tbuckley/cabot-search huggingface dataset:
A Minimally Invasive Endovascular Approach to the Cerebellopontine Angle Cistern Enables Broad CNS Biodistribution of scAAV9-CB-GFP
Authors: Hector Ribeiro Benatti, Vania Anagnostakou, Toloo Taghian, Erin F Hall, Sarah Nath, Carl B Heilman, Brandon M Beneduce, Anita Leporati, Christopher Raskett, Mark Epshtein, Robert King, Matthew J Gounis, Adel M Malek, Heather L Gray-Edwards
Journal: Molecular Therapy (2024)

Neurological disorders pose a challenge for targeted therapy due to restricted access of therapeutic agents to the central nervous system (CNS). Current methods are limited by procedure-related risks, invasiveness, and insufficient CNS biodistribution. A novel percutaneous transvenous technology, currently in clinical trials for communicating hydrocephalus, offers a minimally invasive approach by providing endovascular access to the cerebrospinal fluid-filled cerebellopontine angle (CPA) cistern. We hypothesized that drug delivery to the CPA cistern could yield widespread CNS distribution. Using an ovine model, we compared the biodistribution of scAAV9-CB-GFP following CPA cistern infusion with previously reported cisterna magna (CM) administration. Targeting both the CPA cistern and CM in sheep, we employed a lumbar spine-inserted microcatheter under fluoroscopy. CPA delivery of AAV9 demonstrated biodistribution and transduction in the cerebral cortices, striatum, thalamus, midbrain, cerebellum, and spinal cord, with minor liver distribution comparable to CM. The favorable safety profile in humans with hydrocephalus suggests that percutaneous endovascular injection into the CPA could offer a clinically safer and minimally invasive delivery system for CNS gene and cell-based therapies.Graphical abstract
CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression
Authors: Michael W. Lewis, Caitlin M. King, Kamila Wisniewska, Matthew J. Regner, Alisha Coffey, Michael R. Kelly, Raul Mendez-Giraldez, Eric S. Davis, Douglas H. Phanstiel, Hector L. Franco
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer, which is due in part to the paucity of targeted therapies. A systematic analysis of regulatory elements that extend beyond protein-coding genes could uncover avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with their noncoding enhancer RNA (eRNA) transcripts. The functions of the top 30 eRNA-producing super-enhancers were systematically probed using high-throughput CRISPR-interference assays coupled to RNA sequencing that enabled unbiased detection of target genes genome-wide. Generation of high-resolution Hi-C chromatin interaction maps enabled annotation of the direct target genes for each super-enhancer, which highlighted their proclivity for genes that portend worse clinical outcomes in patients with TNBC. Illustrating the utility of this dataset, deletion of an identified super-enhancer controlling the nearby PODXL gene or specific degradation of its eRNAs led to profound inhibitory effects on target gene expression, cell proliferation, and migration. Furthermore, loss of this super-enhancer suppressed tumor growth and metastasis in TNBC mouse xenograft models. Single-cell RNA sequencing and assay for transposase-accessible chromatin with high-throughput sequencing analyses demonstrated the enhanced activity of this super-enhancer within the malignant cells of TNBC tumor specimens compared with nonmalignant cell types. Collectively, this work examines several fundamental questions about how regulatory information encoded into eRNA-producing super-enhancers drives gene expression networks that underlie the biology of TNBC. Significance: Integrative analysis of eRNA-producing super-enhancers defines molecular mechanisms controlling global patterns of gene expression that regulate clinical outcomes in breast cancer, highlighting the potential of enhancers as biomarkers and therapeutic targets.
Cholangiocyte ciliary defects induce sustained epidermal growth factor receptor signaling
Authors: Kishor Pant, Seth Richard, Estanislao Peixoto, Subheksha Baral, Rendong Yang, Yanan Ren, Tatyana V. Masyuk, Nicholas F. LaRusso, Sergio A. Gradilone
Journal: Hepatology (2024)

The primary cilium, an organelle that protrudes from cell surfaces, is essential for sensing extracellular signals. With disturbed cellular communication and chronic liver pathologies, this organelle's dysfunctions have been linked to disorders, including polycystic liver disease and cholangiocarcinoma. The goal of this study was to elucidate the relationship between primary cilia and the crucial regulator of cellular proliferation, the epidermal growth factor receptor (EGFR) signaling pathway, which has been associated with various clinical conditions.
PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma
Authors: Sarah Spear, Olivia Le Saux, Hasan B. Mirza, Nayana Iyer, Katie Tyson, Fabio Grundland Freile, Josephine B. Walton, Chloe Woodman, Sheba Jarvis, Darren P. Ennis, Carmen Aguirre Hernandez, Yuewei Xu, Pavlina Spiliopoulou, James D. Brenton, Ana P. Costa-Pereira, David P. Cook, Barbara C. Vanderhyden, Hector C. Keun, Evangelos Triantafyllou, James N. Arnold, Iain A. McNeish
Journal: Cancer Research (2024)

High-grade serous ovarian carcinoma (HGSC) remains a disease with poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages were derived from peritoneal fluid macrophages and exhibited a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. In addition, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver, leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages was correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in patients with HGSC. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC. Significance: Macrophages with elevated HMOX1 expression are enriched in PTEN-deficient high-grade serous ovarian carcinoma, promote tumor growth, and represent a potential therapeutic target.
Targeting Galectin-1 Overcomes Paclitaxel Resistance in Esophageal Squamous Cell Carcinoma
Authors: Liting Zhou, Jie Tian, Keke Wang, Yijie Ma, Xiaojie Chen, Hui Luo, Bingbing Lu, Nan Wang, Penglei Wang, Xuejiao Liu, Ran Zhao, Simin Zhao, Jiutao Wang, Wenna Nie, Hong Ge, Wenting Liu, Tingxuan Gu, Kangdong Liu, Mee-Hyun Lee, Xiang Li, Zigang Dong
Journal: Cancer Research (2024)

Resistance to paclitaxel poses a major obstacle in esophageal squamous cell carcinoma (ESCC) treatment. A better understanding of the mechanisms underlying paclitaxel resistance could help identify prognostic biomarkers and improved therapeutic strategies. In this study, we established a patient-derived xenograft model of acquired paclitaxel resistance and used RNA sequencing to identify galectin-1, encoded by LGALS1, as a key mediator of resistance. Integrative analysis of clinical data and physiological studies indicated that serum galectin-1 levels were elevated in resistant patients and correlated with treatment outcomes before and during taxane therapy. Importantly, exposing cells to serum from resistant patients resulted in increased paclitaxel resistance compared to serum from sensitive patients, which was closely associated with galectin-1 concentrations in the serum. The specific clearance of galectin-1 from resistant patient serum significantly restored paclitaxel sensitivity, and inhibiting galectin-1, through knockdown or the pharmacologic inhibitor OTX008, increased sensitivity to paclitaxel. Galectin-1 inhibition reduced the activity of β-catenin, thereby inhibiting stem cell properties induced by the Wnt/β-catenin pathway. Furthermore, galectin-1 regulated MDR1 transcription through increased nuclear accumulation of β-catenin, thus increasing resistance to paclitaxel. Combining OTX008 with clinical taxane formulations effectively reversed paclitaxel resistance in vitro and in vivo. Elevated galectin-1 levels thus serve as an indicator of response to paclitaxel therapy in ESCC, offering a therapeutic intervention strategy to overcome drug resistance. Significance: Galectin-1 is a key mediator of paclitaxel resistance in esophageal squamous cell carcinoma that can be targeted to improve taxane efficacy, suggesting broad therapeutic potential for treating various cancer types.
Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities
Authors: Graham MacLeod, Fatemeh Molaei, Shahan Haider, Maira P. Almeida, Sichun Lin, Michelle Kushida, Haresh Sureshkumar, Jasmine K. Bhatti, Jack Q. Lu, Daniel Schramek, Peter B. Dirks, Stephane Angers
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults and is driven by self-renewing glioblastoma stem cells (GSC) that persist after therapy and seed treatment-refractory recurrent tumors. GBM tumors display a high degree of intra- and intertumoral heterogeneity that is a prominent barrier to targeted treatment strategies. This heterogeneity extends to GSCs that exist on a gradient between two transcriptional states or subtypes termed developmental and injury response. Drug targets for each subtype are needed to effectively target GBM. To identify conserved and subtype-specific genetic dependencies across a large and heterogeneous panel of GSCs, we designed the GBM5K-targeted guide RNA library and performed fitness screens in a total of 30 patient-derived GSC cultures. The focused CRISPR screens identified the most conserved subtype-specific vulnerabilities in GSCs and elucidated the functional dependency gradient existing between the developmental and injury response states. Developmental-specific fitness genes were enriched for transcriptional regulators of neurodevelopment, whereas injury response–specific fitness genes were highlighted by several genes implicated in integrin and focal adhesion signaling. These context-specific vulnerabilities conferred differential sensitivity to inhibitors of β1 integrin, focal adhesion kinase, MEK, and OLIG2. Interestingly, the screens revealed that the subtype-specific signaling pathways drive differential cyclin D (CCND1 vs. CCND2) dependencies between subtypes. These data provide a biological insight and mechanistic understanding of GBM heterogeneity and point to opportunities for precision targeting of defined GBM and GSC subtypes to tackle heterogeneity. Significance: CRISPR-Cas9 screens in a panel of patient-derived glioblastoma stem cells reveal heterogeneity in genetic vulnerabilities across subtypes that have important implications for targeted and combination treatment strategies for glioblastoma.
Tumour’s Digest: Macrophage metabolism creates a barrier to T cells
Authors: Elly J. Tyler, Oliver M.T. Pearce
Journal: Cancer Research (2024)

Changes in the composition and physical properties of the tumor extracellular matrix are linked to poor cytotoxic T-cell infiltration and therapy response, yet the underlying mechanisms remain unclear. Tharp and colleagues revealed a fascinating cascade where tumor fibrosis alters macrophage metabolism, restricting the nutrients available to infiltrating T cells and resulting in their suppression and exclusion from the tumor microenvironment. This study suggests that targeting metabolic pathways could be a promising strategy to overcome the immune suppression induced by the tumor extracellular matrix.
Bottom-up or Top-down: Inflammation Reprograms Paneth Cells to Develop Bowel Cancers
Authors: Julian Chua, Alex Gregorieff, Arshad Ayyaz
Journal: Cancer Research (2024)

The origins of colorectal cancer have long been a subject of intense debate. Early observations noted cancer formation in the human gut slightly above the base of crypts, the structural and functional units of the regenerative compartment of the intestinal epithelium. This suggested that the cells of origin for colorectal cancer reside close to the crypt–villus junction, where more differentiated cells are located. However, the specific induction of early cancer-initiating mutations within differentiated cells failed to initiate cancer. The subsequent identification of long-lived Lgr5+ intestinal stem cells and investigations into their role in cancer development further shifted the earlier views, leading to the widely accepted theory that colorectal cancer arises from stem cells and progenitors located at the base of crypts. A recent study published in Nature Genetics by Mathijs P. Verhagen and colleagues challenges this paradigm, providing compelling evidence that differentiated nonstem cell lineages, particularly Paneth cells, can serve as a source of intestinal tumorigenesis, especially in the context of inflammation and the consumption of a Western-style diet. This work significantly advances our understanding of the colorectal cancer initiation process and provides a new paradigm that may explain the increasingly higher incidence of colorectal cancer in younger people.
Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer
Authors: Mi Li, Amriti R. Lulla, Yan Wang, Spyros Tsavaschidis, Fuchenchu Wang, Cansu Karakas, Tuyen D.T. Nguyen, Tuyen N. Bui, Marc A. Pina, Mei-Kuang Chen, Sofia Mastoraki, Asha S. Multani, Natalie W. Fowlkes, Aysegul Sahin, C. Gary Marshall, Kelly K. Hunt, Khandan Keyomarsi
Journal: Cancer Research (2024)

Abstract Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. The cleavage of full-length cyclin E (FL-cycE) to low–molecular weight isoforms (LMW-E) dramatically alters substrate specificity, promoting G1–S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. In this study, analysis of tumor samples of patients with TNBC revealed that coexpression of LMW-E and PKMYT1-catalyzed CDK1 phosphorylation predicted poor response to neoadjuvant chemotherapy. Compared with FL-cycE, LMW-E specifically upregulates PKMYT1 expression and protein stability, thereby increasing CDK1 phosphorylation. Inhibiting PKMYT1 with the selective inhibitor RP-6306 (lunresertib) elicited LMW-E–dependent antitumor effects, accelerating premature mitotic entry, inhibiting replication fork restart, and enhancing DNA damage, chromosomal breakage, apoptosis, and replication stress. Importantly, TNBC cell line xenografts expressing LMW-E showed greater sensitivity to RP-6306 than tumors with empty vector or FL-cycE. Furthermore, RP-6306 exerted tumor suppressive effects in LMW-E transgenic murine mammary tumors and patient-derived xenografts of LMW-E–high TNBC but not in the LMW-E null models examined in parallel. Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E–high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype. Significance: PKMYT1 upregulation and CDK1 phosphorylation in triple-negative breast cancer expressing low–molecular weight cyclin E leads to suboptimal responses to chemotherapy but sensitizes tumors to PKMYT1 inhibitors, proposing a personalized treatment strategy.
2024 ACC/AHA Key Data Elements and Definitions for Social Determinants of Health in Cardiology
Authors: Alanna A. Morris, Frederick A. Masoudi, Abdul R. Abdullah, Amitava Banerjee, LaPrincess C. Brewer, Yvonne Commodore-Mensah, Peter Cram, Sarah C. DeSilvey, Anika L. Hines, Nasrien E. Ibrahim, Elizabeth A. Jackson, Karen E. Joynt Maddox, Amgad N. Makaryus, Ileana L. Piña, Carla Patricia Rodriguez-Monserrate, Véronique L. Roger, Fran F. Thorpe, Kim A. Williams
Journal: Journal of the American College of Cardiology (2024)
Long-Term Prognosis of Patients With Myocarditis Attributed to COVID-19 mRNA Vaccination, SARS-CoV-2 Infection, or Conventional Etiologies
Authors: Laura Semenzato, Stéphane Le Vu, Jérémie Botton, Marion Bertrand, Marie-Joelle Jabagi, Jérôme Drouin, François Cuenot, Florian Zores, Rosemary Dray-Spira, Alain Weill, Mahmoud Zureik
Journal: JAMA (2024)

Importance Although patients with myocarditis after COVID-19 mRNA vaccination appear to have a good prognosis near hospital discharge, their longer-term prognosis and management remain unknown. Objective To study the cardiovascular complications of post–COVID-19 mRNA vaccination myocarditis and other types of myocarditis during an 18-month follow-up, as well as disease management based on a study of the frequency of medical procedures and drug prescriptions. Design, Setting, and Participants In this cohort study based on the French National Health Data System, all individuals aged 12 to 49 years hospitalized for myocarditis in France between December 27, 2020, and June 30, 2022, were identified. Exposure Individuals were categorized as having postvaccine myocarditis (within 7 days after COVID-19 mRNA vaccine), post–COVID-19 myocarditis (within 30 days of SARS-CoV-2 infection), or conventional myocarditis. Main Outcomes and Measures The occurrence of clinical outcomes (hospital readmission for myopericarditis, other cardiovascular events, all-cause death, and a composite outcome of these events) over the 18 months following hospital admission were analyzed using weighted Cox models to standardize the comparisons with the conventional myocarditis group. Also, medical management after hospital discharge was longitudinally assessed using generalized estimated equation models. Results In total, 4635 individuals were hospitalized for myocarditis: 558 with postvaccine myocarditis, 298 with post–COVID-19 myocarditis, and 3779 with conventional myocarditis. Patients with postvaccine myocarditis were younger than those with post–COVID-19 and conventional myocarditis (mean [SD] age of 25.9 [8.6], 31.0 [10.9], and 28.3 [9.4] years, respectively) and were more frequently men (84%, 67%, and 79%). Patients with postvaccine myocarditis had a lower standardized incidence of the composite clinical outcome than those with conventional myocarditis (32/558 vs 497/3779 events; weighted hazard ratio, 0.55 [95% CI, 0.36-0.86]), whereas individuals with post–COVID-19 myocarditis had similar results (36/298 events; weighted hazard ratio, 1.04 [95% CI, 0.70-1.52]). The standardized frequency of medical procedures and drugs prescribed in patients with postvaccine myocarditis or post–COVID-19 myocarditis followed a similar trend in the 18 months following hospital discharge to that of patients with conventional myocarditis. Conclusions and Relevance Patients with post–COVID-19 mRNA vaccination myocarditis, contrary to those with post–COVID-19 myocarditis, show a lower frequency of cardiovascular complications than those with conventional myocarditis at 18 months. However, affected patients, mainly healthy young men, may require medical management up to several months after hospital discharge.
ACC/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2024 Appropriate Use Criteria for Multimodality Imaging in Cardiovascular Evaluation of Patients Undergoing Nonemergent, Noncardiac Surgery
Authors: John U. Doherty, Stacie L. Daugherty, Smadar Kort, Martin J. London, Roxana Mehran, Geno J. Merli, Paul Schoenhagen, Prem Soman, Randall C. Starling, Drew M. Johnson, Gregory J. Dehmer, Paul Schoenhagen, Drew M. Johnson, Nicole M. Bhave, Robert W. Biederman, Marcio S. Bittencourt, Melissa S. Burroughs, Rami Doukky, Allison G. Hays, Julia H. Indik, Karen M. Kim, Amir S. Lotfi, Anthony J. Macchiavelli, Peter Neuburger, Hena Patel, Patricia A. Pellikka, T. Brett Reece, Lisa Q. Rong
Journal: Journal of the American College of Cardiology (2024)
Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies
Authors: Yu-Wei Li, Lei-Jie Dai, Xiang-Rong Wu, Shen Zhao, Yu-Zheng Xu, Xi Jin, Yi Xiao, Ying Wang, Cai-Jin Lin, Yi-Fan Zhou, Tong Fu, Wen-Tao Yang, Ming Li, Hong Lv, Siyuan Chen, Anita Grigoriadis, Yi-Zhou Jiang, Ding Ma, Zhi-Ming Shao
Journal: Cancer Research (2024)

HER2-positive breast cancer is an aggressive subtype that accounts for 15% to 20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. In this study, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor-positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%) had a poor response to current dual HER2-targeted therapy and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment. Significance: Illumination of the inherent heterogeneity within HER2-positive breast cancers through the delineation of distinct molecular subtypes lays the groundwork for developing more personalized treatment strategies based on specific patient characteristics.
Blunting specific T-dependent antibody responses with engineered 'decoy' B cells
Authors: Ragan A Pitner, Jaime L Chao, Noelle P Dahl, Meng-Ni Fan, Xiaohe Cai, Nathan G Avery, Kelsey Roe, P Clint Spiegel, Carol H Miao, Michael Y Gerner, Richard G James, David J Rawlings
Journal: Molecular Therapy (2024)
Erratum to “Phenylalanine deprivation inhibits multiple myeloma progression by perturbing endoplasmic reticulum homeostasis” [Acta Pharm Sin B 14 (8) (2024) 3493–3512]
Authors: Longhao Cheng, Xiaoxue Wang, Aijun Liu, Ying Zhu, Hu Cheng, Jiangling Yu, Lili Gong, Honglin Liu, Guolin Shen, Lihong Liu
Journal: Acta Pharmaceutica Sinica B (2024)

[This corrects the article DOI: 10.1016/j.apsb.2024.04.021.].