tbuckley/cabot-search huggingface dataset:
A low bleeding risk thrombolytic agent: citPA5
Authors: Shanli Chen, Sudan Fang, Yang Zhou, Zhiwei Huang, Shujuan Yu, Dan Chen, Zhiyou Wang, Yanyan Xu, Peiwen Liu, Yongkun Li, Wei Lin, Longguang Jiang, Cai Yuan, Mingdong Huang
Journal: Cardiovascular Research (2024)

Abstract Aims Alteplase is a cornerstone thrombolytic agent in clinical practice but presents a potential bleeding risk. Stroke patients need pre-screening to exclude haemorrhagic stroke before using alteplase. In this study, we develop a new thrombolytic agent citPA5, characterized by an enhanced safety profile and minimal bleeding tendency. Methods and results A clot lysis agent, named citPA5, is developed based on rtPA with point mutations to completely suppress its proteolytic activity in the absence of fibrin. In the presence of fibrin, citPA5 exhibited significantly higher fibrinolytic activity (a 15.8-fold increase of kcat/Km). Furthermore, citPA5 showed resistance to endogenous fibrinolysis inhibitor, PAI-1, resulting in enhanced potency. In a series of safety evaluation experiments, including thrombelastography assay, mice tail bleeding assay, and a murine intracerebral haemorrhage (ICH) model, citPA5 did not cause systemic bleeding or worsen ICH compared with alteplase. This highlights the low risk of bleeding associated with citPA5. Finally, we found that citPA5 effectively improved cerebral blood flow and reduced infarct volume in a carotid embolism-induced stroke model. Conclusion This clot lysis agent, citPA5, not only exhibits a low risk of bleeding but also demonstrates highly effective thrombolysis capabilities. As a result, citPA5 shows great potential for administration prior to the classification of stroke types, making it possible for use in ambulances at the onset of stroke when symptoms are identified. The findings presented in this study also suggest that this strategy could be applied to develop a new generation of fibrinolytic drugs that offer greater safety and specificity in targeting fibrin.
Correction: Fluctuations in plasma adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis
Journal: Journal for ImmunoTherapy of Cancer (2024)

immune checkpoint inhibitor-related hypophysitis' to 'Fluctuations in plasma adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis'.Relevant corrections were also made throughout the text to update 'serum' to 'plasma' and vice versa.
Dermatologic toxicity associated with targeted and immunotherapies in stage-IV non-small cell lung cancer patients: A 14-year cohort
Authors: Yanmei Peng, Ashok V. Kumar, Zhong Gu, Nikhila Kosuru, Jason A. Wampfler, Pedro A. Reck dos Santos, Nathan Y. Yu, Jonathan D'Cunha, Vinicius Ernani, Collin M. Costello, Ping Yang
Journal: Journal of the American Academy of Dermatology (2024)
Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial
Authors: Linda Stein Gold, David N Adam, Lorne Albrecht, Javier Alonso-Llamazares, Laura K Ferris, Melinda J Gooderham, H Chih-Ho Hong, Steven E Kempers, Leon H Kircik, Mark Lebwohl, Wei Jing Loo, Walter K Nahm, Kim A Papp, Daniel Stewart, Darryl P Toth, Matthew Zirwas, David Krupa, Scott Snyder, Patrick Burnett, Robert Higham, David R Berk
Journal: Journal of the American Academy of Dermatology (2024)
Plasmid DNA ionisable lipid nanoparticles as non-inert carriers and potent immune activators for cancer immunotherapy
Authors: Yue Qin, Nadia Rouatbi, Julie Tzu-Wen Wang, Rafal Baker, James Spicer, Adam A. Walters, Khuloud T. Al-Jamal
Journal: Journal of Controlled Release (2024)

Immunotherapy is currently a standard of care in the treatment of many malignancies. However, predictable side effects caused by systemic administration of highly immunostimulatory molecules have been a serious concern within this field. Intratumoural expression or silencing of immunogenic and immunoinhibitory molecules using nucleic acid-based approaches such as plasmid DNA (pDNA) and small interfering RNA (siRNA), respectively, could represent a next generation of cancer immunotherapy. Here, we employed lipid nanoparticles (LNPs) to deliver either non-specific pDNA and siRNA, or constructs targeting two prominent immunotherapeutic targets OX40L and indoleamine 2,3-dioxygenase-1 (IDO), to tumours in vivo. In the B16F10 mouse model, intratumoural delivery of LNP-formulated non-specific pDNA and siRNA led to strong local immune activation and tumour growth inhibition even at low doses due to the pDNA immunogenic nature. Replacement of these non-specific constructs by pOX40L and siIDO resulted in more prominent immune activation as evidenced by increased immune cell infiltration in tumours and tumour-draining lymph nodes. Consistently, pOX40L alone or in combination with siIDO could prolong overall survival, resulting in complete tumour regression and the formation of immunological memory in tumour rechallenge models. Our results suggest that intratumoural administration of LNP-formulated pDNA and siRNA offers a promising approach for cancer immunotherapy.
Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis
Authors: Jesús E. Campos Pacheco, Tetiana Yalovenko, Azra Riaz, Nikolay Kotov, Camilla Davids, Alva Persson, Peter Falkman, Adam Feiler, Gabriela Godaly, C. Magnus Johnson, Mikael Ekström, Georgia A. Pilkington, Sabrina Valetti
Journal: Journal of Controlled Release (2024)
Targeting ROCK2 improves macromolecular permeability in a 3D fibrotic pancreatic cancer microenvironment model
Authors: Hiroyoshi Y. Tanaka, Takuya Nakazawa, Takuya Miyazaki, Horacio Cabral, Atsushi Masamune, Mitsunobu R. Kano
Journal: Journal of Controlled Release (2024)
STING agonist-based hydrogel enhances immune activation in synergy with radiofrequency ablation for hepatocellular carcinoma treatment
Authors: Feng Ao, Xi Li, Yan Tan, Zebo Jiang, Fan Yang, Jingpei Guo, Qiancheng Zhu, Zhongguo Chen, Bin Zhou, Ke Zhang, Dan Li
Journal: Journal of Controlled Release (2024)
Erratum to ‘JAK1 promotes HDV replication and is a potential target for antiviral therapy’ [J Hepatol 80 (2024) 220-231]
Authors: Margaux J Heuschkel, Charlotte Bach, Laura Meiss-Heydmann, Emma Gerges, Emanuele Felli, Fabio Giannone, Patrick Pessaux, Catherine Schuster, Julie Lucifora, Thomas F Baumert, Eloi R Verrier
Journal: Journal of Hepatology (2024)
PRECISE Version 2: Updated Recommendations for Reporting Prostate Magnetic Resonance Imaging in Patients on Active Surveillance for Prostate Cancer
Authors: Cameron Englman, Davide Maffei, Clare Allen, Alex Kirkham, Peter Albertsen, Veeru Kasivisvanathan, Ronaldo Hueb Baroni, Alberto Briganti, Pieter De Visschere, Louise Dickinson, Juan Gómez Rivas, Masoom A. Haider, Claudia Kesch, Stacy Loeb, Katarzyna J. Macura, Daniel Margolis, Anita M. Mitra, Anwar R. Padhani, Valeria Panebianco, Peter A. Pinto, Guillaume Ploussard, Philippe Puech, Andrei S. Purysko, Jan Philipp Radtke, Antti Rannikko, Art Rastinehad, Raphaele Renard-Penna, Francesco Sanguedolce, Lars Schimmöller, Ivo G. Schoots, Shahrokh F. Shariat, Nicola Schieda, Clare M. Tempany, Baris Turkbey, Massimo Valerio, Arnauld Villers, Jochen Walz, Tristan Barrett, Francesco Giganti, Caroline M. Moore
Journal: European Urology (2024)

The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) recommendations standardise the reporting of prostate magnetic resonance imaging (MRI) in patients on active surveillance (AS) for prostate cancer. An international consensus group recently updated these recommendations and identified the areas of uncertainty.
A complex interplay of intra- and extracellular factors regulates the outcome of fetal- and adult-derived MLL-rearranged leukemia
Authors: Maria Jassinskaja, Sudip Ghosh, Joanna Watral, Mina Davoudi, Melina Claesson Stern, Ugarit Daher, Mohamed Eldeeb, Qinyu Zhang, David Bryder, Jenny Hansson
Journal: Leukemia (2024)

Abstract Infant and adult MLL1/KMT2A -rearranged (MLLr) leukemia represents a disease with a dismal prognosis. Here, we present a functional and proteomic characterization of in utero -initiated and adult-onset MLLr leukemia. We reveal that fetal MLL::ENL -expressing lymphomyeloid multipotent progenitors (LMPPs) are intrinsically programmed towards a lymphoid fate but give rise to myeloid leukemia in vivo, highlighting a complex interplay of intra- and extracellular factors in determining disease subtype. We characterize early proteomic events of MLL::ENL -mediated transformation in fetal and adult blood progenitors and reveal that whereas adult pre-leukemic cells are mainly characterized by retained myeloid features and downregulation of ribosomal and metabolic proteins, expression of MLL::ENL in fetal LMPPs leads to enrichment of translation-associated and histone deacetylases signaling proteins, and decreased expression of inflammation and myeloid differentiation proteins. Integrating the proteome of pre-leukemic cells with their secretome and the proteomic composition of the extracellular environment of normal progenitors highlights differential regulation of Igf2 bioavailability, as well as of VLA-4 dimer and its ligandome, upon initiation of fetal- and adult-origin leukemia, with implications for human MLLr leukemia cells’ ability to communicate with their environment through granule proteins. Our study has uncovered opportunities for targeting ontogeny-specific proteomic vulnerabilities in in utero -initiated and adult-onset MLLr leukemia.
Foundation metrics for evaluating effectiveness of healthcare conversations powered by generative AI
Authors: Mahyar Abbasian, Elahe Khatibi, Iman Azimi, David Oniani, Zahra Shakeri Hossein Abad, Alexander Thieme, Ram Sriram, Zhongqi Yang, Yanshan Wang, Bryant Lin, Olivier Gevaert, Li-Jia Li, Ramesh Jain, Amir M. Rahmani
Journal: npj Digital Medicine (2024)
CCR5 and inflammatory storm
Authors: Yuting Lin, Shasha Liu, Yang Sun, Chen Chen, Songwei Yang, Gang Pei, Meiyu Lin, Jingbo Yu, Xuan Liu, Huiqin Wang, Junpeng Long, Qian Yan, Jinping Liang, Jiao Yao, Fan Yi, Lei Meng, Yong Tan, Naihong Chen, Yantao Yang, Qidi Ai
Journal: Ageing Research Reviews (2024)
Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy
Authors: Mingyang Zhang, Yifan Miao, Can Zhao, Tong Liu, Xiyan Wang, Zixuan Wang, Wenxin Zhong, Zhonggui He, Chutong Tian, Jin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2024)

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.
CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia
Authors: Masoud Nasri, Malte U Ritter, Perihan Mir, Benjamin Dannenmann, Masako M Kaufmann, Patricia Arreba-Tutusaus, Yun Xu, Natalia Borbaran-Bravo, Maksim Klimiankou, Claudia Lengerke, Cornelia Zeidler, Toni Cathomen, Karl Welte, Julia Skokowa
Journal: Molecular Therapy (2024)
Contemporary attitudes and beliefs on coronary artery calcium from social media using artificial intelligence
Authors: Sulaiman Somani, Sujana Balla, Allison W. Peng, Ramzi Dudum, Sneha Jain, Khurram Nasir, David J. Maron, Tina Hernandez-Boussard, Fatima Rodriguez
Journal: npj Digital Medicine (2024)

Abstract Coronary artery calcium (CAC) is a powerful tool to refine atherosclerotic cardiovascular disease (ASCVD) risk assessment. Despite its growing interest, contemporary public attitudes around CAC are not well-described in literature and have important implications for shared decision-making around cardiovascular prevention. We used an artificial intelligence (AI) pipeline consisting of a semi-supervised natural language processing model and unsupervised machine learning techniques to analyze 5,606 CAC-related discussions on Reddit. A total of 91 discussion topics were identified and were classified into 14 overarching thematic groups. These included the strong impact of CAC on therapeutic decision-making, ongoing non-evidence-based use of CAC testing, and the patient perceived downsides of CAC testing (e.g., radiation risk). Sentiment analysis also revealed that most discussions had a neutral (49.5%) or negative (48.4%) sentiment. The results of this study demonstrate the potential of an AI-based approach to analyze large, publicly available social media data to generate insights into public perceptions about CAC, which may help guide strategies to improve shared decision-making around ASCVD management and public health interventions.
Electrospun Scaffolds are Not Necessarily Always Made of Nanofibers as Demonstrated by Polymeric Heart Valves for Tissue Engineering
Authors: Qunsong Wang, Caiyun Gao, Huajuan Zhai, Chen Peng, Xiaoye Yu, Xiaofan Zheng, Hongjie Zhang, Xin Wang, Lin Yu, Shengzhang Wang, Jiandong Ding
Journal: Advanced Healthcare Materials (2024)

Abstract In the last 30 years, there are ≈60 000 publications about electrospun nanofibers, but it is still unclear whether nanoscale fibers are really necessary for electrospun tissue engineering scaffolds. The present report puts forward this argument and reveals that compared with electrospun nanofibers, microfibers with diameter of ≈3 µm (named as “oligo‐micro fiber”) are more appropriate for tissue engineering scaffolds owing to their better cell infiltration ability caused by larger pores with available nuclear deformation. To further increase pore sizes, electrospun poly(ε‐caprolactone) (PCL) scaffolds are fabricated using latticed collectors with meshes. Fiber orientation leads to sufficient mechanical strength albeit increases porosity. The latticed scaffolds exhibit good biocompatibility and improve cell infiltration. Under aortic conditions in vitro, the performances of latticed scaffolds are satisfactory in terms of the acute systolic hemodynamic functionality, except for the higher regurgitation fraction caused by the enlarged pores. This hierarchical electrospun scaffold with sparse fibers in macropores and oligo‐micro fibers in filaments provides new insights into the design of tissue engineering scaffolds, and tissue engineering may provide living heart valves with regenerative capabilities for patients with severe valve disease in the future.
<scp>IgE</scp>‐mediated allergic diseases are associated with Alzheimer's disease
Authors: Andrzej Bozek, Magdalena Krupka‐Olek, Aleksandra Kawczyk Krupka
Journal: Allergy (2024)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Angiogenesis‐Enabled Human Ovarian Tumor Microenvironment‐Chip Evaluates Pathophysiology of Platelets in Microcirculation
Authors: Lopamudra D. Ghosh, Tanmay Mathur, James J. Tronolone, Ashley Chuong, Kelly Rangel, Sara Corvigno, Anil K. Sood, Abhishek Jain
Journal: Advanced Healthcare Materials (2024)

Abstract The tumor microenvironment (TME) promotes angiogenesis for its growth through the recruitment of multiple cells and signaling mechanisms. For example, TME actively recruits and activates platelets from the microcirculation to facilitate metastasis, but platelets may simultaneously also support tumor angiogenesis. Here, to model this complex pathophysiology within the TME that involves a signaling triad of cancer cells, sprouting endothelial cells, and platelets, an angiogenesis‐enabled tumor microenvironment chip (aTME‐Chip) is presented. This platform recapitulates the convergence of physiology of angiogenesis and platelet function within the ovarian TME and describes the contribution of platelets in promoting angiogenesis within an ovarian TME. By including three distinct human ovarian cancer cell‐types, the aTME‐Chip quantitatively reveals the following outcomes—first, introduction of platelets significantly increases angiogenesis; second, the temporal dynamics of angiogenic signaling is dependent on cancer cell type; and finally, tumor‐educated platelets either activated exogenously by cancer cells or derived clinically from a cancer patient accelerate tumor angiogenesis. Further, analysis of effluents available from aTME‐Chip validate functional outcomes by revealing changes in cytokine expression and several angiogenic and metastatic signaling pathways due to platelets. Collectively, this tumor microphysiological system may be deployed to derive antiangiogenic targets combined with antiplatelet treatments to arrest cancer metastasis.
Hypoxic Adaptation of Mitochondria and its Impact on Tumor Cell Function
Authors: Martin Benej, Ioanna Papandreou, Nicholas C. Denko
Journal: Seminars in Cancer Biology (2024)

Mitochondria are the major sink for oxygen in the cell, consuming it during ATP production. Therefore, when environmental oxygen levels drop in the tumor, significant adaptation is required. Mitochondrial activity is also a major producer of biosynthetic precursors and a regulator of cellular oxidative and reductive balance. Because of the complex biochemistry, mitochondrial adaptation to hypoxia occurs through multiple mechanisms and has significant impact on other cellular processes such as macromolecule synthesis and gene regulation. In tumor hypoxia, mitochondria shift their location in the cell and accelerate the fission and quality control pathways. Hypoxic mitochondria also undergo significant changes to fundamental metabolic pathways of carbon metabolism and electron transport. These metabolic changes further impact the nuclear epigenome because mitochondrial metabolites are used as enzymatic substrates for modifying chromatin. This coordinated response delivers physiological flexibility and increased tumor cell robustness during the environmental stress of low oxygen.
Macrophage‐Capturing Self‐Assembly Photosensitizer Nanoparticles Induces Immune Microenvironment Re‐Programming and Golgi‐Responsive Immunogenic Cell Death in Head and Neck Carcinoma
Authors: Zhi‐hang Zhou, Xin‐yu Zhou, Yi‐yi Zhang, Tong‐Chao Zhao, Jiang Li, Lai‐ping Zhong, Yi‐chuan Pang
Journal: Advanced Healthcare Materials (2024)

Abstract Head and neck carcinoma treatment is shifted toward the combination of therapy causing immune checkpoint blockade (ICB) and immunogenic cell death. In this study, a CSFRi‐chimeric TAM CSFR+ ‐targeting extracellular vesicle (EV@CSFRi) platform is developed and designed an intracellular protoporphyrin conjugated with RVRR peptide sequence for furin‐cleavage to perform Golgi‐targeting and generating ROS (GT‐RG). The graphical abstract illustrates the self‐assembly of GT‐RG nanoparticles into nanofiber through the hydrophily of RVRR and hydrophobicity of RG, and the red line indicates the site of furin cleavage. As is shown in the Graphical abstract, the Golgi‐targeting Protoporphyrin‐RVRR platform is composed with CSFRi‐chimeric extracellular vesicles and forms the tumor‐responsive TAM‐reprogramming bilayers (GT‐RG EV @CSFRi). The GT‐RG EV @CSFRi acted as a multifunctional theranostic platform, which can induce immunogenic cell death and further help modulate TAM, thus suppressing the HNC xenograft model by combination therapy with anti‐PD‐1.
MANNosylation of Mesoporous Silica Nanoparticles Modifies TLR4 Localization and NF‐κB Translocation in T24 Bladder Cancer Cells
Authors: Mariam Hohagen, Laura Sánchez, Ann‐Jacqueline Herbst, Hanspeter Kählig, Jae Won Shin, David Berry, Giorgia Del Favero, Freddy Kleitz
Journal: Advanced Healthcare Materials (2024)

Abstract D‐mannose is widely used as non‐antibiotic treatment for bacterial urinary tract infections. This application is based on a well‐studied mechanism of binding to the type 1 bacterial pili and, therefore, blocking bacteria adhesion to the uroepithelial cells. To implement D‐mannose into carrier systems, the mechanism of action of the sugar in the bladder environment is also relevant and requires investigation. Herein, two different MANNosylation strategies using mesoporous silica nanoparticles (MSNs) are described. The impact of different chemical linkers on bacterial adhesion and bladder cell response is studied via confocal microscopy imaging of the MSN interactions with the respective organisms. Cytotoxicity is assessed and the expression of Toll‐like receptor 4 (TLR4) and caveolin‐1 (CAV‐1), in the presence or absence of simulated infection with bacterial lipopolysaccharide (LPS), is evaluated using the human urinary bladder cancer cell line T24. Further, localisation of the transcription factor NF‐κB due to the MANNosylated materials is examined over time. The results show that MANNosylation modifies bacterial adhesion to the nanomaterials and significantly affects TLR4, caveolin‐1, and NF‐κB in bladder cells. These elements are essential components of the inflammatory cascade/pathogens response during urinary tract infections. These findings demonstrate that MANNosylation is a versatile tool to design hybrid nanocarriers for targeted biomedical applications.