bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A013: Shikonin, a strong inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen-Activated Protein (MAP) Kinase pathways, induces cell death in UV-B irradiated B16F10 melanoma cells
Authors: Bhat Aalim Maqsood , Abdullah Sheikh Tasduq
Published: January 2025

Ultraviolet (UV) radiation-induced skin damage plays a pivotal role in the pathogenesis of melanoma, a highly aggressive and fatal form of skin cancer. Shikonin, naturally occurring nathoquinone , is well-known for its inhibitory effects on phosphoinositide 3-kinase (PI3K) and mitogen-activated protein (MAP) kinase signaling pathways. It has previously been demonstrated to exert effects against various non-melanoma skin cancers. In this study, we investigated the effects of Shikonin treatment on UVB-irradiated B16F10 melanoma cells, revealing a dose-dependent reduction in cell viability and an enhancement of apoptosis. Invitro findings indicate that the pro-apoptotic effects of shikonin in UVB-exposed B16F10 cells are mediated by several mechanisms, including the generation of reactive oxygen species (ROS), modulation of the antioxidant defense response, and mitochondrial membrane potential (ΔΨM) depolarization. Further supporting the apoptotic role of Shikonin, we observed DNA fragmentation, caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, and an increase in sub-G2 cell populations. Shikonin treatment also significantly attenuated MEK-ERK signaling, influenced the PI3K/Akt pathway, and potentially inhibited UVB-induced nuclear translocation of NF-κB. Additionally, co-treatment with UVB and Shikonin led to a decrease in the Bcl-2/Bax ratio and upregulated the expression of pro-apoptotic proteins Bax and caspases. Collectively, these data suggest that Shikonin may act as a potential therapeutic agent for melanoma when combined with UVB exposure, providing a novel avenue for future treatment strategies.

Citation Format: Aalim Maqsood Bhat, Sheikh Tasduq Abdullah. Shikonin, a strong inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen-Activated Protein (MAP) Kinase pathways, induces cell death in UV-B irradiated B16F10 melanoma cells. [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 A013.
Abstract A014: Mitochondrial dynamics in insulin-like growth factor binding protein 3-mediated radiosensitivity of oral squamous cell carcinoma cells
Authors: Chen Ya-Wen
Published: January 2025

Radiation therapy, a common adjuvant therapy for oral squamous cell carcinoma (OSCC) patients either received operation or not, efficiently reduces the tumor infiltration area and growth. Insulin-like growth factor binding protein 3 (IGFBP3) is a member of a secretary glycoprotein family. We previously found that IGFBP3 promotes cell migration and lymph node metastasis of OSCC cells. However, OSCC patients with high IGFBP3 expression had a better prognostic outcome than those with low IGFBP3 expression. Moreover, we verified that ectopic expression of IGFBP3 augmented the radiosensitivity, while IGFBP3 knockdown diminished the radio-resistance of OSCC cells. We observed changes in mitochondrial morphology in IGFBP3-expressing OSCC cells after ionizing radiation (IR) treatment; however, the roles of IGFBP3 in mitochondrial dynamics remain unclear. The analyses of cell survival, reactive oxygen species production, and loss of mitochondrial membrane potential were used to verify the IGFBP3-mediated radiosensitivity. Using mitochondria by 3D cell explorer and quantification of mitochondria dynamics by immunofluorescence staining, the fission and fusion mitochondria in irradiated IGFBP3-expressing cells and IGFBP3 knockdown cells were increased, respectively. By western blot, we found phosphorylated dynamin-related protein 1 (DRP1) positively associated with IGFBP3 levels in irradiated cells. By transiently expressing DRP1 in IGFBP3-expressing cells, we found that IGFBP3-mediated radiosensitivity and mitochondrial fission were flattened by DRP1 inhibition, suggesting the role of DRP1 in IGFBP3-mediated mitochondrial fission. Our study is to elucidate the mechanism of IGFBP3-mediated radiosensitivity and hope to provide different strategies to sensitize radiotherapy and enhance the synergy between radiotherapy and immunotherapy.

Citation Format: Ya-Wen Chen. Mitochondrial dynamics in insulin-like growth factor binding protein 3-mediated radiosensitivity of oral squamous cell carcinoma cells. [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 A014
Abstract B002: Pre-vaccine radiation and CTLA-4 blockade increase adjuvant effects of SARS-COV-2 mRNA vaccines
Authors: Grippin Adam , Copling Sage , Kim Andrew , Young Elliana , Kim Betty , Heymach John , Jiang Wen , Lin Steven H
Published: January 2025

Background: We recently reported that SARS-CoV-2 mRNA vaccines stimulate massive production of interferon-⍺ (IFN-⍺) (Grippin, et al., SITC, 2024) that drives a near-doubling of median OS and three-year overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and metastatic melanoma (p<0.003) (Grippin, et al., ESMO, 2024). However, design of prospective clinical trials to validate this effect is limited by insufficient understanding of the interaction of mRNA vaccines, ICIs, and local therapies. We therefore analyzed our clinical dataset to understand whether radiation and specific ICIs augment the adjuvant effects of mRNA vaccines. Methods: We utilized institutional databases to identify and extract clinical data for patients with Stage III and Stage IV non-small cell lung cancer (NSCLC) (n=2406) and metastatic melanoma (n=756) with biopsy specimens between August 2019 and August 2023. Differences in survival between groups were assessed with Gehan-Breslow-Wilcoxon tests. Results: After controlling for 34 covariates including performance status, clinical stage, steroid use, tumor proportion score (TPS) of PDL1, disease burden at presentation, cycle of therapy, mutation status, concurrent therapies, and comorbidities with multivariate Cox-proportional hazards regression, we found that receipt of a COVID mRNA vaccine within 100 days of initiation of treatment with ICI was associated with substantial survival advantage in patients with Stage III (HR 0.46, 05% CI 0.31-0.70) and Stage IV NSCLC (HR 0.46, 95% CI 0.36-0.59). Moreover, patients with Stage III disease treated with chemoradiation followed by durvalumab experienced the greatest benefits of vaccination (HR 0.17, 95% CI 0.06-0.49). Since dual agent immunotherapy was uncommon in patients with NSCLC, we then reviewed data from patients with Stage IV melanoma treated with different ICI regimens. We found that adjuvant effects of mRNA vaccines were magnified in patients who received combination therapy with dual inhibition of CTLA-4 and PD-1 (HR 0.32, 95% CI 0.17-0.60) compared to single-agent PD-1 blockade (HR 0.63, 95% CI 0.33-1.3). Conclusions: Together, this data suggests that pre-vaccine radiation therapy and combination therapy with CTLA-4 blockade enhance the adjuvant effects of mRNA vaccines. Future work will include validation of these findings in preclinical models and prospective clinical trials.

Citation Format: Adam Grippin, Sage Copling, Andrew Kim, Elliana Young, Betty Kim, John Heymach, Wen Jiang, Steven H Lin. Pre-vaccine radiation and CTLA-4 blockade increase adjuvant effects of SARS-COV-2 mRNA vaccines. [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 B002.
Abstract B006: Targeting REV-ERB/RORα/IRF3 axis to enhance radiation-induced immune response in cancer radiotherapy
Authors: LI Nan , Bruan Chen , Lin Steven Hsesheng
Published: January 2025

Radiotherapy is an important component of the therapeutics for cancer. Although the primary objective of RT is the local control of tumors, RT-mediated antitumor adaptive immunity is emerging as a promising tool in cancer treatment. Increasing evidence indicates that RT enhances adaptive anti-tumor immunity by augmenting the innate immune sensing of tumors in a type I IFN-dependent matter. Both retinoic acid-related orphan receptor α (RORα) and nuclear heme receptor Rev-erbα, are core components of the circadian rhythm, all have critical roles in inflammation and immune process. Our preliminary data showed that both RORα inverse agonist (antagonist) SR1001 and Rev-erbα agonist GSK4112 significantly enhanced radiation-induced type I IFN activation. We also found that both RORα and Rev-erbα could associate with IRF3 and regulate IRF3 phosphorylation, which enhance radiation-induced type I IFN activation. Furthermore, our data indicated that radiation induced Type I IFN production may depend on circadian cycle, and SR1001 treatment contribute to antitumor immunity of radiation. These results usher the hypothesis that RORα/Rev-erbα work together to regulate radiation-induced type I IFN response, and contribute to antitumor immunity of RT. Specifically, our data shown the critical role of RORα/Rev-erbα/IRF3 axis in regulating radiation-induced type I IFN activation and targeting RORα/Rev-erbα will synergize with radiotherapy. Altogether, the preliminary data generated from this proposal opens additional avenues of research, both preclinically and clinically, to help better understand the relationship of the circadian rhythm proteins on the RT-immune response.

Citation Format: Nan LI, Chen Bruan, Steven Hsesheng Lin. Targeting REV-ERB/RORα/IRF3 axis to enhance radiation-induced immune response in cancer 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 B006.
Abstract B010: Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma
Authors: Ryu Samuel , Stessin Alexander , Mikell Charles , Kowalska Agnieszka , Seidman Roberta , West Steven , Mani Kartik
Published: January 2025

Background: Preclinical studies with transplanted GL261 glioma in mouse brain treated with radiosurgery and checkpoint blockade showed dramatic improvement of tumor cure and prolonged survival, associated with activated macrophage infiltration in the tumor site. We perform phase I study in patients with glioblastoma to assess safety and local tumor response by combined radiosurgery and checkpoint inhibitor given during window-of-opportunity prior to surgical resection, and progression-free survival and overall survival. Method and Procedure: Biopsy-proven WHO grade 4 glioblastoma patients were enrolled to the study (NCT05423210). Patients were treated with two doses of intravenous Atezolizumab at the beginning and at the end of the two-week period, concomitantly with fractionated radiosurgery (8 Gy x 4 to the grossly enhancing tumor) over 4 days during the course of 2 weeks. Maximal safe surgical resection was subsequently performed within 2 weeks from completion of radiosurgery. Adjuvant radiation 50 Gy over 5 weeks and Temozolomide were given as per standard treatment of GBM along with continuation of Atezolizumab until unacceptable toxicity or tumor progression. The initial biopsy specimen and surgical specimen were collected for laboratory examination of immune profiles. Results: The study plans to enroll total 12 histologically confirmed CNS WHO Grade 4 GBM patients also planned for surgical resection. Six patients were enrolled after consenting so far. There was no grade 3 or 4 toxicity from the window-of-opportunity combination treatment, all 6 patients successfully completing the treatment. Three patients reported fatigue and two patients had skin rash. There was one patient experiencing metallic taste. At present, five patients survive progression-free at 25, 18, 16 and 6 months since the treatment. An unanticipated finding is that there was significantly less intraoperative bleeding in the surgical field than usual brain tumor surgery. Conclusion: Preoperative fractionated radiosurgery and Atezolizumab was well tolerated so far, and appear to improve tumor control. We continue enroll the patients. Lab study of immune cell profile is underway.

Citation Format: Samuel Ryu, Alexander Stessin, Charles Mikell, Agnieszka Kowalska, Roberta Seidman, Steven West, Kartik Mani. Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma. [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 B010.
Abstract B013: Autoimmunity mechanisms in combined radiotherapy and immune-checkpoint inhibitor therapy-induced myocarditis
Authors: Yu Shiguang , Vu Nhan T , Verburg Tyler , Lu Bo
Published: January 2025

Immuno-checkpoint inhibitors (ICI) are frequently used as a major cancer therapy, frequently combined with radiotherapy, particularly among patients with lung cancer. There is an increasing awareness of potential cardiotoxicities from either therapy, thus raising concerns when both therapies are combined. It is likely that radiation-induced cardiac inflammation becomes unchecked when ICIs are administered, contributing to myocarditis although the underlying specific mechanisms have not been characterized. We developed a mouse model of ICI and cardiac irradiation-induced myocarditis through an image-guided small animal irradiator in the A/J mice, which is prone to ICI-induced myocarditis. Our results showed that 20 % of ICI treated mice developed mild myocarditis, whereas 40 to 50% of mice with ICI plus irradiation treatment showed severe myocarditis, characterized by lots of infiltration of CD4+ T cells, CD8+ T cells, B cells and macrophages in hearts. Flow cytometry analysis showed that the number of infiltrated CD4+ T cells is 2 to 3 folds of CD8+ T cells in the heart tissue with disease. Severe fibrosis in hearts was associated with severe myocarditis. The levels of cardiomyocyte-specific protein troponin I in serum was correlated well with the severity of myocarditis, implicating that ICI and irradiation caused many cardiomyocyte damages. ELISA assay showed that serum IL-17 was dramatically increased in mice treated with ICI alone or ICI plus radiation, implying Th17 cells may play a pathogenic role in ICI & irradiation-induced myocarditis. In addition, we compared the myocarditis induced by ICI and irradiation in less susceptible prone of C57 mice with the more susceptible strain of A/J mice. The incidence of myocarditis was significantly lower in C57 mice compared with A/J Mice. Overall, our study indicates that irradiation promotes the pathogenesis of ICI-induced myocarditis, and individuals with autoimmune tendency have a high risk to develop severe myocarditis after administration of combined ICIs and irradiation. (This work is supported by NIH grant R01)

Citation Format: Shiguang Yu, Nhan T Vu, Tyler Verburg, Bo Lu. Autoimmunity mechanisms in combined radiotherapy and immune-checkpoint inhibitor therapy-induced myocarditis. [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 B013.
Abstract B015: PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity
Authors: Dominguez-Vigil Irma G. , Banik Kishore , Baro Marta John , Contessa Joseph N. , Hayman Thomas J.
Published: January 2025

Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and comprises 85% of cases. Despite treatment advances, local control after curative-intent chemoradiation for NSCLC remains suboptimal. Polo-like kinase 4 (PLK4) is a serine-threonine kinase that plays a critical role in the regulation of centrosome duplication and cell cycle progression and is overexpressed in NSCLC, thus, making it a potential therapeutic target. CFI-400945 is an orally available PLK4 inhibitor currently undergoing clinical trial evaluation. As radiation causes cell death primarily by mitotic catastrophe, a process enhanced by alterations in centrosome amplification, we hypothesized that disruption of the mitotic machinery by inhibition of PLK4 would enhance the effects of radiation in NSCLC. PLK4 inhibition by CFI-400945 resulted in radiosensitization of NSCLC cell lines. In contrast, CFI-400945 had no effect on the radiosensitivity of normal lung fibroblasts. PLK4 inhibition did not affect cell-cycle phase distribution prior to radiation, but rather the combination of CFI-400945 and radiation resulted in increased G2/M cell cycle arrest, increased centrosome amplification, and a concomitant increase in cell death through mitotic catastrophe. Lastly, CFI-400945 treatment enhanced the radiation-induced tumor growth delay of NSCLC tumor xenografts. These data indicate that targeting PLK4 is a novel approach to enhance the radiation sensitivity of NSCLC in vitro and in vivo through potentiation of centrosome amplification and cell death through mitotic catastrophe.

Citation Format: Irma G. Dominguez-Vigil, Kishore Banik, Marta John Baro, Joseph N. Contessa, Thomas J. Hayman. PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity. [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 B015.
Abstract B021: FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer
Authors: Ji Lu , Pu Leighton , Cao Hongbin , Melemenidis Stavros , Sinha Subarna , Guan Li , Laseinde Eyiwunmi E. , Richter Sara , Eyben Rie , Casey Kerriann M. , Kong Christina , Graves Edward , Le Quynh-Thu , Rankin Erinn
Published: January 2025

Despite the use of intensive combined modality therapy such as chemoradiation or surgery and radiation, the overall survival rate for patients with HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This underscores the unmet clinical need for the development of more effective drug-radiotherapy combinations to enhance the therapeutic index of radiation therapy (RT). The RNA demethylase enzyme FTO has emerged as a promising target for cancer therapy. However, its role as a radiosensitizer in HNSCC remains unknown. Here, we investigated the potential of targeting FTO to augment the effectiveness of RT in HPV-negative HNSCC. We found that genetic and pharmacologic inhibition of FTO enhanced the efficacy of RT in both human and mouse HNSCC tumor xenografts. Importantly, FTO inhibition did not increase radiation-induced oral mucositis. Mechanistically, FTO inhibition radiosensitizes HPV-negative HNSCC cells through amplifying DNA damage while reducing RAD51 foci formation, providing a molecular rationale for exploiting FTO inhibitors as radiation sensitizers in HNSCC. Collectively, our results suggest that therapeutic targeting of FTO may be an effective strategy to enhance the therapeutic index of RT for the treatment of HNSCC.

Citation Format: Lu Ji, Leighton Pu, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E. Laseinde, Sara Richter, Rie Eyben, Kerriann M. Casey, Christina Kong, Edward Graves, Quynh-Thu Le, Erinn Rankin. FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer. [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 B021.
Abstract B025: Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy
Authors: Kuganesan Nishanth , Melemenidis Stavros , Graves Edward E. , Rankin Erinn B.
Published: January 2025

The RNA demethylase enzyme FTO is emerging as an important oncogenic factor and therapeutic target in a variety of solid tumors. However, its effect on cancer metabolism remains largely unknown. Here we show that FTO promotes cysteine metabolism, a hallmark of metabolic rewiring in non-small cell lung cancer (NSCLC) cells. Mechanistically, FTO inhibition reduces the expression of multiple targets in the cysteine metabolism pathway including the cystine transporter SLC7A11 involved in exogenous cystine uptake as well as two key enzymes cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CTH) involved in de novo cysteine synthesis. Functionally, FTO inhibition reduces cystine uptake and NSCLC growth and survival in a homocysteine-dependent manner. As cysteine plays a crucial role in glutathione biosynthesis and maintenance of cellular redox homeostasis, FTO inhibition decreased glutathione levels and increased reactive oxygen species (ROS) levels in NSCLC cells. To therapeutically exploit the increased oxidative stress in NSCLC cells treated with FTO inhibitors, we combined FTO inhibition with radiation therapy. FTO inhibition enhanced the radiosensitivity of NSCLC cells. Our findings reveal a novel role for FTO in NSCLC cysteine metabolism and oxidative stress, highlighting the therapeutic potential of FTO inhibition as a strategy to enhance the efficacy of radiation therapy for the treatment of NSCLC.

Citation Format: Nishanth Kuganesan, Stavros Melemenidis, Edward E. Graves, Erinn B. Rankin. Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy. [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 B025.
Abstract IA03: Tumor draining lymph nodes: Friends or foes
Authors: Le Quynh-Thu
Published: January 2025

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
Abstract IA04: Evaluating and mitigating medical misinformation risk in large language models
Authors: Chen Shan , Gao Mingye , Sasse Kuleen , Hartvigsen Thomas , Anthony Brian , Fan Lizhou , Gallifant Jack , Bitterman Danielle D.
Published: January 2025

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 IA09: Radiotherapy immunotherapy interactions: What determines success or failure?
Authors: Weichselbaum Ralph R.
Published: January 2025

Radiation therapy (RT) can both stimulate antitumor immunity and induce immunosuppressive responses, complicating its therapeutic efficacy. Data indicate that certain patient subsets—such as those undergoing combination treatment with radiation and immune-oncology drugs and/or targeted therapies may benefit from strategies that target immunosuppression or metastasis-promoting factors. One of the key challenges is the heterogeneous and context-dependent nature of myeloid suppressive states in the tumor microenvironment, which often leads to resistance to RT and immunotherapy. RT has been shown to skew myeloid plasticity towards immune suppression by expanding myeloid-derived suppressor cell (MDSC) populations, increasing their trafficking into tumor tissues, and promoting the development of suppressive macrophage subsets. Targeting myeloid cell plasticity post-RT presents a promising therapeutic strategy. Interventions that block the systemic induction of immunosuppressive myeloid cells to inhibit their trafficking to tumors, or those that promote the conversion of suppressive myeloid cells into anti-tumor populations could enhance the effectiveness of RT. Additionally, radiation-induced proteins that can be inhibited or amplified may provide a potential avenue to overcome the limitations of RT alone, and in combination with immunotherapy.

Citation Format: Ralph R. Weichselbaum. Radiotherapy immunotherapy interactions: What determines success or failure?. [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 IA09
Abstract IA11: FLASH – Where are we and where are we going in the clinical trial future space
Authors: Buchsbaum Jeffrey
Published: January 2025

FLASH is one of the most promising findings in radiation therapy in the last decade. If the FLASH effect takes place, it is thought that normal tissue is spared while tumor tissue is not spared. The biology of FLASH is not fully understood. Exactly when the FLASH effect occurs, if it occurs with every fraction delivered in the same way if it occurs at all, and how to test it in a clinical trial are the real questions that need to be addressed. All of these are complex issues that will be hard to study across OAR’s, populations, and technologies. The first part of the talk will review the published data on clinical trial needs including the quality assurance and other processes needed to open a trial with focus on the NCTN. IROC data and other data will be presented. The second part of the talk will be a review of the clinical data, and pre-clinical data, currently being collected and evaluated. Two P01 grants will be reviewed and discussed (their public components). The talk will conclude with some models for trials that have been proposed as well as a possible thought experiment looking at next steps and moving forward.

Citation Format: Jeffrey Buchsbaum. FLASH – Where are we and where are we going in the clinical trial future space. [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 IA11
Abstract IA12: Enhancing radiation-induced anti-tumoral immune responses with PARP inhibitors in PDAC and DIPG
Authors: Morgan Meredith M.
Published: January 2025

Inhibitors of PARP sensitize cancers to radiation through mechanisms involving DNA damage, replication stress, and PARP trapping. These mechanisms may also activate innate immune signaling leading to Type I Interferon (T1IFN) production. The overall goal of this talk is to explore the hypothesis that PARP inhibitors potentiate radiation-induced T1IFN to activate an anti-tumoral immune response in pancreatic cancer (PDAC) and H3K27 altered-diffuse midline glioma (DMG). Preclinical data supporting this hypothesis will be described including the effects PARP1/2 inhibition (olaparib) as well as PARP1 selective inhibition (AZD5305, AZD4974) in combination with radiation on T1IFN production, modulation of the tumor microenvironment, and the contributions of CD8+ T and NK cells to anti-tumor immune responses in PDAC and DMG, respectively. Furthermore, the translation of these preclinical studies to early phase clinical trials will be discussed.

Citation Format: Meredith M. Morgan. Enhancing radiation-induced anti-tumoral immune responses with PARP inhibitors in PDAC and DIPG. [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 IA12
Abstract P010: Monitoring of cancer ferroptosis with [18F]hGTS13, a system xc- specific radiotracer
Authors: Moses Abraham S. , Malek Rim , Kendirli Mustafa T. , Cheung Pierre , Landry Madeleine , Herrera-Barrera Marco , Khojasteh Abbas , Bukhari Syed , Hooper Jody , Hayden-Gephart Melanie , Dixon Scott J. , Recht Lawrence D. , Beinat Corinne
Published: January 2025

Ferroptosis has emerged as a significant process in cancer biology due to its ability to counteract mechanisms of tumor survival and drug resistance. Exploiting this vulnerability is an emerging therapeutic strategy in cancer treatment. System xc- plays a critical role in ferroptosis by regulating the availability of cysteine, a crucial precursor for glutathione synthesis, thereby influencing the cellular antioxidant defense system. We recently reported the development and validation of [18F]hGTS13, a radiolabeled glutamate derivative, as a novel radiopharmaceutical specific for system xc-. We characterized the sensitivity of various cell lines to pro-ferroptotic compounds and evaluated the ability of [18F]hGTS13 to distinguish between sensitive and resistant cell lines and monitor changes in response to ferroptosis-inducing drugs. We then correlated changes in tracer uptake with cellular glutathione content. Furthermore, we performed PET/CT imaging of C6 glioma-bearing rats with [18F]hGTS13, revealing high, sustained uptake within the intracranial glioma, and demonstrated effective blocking of system xc- in vivo using imidazole ketone erastin. In summary, [18F]hGTS13 represents a promising tool for distinguishing cell types that demonstrate sensitivity or resistance to ferroptotic therapies, and monitoring of ferroptosis-inducing drug engagement. Its successful application in preclinical models make it a valuable asset for advancing our understanding of glioma biology and evaluating the efficacy of emerging ferroptosis-targeted therapies. As synergistic ferroptosis/radionuclide therapies are currently under investigation, [18F]hGTS13 represents a valuable tool for identifying patients who would benefit from combinatorial therapy, and monitoring treatment response in glioma and other cancers.

Citation Format: Abraham S. Moses, Rim Malek, Mustafa T. Kendirli, Pierre Cheung, Madeleine Landry, Marco Herrera-Barrera, Abbas Khojasteh, Syed Bukhari, Jody Hooper, Melanie Hayden-Gephart, Scott J. Dixon, Lawrence D. Recht, Corinne Beinat.Monitoring of cancer ferroptosis with [18F]hGTS13, a system xc- specific radiotracer.[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 P010
Abstract P019: Spatiometabolic mapping of cytoarchitectural changes in lung adenocarcinoma following radiotherapy
Authors: Bouchard Gina
Published: January 2025

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
Computer vision-based sun tracking control for optimizing photovoltaic power generation
Authors: Uchaipichat Nopadol , Wibunsin Chotiwat , Chokjulanon Kewalin , Tanthanuch Nutthaphong
Published: January 2025

As global energy consumption rises and fossil fuel reserves dwindle, the transition to renewable energy sources becomes imperative. Solar photovoltaic (PV) technology, crucial in this shift, faces challenges in efficiency and cost. This study explores a motorized sun-tracking system employing image processing techniques to optimize solar panel orientation and maximize energy capture. Using an Arduino Mega 2560 microcontroller, L298N motor driver, Raspberry Pi 3 Model B, and webcam integration, the system dynamically adjusts solar panels based on real-time sun position detection. Experiments compare the performance of fixed and sun-tracking solar panels, revealing that sun-tracking panels consistently outperform fixed ones, particularly during low sun angles, resulting in up to 84.9% higher power output. These findings underscore the potential of sun-tracking technology to significantly enhance solar energy efficiency and support sustainable energy goals. Future research should focus on refining tracking algorithms and optimizing system design to further boost energy capture and reliability.
Modelling and validation of hybrid series active filter for power quality enhancement using OPAL-RT simulator
Authors: Shrivastava Nitisha , Baliyan Arjun
Published: January 2025

It is a known fact that the quality of power is degrading at a very fast rate. The reason behind this is harmonics in the power supply. The main motive is to reduce the harmonic pollution in the system for various combinations of the load. The method proposed in this paper consists of hybrid series active power filter (HSAPF) which is a combination of an active power filter connected in series and the passive filter in parallel with the load. In order to generate the compensating signals, synchronous reference method has been used and the tuning of the proportional integral (PI) controller is performed with grey wolf optimization technique. It provides the optimized values of controller parameters that are very much necessary to improve not only the transient but also the steady state characteristics of the system. For comparison purposes the tuning of PI controller is also done using the well- known particle swarm optimization technique. A comparative simulation analysis is done in MATLAB as well as the results are verified by using OPAL-RT 4510 real time simulator which proves that the suggested topology gives better results in terms of total harmonic distortion (THD) reduction.
Broken rotor bar detection of three phase induction motor using frequency response analysis
Authors: Khan Rizwanullah , Mohd Yousof Mohd Fairouz , Rahman Rahisham Abd , Azis Norhafiz , Al-Ameri Salem , Ali Asjad
Published: January 2025

Three phase induction motors (TPIMs) are broadly utilized for various applications in the industry, but they are prone to different faults that can affect their performance and reliability. One common fault is a broken rotor bar, which leads to vibration, noise, and reduced efficiency. Therefore, detecting and identifying this fault early is important to avoid further damage and reduce maintenance costs. This paper proposes a novel method using frequency response analysis (FRA) to diagnose broken rotor bars in a TPIM. The response of normal motor is measured to obtain the baseline. Subsequently, the rotor was inflected with physical damage to represent a broken rotor bar. By comparing normal and faulty rotors, the measurement shows that frequency response analysis is sensitive toward various fault severity based on the number of broken rotor bars.
Modelling and control of LCL voltage source converter-based hybrid high voltage alternating current/high voltage direct current system
Authors: Saadeh Mahmood , Hamdan Mohammad , Saadeh Osama
Published: January 2025

Voltage source converters (VSCs) have revolutionized high voltage direct current (HVDC) transmission, offering numerous advantages such as black start capability, absence of commutation failure, and efficient control of bidirectional power flow. This study introduces a comparative analysis of advanced VSC technologies, focusing on a novel series hybrid converter incorporating an inductor-capacitor-inductor (LCL) passive circuit. This configuration is explored for its potential to enhance both high voltage alternating current (HVAC) and high voltage direct current (HVDC) side fault suppression capabilities and improve DC output voltage quality, addressing critical drawbacks of traditional VSCs. Through comprehensive simulations in MATLAB/Simulink, this research evaluates and compares three different converter topologies: the three-level neutral point clamped converter, the hybrid converter with AC side cascaded H-bridge cells, and the LCL hybrid converter. The comparison is based on key performance metrics such as DC output voltage quality, fault suppression capabilities, and system efficiency during normal and fault conditions. The study finds that the LCL hybrid converter outperforms traditional converters by significantly improving DC output voltage quality and enhancing fault suppression capabilities in HVDC systems. It effectively reduces ripple and maintains stability during faults, making it a superior choice for future HVDC converter designs and applications, offering valuable insights for advancing HVDC technology.
Model of semiconductor converters for the simulation of an asymmetric loads in an autonomous power supply system
Authors: Tavarov Saidjon , Senyuk Mihail , Safaraliev Murodbek , Kokin Sergey , Tavlintsev Alexander , Svyatykh Andrey
Published: January 2025

This article is devoted to the development of computer model with semiconductor converters for the simulation of asymmetric loads allowing to solve the voltage symmetry problems under asymmetric loads (active and active-inductive) for isolated electric networks with renewable energy sources (mini hydroelectric power plants). A model of a symmetry device has been developed in the MATLAB/Simulink environment based on a proportional-integral controller and a relay controller - P. The effectiveness of their use depends on the load's nature. The implementation of a voltage converter is presented considering a three-phase inverter with discrete key switching at 120, 150, and 180 degrees with a purely active load. Based on the harmonic analysis of the three-phase voltage at discrete conversion, the value of the first harmonic is determined. Voltage transformations under active-inductive load at 120, 150, and 180 degrees are mathematically described. To determine the harmonic spectrum, an analysis of the fast Fourier transform for the three-phase voltage of a MATLAB/Simulink semiconductor converter was carried out. It is established that the alternating current output voltage is generated on the output side of the inverter of a three-phase voltage source through a three-phase load connected by a star with a harmonic suppression method.
Five-level three phase cascaded H-bridge inverter using digital signal processor control for renewable energy applications
Authors: Hiransing Bancha , Wasuri Boonthong , Kuankid Sanya , Muangpool Thanin
Published: January 2025

This article presents a five-level three-phase cascaded H-bridge inverter for renewable energy applications, aimed at reducing total harmonic distortion (THD) and enhancing efficiency. The inverter uses a digital signal processing board, TMS320F28335, to generate pulse-width modulation signals through MATLAB/Simulink, ensuring precise control. The experimental setup includes an 84 VDC input voltage and a 300-watt load. Simulation and experimental results closely align, validating the accuracy of the simulation model. The output voltage shows a stepped pattern characteristic of multilevel inverters, significantly reducing harmonic distortion. THD analysis reveals a substantial reduction at higher modulation indices, with particularly low THD at a modulation index of 0.95. Consistent THD levels across modulation indices of 0.5, 0.8, and 0.95 demonstrate robust performance under varying conditions. Comparative analysis indicates that the proposed inverter achieves lower THD levels than traditional inverters, enhancing power quality and system efficiency. The five-level three-phase cascaded H-bridge inverter offers a promising solution for renewable energy applications by significantly reducing THD and improving power quality. Its robust performance and scalability potential contribute valuable advancements to renewable energy systems.
Three-phase hybrid active power filter: an overview
Authors: Binh Le Quang , Thuyen Chau Minh
Published: January 2025

Hybrid active power filter (HAPF) is considered an effective solution for filtering harmonics and compensating reactive power in power systems. It is a combination of passive power filters and an active power filter to form many different structures depending on the system voltage and load characteristics. This paper aims to introduce an overall picture of the results of research on three-phase HAPF systems, such as: HAPF models, advantages, disadvantages, and scope of application of each model; methods for determining parameters of passive power filters; structure, response time, resonance, power loss and cost of types of output filters; inverter structure and commonly used pulse width modulation methods in HAPF; control strategies and used controllers are also listed and compared; the DC Link voltage stabilization is also summarized and analyzed. Finally, the existing problems and the development trends of HAPF.
Design and experimental validation of a single phase grid tied inverter for residential low power applications
Authors: Mousmi Ali , Schellmanns Ambroise , Elghadhi Salem , Desouches Quentin
Published: January 2025

This paper presents the design and control of a single phase grid tied inverter intended for low power applications in residential sector as part of smart grid environments or solar photovoltaic source integration. The total cost of the converters used in such applications involving low power rates, generally lower than 1 kW, cannot afford expensive components or complex techniques, so, the optimization of the power circuits as well as the simplification of the control algorithms are necessary to meet the specifications. In this purpose, this work presents the design steps of a single phase grid tied inverter including the structure choice, a synchronization algorithm based on the grid voltage zero crossing method, and the algorithm to control the injected power. Different experimental tests have been carried out and show the good performance of the converter which meets the requirements in terms of total harmonic distortion and efficiency.