tbuckley/cabot-search huggingface dataset:
lncRNAs: the unexpected link between protein synthesis and cancer adaptation
Authors: Mila Gugnoni, Manoj Kumar Kashyap, Kishore K. Wary, Alessia Ciarrocchi
Journal: Molecular Cancer (2025)

Cancer progression relies on the ability of cells to adapt to challenging environments overcoming stresses and growth constraints. Such adaptation is a multifactorial process that depends on the rapid reorganization of many basic cellular mechanisms. Protein synthesis is often dysregulated in cancer, and translational reprogramming is emerging as a driving force of cancer adaptive plasticity. Long non-coding RNAs (lncRNAs) represent the main product of genome transcription. They outnumber mRNAs by an order of magnitude and their expression is regulated in an extremely specific manner depending on context, space and time. This heterogeneity is functional and allows lncRNAs to act as context-specific, fine-tuning controllers of gene expression. Multiple recent evidence underlines how, besides their consolidated role in transcription, lncRNAs are major players in translation control. Their capacity to establish multiple and highly dynamic interactions with proteins and other transcripts makes these molecules able to play a central role across all phases of protein synthesis. Even if through a myriad of different mechanisms, the action of these transcripts is dual. On one hand, by modulating the overall translation speed, lncRNAs participate in the process of metabolic adaptation of cancer cells under stress conditions. On the other hand, by prioritizing the synthesis of specific transcripts they help cancer cells to maintain high levels of essential oncogenes. In this review, we aim to discuss the most relevant evidence regarding the involvement of lncRNAs in translation regulation and to discuss how this specific function may affect cancer plasticity and resistance to stress. We also expect to provide one of the first collective perspectives on the way these transcripts modulate gene expression beyond transcription.
Abstract 1452: Myocyte Aging Conditions Cell Growth and Contractile Function
Authors: Marcello Rota, Antonella De Angelis, Konrad Urbanek, Ezio Musso, Grazia Iaffaldano, Tymoteusz J Kajstura, Federico Mosna, Alessandro Gatti, Susanna Valentini, Francesca Delucchi, Thomas S Mitchell, Annarosa Leri, Edmund H Sonnenblick, Piero Anversa
Journal: Circulation (2006)

The recognition that the heart can replace old dying myocytes by activation of resident cardiac stem cells raises the possibility that organism, organ and cell age do not coincide and that the myoc...
Frailty and outcomes in adults undergoing systemic anti-cancer treatment: a systematic review and meta-analysis
Authors: Jessica Pearce, Sally Martin, Sophie Heritage, Emma G Khoury, Joanna Kucharczak, Thitikorn Nuamek, David A Cairns, Galina Velikova, Suzanne H Richards, Andrew Clegg, Alexandra Gilbert
Journal: JNCI Journal of the National Cancer Institute (2025)

It is increasingly recognised that frailty should be assessed and considered in treatment decision-making in patients with cancer. This review and meta-analysis synthesises existing evidence evaluating the association between baseline frailty and Systemic Anti-Cancer Treatment (SACT) outcomes in adults with cancer. Five databases were systematically searched from database inception to January 2023 to identify prognostic factor studies (cohort/case-control design) reporting the associations between validated frailty assessments (pre-treatment) and follow-up outcomes in adults with solid-organ malignancy undergoing SACT. Risk of bias (RoB) was assessed via Quality of Prognosis Studies in Systematic Reviews tool. Where appropriate, associations between frailty and outcomes (survival, toxicity, treatment tolerance, functional decline/quality of life and hospitalisation) were synthesised in meta-analysis and presented as forest plots. 58 studies met inclusion criteria. They were undertaken in a range of tumour sites and mainly in older patients and advanced disease/palliative settings. Most had low/moderate RoB. Nine frailty assessment tools were evaluated. Four outcomes were synthesised in meta-analysis, which demonstrated the prognostic value of two tools: Geriatric-8 (G8; survival, treatment tolerance, hospitalisation) and Vulnerable Elders Survey-13 (VES13; survival, toxicity, treatment tolerance). Overall pooled estimates indicate that frailty conveys an increased risk of mortality (hazard ratio (HR) 1.68, 95% confidence interval 1.41-2.00), toxicity (odds ratio (OR) 1.83, 1.24-2.68), treatment intolerance (OR 1.68, 1.32-2.12) and hospitalisation (OR 1.94, 1.32-2.83). Simple, brief frailty assessments including G8 and VES13 are prognostic for a range of important outcomes in patients undergoing SACT. Risk estimates should be used to support shared decision-making.
Long-Term Prognostic Implications of Non-Culprit Lesions in Patients Presenting With an Acute Myocardial Infarction: Is It the Angiographic Stenosis Severity or the Underlying High-Risk Morphology?
Authors: Jiannan Dai, Jiawei Zhao, Xueming Xu, Yuzhu Chen, Sibo Sun, Shuang Li, Lina Cui, Yini Wang, Lulu Li, Ruirong Guo, Dongxu Huang, Xianqin Ma, Rui Zhao, Huai Yu, Tao Chen, Jinfeng Tan, Xiaohui Liu, Senqing Jiang, Jingbo Hou, Chao Fang, Gary S. Mintz, Bo Yu
Journal: Circulation (2025)

Patients with acute myocardial infarction and angiographically obstructive non-culprit lesions are at high risk for recurrent major adverse cardiac events (MACEs). However, it remains largely unknown whether events are due to stenosis severity or due to the underlying high-risk lesion morphology. Between January 2017 and December 2021, 1312 patients with acute myocardial infarction underwent optical coherence tomography of all the 3 main epicardial arteries after successful percutaneous coronary intervention. Patients and lesions were categorized according to the presence or absence of (1) 1 or more non-culprit angiographic obstructive stenoses with a visual diameter stenosis of ≥50% and (2) 1 or more lesions with an underlying high-risk morphology defined as an optical coherence tomography thin-cap fibroatheroma (TCFA). Patients were followed for up to 5 years (median 4.1 [interquartile range: 3.0-5.0] years). MACEs comprised cardiac death, non-fatal myocardial infarction, and unplanned coronary revascularization. Overall, 492 patients had at least 1 obstructive non-culprit lesion, 352 had a single lesion, and 140 had multiple obstructive non-culprit lesions. The presence and number of angiographic obstructive non-culprit lesions correlated with the proportion and number of optical coherence tomography-derived TCFAs. At the lesion level, the prevalence of TCFA was twice as high in obstructive lesions compared with nonobstructive lesions. Patients with obstructive non-culprit lesions had an increased risk of overall MACEs (17.7% versus 12.8%; hazard ratio, 1.39 [95% CI, 1.02-1.91]) and non-culprit lesion-related MACEs (8.7% versus 3.9%; HR, 2.13 [95% CI, 1.26-3.59). Results were similar when patients were categorized on the basis of the underlying TCFA. A proportionally higher rate of overall and non-culprit lesion-related MACEs was observed as the number of obstructive stenoses or TCFAs in non-culprit segments increased. The lesion-specific HRs for obstructive lesion and TCFA were 2.03 (95% CI, 1.06-3.89) and 2.39 (95% CI, 1.29-4.43), respectively. Optical coherence tomography-derived TCFA, but not angiographic obstructive stenosis, was independently predictive of recurrent MACEs in both patient-level and lesion-level multivariable models in which these 2 characteristics were introduced simultaneously. The long-term prognostic implications of the presence and extent of angiographic obstructive non-culprit lesions in patients with acute myocardial infarction are primarily due to their correlation with the underlying high-risk morphology, which confers an increased risk of recurrent MACEs.
GBMPurity: A Machine Learning Tool for Estimating Glioblastoma Tumour Purity from Bulk RNA-seq Data
Authors: Morgan P H Thomas, Shoaib Ajaib, Georgette Tanner, Andrew J Bulpitt, Lucy F Stead
Journal: Neuro-Oncology (2025)

Glioblastoma (GBM) presents a significant clinical challenge due to its aggressive nature and extensive heterogeneity. Tumour purity, the proportion of malignant cells within a tumour, is an important covariate for understanding the disease, having direct clinical relevance or obscuring signal of the malignant portion in molecular analyses of bulk samples. However, current methods for estimating tumour purity are non-specific and technically demanding. Therefore, we aimed to build a reliable and accessible purity estimator for GBM. We developed GBMPurity, a deep-learning model specifically designed to estimate the purity of IDH-wildtype primary GBM from bulk RNA-seq data. The model was trained using simulated pseudobulk tumours of known purity from labelled single-cell data acquired from the GBmap resource. The performance of GBMPurity was evaluated and compared to several existing tools using independent datasets. GBMPurity outperformed existing tools, achieving a mean absolute error of 0.15 and a concordance correlation coefficient of 0.88 on validation datasets. We demonstrate the utility of GBMPurity through inference on bulk RNA-seq samples and observe reduced purity of the Proneural molecular subtype relative to the Classical, attributed to the increased presence of healthy brain cells. GBMPurity provides a reliable and accessible tool for estimating tumour purity from bulk RNA-seq data, enhancing the interpretation of bulk RNA-seq data and offering valuable insights into GBM biology. To facilitate the use of this model by the wider research community, GBMPurity is available as a web-based tool at: https://gbmdeconvoluter.leeds.ac.uk/.
Abstract B007: Epigenetic reactivation of transposable elements as prognostic markers for PD1/PDL1 immunotherapy in cancer
Authors: Yixin Wu, Ting Wang, Yonghao Liang
Journal: Cancer Research (2025)

Abstract Transposable elements (TEs), once considered as "junk" DNA, are now recognized for their epigenetic and regulatory influence, especially in cancer. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer, contributing to oncogenesis and altering gene expression patterns. This reactivation results in TE-derived transcripts, which have the potential to be translated and form neoantigens that can be presented by the human leukocyte antigens (HLA) complex and recognized by T cells, ultimately impacting the tumor immune response. In this study, we analyzed RNA-seq data from melanoma patients undergoing PD1/PDL1 immunotherapy. By identifying tumor specific TE-derived transcripts and utilizing in silico translation, we detected TE-derived neoantigens in patients with differing responses to immunotherapy. Our findings indicate that the number of TE-derived neoantigens is correlated with patients' response to immunotherapy, with a higher number of neoantigens observed in patients who responded to treatment compared to those who did not. These results imply that TE-derived neoantigens may serve as potential biomarkers for predicting the prognosis of PD1/PDL1 immunotherapy treatment. Incorporating TE-derived neoantigen profiles into clinical decision-making could enhance patient selection for immunotherapy, thereby improving treatment outcomes. Citation Format: Yixin Wu, Ting Wang, Yonghao Liang. Epigenetic reactivation of transposable elements as prognostic markers for PD1/PDL1 immunotherapy in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B007.
Abstract B023: Harnessing the dual therapeutic approach of CRISPR/CAS9 and CAR-T cell technologies in KRAS mutated solid tumors
Authors: SDanish Kadir
Journal: Cancer Research (2025)

Abstract Kirsten Rat Sarcoma Virus mutation and its complications have been a major concern. Limitations to drawing its accurate configuration, its complications; mutates and thermodynamic properties, have limited their effectiveness as a molecular diagnostic tool. To counteract these challenges, over the years a different set of sophisticated Immunotherapeutic approaches have been adopted such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), Caspase Protein System (CAS), and Chimeric Antigen Receptor-T cell (CAR-T). Some of them have already managed approval of the Food and Drug Administration. One of the primary goals of CRISPR/CAS technology is to correct mutations within the genetic sequence, thereby potentially repairing defective genes like KRAS. Meanwhile, CAR-T immunotherapies capitalise on genetically modified T cells. In comparison to traditional therapies, immunotherapies can offer greater safety and precision. However, their efficacy is still questionable while treating solid tumours. Here authors have covered the various key targets such as p53, p21, WNT, and RAS, their success stories over the years and have proposed the importance of targets like KRAS oncogene to manage a better output. KRAS is a RAS family oncoprotein responsible for the development of 85% of different cancers. The missense mutations at the various KRAS hotspots can lead to the development of lung and Pancreatic Cancers. Some of the most recently conducted revolutionary studies synthesize CAR-NK, CAR-M, and CRISPR-Cas9/3/10/Novel CAS systems, as well as their prospective molecular combination to target the KRAS. The purpose of this study is to provide a present status of these therapies, limitations, clinical trials, and a proposal to sketch a combinatorial impact via the PRISMA model for 62 different manuscripts (2001-2024). This format aligns and organizes everything in Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, providing a clear and systematic infographic that represents the process, including stages of selection, screening, and documentation. Citation Format: SDanish Kadir. Harnessing the dual therapeutic approach of CRISPR/CAS9 and CAR-T cell technologies in KRAS mutated solid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B023.
Abstract A007: Regulation of DNA methylation and gene expression in T-cell acute lymphoblastic leukemia by IKAROS tumor suppressor
Authors: Yali Ding, Bing He, Daniel Bogush, Joseph W Schramm, Dhimant Desai, Sinisa Dovat
Journal: Cancer Research (2025)

Abstract The IKZF1 gene encodes IKAROS - a DNA-binding zinc finger protein that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). Deletion of IKZF1 results in the development of high-risk leukemia. The mechanisms through which IKAROS regulates gene expression and cellular proliferation in T-ALL are largely unknown. We studied IKAROS role in regulation of DNA methylation and epigenomic regulation of gene expression in Ikzf1-null mouse T-ALL cells and following Ikzf1 re-introduction into Ikzf1-null mouse T-ALL cells. We used reduced representation bisulfite sequencing (RRBS), with ChIP-seq of IKAROS, histone deacetylase 1 (HDAC1), EZH2, and ATAC-seq along with CUT&amp;Tag of histone modification markers, coupled with RNA-seq to study dynamic effect of IKAROS in IKZF1-null T-ALL and at several time points following Ikzf1 re-introduction. Deletion of Ikzf1 results in severe depletion of facultative heterochromatin, associated with DNA methylation at promoters of several tumor suppressor genes. Re-introduction of Ikzf1 within 24 hours results in global re-distribution of DNA methylation. IKAROS DNA binding was directly associated with de novo DNA methylation at promoters of genes that positively regulate several oncogenic pathways. DNA binding of IKAROS also resulted in the loss of DNA methylation, HDAC1 recruitment to promoters, EZH2 re-distribution, and de novo formation of H3K27me3 facultative heterochromatin. This was associated with cessation of cellular proliferation and induction of T-cell differentiation. Dynamic analysis of DNA methylation for 3 days following Ikzf1 re-introduction, revealed that the large fraction of DNA with altered methylation status due to IKAROS binding, preserved the altered DNA methylation pattern for at least two additional days, despite lack of IKAROS DNA binding in subsequent days following Ikzf1 re-introduction. In conclusion, our results demonstrated that IKAROS’ tumor suppressor function in T-ALL, occurs via regulation of DNA methylation and recruitment of HDAC1 and EZH2 to the promoters of its target genes. Results provide novel insight into the role of DNA methylation in regulation of gene expression in T-ALL with IKZF1-deletion and epigenomic regulation of tumor suppression in T-ALL. Citation Format: Yali Ding, Bing He, Daniel Bogush, Joseph W Schramm, Dhimant Desai, Sinisa Dovat. Regulation of DNA methylation and gene expression in T-cell acute lymphoblastic leukemia by IKAROS tumor suppressor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A007.
Abstract A020: Clonal hematopoiesis is associated with acute kidney injury in the context of breast, endometrial, and ovarian cancers
Authors: Neil Ruthen, Minsoo Kim, Hui Zhuan Tan, Yash Khandwala, A. Ari Hakimi, Alice Won, Ed Reznik, Edgar A Jaimes
Journal: Cancer Research (2025)

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) has been linked to a higher risk for acute kidney injury (AKI) (Vlasschaert et al. 2024). The high rate of AKI in the context of cancer is often attributed to the administration of nephrotoxic therapies or comorbidities. However, the effect of the interplay between tumor-associated physiologies, treatment, and CHIP on AKI incidence has yet to be characterized. Here, we model the prognostic value of CHIP in predicting AKI across twenty cancer types. Leveraging a single institutional database, we identified 25,189 patients with longitudinal serum creatinine (sCr) measurements, targeted sequencing of paired tumor and blood samples (MSKCC-IMPACT), and well-documented treatment histories. We called AKI events directly from longitudinal measurements by evaluating increases in sCr compared to the average sCr over the prior 90-day window using diagnostic criteria from the Kidney Disease Improving Global Outcomes (KDIGO) consortium. CHIP mutations were called using a previously reported two-tiered filtering schema (Bolton et al. 2020). In our cohort, we found that 26.5% of patients experienced at least one AKI event and 38.0% of patients presented with at least one CHIP mutation. We then performed competing risks analyses over cox proportional hazards models to test for the association of CHIP and time to AKI from the first creatinine measurement, adjusting for age, gender, histories of diabetes, smoking, and prior receipt of cisplatin. CHIP was significantly associated with decreased time to AKI in the context of breast, endometrial, and ovarian cancers (Benjamini-Hochberg-corrected p &amp;lt; 0.05). Subsequent univariate Kaplan-Meier analyses revealed TP53, PPM1D, SRFS2 mutations were associated with 7.50, 9.05, and 9.73-year decreases in median time to AKI (p &amp;lt; 0.01). Our study reveals specific CHIP mutations as prognostic markers for AKI for patients with breast, endometrial, and ovarian cancers. These findings may guide future clinical decision-making regarding treatment for patients with CHIP mutations. Citation Format: Neil Ruthen, Minsoo Kim, Hui Zhuan Tan, Yash Khandwala, A. Ari Hakimi, Alice Won, Ed Reznik, Edgar A Jaimes. Clonal hematopoiesis is associated with acute kidney injury in the context of breast, endometrial, and ovarian cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A020.
Abstract IA014: Clinial implications of clonal hematopoiesis - and the role of Vitamin C
Authors: Kirsten Grønbæk
Journal: Cancer Research (2025)

Abstract Dr Grønbæk will discuss the management of clonal hematopoiesis (CH) in clinical practice, focusing on how people with CH are identified. She will elaborate on the importance of identifying and following high-risk individuals/patients while sparing low risk individuals unnecessary worries. The role of DNA methylation changes in CH and low risk myeloid cancer will be discussed, including how preclinical studies have fostered the first clinical trials in CH. A special focus will be on the role of ascorbic acid (vitamin C) in CH and myeloid precursor conditions. Clinical- and correlative data from a randomized placebo controlled clinical trial: NCT03682029: A randomized, placebo-controlled, blinded, parallel-group clinical phase 2 study of oral vitamin C vs Placebo in CCUS/LR-MDS (EVITA) will be presented. The importance of enrolling these individuals/patients in clinical trials will be discussed including the optimal trials designs. Citation Format: Kirsten Grønbæk. Clinial implications of clonal hematopoiesis - and the role of Vitamin C [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr IA014
Abstract B027: Modeling age-related DNA methylation changes with intestinal organoids
Authors: Himani Vaidya, Gennaro Calendo, Anthomy Pompetti, Curt Balch, Kelsey Keith, Jozef Mazdo, Jaroslav Jelinek, Jean-Pierre Issa
Journal: Cancer Research (2025)

Abstract Intestinal organoids, three-dimensional cultures from intestinal stem cells, are a potential model for studying aging. DNA methylation can serve as biological clock of aging, and we hypothesized that organoid DNA methylation could be a valuable tool for aging research. We compared DNA methylation in organoids to that seen in primary aging intestinal epithelium. Genome wide, we found very substantial DNA methylation changes during organoid establishment and culture, with 27% of total CpG sites undergoing loss of methylation (hypomethylation), and 11% gaining methylation (hypermethylation). The observed hypermethylation primarily affected CpG islands and corresponded to CpG sites susceptible to age-related methylation in-vivo (p &amp;lt; 0.001 compared to unchanged sites). Early-passage (P0 and P2) organoids derived from 4- and 24-month-old mice, preserved aging-specific methylation patterns, with a correlation coefficient of 0.48 (p &amp;lt; 0.001) between methylation differences in-vivo and in-vitro. Age-related hypermethylation continued to change with passage, and linear modeling indicated that organoids age at an average rate of 0.46 months per week in culture. By contrast, hypomethylation occurred predominantly in non-aging-associated genomic regions such as non-promoter, non-CpG island regions (including transposable elements), and correlated neither with differentiation nor aging in-vivo. Thus, methylation changes in organoids reflect at least two different biological processes – aging, as measured by CpG island hypermethylation, and an unexplained stochastic hypomethylation defect. Treatment with the DNA methylation inhibitor decitabine lowered the methylation age of organoids from 22 months to 10 months, showing the potential of organoids to model extrinsic effects on age-related DNA hypermethylation. Citation Format: Himani Vaidya, Gennaro Calendo, Anthomy Pompetti, Curt Balch, Kelsey Keith, Jozef Mazdo, Jaroslav Jelinek, Jean-Pierre Issa. Modeling age-related DNA methylation changes with intestinal organoids [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B027.