tbuckley/cabot-search huggingface dataset:
Intranasal and inhaled delivery systems for targeting circadian dysfunction in neurodegenerative disorders, perspective and future outlook
Authors: Rhearne Ryan, Mathew N Leslie, Patrick He, Paul M Young, Camilla M Hoyos, Hui Xin Ong, Daniela Traini
Journal: Advanced Drug Delivery Reviews (2025)

Synchronisation of the suprachiasmatic nucleus (SCN) driven endogenous clock, located within the central nervous system (CNS), and exogenous time cues, is essential for maintaining circadian rhythmicity, homeostasis and overall wellbeing. Disordered circadian rhythms have been associated with various conditions, inclusive of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Traditional pharmacological approaches to circadian dysfunction in neurodegenerative disorders have primarily focused on oral drug delivery. Oral medications often face challenges in achieving the necessary systemic circulation to effectively bypass the blood brain barrier (BBB) and reach the CNS, primarily due to low or variable bioavailability. Advancements in non-invasive delivery methods, such as orally inhaled and intranasal formulations, present promising alternatives for targeting the CNS. Orally inhaled and intranasal drug delivery allows for medications to rapidly achieve high systemic circulation through increased bioavailability and fast onset of action. Additionally, intranasal delivery allows for therapies to bypass the BBB through the olfactory or trigeminal nerve pathways to directly enter the CNS. This review assesses the potential for orally inhaled and intranasal therapies to treat circadian disorders in neurodegenerative conditions. In addition, this review will explore melatonin as an example of enhancing therapeutic outcomes by adopting inhaled or intranasal drug delivery formulations to improve drug absorption and target circadian disorder more effectively.
Enhancing antitumor immunity through chemotherapeutic-derived lipid nanoparticle-induced immunogenic cell death and CD40L/Flt3L mRNA-mediated dendritic cell activation
Authors: Xucheng Hou, Chang Wang, Yichen Zhong, Leiming Wang, Diana D Kang, Gabrielle Lubitz, Yonger Xue, Zhengwei Liu, Siyu Wang, Haoyuan Li, Meng Tian, Dinglingge Cao, Kaiyuan Guo, Binbin Deng, David W McComb, Thomas Marron, Brian D Brown, Miriam Merad, Joshua D Brody, Yizhou Dong
Journal: Journal of Controlled Release (2025)
Design of lipid-based formulations for oral delivery of a BASP1 peptide targeting MYC-dependent gastrointestinal cancer cells
Authors: Dennis To, Christian Steinbring, Leonie I Weber, Fabrizio Ricci, Ilaria Polidori, Annika Postina, Markus Hartl, Andreas Bernkop-Schnürch
Journal: Journal of Controlled Release (2025)

Oral delivery of the proliferation-inhibiting brain acid-soluble protein 1 effector domain peptide (Myr-NT) towards MYC-dependent gastrointestinal tumors can be achieved by forming hydrophobic ion pairs (HIPs) and incorporating them into lipid-based formulations. Hydrophobic ion pairing of fluorescently-labelled Myr-NT (Myr-NT-TAMRA) was performed, increase in lipophilicity was assessed, and the most promising HIP was subsequently incorporated into a nanoemulsion. Stability of the peptide towards degradation by trypsin was evaluated. Anti-proliferative and anti-invasive measurements were performed upon application of the loaded nanoemulsion on various MYC-dependent human cancer cell lines. Cellular uptake and molecular effect were complementary investigated by confocal laser scanning microscopy (CLSM) and by immunoblot analyses, respectively. HIPs of Myr-NT-TAMRA exhibited up to 10,000-fold increase in lipophilicity, thereby enabling incorporation into a nanoemulsion. The formulation significantly boosted stability of incorporated peptide towards enzymatic degradation by trypsin. Furthermore, anti-proliferative measurements on human cancer cell lines revealed superior biological activity of the loaded nanoemulsion compared to the native peptide particularly in lymphoma cells, but also in colorectal cancer cells. Thereby, a correlation with proliferation inhibition as well as differences in MYC protein expression were observed. Finally, CLSM imaging revealed up to 15-fold increased cellular uptake of Myr-NT-TAMRA from the nanoemulsion confirming efficient intracellular delivery of the peptide. Myr-NT can be efficiently delivered into intestinal tumor cells using orally administered lipid-based formulations.
Engineering durable antioxidative nanoreactors as synthetic organelles for autoregulatory cellular protection against oxidative stress
Authors: Panyue Wen, Anjaneyulu Dirisala, Haocheng Guo, Xueying Liu, Shingo Kobayashi, Hiroaki Kinoh, Takahisa Anada, Masaru Tanaka, Kazunori Kataoka, Junjie Li
Journal: Journal of Controlled Release (2025)
PD-L1 targeted antibody-polymer-Epirubicin conjugate prolongs survival in a preclinical murine model of advanced ovarian cancer
Authors: Jiahui Li, Hasan Al Faruque, Shannuo Li, Monika Sima, Douglas Sborov, Siwen Hu-Lieskovan, Theresa Werner, Jindřich Kopeček, Jiyuan Yang
Journal: Journal of Controlled Release (2025)

Following successful design of polymer enhanced rituximab-epirubicin (EPI) conjugates targeted to non-Hodgkin lymphoma (Zhang et al. 2017), we developed U6244-051 that consists of anti-PD-L1 antibody (αPD-L1) and semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates (ST-P-EPI); the latter is attached to αPD-L1 via Cu-free azide/alkyne cycloaddition. This new polymer-enhanced antibody-drug conjugate (pADC) not only exhibits a high drug-to-antibody ratio (DAR ~ 30-40) but also integrates immune checkpoint blockade with long-lasting immunogenic anticancer chemotherapy, providing an innovative chemo-immuno combination modality. The biological properties of U6244-051 were evaluated using ID8-Luc murine ovarian cancer cells in vitro and in vivo. In vitro, U6244-051 treatment induced immunomodulatory changes, including upregulation of calreticulin, PD-L1, and MHC I, suggesting enhanced tumor cell visibility to the immune system. In vivo efficacy was assessed in a syngeneic murine model (C57BL/6 J mice inoculated with 5 × 106 ID8-Luc cells/mouse). U6244-051 treatment resulted in 100 % survival at day 100, despite initiation at an advanced disease stage. Treatment modulated the tumor immune microenvironment by reducing immunosuppressive populations (TAMs and MDSCs) and enhancing T cell recruitment and activation. A decrease in PD-L1 expression and increased MHC I upregulation correlated with enhanced immune-mediated tumor clearance. Additionally, reduced Treg levels and increased CD8+ T cell activation contributed to a more effective antitumor response. Repeated dosing amplified immunomodulatory effects, leading to durable immunity. These results highlight U6244-051 as a next-generation pADC with high translational potential, offering enhanced efficacy and reduced on-target, off-tumor toxicity.
FAP-targeted delivery of radioiodinated probes: A progressive albumin-driven strategy for tumor theranostics
Authors: Huifeng Li, Dongsheng Xia, Lingxin Meng, Jingru Zhang, Xuedong Chen, Rongqiang Zhuang, Jinxiong Huang, Yesen Li, Jianyang Fang, Xianzhong Zhang, Zhide Guo
Journal: Journal of Controlled Release (2025)
Monocyte-adhesive peptidyl liposomes for harnessing monocyte homing to tumor tissues
Authors: Chia-Yu Chang, Shih-Hsun Huang, Chong-Yan Chen, Cheng-Bang Jian, Ching-Chung Chang, Yu-Yao Chang, Mira Jung, Hsien-Ming Lee, Bill Cheng
Journal: Journal of Controlled Release (2025)
TGFBI R124H mutant allele silencing in granular corneal dystrophy type 2 using topical siRNA delivery
Authors: Andrew McLain, Amanda Kowalczyk, Paulina Baran-Rachwalska, Flavia Maria Sutera, Louise J Robertson, Nadia Sukusu Nielsen, Jan J Enghild, Diego Cobice, Filippo Bonelli, Vanessa Barbaro, Stefano Ferrari, Benjamin Patterson, Luca Moore, John Marshall, M Andrew Nesbit, Tara Moore
Journal: Journal of Controlled Release (2025)
Risk stratification by noninvasive tests in patients with metabolic dysfunction-associated steatotic liver disease
Authors: Hye Won Lee, Jae Seung Lee, Mi Na Kim, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Seung Up Kim
Journal: Clinical and Molecular Hepatology (2025)

Recently, the Korean Association for the Study of the Liver (KASL) introduced a noninvasive test (NIT)-based approach that uses the fibrosis-4 (FIB-4) index followed by vibration-controlled transient elastography (VCTE) to identify high-risk patients with metabolic-associated steatotic liver disease (MASLD). In this study, the KASL two-step approach was validated by assessing the risk of liver-related event (LRE) development. We retrospectively analyzed 8,131 patients with MASLD who underwent VCTE between 2012 and 2020. The index date was defined as the date of the VCTE measurement. Using the KASL two-step approach (FIB-4 index and subsequent VCTE), patients were stratified into four groups (low-, intermediate-low-, intermediate-high-, and high-risk groups). Outcomes, including LREs such as decompensation (DCC) or hepatocellular carcinoma (HCC) were evaluated. During the follow-up (median 46.6 months), 86 (1.1%) patients developed LREs (39 [0.5%] with DCC and 47 [0.6%] with HCC). The KASL two-step approach classified 67.6%, 17.7%, 5.7% and 9.0% of patients in the low-, intermediate-low-, intermediate-high-, and high-risk groups, respectively. The cumulative incidences of LREs increased proportionally according to risk stratification (0.07%, 0.10%, 0.29%, and 1.51% at 3 years and 0.35%, 0.26%, 1.94% and 5.46% at 5 years). The overall accuracy in predicting LREs ranged from 67.7-99.8%. The FIB-4 index and subsequent Agile3+, Agile 4, or FibroScan aspartate aminotransferase (FAST) scores showed similar predictive abilities compared to the KASL approach. The KASL two-step approach is an effective and practical method for risk stratification in patients with MASLD, optimizing patient care through early identification of high-risk individuals.
Cryo-EM as a tool for illuminating activation mechanisms of human class A orphan GPCRs
Authors: Isabella C Russell, Dongju Lee, Denise Wootten, Patrick M Sexton, Fabian Bumbak
Journal: Pharmacological Reviews (2025)

G protein-coupled receptors (GPCRs) are critically important medicinal targets, and the cryogenic electron microscopy (cryo-EM) revolution is providing novel high-resolution GPCR structures at a rapid pace. Orphan G protein-coupled receptors (oGPCRs) are a group of approximately 100 nonolfactory GPCRs for which endogenous ligands are unknown or not validated. The absence of modulating ligands adds difficulties to understanding the physiologic significance of oGPCRs and in the determination of high-resolution structures of isolated receptors that could facilitate drug discovery. Despite the challenges, cryo-EM structures of oGPCR-G protein complexes are emerging. This is being facilitated by numerous developments to stabilize GPCR-G protein complexes such as the use of dominant-negative G proteins, mini-G proteins, complex-stabilizing nanobodies or antibody fragments, and protein tethering methods. Moreover, many oGPCRs are constitutively active, which can facilitate complex formation in the absence of a known activating ligand. Consequently, in addition to providing templates for drug discovery, active oGPCR structures shed light on constitutive GPCR activation mechanisms. These comprise self-activation, whereby mobile extracellular portions of the receptor act as tethered agonists by occupying a canonical orthosteric-binding site in the transmembrane core, constitutive activity due to alterations to conserved molecular switches that stabilize inactive states of GPCRs, as well as receptors activated by cryptic ligands that are copurified with the receptor. Cryo-EM structures of oGPCRs are now being determined at a rapid pace and are expected to be invaluable tools for oGPCR drug discovery. SIGNIFICANCE STATEMENT: Orphan G protein-coupled receptors (GPCRs) provide large untapped potential for development of new medicines. Many of these receptors display constitutive activity, enabling structure determination and insights into observed GPCR constitutive activity including (1) self-activation by mobile receptor extracellular portions that function as tethered agonists, (2) modification of conserved motifs canonically involved in receptor quiescence and/or activation, and (3) activation by cryptic lipid ligands. Collectively, these studies advance fundamental understanding of GPCR function and provide opportunities for novel drug discovery.
An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer
Authors: Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao
Journal: Molecular Therapy (2025)
The advent of clinical self-amplifying RNA vaccines
Authors: Irafasha C Casmil, Jongwoo Jin, Eun-Jeong Won, Cynthia Huang, Suiyang Liao, Hyunjoo Cha-Molstad, Anna K Blakney
Journal: Molecular Therapy (2025)

Self-amplifying RNA (saRNA) technology is an emerging platform for vaccine development, offering significant advantages over conventional mRNA vaccines. By enabling intracellular amplification of RNA, saRNA facilitates robust antigen expression at lower doses, thereby enhancing both immunogenicity and cost-effectiveness. This review examines the latest advancements in saRNA vaccine development, highlighting its applications in combating infectious diseases, including viral pathogens such as SARS-CoV-2, influenza, and emerging zoonotic threats. We discuss the design and optimization of saRNA vectors to maximize antigen expression while minimizing adverse immune responses. Recent studies demonstrating the safety, efficacy, and scalability of saRNA-based vaccines in clinical settings are also discussed. We address challenges related to delivery systems, stability, and manufacturing, along with novel strategies being developed to mitigate these challenges. As the global demand for rapid, flexible, and scalable vaccine platforms grows, saRNA presents a promising solution with enhanced potency and durability. This review emphasizes the transformative potential of saRNA vaccines to shape the future of immunization strategies, particularly in response to pandemics and other global health threats.
Hexosamine biosynthesis dysfunction-induced LIFR N-glycosylation deficiency exacerbates steatotic liver ischemia/reperfusion injury
Authors: Ran Liu, Gengqiao Wang, Yongbing Qian, Zhengting Jiang, Weimin Wang, Mao Cai, Shuhua Zhang, Guoliang Wang, Chuanzheng Wang, Tianhao Zou, Huan Cao, Di Zhang, Xueling Wang, Shenghe Deng, Tongxi Li, Jinyang Gu
Journal: Metabolism (2025)

More and more steatotic livers undergo resection or transplantation but they exhibit higher susceptibility to ischemia-reperfusion injury (IRI), which results in increased perioperative complication morbidity and mortality. IRI is driven by various cytokines and receptors, both of which are extensively modified by N-glycosylation. We aim to elucidate susceptibility of steatotic livers to IRI from the perspective of N-glycosylation. Differentially expressed genes and glycoproteins were identified with RNA-seq and N-glycoproteomics. Myeloid LIF or hepatocyte LIFR knockout mice were developed to examine the function of LIF and LIFR. Modalities including phosphoproteomics, ChIP-seq, single cell RNA-seq, metabolomics and immunoblotting were utilized to investigate underlying mechanisms. LIF transcription in myeloid cells and LIFR N-glycosylation in hepatocytes were substantially induced by IRI of normal livers. LIF and LIFR protected normal livers from IRI through activating STAT3 and promoting downstream TNFAIP3 expression, which was facilitated by LIFR N-glycosylation. Mechanistically, N-glycosylation at N238 stabilized LIFR protein by disrupting TRIM28-mediated K48 ubiquitination at LIFR K254. Furthermore, N-glycosylation at N358/N658/N675 of LIFR facilitated LIF/LIFR/gp130 complex formation and subsequent signal transduction. However, in steatotic livers, myeloid cell LIF transcription was partially inhibited due to hepatic microenvironment L-arginine insufficiency, while hepatocyte LIFR N-glycosylation was defective due to intracellular UDP-GlcNAc exhaustion. Importantly, combined L-arginine and GlcNAc treatment reversed LIF expression and LIFR N-glycosylation insufficiency, which represents potential therapeutic strategy to protect steatotic livers. LIF expression and LIFR N-glycosylation insufficiency aggravates steatotic liver IRI, which can be reversed by combined L-arginine and GlcNAc treatment.
Implementation of a national AI technology program on cardiovascular outcomes and the health system
Authors: Timothy A Fairbairn, Liam Mullen, Edward Nicol, Gregory Y H Lip, Matthias Schmitt, Matthew Shaw, Laurence Tidbury, Ian Kemp, Jennifer Crooks, Girvan Burnside, Sumeet Sharma, Anoop Chauhan, Chee Liew, Sawan Waidyanatha, Sri Iyenger, Andrew Beale, Imran Sunderji, John P Greenwood, Manish Motwani, Anna Reid, Anna Beattie, Justin Carter, Peter Haworth, Nicholas Bellenger, Benjamin Hudson, Jonathan Rodrigues, Oliver Watson, Vinod Venugopal, Russell Bull, Peter O'Kane, Aparna Deshpande, Gerald P McCann, Simon Duckett, Hatef Mansoubi, Victoria Parish, Joban Sehmi, Campbell Rogers, Sarah Mullen, Jonathan Weir-McCalL
Journal: Nature Medicine (2025)

Abstract Coronary artery disease (CAD) is a major cause of ill health and death worldwide. Coronary computed tomographic angiography (CCTA) is the first-line investigation to detect CAD in symptomatic patients. This diagnostic approach risks greater second-line heart tests and treatments at a cost to the patient and health system. The National Health Service funded use of an artificial intelligence (AI) diagnostic tool, computed tomography (CT)-derived fractional flow reserve (FFR-CT), in patients with chest pain to improve physician decision-making and reduce downstream tests. This observational cohort study assessed the impact of FFR-CT on cardiovascular outcomes by including all patients investigated with CCTA during the national AI implementation program at 27 hospitals (CCTA n = 90,553 and FFR-CT n = 7,863). FFR-CT was safe, with no difference in all-cause ( n = 1,134 (3.2%) versus 1,612 (2.9%), adjusted-hazard ratio (aHR) 1.00 (0.93–1.08), P = 0.97) or cardiovascular mortality ( n = 465 (1.3%) versus 617 (1.1%), aHR 0.96 (0.85–1.08), P = 0.48), while reducing invasive coronary angiograms ( n = 5,720 (16%) versus 8,183 (14.9%), aHR 0.93 (0.90–0.97), P &lt; 0.001) and noninvasive cardiac tests (189/1,000 patients versus 167/1,000), P &lt; 0.001). Implementation of an AI-diagnostic tool as part of a health intervention program was safe and beneficial to the patient pathway and health system with fewer cardiac tests at 2 years.
Detection of tick-borne encephalitis virus RNA in patient samples at different stages of infection
Authors: Michal Frantisek Kriha, Jan Kamis, Marketa Dvorakova, Luc Tardy, Jana Elsterova, Dana Teislerova, Ales Chrdle, Martin Palus, Daniel Ruzek, Vaclav Hönig
Journal: Journal of Infection (2025)

The aim of the study was to evaluate the efficiency of molecular diagnostics of tick-borne encephalitis (TBE) and to correlate viral RNA (vRNA) detection with the clinical and laboratory data. Clinical samples from 1125 patients from South Bohemia, Czech Republic, a highly endemic TBE region, were screened for TBE virus (TBEV) RNA by RT-qPCR. Samples included blood, serum, cerebrospinal fluid (CSF), and urine. TBEV RNA was detected in 14 patients with clinically proven TBE. TBEV RNA was most frequently detected in sera during early infection (11/37 patients tested, 29.7%) but decreased with rising IgG antibody response (3/228, 1.3%). Detection in CSF and urine was infrequent (1/30, 3.3% and 1/52, 1.9%, respectively). Additionally, five patients initially not diagnosed with TBE were retrospectively found to have TBEV RNA in serum, indicating possible underdiagnosis, particularly in mild or atypical presentations. The study also highlighted the diagnostic challenge of an immunocompromised patient whose delayed antibody response hindered timely diagnosis. In such cases, RT-qPCR could significantly shorten the diagnostic timeline. These findings underscore the value of early RNA detection in improving the diagnosis of TBE and may in the future facilitate the early administration of potential treatment, thereby improving patient outcomes.
An eRNA transcription checkpoint for diverse signal-dependent enhancer activation programs
Authors: Lishuan Wang, Wei Yuan, Amir Gamliel, Wubin Ma, Seowon Lee, Yuliang Tan, Zeyu Chen, Havilah Taylor, Kenneth Ohgi, Soohwan Oh, Aneel K Aggarwal, Michael G Rosenfeld
Journal: Nature Genetics (2025)
Allogeneic NK cells with a bispecific innate cell engager in refractory relapsed lymphoma: a phase 1 trial
Authors: Yago Nieto, Pinaki Banerjee, Indreshpal Kaur, Rafet Basar, Ye Li, May Daher, Hind Rafei, Lucila N Kerbauy, Mecit Kaplan, David Marin, Lori Griffin, Melissa Barnett, Roland Bassett, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Sanjida Islam, Christina Ganesh, Zephanie Borneo, Jeremy Ramdial, Alejandro Ramirez, Chitra Hosing, Amin Alousi, Uday Popat, Muzaffar Qazilbash, Sairah Ahmed, Swaminathan Iyer, Tania P Sainz, Francisco Vega, Natalie W Fowlkes, Karenza Alexis, Michael Emig, Andreas Harstrick, Andre Overesch, Elizabeth J Shpall, Katayoun Rezvani
Journal: Nature Medicine (2025)
Publisher Correction: Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function
Authors: Sajjad Khani, Hande Topel, Ronja Kardinal, Ana Rita Tavanez, Ajeetha Josephrajan, Bjørk Ditlev Marcher Larsen, Michael James Gaudry, Philipp Leyendecker, Nadia Meincke Egedal, Aylin Seren Güller, Natasa Stanic, Phillip M M Ruppert, Isabella Gaziano, Nils Rouven Hansmeier, Elena Schmidt, Paul Klemm, Lara-Marie Vagliano, Rainer Stahl, Fraser Duthie, Jens-Henning Krause, Ana Bici, Christoph Andreas Engelhard, Sabrina Gohlke, Peter Frommolt, Thorsten Gnad, Alvaro Rada-Iglesias, Marta Pradas-Juni, Tim Julius Schulz, Frank Thomas Wunderlich, Alexander Pfeifer, Alexander Bartelt, Martin Jastroch, Dagmar Wachten, Jan-Wilhelm Kornfeld
Journal: Nature Metabolism (2025)
CLL cell-derived exosomes alter the immune and hematopoietic systems
Authors: Ivo Veletic, David M Harris, Uri Rozovski, Maria Teresa S Bertilaccio, George A Calin, Koichi Takahashi, Ping Li, Zhiming Liu, Taghi Manshouri, Rares-Constantin Drula, Ken Furudate, Muharrem Muftuoglu, Anwar Hossain, William G Wierda, Michael J Keating, Zeev Estrov
Journal: Leukemia (2025)
Best practices for developing microbiome-based disease diagnostic classifiers through machine learning
Authors: Peikun Li, Min Li, Wei-Hua Chen
Journal: Gut Microbes (2025)

The human gut microbiome, crucial in various diseases, can be utilized to develop diagnostic models through machine learning (ML). The specific tools and parameters used in model construction such as data preprocessing, batch effect removal and modeling algorithms can impact model performance and generalizability. To establish an generally applicable workflow, we divided the ML process into three above-mentioned steps and optimized each sequentially using 83 gut microbiome cohorts across 20 diseases. We tested a total of 156 tool-parameter-algorithm combinations and benchmarked them according to internal- and external- AUCs. At the data preprocessing step, we identified four data preprocessing methods that performed well for regression-type algorithms and one method that excelled for non-regression-type algorithms. At the batch effect removal step, we identified the "ComBat" function from the sva R package as an effective batch effect removal method and compared the performance of various algorithms. Finally, at the ML algorithm selection step, we found that Ridge and Random Forest ranked the best. Our optimized work flow performed similarly comparing with previous exhaustive methods for disease-specific optimizations, thus is generally applicable and can provide a comprehensive guideline for constructing diagnostic models for a range of diseases, potentially serving as a powerful tool for future medical diagnostics.