancing tissue regeneration.
ARI0003: Co-transduced CD19/BCMA Dual-targeting CAR-T Cells for the Treatment of Non-Hodgkin Lymphoma
Authors: Mireia Bachiller, Nina Barceló-Genestar, Alba Rodriguez-Garcia, Leticia Alserawan, Cèlia Dobaño-López, Marta Giménez-Alejandre, Joan Castellsagué, Salut Colell, Marc Otero-Mateo, Asier Antoñana-Vildosola, Marta Español-Rego, Noelia Ferruz, Mariona Pascal, Beatriz Martín-Antonio, Xavier M Anguela, Cristina Fillat, Eulàlia Olesti, Gonzalo Calvo, Manel Juan, Julio Delgado, Patricia Pérez-Galán, Álvaro Urbano-Ispizua, Sonia Guedan
Journal: Molecular Therapy (2024)
TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion
Authors: Anais Debesset, Caroline Pilon, Sylvain Meunier, Orianne Cuelenaere-Bonizec, Wilfrid Richer, Allan Thiolat, Claire Houppe, Matteo Ponzo, Jeanne Magnan, Jonathan Caron, Pamela Caudana, Jimena Tosello Boari, Sylvain Baulande, Nhu Han To, Benoit Laurent Salomon, Eliane Piaggio, Ilaria Cascone, José Laurent Cohen
Journal: Journal for ImmunoTherapy of Cancer (2024)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in patients with PDAC. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing antitumoral responses. To support this hypothesis, we first described TNFR2 expression in a cohort of 24 patients with PDAC from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as the effect on tumor progression. Patients with PDAC exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells and lower level in tumor cells. By flow cytometry and single-cell RNA-seq analysis, we identified two Treg populations in orthotopic mouse models: Resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAb promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice. Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for patients with PDAC.
Association of cardiorespiratory fitness with dementia risk across different levels of genetic predisposition: a large community-based longitudinal study
Authors: Shuqi Wang, Liyao Xu, Wenzhe Yang, Jiao Wang, Abigail Dove, Xiuying Qi, Weili Xu
Journal: British Journal of Sports Medicine (2024)

Objective We aimed to investigate the association of cardiorespiratory fitness (CRF) with cognitive function and dementia risk, taking genetic predisposition for dementia into account. Methods Within the UK Biobank, 61 214 dementia-free participants aged 39–70 years were followed for up to 12 years. CRF score was estimated using a 6 min submaximal exercise test on a stationary bike and divided into tertiles (ie, low, moderate, and high; standardised by age and sex). Global cognitive function was evaluated at baseline. Dementia was identified based on medical history and medical records. Genetic predisposition for dementia was estimated using the polygenic risk score for Alzheimer’s disease (PRS AD ), tertiled as low, moderate, or high. Data were analysed using linear regression, Poisson regression, and Laplace regression. Results Compared with low CRF, high CRF was related to better global cognitive function (β=0.05, 95% CI 0.04 to 0.07). Over the follow-up period, 553 individuals developed dementia. Compared with low CRF, the incidence rate ratio (IRR) of all dementia was 0.60 (95% CI 0.48 to 0.76) for high CRF, and the onset of all dementia was delayed by 1.48 (95% CI 0.58 to 2.39) years among people with high versus low CRF. Among people with a moderate/high polygenic risk score, high CRF attenuated all dementia risk by 35% (IRR 0.65, 95% CI 0.52 to 0.83). Conclusion High CRF is associated with better cognitive performance at baseline, and lower dementia risk long-term. High CRF could mitigate the impact of genetic predisposition on the development of dementia by 35%.
Paediatric acute liver failure: a multidisciplinary perspective on when a critically ill child is unsuitable for liver transplantation
Authors: Akash Deep, Emma C Alexander, Joe Brierley, Mihaela Damian, Anish Gupta, Valerie McLin, Moinak Sen Sarma, James E Squires, Barbara E Wildhaber
Journal: The Lancet Child & Adolescent Health (2024)
An iterative approach for estimating domain-specific cognitive abilities from large scale online cognitive data
Authors: Valentina Giunchiglia, Dragos-Cristian Gruia, Annalaura Lerede, William Trender, Peter Hellyer, Adam Hampshire
Journal: npj Digital Medicine (2024)

Abstract Online cognitive tasks are gaining traction as scalable and cost-effective alternatives to traditional supervised assessments. However, variability in peoples’ home devices, visual and motor abilities, and speed-accuracy biases confound the specificity with which online tasks can measure cognitive abilities. To address these limitations, we developed IDoCT (Iterative Decomposition of Cognitive Tasks), a method for estimating domain-specific cognitive abilities and trial-difficulty scales from task performance timecourses in a data-driven manner while accounting for device and visuomotor latencies, unspecific cognitive processes and speed-accuracy trade-offs. IDoCT can operate with any computerised task where cognitive difficulty varies across trials. Using data from 388,757 adults, we show that IDoCT successfully dissociates cognitive abilities from these confounding factors. The resultant cognitive scores exhibit stronger dissociation of psychometric factors, improved cross-participants distributions, and meaningful demographic’s associations. We propose that IDoCT can enhance the precision of online cognitive assessments, especially in large scale clinical and research applications.
What have we learned about TP53-mutated acute myeloid leukemia?
Authors: Moazzam Shahzad, Muhammad Kashif Amin, Naval G. Daver, Mithun Vinod Shah, Devendra Hiwase, Daniel A. Arber, Mohamed A. Kharfan-Dabaja, Talha Badar
Journal: Blood Cancer Journal (2024)

TP53 is a tumor suppressor gene frequently mutated in human cancers and is generally associated with poor outcomes. TP53 mutations are found in approximately 5% to 10% of patients with de novo acute myeloid leukemia (AML), more frequently observed in elderly patients and those with therapy-related AML. Despite recent advances in molecular profiling and the emergence of targeted therapies, TP53-mutated AML remains a challenge to treat. Current treatment strategies, including conventional chemotherapy, hypomethylating agents, and venetoclax-based therapies, have shown limited efficacy in TP53-mutated AML, with low response rates and poor overall survival. Allogeneic hematopoietic stem cell transplantation is a potentially curative option; however, its efficacy in TP53-mutated AML depends on comorbid conditions and disease status at transplantation. Novel therapeutic modalities, including immune-based therapies, did show promise in early-phase studies but did not translate into effective therapies in randomized controlled trials. This review provides a comprehensive overview of TP53 mutations in AML, outcomes based on allelic burden, clinical implications, and therapeutic challenges.
A reduced-dose recombinant pertussis vaccine booster in Thai adolescents: a phase 2/3, observer-blinded, randomised controlled, non-inferiority trial
Authors: Thanyawee Puthanakit, Auchara Tangsathapornpong, Suvaporn Anugulruengkitt, Rapisa Nantanee, Pornumpa Bunjoungmanee, Souad Mansouri, Librada Fortuna, Wassana Wijagkanalan, Terapong Tantawichien
Journal: The Lancet Child & Adolescent Health (2024)
Transdermal delivery of PeptiCRAd cancer vaccine using microneedle patches
Authors: Carmine D'Amico, Manlio Fusciello, Firas Hamdan, Federica D'Alessio, Paolo Bottega, Milda Saklauskaite, Salvatore Russo, Justin Cerioni, Khalil Elbadri, Marianna Kemell, Jouni Hirvonen, Vincenzo Cerullo, Hélder A Santos
Journal: Bioactive Materials (2024)
Frontline Ph-negative B-cell precursor acute lymphoblastic leukemia treatment and the emerging role of blinatumomab
Authors: Elias J. Jabbour, Hagop M. Kantarjian, Nicola Goekbuget, Bijal D. Shah, Sabina Chiaretti, Jae H. Park, Anita W. Rijneveld, Lia Gore, Shaun Fleming, Aaron C. Logan, Josep M. Ribera, Tobias F. Menne, Khalid Mezzi, Faraz Zaman, Kelly Velasco, Nicolas Boissel
Journal: Blood Cancer Journal (2024)

This narrative review seeks to summarize chemotherapeutic regimens commonly used for patients with newly diagnosed Philadelphia (Ph) chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in the frontline setting and to describe the latest clinical research using the bispecific T-cell–engaging immunotherapy blinatumomab in the first-line treatment setting. Current standard-of-care chemotherapeutic backbones for newly diagnosed Ph-negative BCP-ALL are based on the same overarching treatment principle: to reduce disease burden to undetectable levels and maintain lasting remission. The adult treatment landscape has progressively evolved following the adoption of pediatric-inspired regimens. However, these intense regimens are not tolerated by all, and high-risk patients still have inferior outcomes. Therefore, designing more effective and less toxic strategies remains key to further improving efficacy and safety outcomes. Overall, the treatment landscape is evolving in the frontline, and integration of blinatumomab into different standard frontline regimens may improve overall outcomes with a favorable safety profile.
Overcoming the global tuberculosis crisis with urgent country-level political and financial action
Authors: Suvanand Sahu, Lucica Ditiu, Rizwan Ahmed, Adam Zumla, Eleni Aklillu, Urvashi B Singh, Dorothy Yeboah-Manu, Danny Asogun, David S Hui, Alimuddin Zumla
Journal: The Lancet Infectious Diseases (2024)
DoxyPEP: real-life effectiveness in a cohort of men who have sex with men in Milan, Italy
Authors: Angelo Roberto Raccagni, Sara Diotallevi, Riccardo Lolatto, Elena Bruzzesi, Gaia Catalano, Ilaria Mainardi, Chiara Maci, Caterina Candela, Camilla Muccini, Antonella Castagna, Silvia Nozza
Journal: The Lancet Infectious Diseases (2024)
Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders
Authors: Melanie Loix, Sam Vanherle, Marta Turri, Stephan Kemp, Karl J. L. Fernandes, Jerome J. A. Hendriks, Jeroen F. J. Bogie
Journal: Molecular Neurodegeneration (2024)

Abstract Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.
Sarcopenia and the biological determinants of aging: A narrative review from a geroscience perspective
Authors: Mariá Nunes-Pinto, Renato Gorga Bandeira de Mello, Milena Nunes Pinto, Cédric Moro, Bruno Vellas, Laurent O Martinez, Yves Rolland, Philipe de Souto Barreto
Journal: Ageing Research Reviews (2024)
Neuroplasticity-enhancing therapy using glia-like cells derived from human mesenchymal stem cells for the recovery of sequelae of cerebral infarction
Authors: Eun Ji Lee, Min-Ju Lee, Ye Jin Ryu, Sang-Hyeon Nam, Rokhyun Kim, Sehyeon Song, Kyunghyuk Park, Young Jun Park, Jong-Il Kim, Seong-Ho Koh, Mi-Sook Chang
Journal: Molecular Therapy (2024)
Prognostic Communication, Symptom Burden, Psychological Distress, and Quality of Life Among Patients with Decompensated Cirrhosis
Authors: John Donlan, Alyson Kaplan, Alan Noll, Kedie Pintro, Nora Horick, Chengbo Zeng, Maria Edelen, Zainab Soetan, Cameron Comrie, Teresa Indriolo, Lucinda Li, Enya Zhu, Malia E Armstrong, Leah L Thompson, Joyce Zhou, Michelle S Diop, Nancy Mason, Kirsten G Engel, Michaela Rowland, Sara Kenimer, Karen O'Brien, Jennifer C Lai, Vicki Jackson, Raymond T Chung, Areej El-Jawahri, Nneka N Ufere
Journal: Clinical Gastroenterology and Hepatology (2024)
The autoimmune architecture of childhood idiopathic nephrotic syndrome
Authors: Tho-Alfakar Al-Aubodah, Ciriaco A Piccirillo, Howard Trachtman, Tomoko Takano
Journal: Kidney International (2024)

Idiopathic nephrotic syndrome (INS), the most common glomerular disorder in children, has long been considered an immune-mediated disease based on the efficacy of glucocorticoids at inducing remission. Nevertheless, the immune processes leading to podocytopathy have largely remained elusive. The success of B cell-depletion with rituximab, descriptions of B cell dysregulation during active disease, and the most recent discovery of autoantibodies targeting the major podocyte antigen Nephrin denote an autoimmune humoral etiology for INS. Research into the immune factors involved in INS pathogenesis have uncovered common features with other autoimmune disorders that will aid in prognostication and in guiding the expansion of our glucocorticoid-sparing therapeutic arsenal. In this review, we discuss the emerging autoimmune architecture of INS, with a specific focus on pediatric steroid-sensitive disease, including the podocyte-reactive B cell response that gives rise to anti-podocyte antibodies (APAs), the predisposing genetic factors that shape the podocyte-reactive immune landscape, and the immune triggers driving active disease.