tbuckley/cabot-search huggingface dataset:
Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells
Authors: Chirayu R Chokshi, Muhammad Vaseem Shaikh, Benjamin Brakel, Martin A Rossotti, David Tieu, William Maich, Alisha Anand, Shawn C Chafe, Kui Zhai, Yujin Suk, Agata M Kieliszek, Petar Miletic, Nicholas Mikolajewicz, David Chen, Jamie D McNicol, Katherine Chan, Amy H Y Tong, Laura Kuhlmann, Lina Liu, Zahra Alizada, Daniel Mobilio, Nazanin Tatari, Neil Savage, Nikoo Aghaei, Shan Grewal, Anish Puri, Minomi Subapanditha, Dillon McKenna, Vladimir Ignatchenko, Joseph M Salamoun, Jacek M Kwiecien, Peter Wipf, Elizabeth R Sharlow, John P Provias, Jian-Qiang Lu, John S Lazo, Thomas Kislinger, Yu Lu, Kevin R Brown, Chitra Venugopal, Kevin A Henry, Jason Moffat, Sheila K Singh
Journal: Nature Medicine (2024)
Structure and position-aware graph neural network for airway labeling
Authors: Weiyi Xie, Colin Jacobs, Jean-Paul Charbonnier, Bram van Ginneken
Journal: Medical Image Analysis (2024)

We present a novel graph-based approach for labeling the anatomical branches of a given airway tree segmentation. The proposed method formulates airway labeling as a branch classification problem in the airway tree graph, where branch features are extracted using convolutional neural networks and enriched using graph neural networks. Our graph neural network is structure-aware by having each node aggregate information from its local neighbors and position-aware by encoding node positions in the graph. We evaluated the proposed method on 220 airway trees from subjects with various severity stages of Chronic Obstructive Pulmonary Disease (COPD). The results demonstrate that our approach is computationally efficient and significantly improves branch classification performance than the baseline method. The overall average accuracy of our method reaches 91.18% for labeling 18 segmental airway branches, compared to 83.83% obtained by the standard CNN method and 87.37% obtained by the existing method. Furthermore, the reader study done on an additional set of 40 subjects shows that our algorithm performs comparably to human experts in labeling segmental-airways. We published our source code at https://github.com/DIAGNijmegen/spgnn. The proposed algorithm is also publicly available at https://grand-challenge.org/algorithms/airway-anatomical-labeling/.
Proton pump inhibitor effect on esophageal protein signature of eosinophilic esophagitis, prediction, and evaluation of treatment response
Authors: Francisca Molina‐Jiménez, Lola Ugalde‐Triviño, Laura Arias‐González, Elisa Armenteros, Carlos Relaño‐Rupérez, Sergio Casabona, José Andrés Moreno‐Monteagudo, María Teresa Pérez‐Fernández, Verónica Martín‐Domínguez, Jennifer Fernández‐Pacheco, Emilio José Laserna‐Mendieta, Patricia Muñoz‐Hernández, Jorge García‐Martínez, Javier Muñoz, Alfredo J. Lucendo, Cecilio Santander, Pedro Majano
Journal: Allergy (2024)

Abstract Background Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients including proteins associated with inflammation and epithelial barrier function; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response. Methods We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE ( n = 25) patients and healthy controls (C) ( n = 10). In EoE patients, esophageal biopsies were taken before (pre) and after (post) an 8‐week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non‐responders (non‐responder) and &lt; 15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins were characterized to identify altered biological processes and signaling pathways. Results Comparative analysis of differentially accumulated proteins between groups revealed common signatures between three groups of patients with inflammation (responder‐PrePPI, non‐responder‐PrePPI, and non‐responder‐PostPPI) and without inflammation (controls and responder‐PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in responder‐PostPPI. Furthermore, we identified a set of candidate proteins to differentiate responder‐PrePPI and non‐responder‐PrePPI EoE patients before treatment. Conclusion These findings provide evidence that PPI therapy reverses the alterations in esophageal inflammatory and epithelial proteins characterizing EoE, thereby providing new insights into the mechanism of PPI clinical response. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE.
Microglial heterogeneity in the ischemic stroke mouse brain of both sexes
Authors: Ángela del Águila, Ran Zhang, Xinyuan Yu, Lihong Dang, Feng Xu, Jin Zhang, Vaibhav Jain, Jilin Tian, Xiao-Ping Zhong, Huaxin Sheng, Wei Yang
Journal: Genome Medicine (2024)

Ischemic stroke elicits a complex and sustained immune response in the brain. Immunomodulatory treatments have long held promise for improving stroke outcomes, yet none have succeeded in the clinical setting. This lack of success is largely due to our incomplete understanding of how immune cells respond to stroke. The objective of the current study was to dissect the effect of permanent stroke on microglia, the resident immune cells within the brain parenchyma. A permanent middle cerebral artery occlusion (pMCAO) model was used to induce ischemic stroke in young male and female mice. Microglia were sorted from fluorescence reporter mice after pMCAO or sham surgery and then subjected to single-cell RNA sequencing analysis. Various methods, including flow cytometry, RNA in situ hybridization, immunohistochemistry, whole-brain imaging, and bone marrow transplantation, were also employed to dissect the microglial response to stroke. Stroke outcomes were evaluated by infarct size and behavioral tests. First, we showed the morphologic and spatial changes in microglia after stroke. We then performed single-cell RNA sequencing analysis on microglia isolated from sham and stroke mice of both sexes. The data indicate no major sexual dimorphism in the microglial response to permanent stroke. Notably, we identified seven potential stroke-associated microglial clusters, including four major clusters characterized by a disease-associated microglia-like signature, a highly proliferative state, a macrophage-like profile, and an interferon (IFN) response signature, respectively. Importantly, we provided evidence that the macrophage-like cluster may represent the long-sought stroke-induced microglia subpopulation with increased CD45 expression. Lastly, given that the IFN-responsive subset constitutes the most prominent microglial population in the stroke brain, we used fludarabine to pharmacologically target STAT1 signaling and found that fludarabine treatment improved long-term stroke outcome. Our findings shed new light on microglia heterogeneity in stroke pathology and underscore the potential of targeting specific microglial populations for effective stroke therapies.
Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy
Authors: Yumi Oh, Sujeong Kim, Yunjae Kim, Hyun Kim, Dongjun Jang, Seungjae Shin, Soo-Jin Lee, Jiwon Kim, Sang Eun Lee, Jaeik Oh, Yoojin Yang, Dohee Kim, Hae Rim Jung, Sangjin Kim, Jihui Kim, Kyungchan Min, Beomki Cho, Hoseok Seo, Dohyun Han, Hansoo Park, Sung-Yup Cho
Journal: Molecular Cancer (2024)

Abstract Background Immune checkpoint therapy (ICT) provides durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. Tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, has been suggested to modulate the extracellular protein-protein interactions, but its specific role in cancer immunity remains largely unexplored. Methods To explore tumor cell-intrinsic factors influencing anti-PD1 responsiveness, we conducted a pooled loss-of-function genetic screen in humanized mice engrafted with human immune cells. The responsiveness of cancer cells to interferon-γ (IFNγ) was estimated by evaluating IFNγ-mediated induction of target genes, STAT1 phosphorylation, HLA expression, and cell growth suppression. The sulfotyrosine-modified target gene of TPST2 was identified by co-immunoprecipitation and mass spectrometry. The in vivo effects of TPST2 inhibition were evaluated using mouse syngeneic tumor models and corroborated by bulk and single-cell RNA sequencing analyses. Results Through in vivo genome-wide CRISPR screening, TPST2 loss-of-function emerged as a potential enhancer of anti-PD1 treatment efficacy. TPST2 suppressed IFNγ signaling by sulfating IFNγ receptor 1 at Y397 residue, while its downregulation boosted IFNγ-mediated signaling and antigen presentation. Depletion of TPST2 in cancer cells augmented anti-PD1 antibody efficacy in syngeneic mouse tumor models by enhancing tumor-infiltrating lymphocytes. RNA sequencing data revealed TPST2’s inverse correlation with antigen presentation, and increased TPST2 expression is associated with poor prognosis and altered cancer immunity across cancer types. Conclusions We propose TPST2’s novel role as a suppressor of cancer immunity and advocate for its consideration as a therapeutic target in ICT-based treatments.
Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts
Authors: De-Zhen Guo, Xin Zhang, Sen-Quan Zhang, Shi-Yu Zhang, Xiang-Yu Zhang, Jia-Yan Yan, San-Yuan Dong, Kai Zhu, Xin-Rong Yang, Jia Fan, Jian Zhou, Ao Huang
Journal: Molecular Cancer (2024)

Abstract Background Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. Methods Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. Results We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1 + metabolism subtype (Metab-subtype), TOP2A + proliferation phenotype (Prol-phenotype), and S100A6 + pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-β signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-β-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis. Conclusion By establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6 + tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.
Biomimetic Nanodisks Are Effective Against Tubulointerstitial Fibrosis via Targeting Interstitial Microenvironment
Authors: Chuchu Zhou, Rou Tang, Huajin Tan, Yige Yang, Peipei Meng, He Li, Kaichao Song, Xiaochuan Tan, Xiuping Guo, Ling Ren, Shuwang He, Ya Meng, Yumei Hao, Mingbao Lin, Yujia Zhang, Hongdong Huang, Lulu Wang, Wensheng Zheng
Journal: Circulation Research (2024)
Intramyocardial Sprouting Tip Cells Specify Coronary Arterialization
Authors: Elena Cano, Jennifer Schwarzkopf, Masatoshi Kanda, Eric L. Lindberg, Irene Hollfinger, Cristina Pogontke, Caroline Braeuning, Cornelius Fischer, Norbert Hübner, Holger Gerhardt
Journal: Circulation Research (2024)

BACKGROUND: The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart. METHODS: Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species. RESULTS: We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. Esm1 -lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism. CONCLUSIONS: A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.
Cancer, metastasis, and the epigenome
Authors: Saurav Kiri, Tyrone Ryba
Journal: Molecular Cancer (2024)

Abstract Cancer is the second leading cause of death worldwide and disease burden is expected to increase globally throughout the next several decades, with the majority of cancer-related deaths occurring in metastatic disease. Cancers exhibit known hallmarks that endow them with increased survival and proliferative capacities, frequently as a result of de-stabilizing mutations. However, the genomic features that resolve metastatic clones from primary tumors are not yet well-characterized, as no mutational landscape has been identified as predictive of metastasis. Further, many cancers exhibit no known mutation signature. This suggests a larger role for non-mutational genome re-organization in promoting cancer evolution and dissemination. In this review, we highlight current critical needs for understanding cell state transitions and clonal selection advantages for metastatic cancer cells. We examine links between epigenetic states, genome structure, and misregulation of tumor suppressors and oncogenes, and discuss how recent technologies for understanding domain-scale regulation have been leveraged for a more complete picture of oncogenic and metastatic potential.
Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer
Authors: Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D. Butner, Carmine Schiavone, Dan G. Duda, Ahmed O. Kaseb, Caroline Chung, Eugene J. Koay, Vittorio Cristini, Bulent Ozpolat, George A. Calin, Zhihui Wang
Journal: Molecular Cancer (2024)

Abstract Background Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. Methods We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Results Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. Conclusions This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.
Drug discovery targeting thyroid hormone receptor β (THRβ) for the treatment of liver diseases and other medical indications
Authors: Kean Wang, Feiyang Chen, Jiang Wang, Hong Liu
Journal: Acta Pharmaceutica Sinica B (2024)

Thyroid hormone receptors (THRs), a crucial nuclear receptor protein family, primarily consist of two categories: α receptors and β receptors. Among them, THRβ is the primary subtype of thyroid hormone that confers benefits to the liver. In the last two decades, there have been efforts to develop THRβ agonists that selectively yield beneficial effects on the liver, such as lowering triglycerides and cholesterol, while reducing adverse effects on the heart, muscle, and bone. This paper systematically reviews strategies to enhance the safety of THRβ agonists for the treatment of MASH, with a focus on improving the selectivity of THRα and increasing the distribution of the drug in the liver. Additionally, we explore the potential application of this target in addressing other medical indications.
Advancements and challenges in immunocytokines: A new arsenal against cancer
Authors: Wenqiang Shi, Nan Liu, Huili Lu
Journal: Acta Pharmaceutica Sinica B (2024)

Immunocytokines, employing targeted antibodies to concentrate cytokines at tumor sites, have shown potential advantages such as prolonged cytokine half-lives, mitigated adverse effects, and synergistic antitumor efficacy from both antibody and cytokine components. First, we present an in-depth analysis of the advancements of immunocytokines evaluated in preclinical and clinical applications. Notably, anti-PD-1-based immunocytokines can redirect cytokines to intratumoral CD8
The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics
Authors: Jai Prakash, Yuval Shaked
Journal: Cancer Discovery (2024)

Abstract The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies induce ECM remodeling, resulting in therapy resistance and tumor progression. This review discusses critical issues in this field including how the ECM influences treatment outcome, how cancer therapies affect ECM remodeling, and the challenges associated with targeting the ECM. Significance: The intricate relationship between the extracellular matrix (ECM) and cancer therapeutics reveals novel insights into tumor biology and its effective treatment. While the ECM may protect tumors from anti-cancer agents, recent research highlights the paradoxical role of therapy-induced ECM remodeling in promoting treatment resistance and tumor progression. This review explores the key aspects of the interplay between ECM and cancer therapeutics.
Highlighted research articles
Journal: Cancer Discovery (2024)

In This Issue| August 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 (8): 1363–1365. https://doi.org/10.1158/2159-8290.CD-14-8-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 August 2 2024 Citation Highlighted research articles. Cancer Discov 1 August 2024; 14 (8): 1363–1365. https://doi.org/10.1158/2159-8290.CD-14-8-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 You do not currently have access to this content.
Lung Cancer Adoptive Cell Therapy: Inspiring TIL ACT Comes Center Stage
Authors: Michael T. Lotze, Markus Maeurer, Sergio A. Quezada, George Coukos
Journal: Cancer Discovery (2024)

Schoenfeld and colleagues report, in this issue, a measurable objective response rate in 6/28 (21.4%) of patients with advanced non-small cell lung cancer treated with lifileucel, a cell therapy product based on autologous tumor-infiltrating lymphocytes (TIL). Extending solid evidence in advanced melanoma that led to FDA approval of lifileucel, this new evidence bodes well for treating patients with other common tumor histologies, justifying important efforts by a large number of academic and biotechnology companies engaged in improving the TIL process. See related article by Schoenfeld et al., p. 1389 (1).
Iron: The Secret Ingredient Breaking PARPi Resistance
Authors: Hamed Alborzinia, José Pedro Friedmann Angeli
Journal: Cancer Discovery (2024)

PARP inhibitors (PARPi) are used as a first-line treatment option for cancers with BRCA1/2 mutations, yet a significant number of patients show a limited response to these agents. In the present study, Lei and colleagues demonstrate that PARPi promote increased ferroptosis sensitivity and this can be exploited therapeutically to improve the response to PARPi, marking an important therapeutic concept to exploit ferroptosis-based strategies in clinical settings. See related article by Lei et al., p. 1476 (2).