tbuckley/cabot-search huggingface dataset:
Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long non-coding transcriptome
Authors: Laura J Schwarzmueller, Ronja S Adam, Leandro F Moreno, Lisanne E Nijman, Adrian Logiantara, Steven Eleonora, Oscar Bril, Sophie Vromans, Nina E de Groot, Francesca Paola Giugliano, Ekaterina Stepanova, Vanesa Muncan, Clara C Elbers, Kristiaan J Lenos, Danny A Zwijnenburg, Monique A J van Eijndhoven, Dirk Michiel Pegtel, Sanne M van Neerven, Fabricio Loayza-Puch, Tulin Dadali, Wendy J Broom, Martin A Maier, Jan Koster, Louis Vermeulen, Nicolas Léveillé
Journal: Gut (2024)

Background Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved. Objective In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets. Design We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC. Results We uncovered that LINC02418 is essential for cancer cell clonogenic outgrowth. Mechanistically, LINC02418 regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target LINC02418 RNA in vivo . Conclusion We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition.
Liquid biopsy to identify Barrett’s oesophagus, dysplasia and oesophageal adenocarcinoma: the<i>EMERALD</i>multicentre study
Authors: Jinsei Miyoshi, Alessandro Mannucci, Marco Scarpa, Feng Gao, Shusuke Toden, Timothy Whitsett, Landon J Inge, Ross M Bremner, Tetsuji Takayama, Yulan Cheng, Teodoro Bottiglieri, Iris D Nagetaal, Martha J Shrubsole, Ali H Zaidi, Xin Wang, Helen G Coleman, Lesley A Anderson, Stephen J Meltzer, Ajay Goel
Journal: Gut (2024)

Background There is no clinically relevant serological marker for the early detection of oesophageal adenocarcinoma (EAC) and its precursor lesion, Barrett’s oesophagus (BE). Objective To develop and test a blood-based assay for EAC and BE. Design Oesophageal MicroRNAs of BaRRett, Adenocarcinoma and Dysplasia ( EMERALD ) was a large, international, multicentre biomarker cohort study involving 792 patient samples from 4 countries ( NCT06381583 ) to develop and validate a circulating miRNA signature for the early detection of EAC and high-risk BE. Tissue-based miRNA sequencing and microarray datasets (n=134) were used to identify candidate miRNAs of diagnostic potential, followed by validation using 42 pairs of matched cancer and normal tissues. The usefulness of the candidate miRNAs was initially assessed using 108 sera (44 EAC, 34 EAC precursors and 30 non-disease controls). We finally trained a machine learning model (XGBoost+AdaBoost) on RT-qPCR results from circulating miRNAs from a training cohort (n=160) and independently tested it in an external cohort (n=295). Results After a strict process of biomarker discovery and selection, we identified six miRNAs that were overexpressed in all sera of patients compared with non-disease controls from three independent cohorts of different nationalities (miR-106b, miR-146a, miR-15a, miR-18a, miR-21 and miR-93). We established a six-miRNA diagnostic signature using the training cohort (area under the receiver operating characteristic curve (AUROC): 97.6%) and tested it in an independent cohort (AUROC: 91.9%). This assay could also identify patients with BE among patients with gastro-oesophageal reflux disease (AUROC: 94.8%, sensitivity: 92.8%, specificity: 85.1%). Conclusion Using a comprehensive approach integrating unbiased genome-wide biomarker discovery and several independent experimental validations, we have developed and validated a novel blood test that might complement screening options for BE/EAC. Trial registration number NCT06381583 .
TRAIL induces podocyte PANoptosis via death receptor 5 in diabetic kidney disease.
Authors: Zhimei Lv, Jinxiu Hu, Hong Su, Qun Yu, Yating Lang, Meilin Yang, Xiaoting Fan, Yue Liu, Bing Liu, Yanfang Zhao, Cheng Wang, Shangwei Lu, Ning Shen, Rong Wang
Journal: Kidney International (2024)
Neuroimmune-competent human brain organoid model of Diffuse Midline Glioma
Authors: Katharina Sarnow, Emma Majercak, Qurbonali Qurbonov, Gustavo A V Cruzeiro, Daeun Jeong, Ishraq A Harque, Andrew Khalil, Lissa C Baird, Mariella G Filbin, Xin Tang
Journal: Neuro-Oncology (2024)

Abstract Background Pediatric high-grade gliomas, such as diffuse midline glioma (DMG), have a poor prognosis and lack curative treatments. Current research models of DMG primarily rely on human DMG cell lines cultured in vitro or xenografted into the brains of immunodeficient mice. However, these models are insufficient to recapitulate the complex cell-cell interactions between DMG and the tumor immune microenvironment (TIME), therefore fall short of accurately reflecting how efficacious therapeutic agents or combinations will be in the clinical setting. Methods To address these challenges, we developed a neuroimmune-competent brain/tumor fusion organoid model system consisting entirely of human cells to investigate the interactions between DMG cells and the primary innate immune cells of the brain, microglia, in the TIME at both cellular and subcellular levels. We generated microglia-containing brain organoids (MiCBO) that carry morphologically mature, motile microglia and multiple subtypes of neurons to mimic the brain tumor microenvironment. These organoids were then fused with H3K27M mutant, TP53P27R/K132R DMG tumor spheroids to create the MiCBO-tumor fusion (MiCBO-TF) model. Results We utilized live imaging methods to simultaneously track the mobility of microglial cell bodies and the motility of their process, as well as the behavior of tumor cells within a human brain tissue environment. Our MiCBO-TF model faithfully recapitulated the diffuse infiltration pattern of DMG into brain tissue and revealed that microglial mobility and interactions with tumor cells are highly influenced by external factors and surrounding tissue environment. Conclusions The MiCBO-TF model represents a powerful platform for both mechanistic investigations and the development of precision medicine approaches for DMG.
Effective Preparation of FFPE Tissue Samples for Preserving Appropriate Nucleic Acid Quality for Genomic Analysis in Thyroid Carcinoma
Authors: Yoichiro Okubo, Nagisa Toyama, Rika Kasajima, Soji Toda, Hiroyuki Hayashi, Emi Yoshioka, Kota Washimi, Shinya Sato, Yukihiko Hiroshima, Chie Hasegawa, Shu Yuguchi, Mei Kadoya, Hiroto Narimatsu, Katsuhiko Masudo, Hiroyuki Iwasaki, Tomoyuki Yokose, Yohei Miyagi
Journal: Endocrine Pathology (2024)

Abstract Formalin-fixed paraffin-embedded (FFPE) tissue samples are important for genomic analysis of thyroid carcinomas, particularly for various molecularly targeted therapies. Therefore, this study developed and validated a technique for preparing FFPE tissue samples that preserves nucleic acid quality, which is fundamental for precise genomic analysis, more effectively than conventional methods. We analyzed surgically resected thyroid gland tumors, lymph node metastases, and separately fixed tumor samples to optimize formalin fixation and assess the influence of specimen type and preparation methods on nucleic acid quality. We assessed several quality indicators, including the DNA integrity number, cycle threshold ratio, RNA integrity number, and DV200. Separately fixed tumor samples consistently exhibited higher DNA and RNA quality than conventionally processed samples. Additionally, lymph node metastases often exhibit nucleic acid quality matching or exceeding that of thyroid gland tumors, highlighting their potential reliability for genomic analysis. These findings suggest the utility of various specimen types for the comprehensive genetic profiling of thyroid carcinomas. In conclusion, this study demonstrated that preparing separately fixed tumor samples is an effective method for preserving DNA and RNA quality for genomic analyses. Biopsy punches enable specimen collection at various facilities, including those without the ability to handle frozen specimens. This contributes to the development of a method for obtaining high-quality pathological samples that can be widely used in general medical practice. Moreover, lymph node metastases often exhibit nucleic acid quality equal to or superior to that of thyroid gland tumors, highlighting their potential as acceptable sources for genomic analyses.
Graft-versus-host disease after anti-CD19 chimeric antigen receptor T-cell therapy following allogeneic hematopoietic cell transplantation: a transplant complications and paediatric diseases working parties joint EBMT study
Authors: Guillermo Ortí, Christophe Peczynski, William Boreland, Maeve O’Reilly, Malte von Bonin, Adriana Balduzzi, Caroline Besley, Krzysztof Kalwak, Samppa Ryhänen, Tayfun Güngör, Robert F. Wynn, Peter Bader, Stephan Mielke, Didier Blaise, Persis Amrolia, Ibrahim Yakoub-Agha, Friso Calkoen, Maria-Luisa Schubert, Victoria Potter, Herbert Pichler, Nicolaus Kröger, Mi Kwon, Henrik Sengeloev, Anna Torrent, Yves Chalandon, Gwendolyn van Gorkom, Christian Koenecke, Charlotte Graham, Helene Schoemans, Ivan Moiseev, Olaf Penack, Zinaida Peric
Journal: Leukemia (2024)
G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates
Authors: Ramesh C. Nayak, Sana Emberesh, Lisa Trump, Ashley Wellendorf, Abhishek Singh, Brice Korkmaz, Marshall S. Horwitz, Kasiani C. Myers, Theodosia A. Kalfa, Carolyn Lutzko, Jose A. Cancelas
Journal: Journal of Clinical Investigation (2024)

Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.
Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells
Authors: Mei-Qi Yang, Shu-Ling Zhang, Li Sun, Le-Tian Huang, Jing Yu, Jie-Hui Zhang, Yuan Tian, Cheng-Bo Han, Jie-Tao Ma
Journal: Molecular Cancer (2024)

Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.
Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition
Authors: Kristen E. Kay, Juyeun Lee, Ellen S. Hong, Julia Beilis, Sahil Dayal, Emily R. Wesley, Sofia Mitchell, Sabrina Z. Wang, Daniel J. Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K. Narayana, Saskia Freytag, Sarah A. Best, James R. Whittle, Zeneng Wang, Ofer Reizes, Jennifer S. Yu, Stanley L. Hazen, J. Mark Brown, Defne Bayik, Justin Lathia
Journal: Journal of Clinical Investigation (2024)

The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.
An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety
Authors: Kok-Siong Chen, Sarah Manoury-Battais, Nobuhiko Kanaya, Ioulia Vogiatzi, Paulo Borges, Sterre J. Kruize, Yi-Ching Chen, Laura Y. Lin, Filippo Rossignoli, Natalia Claire Mendonca, Khalid Shah
Journal: Journal of Clinical Investigation (2024)

Recent progress in cancer cell-based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible RIPK3-driven necroptotic system that serves as a dual function of safety switch as well as inducing immunogenic cell death which in turn stimulates antitumor immune responses. We showed that activating RIPK3 safety switch triggered immunogenic responses marked by an increased release of adenosine triphosphate (ATP) and damage-associated molecular patterns (DAMPs). Compared to other existing safety switches, incorporating RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, RIPK3 system reinvigorated the TIME by promoting dendritic cell (DC) maturation, polarizing the macrophages towards the M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies.
Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice
Authors: Katherine L. Morel, Beatriz Germán, Anis A. Hamid, Jagpreet S. Nanda, Simon Linder, Andries M. Bergman, Henk van der Poel, Ingrid Hofland, Elise M. Bekers, Shana Y. Trostel, Deborah L. Burkhart, Scott Wilkinson, Anson T. Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T. Plummer, Sungyong You, Xiaofeng A. Su, Wilbert Zwart, Adam G. Sowalsky, Christopher J. Sweeney, Leigh Ellis
Journal: Journal of Clinical Investigation (2024)

Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance to androgen receptor (AR)-targeted therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it's critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP, gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo, induced prostatic intraepithelial neoplasia, and, with Pten co-deletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, demonstrated by enrichment of EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor, dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.
Discontinuation of Cholinesterase Inhibitors Following Initiation of Memantine and Admission to Long-Term Care Among Older Adults
Authors: Yu-Chien Lee, Sandra M. Shi, Stephanie M. Sison, Chan Mi Park, Gahee Oh, Sohyun Jeong, Ellen P. McCarthy, Dae Hyun Kim
Journal: JAMA Network Open (2024)

Importance Discontinuing cholinesterase inhibitors when initiating memantine in patients with dementia may be reasonable to reduce treatment burden, costs, and the risk of adverse drug events. Objective To assess the association of cholinesterase inhibitor discontinuation on long-term care institutionalization among older adults with dementia who initiate memantine. Design, Setting, and Participants This retrospective propensity score-matched cohort study used Medicare claims data from January 2014 to December 2019. Participants included fee-for-service Medicare beneficiaries with dementia. Data were analyzed from September 2021 to August 2024. Exposures Discontinuation vs continuation of cholinesterase inhibitor. Main Outcomes and Measures The primary outcome was 1-year long-term care institutionalization-free days. Secondary outcomes include all-cause death and adverse drug events over 1 year. We performed subgroup analyses based on age, sex, dementia type (Alzheimer disease vs other), frailty, and dementia severity (mild vs moderate or severe) based on claims-based algorithms. The primary outcome was analyzed using nonparametric restricted mean survival time analysis. Results Among 16 292 beneficiaries who initiated memantine, 1820 (11.2%) discontinued cholinesterase inhibitors. In the propensity score-matched cohort of 3612 beneficiaries, the mean (SD) age was 80.7 (6.7) years, 2261 (62.6%) were female, and 1989 (55.0%) had a diagnosis of Alzheimer disease. Over 1 year, long-term care institutionalization occurred in 51 of 1806 beneficiaries (2.8%) who discontinued cholinesterase inhibitors (3.4 per 100 person-years) and 62 of 1806 beneficiaries (3.4%) who continued (4.1 per 100 person-years). There was no statistically significant difference in the 1-year mean institutionalization-free days between discontinuation and continuation groups (360.6 [95% CI, 359.3 to 362.0] days vs 359.1 [95% CI, 357.5 to 360.6] days; mean difference, 1.5 [95% CI,−0.5 to 3.6] days). The mean difference in the long-term care institutionalization-free days did not differ by age category, sex, dementia type, frailty, or dementia stage. Individuals who discontinued had a lower rate of fall-related injury (0.9 vs 2.0 per 100 person-years; hazard ratio [HR], 0.47 [95% CI, 0.25 to 0.88]). There was no difference between the discontinuation and continuation groups in all-cause death (10.4 vs 11.6 per 100 person-years; HR, 0.89 [95% CI, 0.72 to 1.10]). Conclusions and Relevance In this study, discontinuing cholinesterase inhibitors upon memantine initiation was not associated with an increased risk of long-term care institutionalization but with a lower risk of fall-related injury among older adults with dementia. These findings offer valuable insights for clinicians aiming to reduce treatment burden in this population.
Opioids and Dementia in the Danish Population
Authors: Nelsan Pourhadi, Janet Janbek, Christiane Gasse, Thomas Munk Laursen, Gunhild Waldemar, Christina Jensen-Dahm
Journal: JAMA Network Open (2024)

Importance Opioids have been studied as a potential risk factor for dementia, but evidence concerning long-term noncancer opioid use and exclusive use of weak opioids and associated dementia risk is sparse. Objective To assess the association between cumulative noncancer use of opioids and risk of age-related all-cause dementia. Design, Setting, and Participants This nested case-control study within a population-based cohort included 1 872 854 individuals without previous dementia, cancer, opioid addiction, or opioid use in terminal illness. Data were obtained from national Danish registers. Each individual who developed dementia during follow-up was incidence-density matched to 5 dementia-free controls. Statistical analysis was performed from August 2023 to March 2024. Exposure Cumulative opioid exposure was based on filled prescriptions available from 1995 through 2020. Main Outcomes and Measures Conditional logistic regression provided adjusted incidence rate ratios (IRRs) for associations between opioids and dementia. Results Among 1 872 854 individuals without previous dementia, cancer, opioid addiction, or opioid use in terminal illness included in the study, 93 638 (5.0%) developed all-cause dementia during follow-up (51 469 [55.0%] female; median [IQR] age, 78.1 [73.0-82.8] years) and were matched to 468 190 control individuals (257 345 [55.0%] female; median [IQR] age, 78.0 [73.0-82.8] years). Opioid use up to 90 total standardized doses (TSDs) was not consistently associated with dementia risk. Opioid exposure above 90 TSDs yielded increased IRRs of dementia occurring before age 90 years ranging from 1.29 (95% CI, 1.17-1.42) for 91 to 200 TSDs to 1.59 (95% CI, 1.44-1.76) for greater than 500 TSDs for age-band 60 to 69 years at dementia diagnosis. Corresponding IRRs were 1.16 (95% CI, 1.11-1.22) to 1.49 (95% CI, 1.42-1.57) for age-band 70 to 79 years and 1.08 (95% CI, 1.03-1.14) to 1.21 (95% CI, 1.16-1.27) for 80 to 89 years. Sensitivity analyses corroborated associations in individuals with chronic noncancer pain and with use of weak opioids. Conclusions and Relevance This study found that opioid use of less than 90 TSDs was not significantly associated with increased dementia risk. Above 90 TSDs of opioid use was associated with an elevated dementia risk before age 90 years, which persisted in individuals with chronic noncancer pain and in individuals solely exposed to weak opioids. Further research should ascertain whether the findings denote causality between opioids and dementia risk.