tbuckley/cabot-search huggingface dataset:
Abstract P019: Spatiometabolic mapping of cytoarchitectural changes in lung adenocarcinoma following radiotherapy
Authors: Gina Bouchard
Journal: Clinical Cancer Research (2025)

Abstract Understanding how radiotherapy induces metabolic reprogramming and reshapes the cytoarchitecture of the tumor microenvironment (TME) is essential for improving treatment outcomes and overcoming resistance. Despite its importance, no studies have used computational tools to quantitatively assess these cytoarchitectural rearrangements in the TME following radiotherapy. In previous work, we developed a quantitative method called “colocatome analysis,” a spatial -omic approach that catalogs statistically significant colocalizations between pairs of cell subpopulations or states. Through a normalization process, this method enables direct comparisons of spatial features across different conditions, including comparisons between in vitro models and tissue samples. We applied colocatome analysis to multiplexed immunofluorescence images of lung adenocarcinoma specimens, examining differences between naïve and recurrent tumors following radiotherapy using a panel of markers that represent primary tumor compartments (endothelial, malignant, fibroblast, and immune) and include markers for the hexosamine biosynthesis pathway (HBP), glycans, key metabolic enzymes, proliferation, cell death, DNA damage, hypoxia, and EMT. Our preliminary results indicate significant cytoarchitectural differences: tumors that recurred after radiotherapy exhibited a lower epithelial-to-mesenchymal cancer cell ratio and were enriched in FAP+ cancer-associated fibroblasts (CAFs). Although the overall proportions of macrophages and other immune cells remained consistent across samples, their spatial organization differed. In naïve tumors, immune cells were largely segregated from cancer cells, while recurrent tumors showed a more homogeneous mixture of cancer and immune cells. Additionally, CAFs were markedly increased in recurrent tumors. Lastly, cancer cells in naïve tumors displayed high levels of O-GlcNAc, which significantly decreased in recurrent tumors. These findings provide insights into the impact of metabolic reprogramming towards HBP in the TME and highlight its potential role in mediating radioresistance. Citation Format: Gina Bouchard.Spatiometabolic mapping of cytoarchitectural changes in lung adenocarcinoma following radiotherapy.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P019
When machines start examining tissue specimens on their own
Authors: Manabu Kinoshita, Yoshiko Okita, Haruhiko Kishima
Journal: Neuro-Oncology (2025)

Journal Article Accepted manuscript When machines start examining tissue specimens on their own Get access Manabu Kinoshita, Manabu Kinoshita Department of Neurosurgery, Asahikawa Medical University, Midorigaoka-higashi 2-1-1-1, Asahikawa, Hokkaido 078-8510 JapanDepartment of Neurosurgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 Japan Corresponding Author: Manabu Kinoshita, MD, PhD, Department of Neurosurgery, Asahikawa Medical University, Midorigaoka-higashi 2-1-1-1, Asahikawa, Hokkaido 078-8510 Japan ([email protected]). https://orcid.org/0000-0001-7923-6902 Search for other works by this author on: Oxford Academic PubMed Google Scholar Yoshiko Okita, Yoshiko Okita Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Neurosurgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Haruhiko Kishima Haruhiko Kishima Department of Neurosurgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noaf021, https://doi.org/10.1093/neuonc/noaf021 Published: 26 January 2025 Article history Received: 19 January 2025 Published: 26 January 2025
Abstract IA02: Preserving tumor-draining lymph nodes in the era of immuno-oncology: Opportunities for precision chemo-radio-immunotherapy
Authors: J. Silvio Gutkind
Journal: Clinical Cancer Research (2025)

Abstract The advent of the current cancer immunotherapy era based on the success of immune checkpoint blockade (ICB) inhibiting programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) has revolutionized the standard of care for cancer treatment. However, the limited response rates to ICB across multiple cancer types suggest that new approaches and treatment strategies are needed in order to achieve durable cancer remission. This includes re-examining the possibility that standard of care treatments, including surgery and chemo-radiation, may compromise the tumor response when delivered in concert with ICB. In particular, many cancer types, including head and neck squamous cell carcinoma (HNSCC), have a propensity to metastasize to locoregional lymph nodes, and standard oncologic management often involves elective ablation of tumor draining lymph nodes (tdLN). In a recent study, we have used tobacco-signature HSNCC syngeneic mouse models and showed that tdLN ablation by surgery or radiation therapy limits the tumor ICB response, thereby worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, we provided evidence that cDC1 dendritic cells in the tumor lesions and tdLN are required for an effective anti-tumor immune response. Recently, we have cross-integrated large single-cell RNA-sequencing datasets from intratumoral immune cells and identified a novel mechanism by which antigen-specific CD8+ T cells promote intratumoral cDC1 accumulation and T cell persistence, leading to improved overall survival. As a multipronged approach, we have also built on this computational pipeline to identify druggable oncogenic signaling networks that override cancer immune surveillance. Evidence will be presented that disruption of specific HNSCC driving signaling axes is sufficient to sculp the tumor immune microenvironment and disable their immune evasive mechanisms, thereby providing opportunities for the development of new precision therapies increasing the response ICB. The emerging information also provided a rationale for investigating the use of a new generation of radiation-sensitizing antibody drug conjugates targeting cancer-specific oncosignaling drivers, in combination with radiotherapy and ICB in the neoadjuvant setting, when tdLN are still intact. Ultimately, evidence will be presented supporting the future evaluation of spatially precise radiosensitizing antibody drug conjugate-directed chemo-radio-immunotherapy for precision cancer care in HNSCC and other malignancies. Citation Format: J. Silvio Gutkind. Preserving tumor-draining lymph nodes in the era of immuno-oncology: Opportunities for precision chemo-radio-immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA02
Abstract B032: Concurrent mutant KRAS inhibition and Stereotactic Body Radiation Therapy (SBRT) for preclinical KRASG12D-Driven Pancreatic Ductal Adenocarcinoma (PDAC) treatment
Authors: Tianyu Wang, Jasper R Chen, Vincent Bernard Pagan, Liang Wang, Youming Guo, Ling Xia, Pankaj K. Singh, Dadi Jiang, Albert Koong
Journal: Clinical Cancer Research (2025)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is known for its extensive intrinsic and acquired resistance to standard of care therapies. With the KRASG12D mutation being a key driver, MRTX1133, a selective small molecule KRASG12D inhibitor, has demonstrated superior anti-tumor efficacy in preclinical PDAC models. However, tumor resistance to MRTX1133 is expected to occur inevitably. We hypothesize that combining MRTX1133 with stereotactic body radiation therapy (SBRT) can enhance local tumor control and minimize tumor recurrence after treatment. Methods: C57Bl/6J mice orthotopically transplanted with luciferase-tagged mouse KPC PDAC cells (KrasG12D; Trp53R172H; Pdx1-Cre) were assigned to 4 treatment groups: (1) vehicle, (2) SBRT (8 Gy x 5), (3) MRTX1133 (30 mg/kg I.P. BID), and (4) SBRT + MRTX1133. Tumor progression was monitored with IVIS luciferase imaging, and survival data were collected and analyzed using a Log-rank test. At the study endpoint, tumors as well as normal tissues were collected for histological analysis to evaluate immune cell infiltration, tumor proliferation and differentiation, and normal tissue toxicity. Results: SBRT + MRTX1133 combination therapy significantly enhanced local tumor control and prolonged mouse survival when compared to either MRTX1133 or SBRT alone. The median survival in the combination group exceeded 120 days, with significantly reduced tumor burden, suggesting a synergistic effect between SBRT and MRTX1133 in suppressing KPC tumor progress in vivo. Conclusion: Our findings demonstrate that MRTX1133 combined with SBRT improves tumor control and overall survival in a preclinical KRASG12D-driven PDAC tumor model. This combination strategy has the potential for clinical translation, offering a promising therapeutic approach to overcome resistance and improve outcomes in PDAC patients. Citation Format: Tianyu Wang, Jasper R Chen, Vincent Bernard Pagan, Liang Wang, Youming Guo, Ling Xia, Pankaj K. Singh, Dadi Jiang, Albert Koong. Concurrent mutant KRAS inhibition and Stereotactic Body Radiation Therapy (SBRT) for preclinical KRASG12D-Driven Pancreatic Ductal Adenocarcinoma (PDAC) treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B032.
Abstract IA04: Evaluating and mitigating medical misinformation risk in large language models
Authors: Shan Chen, Mingye Gao, Kuleen Sasse, Thomas Hartvigsen, Brian Anthony, Lizhou Fan, Jack Gallifant, Danielle D. Bitterman
Journal: Clinical Cancer Research (2025)

Abstract Background: Large language models (LLMs) are increasingly used to generate medical content, yet their inherent design to follow user instructions may leave them vulnerable to producing misinformation. This risk becomes especially pronounced when LLMs generate incorrect medical information that could adversely affect human health. A propensity to comply with prompts, even when these lead to illogical or false information, highlights a critical gap in their safety, especially in high-stakes fields like healthcare. Methods: We evaluated the behavior of five LLMs—Llama3-8B, Llama3-70B, GPT4o-mini, GPT4o, and GPT-4-0613—by observing their compliance with prompts to generate misleading medical information. Specifically, the LLMs were prompted to suggest that a brand name drug was safer than its generic counterpart, a request with no basis in factual medical reasoning. We tested whether using prompt-based methods and instruction-tuning could enhance the models' ability to detect and resist generating content based on illogical premises. These safety approaches were evaluated in both medical and non-medical contexts to assess generalizability. Results: All five LLMs, despite accurately identifying the equivalence between brand and generic drugs, generated misleading medical content in response to overtly false prompts in over 50% of cases. Instruction-tuning and prompt-based techniques showed promise in reducing misinformation: models became better at detecting logical inconsistencies and were more likely to refuse requests that would result in misinformation, often providing explanations for their refusals. Furthermore, instruction-tuned LLMs showed improved safety behavior not only in medical contexts but also in non-medical domains without compromising performance on standard benchmarks. Conclusions: This study highlights a key vulnerability in LLMs: their tendency to comply with user requests even when it leads to medical misinformation. This compliance, particularly in generating content with flawed or incorrect logic, poses a significant safety issue for both individual and public health. The current safety and performance benchmarks for LLMs fail to account for this harmful behavior, underscoring an urgent need for new development approaches that prioritize logic and factual accuracy. Addressing this issue is essential to creating LLMs that are both useful and safe in medical and other high-stakes applications. Citation Format: Shan Chen, Mingye Gao, Kuleen Sasse, Thomas Hartvigsen, Brian Anthony, Lizhou Fan, Jack Gallifant, Danielle D. Bitterman. Evaluating and mitigating medical misinformation risk in large language models. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA04
Abstract IA06: Targeting ferroptosis in radioresistance
Authors: Boyi Gan
Journal: Clinical Cancer Research (2025)

Abstract Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation, which disrupts cellular homeostasis and viability. Recent studies, including our own, have demonstrated that radiotherapy (RT) is a potent inducer of ferroptosis. These findings have uncovered a critical link between ferroptosis and RT-mediated tumor suppression. Moreover, we and others have identified ferroptosis inducers (FINs) as promising radiosensitizers that enhance the efficacy of RT, particularly in tumors exhibiting intrinsic or acquired radioresistance. In this presentation, I will provide an overview of the fundamental biology of ferroptosis, emphasizing its unique characteristics and mechanisms. I will highlight our discoveries on the role of ferroptosis in RT-mediated cell death and tumor control. Additionally, I will delve into the mechanisms underlying ferroptosis-driven radiosensitization and present evidence supporting the use of FINs as a novel strategy to overcome radioresistance. Finally, I will discuss the potential clinical implications of combining FINs with RT, offering insights into how these advancements might improve outcomes for patients with challenging radioresistant tumors. Citation Format: Boyi Gan. Targeting ferroptosis in radioresistance. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA06
Abstract IA01: Moving forward translation of targeted therapy with external beam radiation
Authors: Michael Baumann
Journal: Clinical Cancer Research (2025)

Radiotherapy is an anatomically highly targeted treatment modality capable of eradicating cancer cells, including cancer stem cells (CSC). This precision makes radiotherapy an ideal partner for synergistic treatment with targeted drugs, combining local effects on the tumor with systemic molecular interventions. To evaluate the efficacy of such combined treatments on inactivation of CSC in translational research, it is essential to select the appropriate clinical endpoints for preclinical experiments, most importantly inactivation of CSC in vitro or local tumor control in vivo. This ensures that preclinical findings are better translatable to the clinical setting, bridging the gap between experimental models and patient outcomes. A critical factor in this translational pipeline is the use of appropriate in vitro and animal or explant models that as accurate as possible mimic the clinical tumor microenvironment and response dynamics. To account for inter-tumor heterogeneity, it is necessary to apply a panel of models that are well characterized on a molecular biological level. With the right preclinical systems in place, combination strategies can be refined to optimize timing, dosing and sequencing of therapies to maximize tumor control while minimizing damage to normal tissues. Biomarker-driven approaches and molecular pathway analysis are increasingly guiding patient selection and therapeutic personalization, thereby improving the likelihood of clinical success. Examples include biomarker-based studies such as the DELPHI trial for dose de-escalation in post-op HPV-positive head and neck cancer (HNSCC) and the INDIRA Miso study on escalation of PET hypoxic HNSCC. Promising examples of novel combinations with radiotherapy include not only small molecule or Immunotherapeutics, but also the use of radiotherapy integration with novel theranostic radiopharmaceuticals, genomic and radiomic data for adaptive treatment planning. By aligning preclinical and clinical strategies, these efforts are advancing the integration of targeted therapies with radiotherapy and improve loco-regional control, overall survival and quality of life for patients. Citation Format: Michael Baumann. Moving forward translation of targeted therapy with external beam radiation. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA01
Abstract IA03: Tumor draining lymph nodes: Friends or foes
Authors: Quynh-Thu Le
Journal: Clinical Cancer Research (2025)

Abstract Nodal metastasis is the most common pattern of spread in head and neck squamous cell carcinoma (HNSCC). Nodal involvement has been linked to tumor aggressiveness and poor prognosis as reflected in the staging system. It also leads to the current surgical and radiation managements of HNSCC that include elective nodal treatment in addition to addressing gross disease. Yet, elective nodal treatment (either with surgery or radiation) has been linked to immune suppression since the tumor-draining lymph nodes (TDLN) are crucial for the development of a tumor-directed adaptive immune response, particularly in T-cell priming. Here I will touch on some recent work showing: (1) how nodal metastasis can influence tumor distant spread; (2) potential role of B cells in the TDLNs in driving anti-tumor T cell immunity through the recognition of extracellular vesicle-linked antigens, (3) potential treatment approaches of HNSCC that can mitigate the negative consequences of targeting TDLN. Citation Format: Quynh-Thu Le. Tumor draining lymph nodes: Friends or foes. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA03
Safety and Immunogenicity of Omicron Protein Vaccines in mRNA-Vaccinated Adolescents: A Phase 3, Randomised Trial
Authors: Chijioke Bennett, Gordon Chau, Erika Clayton, Laurence Chu, Jacqueline Alvarez, Ausberto B Hidalgo, Khozema Palanpurwala, Joyce S Plested, Mingzhu Zhu, Shane Cloney-Clark, Zhaohui Cai, Raj Kalkeri, Karim Hegazy, Katherine Smith, Susan Neal, Fernando Noriega, Raburn M Mallory, Jeffrey M Adelglass
Journal: Journal of Infection (2025)
Minority stress and protective factors for body image concerns and disordered eating among a cohort of transgender and nonbinary youth: A preliminary longitudinal study
Authors: Emmett C. Line, Dougie Zubizarreta, Stephanie L. Budge, Ryan J. Watson, Allegra R. Gordon, S. Bryn Austin, Sabra L. Katz-Wise
Journal: International Journal of Transgender Health (2025)
Author Correction: Global loss of promoter–enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis
Authors: Yizhou Zhu, Hayan Lee, Shannon White, Annika K. Weimer, Emma Monte, Aaron Horning, Stephanie A. Nevins, Edward D. Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Roxanne Chiu, Rozelle Laquindanum, Thomas V. Karathanos, Melissa W. Y. Chua, Meredith Mills, Uri Ladabaum, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J. Greenleaf, Christina Curtis, James M. Ford, Michael P. Snyder
Journal: Nature Cancer (2025)
Machine learning approach for noninvasive intracranial pressure estimation using pulsatile cranial expansion waveforms
Authors: Gustavo Frigieri, Sérgio Brasil, Danilo Cardim, Marek Czosnyka, Matheus Ferreira, Wellingson S. Paiva, Xiao Hu
Journal: npj Digital Medicine (2025)

Abstract Noninvasive methods for intracranial pressure (ICP) monitoring have emerged, but none has successfully replaced invasive techniques. This observational study developed and tested a machine learning (ML) model to estimate ICP using waveforms from a cranial extensometer device (brain4care [B4C] System). The model explored multiple waveform parameters to optimize mean ICP estimation. Data from 112 neurocritical patients with acute brain injuries were used, with 92 patients randomly assigned to training and testing, and 20 reserved for independent validation. The ML model achieved a mean absolute error of 3.00 mmHg, with a 95% confidence interval within ±7.5 mmHg. Approximately 72% of estimates from the validation sample were within 0-4 mmHg of invasive ICP values. This proof-of-concept study demonstrates that noninvasive ICP estimation via the B4C System and ML is feasible. Prospective studies are needed to validate the model’s clinical utility across diverse settings.
Maternal weight during pregnancy and risk of childhood acute lymphoblastic leukemia in offspring
Authors: Jiaye Liu, Elham Kharazmi, Qunfeng Liang, Yafei Chen, Jan Sundquist, Kristina Sundquist, Mahdi Fallah
Journal: Leukemia (2025)

In addition to biological factors, maternal exposures during pregnancy can contribute to leukemogenesis in offspring. We conducted a population-based cohort study in Sweden to investigate the association between risk of acute lymphoblastic leukemia (ALL) in offspring and maternal anthropometrics during pregnancy. A total of 2,961,435 live-born singletons during 1983-2018 were followed from birth to ALL diagnosis, end of age 18, or end of 2018. 1388 children were diagnosed with ALL (55.6% boys). We observed an increased risk of ALL among daughters of overweight/obese mothers in early pregnancy [Body mass index (BMI) ≥ 25 kg/m2; Standardized incidence ratio (SIR) = 1.4, 95% CI: 1.2-1.6] compared with the risk in daughters of mothers with normal BMI. This association was not found in their sons (SIR = 1.0, 95% CI: 0.9-1.1). Similar results were found for the association between ALL and maternal BMI before delivery. We did not find an association between low or high gestational weight gain (GWG) and risk of ALL (both SIRs = 1.0) in male/female offspring. These suggest that maternal overweight/obesity are important risk factors for childhood ALL in daughters, whereas GWG is not associated with risk of ALL. Further research on this mother-daughter association may shed light on a possible sex hormone/chromosome-related etiology of ALL.