tbuckley/cabot-search huggingface dataset:
First clinical utility of sensing Ultrasound Localization Microscopy (sULM): identifying renal pseudotumors
Authors: Sylvain Bodard, Louise Denis, Georges Chabouh, Dany Anglicheau, Olivier Hélénon, Jean-Michel Correas, Olivier Couture
Journal: Theranostics (2024)

Rationale: Renal pseudotumors, which mimic tumors on imaging, pose diagnostic challenges that can lead to unnecessary interventions. Sensing ultrasound localization microscopy (sULM) is an advanced imaging technique that uses ultrasound imaging and microbubbles as sensors to visualize kidney functional units. This study aims to investigate whether sULM could differentiate between renal pseudotumors and tumors based on the presence of glomeruli. Methods: Eleven patients (6 tumors, 6 pseudotumors - 1 patient with 2 pseudotumors) were included. Data on patient demographics, tumor characteristics, and sULM metrics were collected. Glomeruli were quantified and compared among tumors, pseudotumors, and renal cortex using sULM. Additional metrics, i.e., normalized speed and dispersity, were also analyzed. Results: Renal tumors exhibited fewer detected glomeruli paths (mean: 10 ± 6 /cm2 [range: 4-20]) compared to pseudotumors (26 ± 5 /cm2 [19-32], p < 0.001) and normal renal cortex (26 ± 6 /cm2 [15-35], p < 0.01). Tumors displayed lower dispersity (0.13 ± 0.06 arbitrary units [a.u.] [0.07-0.20]) than both the renal cortex (0.3 ± 0.1 a.u. [0.1-0.4], p = 0.0012) and pseudotumors (0.22 ± 0.05 a.u. [0.16-0.25], p = 0.0389), and lower normalized speeds of 0.08 ± 0.04 without units (w.u.) [range: 0.03-0.17] compared to the renal cortex (0.18 ± 0.07 w.u. [0.11-0.28], p = 0.0014) and pseudotumors (0.14 ± 0.02 w.u. [0.12-0.16], p = 0.0497). sULM could effectively differentiate renal pseudotumors from tumors based on glomerular detection and metrics estimation. Conclusion: This initial exploration into the clinical utility of sULM suggests it could provide a noninvasive tool to support patient management, particularly for individuals with contraindications to conventional imaging methods. Further studies are needed to confirm these preliminary findings.
CD63 as novel target for nanoemulsion-based <sup>19</sup>F MRI imaging and drug delivery to activated cardiac fibroblasts
Authors: Arlen Aurora Euan Martínez, Ann Kathrin Bergmann, Frederik Tellkamp, Stephan Schott-Verdugo, Pascal Bouvain, Julia Steinhausen, Jasmin Bahr, Vivien Kmietczyk, Maja Bencun, Ulrich Flögel, Jörg H W Distler, Marcus Krueger, Mirko Völkers, Constantin Czekelius, Holger Gohlke, Sebastian Temme, Julia Hesse, Jürgen Schrader
Journal: Theranostics (2024)

Rationale: Cardiac fibroblasts are activated following myocardial infarction (MI) and cardiac fibrosis is a major driver of the growing burden of heart failure. A non-invasive targeting method for activated cardiac fibroblasts would be advantageous because of their importance for imaging and therapy. Methods: Targeting was achieved by linking a 7-amino acid peptide (EP9) to a perfluorocarbon-containing nanoemulsion (PFC-NE) for visualization by 19F-combined with 1H-MRI. In vivo and ex vivo 1H/19F MRI was performed on a Bruker 9.4 T AVANCE III wide-bore nuclear magnetic resonance spectrometer. Photoaffinity labeling (diazirine photolinker) and mass spectrometry were used to identify the peptide-binding protein. Molecular modeling studies used ColabFold and AlphaFold 3. EP9-decorated liposomes containing modified mRNA for luciferase (mRNA-LUC) were used for the study of the cellular uptake process. Results: After injection of EP9-PFC-NE, the in-vivo 19F signal localized to the infarcted area of the heart and was EP9-specific, as verified by the use of a mutated peptide. The plasma half-life of the nanoemulsion was 20 h and electron microscopy identified cardiac fibroblasts and epicardial stromal cells to be the main populations for cellular uptake. Photoaffinity labeling identified the tetraspanin CD63 as the main EP9-binding protein, which was supported by CD63-EP9 modeling data. Expression of CD63 was significantly upregulated in infarct-activated fibroblasts of mice and humans. Cellular uptake may involve caveolae and/or clathrin-coated pits as suggested by scRNAseq data. Uptake studies with mRNA-LUC-loaded EP9-PFC-NE confirmed internalization after binding to fibroblast CD63. Conclusions: CD63 was identified to contain a specific EP9 binding motive that triggers endocytosis of EP9-PFC-NE in activated cardiac fibroblasts. This targeted nanoemulsion can therefore be used for in vivo imaging and has the potential for fibroblast-specific drug delivery.
Big data analytics and scRNA-seq in human aortic aneurysms and dissections: role of endothelial MerTK
Authors: Shijie Liu, Jinzi Wu, Oishani Banerjee, Bingzhong Xue, Hang Shi, Zufeng Ding
Journal: Theranostics (2024)

Aortic aneurysms and dissections (AAD) cause more than 10,000 deaths in the United States each year. However, there are no medications that can effectively prevent the pathogenesis of AAD. MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. Here, we mainly focused on ascending aortic aneurysms and dissections (AAAD) and investigated the role of endothelial MerTK in AAAD progression.
PIM1 instigates endothelial-to-mesenchymal transition to aggravate atherosclerosis
Authors: Zhiwei Xue, Mengtao Han, Tao Sun, Yanzhao Wu, Wenchen Xing, Feiyu Mu, Zhihan Zhang, Junzhi Liu, Xiangjun Liang, Lu Ling, Jian Wang, Jiwei Wang, Xingang Li, Bin Huang, Donghai Wang
Journal: Theranostics (2024)

Endothelial-to-mesenchymal transition (EndMT) is a cellular reprogramming mechanism by which endothelial cells acquire a mesenchymal phenotype. Endothelial cell dysfunction is the initiating factor of atherosclerosis (AS). Increasing evidence suggests that EndMT contributes to the occurrence and progression of atherosclerotic lesions and plaque instability. However, the mechanisms leading to EndMT in atherosclerotic plaques' microenvironment are poorly understood.
A H2S-activated NIR-II imaging probe for precise diagnosis and pathological evaluation of colorectal tumor
Authors: Yu Ji, Qinxian Huang, Qian Jia, Haohao Yan, Yajing Chi, Yuanyuan Jia, Chaoqiang Qiao, Yanbin Feng, Zuo Yang, Ruili Zhang, Zhongliang Wang
Journal: Theranostics (2024)

The quick and accurate detection of colorectal cancer (CRC) is essential for improving the treatment efficacy and patient survival, which nevertheless remains challenging due to low specificity and sensitivity of current CRC diagnostic approaches. Therefore, providing a robust solution for real-time and accurate tumor delineation is highly desirable.
Inhibition of Bruton's tyrosine kinase restricts neuroinflammation following intracerebral hemorrhage
Authors: Hongying Hao, Tingyu Yin, Tuo Li, Xu Zhou, Honglei Ren, Mingming Liu, Huachen Huang, Caiyun Qi, Yuwen Xiu, Wenjin Qiu, Danni Wang, Mengxuan Shi, Xiaoying Wang, Aaron S Dumont, Qiang Liu
Journal: Theranostics (2024)

Background: Intracerebral hemorrhage (ICH) is a devastating form of stroke with a lack of effective treatments. Following disease onset, ICH activates microglia and recruits peripheral leukocytes into the perihematomal region to amplify neural injury. Bruton's tyrosine kinase (BTK) controls the proliferation and survival of various myeloid cells and lymphocytes. However, the role of BTK in neuroinflammation and ICH injury remains poorly understood. Methods: Peripheral blood samples were collected from ICH patients and healthy controls to measure BTK expression profile in immune cell subsets. C57BL/6 mice were used to measure BTK expression and the activity of immune cell subsets following ICH induction. Neurological tests, brain water content, Evans blue leakage, MRI were used to assess the therapeutic effects of ibrutinib on ICH injury. Flow cytometry was used to investigate immune cell infiltration and microglial activity. Microglia were depleted using a CSF1R inhibitor PLX5622. Gr-1+ myeloid cells and B cells were depleted using monoclonal antibodies. Microglia-like BV2 cells were cultured to test the effects of BTK inhibition on these cells. Results: In humans and mice, we found that BTK was remarkably upregulated in myeloid cells after ICH. Inhibition of BTK using ibrutinib led to reduced neurological deficits, perihematomal edema, brain water content and blood-brain barrier disruption. BTK inhibition suppressed the inflammatory activity of microglia and brain infiltration of leukocytes. In contrast, BTK inhibition did not alter the counts of peripheral immune cells other than B cells. Further, the depletion of microglia or Gr-1+ myeloid cells ablated the protective effects of BTK inhibition against ICH injury. Notably, the depletion of B cells did not alter the protective effects of BTK inhibition against ICH injury. This suggests that the benefit of BTK inhibition in ICH mainly involves its impact on microglia and Gr-1+ myeloid cells. Conclusion: Our findings demonstrate that BTK inhibition attenuates neuroinflammation and ICH injury, which warrants further investigation as a potential therapy for ICH.
Development of dual aptamers-functionalized c-MET PROTAC degraders for targeted therapy of osteosarcoma
Authors: Xuekun Fu, Jie Huang, Xinxin Chen, Duoli Xie, Hongzhen Chen, Zhijian Liang, Zhuqian Wang, Yiying Liang, Aiping Lu, Chao Liang
Journal: Theranostics (2024)

Rationale: Osteosarcoma (OS) is the most common bone malignancy. c-MET is recognized as a therapeutic target. However, traditional c-MET inhibitors show compromised efficacy due to the acquired resistance and side effects. PROTACs targeting c-MET have displayed improved antitumor efficacy by overcoming drug resistance, whereas safety concern caused by lack of tumor-targeting ability is still a pending issue. AS1411 is an aptamer that recognizes and penetrates tumors by targeting nucleolin (NCL) overexpressed on the surface of tumor cells. Since NCL interacts with an E3 ligase MDM2 intracellularly, we repurposed AS1411 as an MDM2 recruiter by employing NCL as a bridge. Methods: We select the ssDNA c-MET aptamer SL1 as the c-MET ligand to design dual aptamer-functionalized PROTACs, as SL1 can be easily conjugated to AS1411 through base-pair complementarity using a nucleic acid linker. Four AS1411-SL1 chimeras are generated by linking AS1411 to either the 5' or 3' terminus of SL1 via two different lengths of nucleic acid linkers. The therapeutic efficacy of these PROTACs is evaluated through both in vitro and in vivo experiments. Results: The PROTACs enable the ubiquitination and degradation of c-MET. The PROTACs effectively inhibit growth, enhance apoptosis, and overcome drug resistance of OS cells in vitro. The PROTACs demonstrate in vivo tumor-targeting ability and facilitate the OS treatment with no detectable toxicity. Conclusion: This study suggests that the AS1411-SL1 chimeras could be promising c-MET degraders for targeted therapy of OS.
18F-5-fluoro-aminosuberic acid PET/CT imaging of oxidative-stress features during the formation of DEN-induced rat hepatocellular carcinoma
Authors: Feng Xiong, Yilin Yang, Zhengru Han, Buchuan Zhang, Kijung Kwak, Pei Wang, Qiaorong Chen, Ziqiang Wang, Jingfei Yang, Xiaoyun Deng, Sijuan Zou, Zhuoli Zhang, Pengtao You, Bo Yu, Xiaohua Zhu
Journal: Theranostics (2024)

The role of oxidative stress metabolism during hepatocellular carcinoma (HCC) formation potentially allows for positron emission tomography (PET) imaging of oxidative stress activity for early and precise HCC detection. However, there is currently limited data available on oxidative-stress-related PET imaging for longitudinal monitoring of the pathophysiological changes during HCC formation. This work aimed to explore PET-based longitudinal monitoring of oxidative stress metabolism and determine the sensitivity of [18F]-5-fluoroaminosuberic acid ([18F]FASu) for assessing pathophysiological processes in diethylnitrosamine (DEN) induced rat HCC.
Integrating oxygen-boosted sonodynamic therapy and ferroptosis <i>via</i> engineered exosomes for effective cancer treatment
Authors: Mingbo Wu, Zhanlin Zhang, Dong Li, Xiaomiao Ruan, Jingwen Yang, Siyi Chen, Xin Li, Wenwu Ling
Journal: Theranostics (2024)

Rationale: Ferroptosis and sonodynamic therapy (SDT) are both promising therapeutic modalities, but their clinical application remains challenging due to the hypoxic tumor microenvironment and limited supply of polyunsaturated fatty acids. Developing an agent with oxygen-enhanced SDT and increased ferroptosis sensitivity is crucial for advancing tumor therapy. Methods: In this study, catalase (Cat) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) highly expressed 4T1 cells were constructed via lentivirus transfection. Cat and ACSL4 enriched exosomes (EXO@CA) were then extracted and loaded with the sonosensitizer tetrakis (4-carboxyphenyl) porphyrin (TCPP) through electroporation to create engineered exosomes (EXO@CAT). We evaluated the ability of EXO@CAT to generate oxygen in a hydrogen peroxide environment and investigated its effect on motion profiles and permeability of EXO@CAT. The in vitro antitumor activity was assessed via cytotoxicity, ROS levels, live/dead staining, and apoptosis, with ferroptosis biomarkers confirming ferroptosis activation. We also evaluated the in vivo anticancer efficacy of EXO@CAT by tumor growth analysis and histological and immunohistochemical staining in mouse models bearing breast tumor. Results: EXO@CAT harnesses ultrasound stimulation to facilitate oxygen-enriched SDT, demonstrating significant capacity for singlet oxygen (1O2) generating, which promotes the accumulation of lipid peroxidation (LPO), ultimately leading to the induction of ferroptosis. Concurrently, ACSL4 released from EXO@CAT also increases LPO accumulation by modifying cellular lipid composition, thereby enhancing cellular sensitivity to ferroptosis. Moreover, both in vitro and in vivo experiments demonstrate that the homologous targeting ability of EXO@CAT enables its efficient accumulation in tumor tissues, and the oxygen generation catalyzed by Cat not only alleviates tumor hypoxia but also facilitates the penetration of EXO@CAT into deeper layers of tumor tissue. Conclusions: EXO@CAT combines endogenous proteins, which are prone to inactivation, with an exogenous sonosensitizer, allowing synergistic anticancer treatment of both ferroptosis and SDT with improved efficacy.
A fluorogenic ROS-triggered hydrogen sulfide donor for alleviating cerebral ischemia-reperfusion injury
Authors: Huangjie Lu, Huiying Zeng, Wenlong Wei, Yuying Chen, Ziqiang Zhou, Xuyang Ning, Ping Hu
Journal: Theranostics (2024)

Cerebral ischemia-reperfusion injury is a severe neurovascular disease that urgently requires effective therapeutic interventions. Recently, hydrogen sulfide (H
Detecting metastatic potential of cancer through longitudinal vasculature imaging of biomaterial scaffold using non-invasive <i>in vivo</i> photoacoustic microscopy and optical coherence tomography
Authors: Zhanpeng Xu, Guillermo Escalona, Ian Schrack, Wei Zhang, Tianqu Zhai, Lonnie D Shea, Xueding Wang
Journal: Theranostics (2024)

Metastasis represents a stage in which the therapeutic objective changes from curing disease to prolonging survival, as detection typically occurs at advanced stages. Technologies for the early identification of disease would enable treatment at a lower disease burden and heterogeneity. Herein, we investigate the vascular dynamics within a synthetic metastatic niche as a potential marker of disease progression.
P2X7R antagonism suppresses long-lasting brain hyperexcitability following traumatic brain injury in mice
Authors: Mariana Alves, Laura de Diego-Garcia, Gloria Vegliante, Oscar Moreno, Beatriz Gil, Pedro Ramos-Cabrer, Meghma Mitra, Ana Fernandez Martin, Aida Menéndez-Méndez, Yitao Wang, Nathan Ryzewski Strogulski, Meng-Juan Sun, Ciara Melia, Giorgia Conte, Sandra Plaza-García, Igor Khalin, Xinchen Teng, Nikolaus Plesnila, Bert Klebl, Klaus Dinkel, Michael Hamacher, Anindya Bhattacharya, Marc Ceusters, James Palmer, David J Loane, Jordi Llop, David C Henshall, Tobias Engel
Journal: Theranostics (2024)

Purpose: Post-traumatic epilepsy (PTE) is one of the most common life-quality reducing consequences of traumatic brain injury (TBI). However, to date there are no pharmacological approaches to predict or to prevent the development of PTE. The P2X7 receptor (P2X7R) is a cationic ATP-dependent membrane channel that is expressed throughout the brain. While increasing evidence suggests a role for the P2X7R during seizures and epilepsy, it is unclear if changes in P2X7R expression can predict TBI-induced epilepsy development, and whether P2X7R antagonism can protect against long-lasting brain hyperexcitability caused by TBI. Methods: TBI was induced in adult male mice using the controlled cortical impact model (CCI). To test the anti-epileptogenic effects of P2X7R antagonism, mice were treated with brain-penetrant P2X7R antagonists JNJ-54175446 (30 mg/kg) or AFC-5128 (30 mg/kg) for 7 days post-CCI. The cell-type specific effects of P2X7Rs on TBI-induced hyperexcitability were analyzed in mice lacking exon 2 of the P2rx7 gene selectively in microglia (P2rx7:Cx3cr1-Cre). Static positron emission tomography (PET) via an intravenous injection of the P2X7R radioligand 18F-JNJ-64413739 and magnetic resonance imaging (MRI) were conducted twice during the first- and third-week post-injury. Results: Following TBI, while there were no obvious changes in P2X7R protein levels in the ipsilateral hippocampus post-injury, there was a delayed increase in P2X7R protein levels in the ipsilateral cortex at 3 months post-injury. Treatment with P2X7R antagonists shortly after TBI reduced long-lasting brain hyperexcitability, reduced cortical contusion volume, and normalized injury-induced hyperactivity to control sham-levels at 3 weeks post-TBI. Notably, mice lacking P2rx7 in microglia had an increased seizure threshold after TBI, suggesting that P2X7R contributed to brain hyperexcitability via its effects on microglia. Finally, P2X7R radioligand uptake after TBI correlated with seizure threshold at 3 weeks post-injury. Conclusions: Our results demonstrate the antiepileptogenic potential of P2X7R antagonism to prevent TBI-induced epilepsy and indicate that P2X7R-based PET imaging may be a useful diagnostic tool to identify people at risk of developing PTE.
Platelet membrane decorated exosomes enhance targeting efficacy and therapeutic index to alleviate arterial restenosis
Authors: Shan Lu, Ruihan Wang, Minghao Cai, Chen Yuan, Bin Gao, Daqiao Guo, Yisheng Xu, Weiguo Fu, Xiaohua Yu, Yi Si
Journal: Theranostics (2024)

Rationale: Postinterventional restenosis is a major challenge in the treatment of peripheral vascular disease. Current anti-restenosis drugs inhibit neointima hyperplasia but simultaneously impair endothelial repair due to indiscrminative cytotoxity. Stem cell-derived exosomes provide multifaceted therapeutic effects by delivering functional miRNAs to endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs). However, their clinical application is severly limited by poor targeting and low tissue uptake in injured vessel. Methods: To address this challenge, we constructed platelet-mimetic exosomes (PM-EXOs) by fusing mesenchymal stem cell (MSC)-derived exosomes with platelet membrane in order to harness the natural ability of platelets to target vascular injury, evade clearance by the mononuclear phagocyte system, and penetrate into the intima by hitchhiking on inflammatory monocytes. Results: PM-EXOs demonstrated enhanced cellular uptake by endothelial cells and macrophages, exerting proangiogenic and immunomodulatory effects via the delivery of functional miRNAs in vitro. The intravenously administrated PM-EXOs exhibited extended circulation time and a 4-fold enhancement in targeting injured arteries compared to unmodified exosomes. In mouse and rat carotid artery injury models, PM-EXOs were shown to promote endothelial repair on the denuded arterial wall, lower the M1/M2 ratio of infiltrated macrophages, and eventually inhibit phenotypic switch of vascular smooth muscle cells and reduce the formation of neointima without causing systemic toxicity. Conclusions: This biomimetic strategy may be leveraged to boost the therapeutic index of exosomes and realize the multifaceted treatment of arterial restenosis.
Cancer in 2024
Journal: Cancer Discovery (2024)

Summary: Excerpts from the 14th edition of the annual American Association for Cancer Research Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) and the third edition of the American Association for Cancer Research Cancer Disparities Progress Report (https://cancerprogressreport.aacr.org/disparities/) to US Congress and the public, both released in 2024, highlight significant strides made possible through medical research, much of which is supported by federal investments in the NIH, NCI, FDA, and Centers for Disease Control and Prevention, as well as recent progress in understanding the overlapping and intersecting causes of cancer disparities and in addressing health inequities through evidence-based public policies.
Highlighted research articles
Journal: Cancer Discovery (2024)

In This Issue| December 02 2024 Highlighted research articles Author & Article Information Online ISSN: 2159-8290 Print ISSN: 2159-8274 ©2024 American Association for Cancer Research2024American Association for Cancer Research Cancer Discov (2024) 14 (12): 2305–2307. https://doi.org/10.1158/2159-8290.CD-14-12-ITI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record December 2 2024 Citation Highlighted research articles. Cancer Discov 1 December 2024; 14 (12): 2305–2307. https://doi.org/10.1158/2159-8290.CD-14-12-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Novel biological markers are needed to personalize the treatment of patients with head and neck squamous cell carcinoma (HNSCC). In this study, Gessain and colleagues identified multinucleated giant cells (MGC), a subtype of TREM2-expressing tumor-associated macrophages (TAM), to be associated with longer overall survival. They developed a deep-learning model to automate MGC quantification on routine H&E/HES digital microscopy slides, facilitating its integration into clinical practice. Using spatial transcriptomics and proteomics, they revealed that TREM2-expressing MGCs and mononuclear TAMs clustered in keratin-rich granulomas. These findings challenge current knowledge about TREM2 TAMs and propose MGC density as a promising prognostic tool in HNSCC. See article, p. 2352. Oncogenic ALK alterations drive non-small cell lung cancer and other cancers. In this study, Lin and colleagues disclosed NVL-655, a macrocyclic ALK inhibitor designed to address limitations of approved ALK therapies. NVL-655 and up to 7 other ALK inhibitors were profiled across 20 ALK... You do not currently have access to this content.
Reflections on Advances in Cancer Research in 2024
Authors: Katherine M. Aird, Aadel A. Chaudhuri, Jennifer L. Guerriero, Shiri Gur-Cohen, Benjamin Izar, Brittany D. Jenkins, Delphine Merino, Alejo E. Rodriguez-Fraticelli, Shensi Shen, Itai Yanai
Journal: Cancer Discovery (2024)
Precision Oncology: 2024 in Review
Authors: Matteo Repetto, Nicole Fernandez, Alexander Drilon, Debyani Chakravarty
Journal: Cancer Discovery (2024)

Summary: This article discusses the specific advances made in precision oncology in 2024. We comment on the evolving nature of predictive molecular events used to select patients who will most benefit clinically from treatment. We also discuss advances in the development of strategic treatment regimens for combination therapies, rational drug design of small-molecule inhibitors, and structurally informed drug repurposing.