tbuckley/cabot-search huggingface dataset:
Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer
Authors: Yutaro Mori, Yoshie Okimoto, Hiroaki Sakai, Yusuke Kanda, Hirokazu Ohata, Daisuke Shiokawa, Mikiko Suzuki, Hiroshi Yoshida, Haruka Ueda, Tomoyuki Sekizuka, Ryo Tamura, Kaoru Yamawaki, Tatsuya Ishiguro, Raul Nicolas Mateos, Yuichi Shiraishi, Yasushi Yatabe, Akinobu Hamada, Kosuke Yoshihara, Takayuki Enomoto, Koji Okamoto
Journal: Cell Reports Medicine (2024)

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.
A PET probe targeting polyamine transport system for precise tumor diagnosis and therapy
Authors: Ming Zhou, Xiaoqin Yin, Bei Chen, Shuo Hu, Wenhu Zhou
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Polyamine metabolism dysregulation is a hallmark of many cancers, offering a promising avenue for early tumor theranostics. This study presents the development of a nuclear probe derived from spermidine (SPM) for dual-purpose tumor PET imaging and internal radiation therapy. The probe, radiolabeled with either [68Ga]Ga for diagnostic applications or [177Lu]Lu for therapeutic use, was synthesized with exceptional purity, stability, and specific activity. Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells, showcasing outstanding tumor localization and target-to-non-target ratio. Mechanistic investigations employing polyamines, non-labeled precursor, and polyamine transport system (PTS) inhibitor, consistently affirmed the probe's targetability through recognition of the PTS. Notably, while previous reports indicated PTS upregulation in various tumor types for targeted therapy, this study observed no positive signals, highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis. Furthermore, when labeled with [177Lu], the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival. Investigations into biodistribution, excretion, and biosafety in healthy humans laid a robust foundation for clinical translation. This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics, offering promising prospects for clinical implementation.
An orally administered bacterial membrane protein nanodrug ameliorates doxorubicin cardiotoxicity through alleviating impaired intestinal barrier
Authors: Zhen Li, Junyue Xing, Xiaohan Ma, Wanjun Zhang, Chuan Wang, Yingying Wang, Xinkun Qi, Yanhui Liu, Dongdong Jian, Xiaolei Cheng, Yanjie Zhu, Chao Shi, Yongjun Guo, Huan Zhao, Wei Jiang, Hao Tang
Journal: Bioactive Materials (2024)

The cardiotoxicity caused by Dox chemotherapy represents a significant limitation to its clinical application and is a major cause of late death in patients undergoing chemotherapy. Currently, there are no effective treatments available. Our analysis of 295 clinical samples from 132 chemotherapy patients and 163 individuals undergoing physical examination revealed a strong positive correlation between intestinal barrier injury and the development of cardiotoxicity in chemotherapy patients. We developed a novel orally available and intestinal targeting protein nanodrug by assembling membrane protein Amuc_1100 (obtained from intestinal bacteria
Durable immunomodulatory hierarchical patch for rotator cuff repairing
Authors: Liren Wang, Yonghang Liu, Zhiqi Lin, Huiang Chen, Bowen Liu, Xiaoyu Yan, Tonghe Zhu, Qin Zhang, Jinzhong Zhao
Journal: Bioactive Materials (2024)

Degradable rotator cuff patches, followed over five years, have been observed to exhibit high re-tear rates exceeding 50%, which is attributed to the inability of degradable polymers alone to restore the post-rotator cuff tear (RCT) inflammatory niche. Herein, poly(ester-ferulic acid-urethane)urea (PEFUU) was developed, featuring prolonged anti-inflammatory functionality, achieved by the integration of ferulic acid (FA) into the polyurethane repeating units. PEFUU stably releases FA in vitro, reversing the inflammatory niche produced by M1 macrophages and restoring the directed differentiation of stem cells. Utilizing PEFUU, hierarchical composite nanofiber patch (HCNP) was fabricated, simulating the natural microstructure of the tendon-to-bone interface with an aligned-random alignment. The incorporation of enzymatic hydrolysate derived from decellularized Wharton jelly tissue into the random layer could further enhance cartilage regeneration at the tendon-to-bone interface. Via rat RCT repairing model, HCNP possessing prolonged anti-inflammatory properties uniquely facilitated physiological healing at the tendon-to-bone interface's microstructure. The alignment of fibers was restored, and histologically, the characteristic tripartite distribution of collagen I - collagen II - collagen I was achieved. This study offers a universal approach to the functionalization of degradable polymers and provides a foundational reference for their future applications in promoting the in vivo regeneration of musculoskeletal tissues.
Bioinspired super-hydrophilic zwitterionic polymer armor combats thrombosis and infection of vascular catheters
Authors: You Ke, Haotian Meng, Zeyu Du, Wentai Zhang, Qing Ma, Yuting Huang, Linxian Cui, Yifeng Lei, Zhilu Yang
Journal: Bioactive Materials (2024)

Thrombosis and infection are two major complications associated with central venous catheters (CVCs), which significantly contribute to morbidity and mortality. Antifouling coating strategies currently represent an efficient approach for addressing such complications. However, existing antifouling coatings have limitations in terms of both duration and effectiveness. Herein, we propose a durable zwitterionic polymer armor for catheters. This armor is realized by pre-coating with a robust phenol-polyamine film inspired by insect sclerotization, followed by grafting of poly-2-methacryloyloxyethyl phosphorylcholine (pMPC) via
Cryomicroneedle delivery of nanogold-engineered Rhodospirillum rubrum for photochemical transformation and tumor optical biotherapy
Authors: Qingxia Shi, Ting Yin, Cuiping Zeng, Hong Pan, Ze Chen, Lin Wang, Bo Wang, Mingbin Zheng, Lintao Cai
Journal: Bioactive Materials (2024)

Tumor metabolite regulation is intricately linked to cancer progression. Because lactate is a characteristic metabolite of the tumor microenvironment (TME), it supports tumor progression and drives immunosuppression. In this study, we presented a strategy for antitumor therapy by developing a nanogold-engineered
Facile and rapid fabrication of a novel 3D-printable, visible light-crosslinkable and bioactive polythiourethane for large-to-massive rotator cuff tendon repair
Authors: Xu Zhang, Ke Li, Chenyang Wang, Ying Rao, Rocky S. Tuan, Dan Michelle Wang, Dai Fei Elmer Ker
Journal: Bioactive Materials (2024)

Facile and rapid 3D fabrication of strong, bioactive materials can address challenges that impede repair of large-to-massive rotator cuff tears including personalized grafts, limited mechanical support, and inadequate tissue regeneration. Herein, we developed a facile and rapid methodology that generates visible light-crosslinkable polythiourethane (PHT) pre-polymer resin (∼30 min at room temperature), yielding 3D-printable scaffolds with tendon-like mechanical attributes capable of delivering tenogenic bioactive factors. Ex vivo characterization confirmed successful fabrication, robust human supraspinatus tendon (SST)-like tensile properties (strength: 23 MPa, modulus: 459 MPa, at least 10,000 physiological loading cycles without failure), excellent suture retention (8.62-fold lower than acellular dermal matrix (ADM)-based clinical graft), slow degradation, and controlled release of fibroblast growth factor-2 (FGF-2) and transforming growth factor-β3 (TGF-β3). In vitro studies showed cytocompatibility and growth factor-mediated tenogenic-like differentiation of mesenchymal stem cells. In vivo studies demonstrated biocompatibility (3-week mouse subcutaneous implantation) and ability of growth factor-containing scaffolds to notably regenerate at least 1-cm of tendon with native-like biomechanical attributes as uninjured shoulder (8-week, large-to-massive 1-cm gap rabbit rotator cuff injury). This study demonstrates use of a 3D-printable, strong, and bioactive material to provide mechanical support and pro-regenerative cues for challenging injuries such as large-to-massive rotator cuff tears.
Use of a pH-responsive imatinib mesylate sustained-release hydrogel for the treatment of tendon adhesion by inhibiting PDGFRβ/CLDN1 pathway
Authors: Sa Pang, Rongpu Wu, Wenxin Lv, Jian Zou, Yuange Li, Yanhao Li, Peilin Zhang, Xin Ma, Yi Wang, Shen Liu
Journal: Bioactive Materials (2024)

Adhesion after tendon injury, which can result in limb movement disorders, is a common clinical complication; however, effective treatment methods are lacking. Hyaluronic acid hydrogels are a new biomedical material used to prevent tendon adhesion owing to their good biocompatibility. In addition, potential drugs that inhibit adhesion formation have gradually been discovered. The anti-adhesion effects of a combination of loaded drugs into hydrogels have become an emerging trend. However, current drug delivery systems usually lack specific regulation of drug release, and the effectiveness of drugs for treating tendon adhesions is mostly flawed. In this study, we identified a new drug, imatinib mesylate (IM), that prevents tendon adhesion and explored its related molecular pathways. In addition, we designed a pH-responsive sustained-release hydrogel for delivery. Using the metal-organic framework ZIF-8 as a drug carrier, we achieved controlled drug release to increase the effective drug dose at the peak of adhesion formation to achieve better therapeutic effects. The results showed that IM blocked the formation of peritendon adhesions by inhibiting the PDGFRβ/ERK/STAT3/CLDN1 pathway. Furthermore, the hydrogel with ZIF-8 exhibited better physical properties and drug release curves than the hydrogel loaded only with drugs, showing better prevention and treatment effects on tendon adhesion.
An overview of sphingosine‐1‐phosphate receptor 2: Structure, biological function, and small‐molecule modulators
Authors: Wanting Hao, Dongdong Luo, Yuqi Jiang, Shengbiao Wan, Xiaoyang Li
Journal: Medicinal Research Reviews (2024)

Abstract Over the past decade, there has been a notable increase in research on sphingosine‐1‐phosphate receptor 2 (S1PR2), which is a type of G‐protein‐coupled receptor. Upon activation by S1P or other ligands, S1PR2 initiates downstream signaling pathways such as phosphoinositide 3‐kinase (PI3K), Mitogen‐activated protein kinase (MAPK), Rho/Rho‐associated coiled‐coil containing kinases (ROCK), and others, contributing to the diverse biological functions of S1PR2 and playing a pivotal role in various physiological processes and disease progressions, such as multiple sclerosis, fibrosis, inflammation, and tumors. Due to the extensive biological functions of S1PR2, many S1PR2 modulators, including agonists and antagonists, have been developed and discovered by pharmaceutical companies (e.g., Novartis and Galapagos NV) and academic medicinal chemists for disease diagnosis and treatment. However, few reviews have been published that comprehensively overview the functions and regulators of S1PR2. Herein, we provide an in‐depth review of the advances in the function of S1PR2 and its modulators. We first summarize the structure and biological function of S1PR2 and its pathological role in human diseases. We then focus on the discovery approach, design strategy, development process, and biomedical application of S1PR2 modulators. Additionally, we outline the major challenges and future directions in this field. Our comprehensive review will aid in the discovery and development of more effective and clinically applicable S1PR2 modulators.
Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer
Authors: Xiaochao Tan, Shike Wang, Guan-Yu Xiao, Chao Wu, Xin Liu, Biyao Zhou, Jiang Yu, Dzifa Yawa Duose, Yuanxin Xi, Jing Wang, Kunika Gupta, Apar Pataer, Jack A Roth, Michael P Kim, Fengju Chen, Chad J Creighton, William K Russell, Jonathan M Kurie
Journal: Journal of Clinical Investigation (2024)

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases
Authors: Sanne Bootsma, Mark P G Dings, Job Kesselaar, Roxan F C P A Helderman, Kyah van Megesen, Alexander Constantinides, Leandro Ferreira Moreno, Ellen Stelloo, Enzo M Scutigliani, Bella Bokan, Arezo Torang, Sander R van Hooff, Danny A Zwijnenburg, Valérie M Wouters, Vincent C J van de Vlasakker, Laskarina J K Galanos, Lisanne E Nijman, Adrian Logiantara, Veronique L Veenstra, Sophie Schlingemann, Sterre van Piggelen, Nicole van der Wel, Przemek M Krawczyk, Johannes J Platteeuw, Jurriaan B Tuynman, Ignace H de Hingh, Jan P G Klomp, Arthur Oubrie, Petur Snaebjornsson, Jan Paul Medema, Arlene L Oei, Onno Kranenburg, Clara C Elbers, Kristiaan J Lenos, Louis Vermeulen, Maarten F Bijlsma
Journal: Cell Reports Medicine (2024)

Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.
CRISPR-Cas9-mediated deletion of carbonic anhydrase 2 in the ciliary body to treat glaucoma
Authors: Jiaxuan Jiang, Kangjie Kong, Xiuli Fang, Deming Wang, Yinhang Zhang, Peiyuan Wang, Zefeng Yang, Yuwei Zhang, Xiaoyi Liu, Tin Aung, Fei Li, Patrick Yu-Wai-Man, Xiulan Zhang
Journal: Cell Reports Medicine (2024)

Highlights•Carbonic anhydrase 2 (Car2) gene knockout can reduce intraocular pressure•Dual-target CRISPR system mediates efficient knockout of Car2 gene in vivo•A single intravitreal injection can maintain long-term IOP reduction•CRISPR-Cas9-mediated Car2 gene knockout as a gene therapy for glaucomaSummaryThe carbonic anhydrase 2 (Car2) gene encodes the primary isoenzyme responsible for aqueous humor (AH) production and plays a major role in the regulation of intraocular pressure (IOP). The CRISPR-Cas9 system, based on the ShH10 adenovirus-associated virus, can efficiently disrupt the Car2 gene in the ciliary body. With a single intravitreal injection, Car2 knockout can significantly and sustainably reduce IOP in both normal mice and glaucoma models by inhibiting AH production. Furthermore, it effectively delays and even halts glaucomatous damage induced by prolonged high IOP in a chronic ocular hypertension model, surpassing the efficacy of clinically available carbonic anhydrase inhibitors such as brinzolamide. The clinical application of CRISPR-Cas9 based disruption of Car2 is an attractive therapeutic strategy that could bring additional benefits to patients with glaucoma.Graphical abstract
Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells
Authors: Toshiaki Yoshikawa, Yusuke Ito, Zhiwen Wu, Hitomi Kasuya, Takahiro Nakashima, Sachiko Okamoto, Yasunori Amaishi, Haosong Zhang, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya
Journal: Cell Reports Medicine (2024)

Highlights•A chimeric cytokine receptor G6/7R captures IL-6 via extracellular IL-6 receptors•G6/7R CAR-T cells show constitutively active IL-7 signaling•G6/7R promotes CAR-T cell proliferation and effector functions•G6/7R enhances antitumor efficacy of CAR-T cells in vivoSummaryThe efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most cancers, necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived interleukin-6 (IL-6). Thus, an approach to simultaneously enhance therapeutic efficacy and safety is warranted. Here, we develop a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activates the JAK-STAT pathway (G6/7R or G6/7R-M452L). CAR-T cells with G6/7R efficiently absorb and degrade monocyte-derived IL-6 in vitro. The G6/7R-expressing CAR-T cells show superior expansion and persistence in vivo, resulting in durable antitumor response in both liquid and solid tumor mouse models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.Graphical abstract
Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring
Authors: Jonathan Sun, Enric Esplugues, Alicia Bort, Magdalena P Cardelo, Inmaculada Ruz-Maldonado, Pablo Fernández-Tussy, Clara Wong, Hehe Wang, Iwao Ojima, Martin Kaczocha, Rachel Perry, Yajaira Suárez, Carlos Fernández-Hernando
Journal: Nature Metabolism (2024)
Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination
Authors: Robert A Watson, Weiyu Ye, Chelsea A Taylor, Elsita Jungkurth, Rosalin Cooper, Orion Tong, Tim James, Brian Shine, Monika Hofer, Damian Jenkins, Robert Pell, Eleni Ieremia, Stephanie Jones, David Maldonado-Perez, Ian S D Roberts, Nicholas Coupe, Mark R Middleton, Miranda J Payne, Benjamin P Fairfax
Journal: Journal for ImmunoTherapy of Cancer (2024)

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.