bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 200: Patient-derived cervical cancer organoids as a pre-clinical model predicting drug and radiation response
Authors: Oh Ju Hee , Seol Hyang Sook , Choi Eun Hye , Lee Yong Jae Lee , Lee Jung-Yun , Kim Sang Wun , Kim Sunghoon , Kim Young Tae , Kim Hyun Ki , Lee Young Joo , Nam Eun Ji 
Published: April 2023

Abstract
Objective: Advanced cervical cancer is still difficult to treat and in the case of recurrent cancer, it is desirable to utilize personalized treatment rather than uniform treatment because the type of recurrence is different for each individual. Therefore, this study aimed to establish patients-derived organoid platform to determine the effects of chemotherapy, radiation therapy, and targeted therapy in cervical cancer.
Methods: We established organoids from four patients with various types of cervical cancer. The histopathological and gene profiles of these organoid models were compared to determine their characteristics and the maintenance of the patient phenotype. Each type of organoid was also subjected to anticancer drug screening and radiation therapy to evaluate its sensitivity.
Results: We established patient-derived organoids recapitulated the main elements of the original patient tumors, including the DNA copy number and mutational profile. We screened seven drugs that showed growth inhibition in cervical cancer organoids using two analytical tools (individual drugs and an FDA-approved drug library). Moreover, squamous cell carcinoma and villoglandular carcinoma showed significant response to radiation therapy, however, adenocarcinoma and large-cell neuroendocrine carcinoma showed relative resistance to radiation therapy.
Conclusion: Our results showed patient-derived cervical cancer organoid can be used as a pre-clinical model for drug and radiation sensitivity test. These findings suggest that patient-derived cervical cancer organoids could be used as a personalized medicine confirmation tool and to improve treatment options for patients with various subtypes of cervical cancer.
Citation Format: Ju Hee Oh, Hyang Sook Seol, Eun Hye Choi, Yong Jae Lee Lee, Jung-Yun Lee, Sang Wun Kim, Sunghoon Kim, Young Tae Kim, Hyun Ki Kim, Young Joo Lee, Eun Ji Nam. Patient-derived cervical cancer organoids as a pre-clinical model predicting drug and radiation response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 200.
Abstract 2003: Evaluation of liposome encapsulated sunitinib efficacy and immune modulation on renal cell carcinoma
Authors: Yueh Po-Fu , Chang Yuan , Lan Keng-Li , Hsu Fei-Ting 
Published: April 2023

Abstract
Renal cell carcinoma (RCC) is one of the deadliest malignant tumors worldwide. The RCC’s standard treatments are including surgery, radiation, and chemotherapy. SUTENT® (sunitinib) was approved by US Food and Drug Administration (FDA) in 2016 to treat advanced RCC. According to the results from the clinical trial, sunitinib is associated with a higher objective response rate and survival rate than IFN-α, which indicates that it is an effective multiple tyrosine kinase inhibitor (TKi) against advanced RCC. Meanwhile, recent studies demonstrated sunitinib could cause tumor immune surveillance by upregulated autophagy to inhibit tumor PD-L1 expression. However, sunitinib targets not only tumor tissue but also multiple organs in the human body, which causes many serious side effects and even leads to death. In order to reduce the toxicity of sunitinib, our group design a novel nanocarrier by PEGylated liposome to encapsulate sunitinib (lipo-sunitinib). The PEGylated liposome could passively target tumor tissue by extravasation of nanoparticles through increased permeability of the tumor vasculature (enhanced permeability and retention, EPR effect). Moreover, the PEGylation on the liposome surface could prolong liposome half-life in the body through increased particle size. Through the EPR effect and PEGylation of lipo-sunitinib to target tumor cells precisely, we successfully increased RCC orthotopic tumor inhibition in mouse models compared with vehicle and sunitinib groups. Furthermore, the RCC tumor immunofluorescence staining revealed lipo-sunitinib had higher activated effector T cells (CD8+IL-2+IFN-γ+) and type 1 dendritic cells (CD11c+CD24+MHCII+) infiltration and lower vessel formation than sunitinib group. The flow cytometry also demonstrated that lipo-sunitinib had increased anti-tumor immune cells and inhibited immune suppressors in the systemic system. More importantly, lipo-sunitinib showed lower toxicity in mouse livers, hearts, and kidneys compared to the sunitinib group. Our results suggested lipo-sunitinib could inhibit tumor growth and prolong survival rate by modulating a positive anti-tumor microenvironment and anti-angiogenesis effects. In sum, with the polish of the delivery system, our novel nanodrug lipo-sunitinib could be a potential new treatment strategy for RCC patients.
Citation Format: Po-Fu Yueh, Yuan Chang, Keng-Li Lan, Fei-Ting Hsu. Evaluation of liposome encapsulated sunitinib efficacy and immune modulation on renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2003.
Abstract 2074: Genome Integrity assessment and verification by optical genome mapping for cell manufacturing/bioprocessing applications
Authors: Hastie Alex R. 
Published: April 2023

Abstract
Cells and cell lines are used for multiple applications such as bioprocessing, therapy, and research. To ensure quality of cells and downstream applications, appropriate quality control (QC) methods are critical. Historically, karyotyping has been employed, but it is limited by its very low resolution and tedious laboratory workflow. Other methods such as PCR and targeted sequencing can characterize only small genomic variants at specific loci. Whole genome sequencing can detect small variants genome-wide but has limited sensitivity in detecting structural variants (SVs). Optical genome mapping (OGM) is a novel genome analysis technique that can fill many of the gaps in current capabilities for assessing genome integrity. To find clonal variants, 400 Gbp of data is collected from the parental/control and test samples. For both samples, a de novo assembly is constructed, and homozygous or heterozygous SVs are assessed. Subsequently, Bionano Access software’s dual variant annotation pipeline identifies unique SVs in the test sample compared to the parental sample. To discover subclonal SVs down to 5% variant allele fraction (VAF), the workflow leverages the generation of 1.5 Tbp of data, requiring a simple adjustment to longer data collection time. Comparison of test sample to parental sample easily enables the determination of acquired variants. Finally, generation of ~5 Tbp of data, requiring 2-3 flow cells to be run, enables the detection of SVs at ultra-low VAF down to ~1%. In this study, several dilutions and simulations were performed to examine OGM’s limit of detection. Targeting a coverage of 5 Tbp and analysis using the somatic SV-analysis workflow revealed that OGM has the sensitivity to detect deletions &gt;50kbp, insertions &gt;20kbp, duplications &gt;100 kbp, and translocations at ~1% VAF.
We have applied the clonal and somatic workflows to verify genomes’ integrity after cell immortalization, induced pluripotency, transgene-integration, and gene-editing. The data using the robust and sensitive workflows demonstrate that the OGM platform is a cost-effective solution for cell manufacturing/bioprocessing QC applications.
Citation Format: Alex R. Hastie. Genome Integrity assessment and verification by optical genome mapping for cell manufacturing/bioprocessing applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2074.
Abstract 2134: Microsatellite instability status and high risk features in decision making for adjuvant chemotherapy in stage 2 colon cancer
Authors: Bae Sung Uk , Jeong Woon Kyung , Baek Seong Kyu 
Published: April 2023

Abstract
Background: The impact of adjuvant chemotherapy for patients with stage II colon cancer has been addressed in several clinical trials. NCCN guideline recommends that patients with stage II disease that is MSS/pMMR and at high risk for systemic recurrence can be considered adjuvant chemotherapy. However, research on whether these high-risk features or status of microsatellite instability (MSI) are predictive markers for adjuvant chemotherapy (ACT) is insufficient.
Materials and Methods: We assessed the efficacy of ACT and possible interaction with MSI status and high-risk features for recurrence in patients with resected stage II colon diagnosed at 16 tertiary referral hospitals between January 2010 and December 2017.
Results: According to MSI status, 394 patients (21.8%) had MSI-high tumors and 1416 (78.2%) had MSI-low or microsatellite stable (MSS) tumors. There were 881 patients (48.7%) with one or more high-risk feature for recurrence. Among 161 patients with MSI-high and high-risk features, the 5-year disease-free survival (DFS) and overall survival (OS) of patients who
received no ACT, 5-FU chemotherapy, and oxaliplatin-based chemotherapy were 65.5% and 72.3%, 89.4% and 97.9%, and 88.2% 92.0%, respectively (DFS and OS: 5-FU vs. Oxaliplatin, p=0.972 and p=0.233, Oxaliplatin vs. no chemotherapy, p=0.016 and p=0.032, 5-FU vs. no chemotherapy, p=0.025 and p=0.003, respectively). Among 720 patients with MSI-low or MSS and high-risk features, the 5-year DFS and OS of patients who received no ACT, 5-FU, and oxaliplatin-based were 77.1% and 87.2%, 90.4% and 95.6%, and 86.9% 93.5%, respectively (DFS and OS: 5-FU vs. Oxaliplatin, p=0.580 and p=0.492, Oxaliplatin vs. no chemotherapy, p=0.037 and p=0.077, 5-FU vs. no chemotherapy, p=0.009 and p=0.012, respectively). In patients without risk factors, there was no benefit from ACT regardless of MSI status.
Conclusions: 5-FU chemotherapy can be recommended in patients with one or more high-risk features for recurrence regardless of MSI status in stage II colon cancer.
Keyword: Colonic Neoplasms, Adjuvant Chemotherapy, Microsatellite Instability, Risk Factors
Citation Format: Sung Uk Bae, Woon Kyung Jeong, Seong Kyu Baek. Microsatellite instability status and high risk features in decision making for adjuvant chemotherapy in stage 2 colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2134.
Abstract 2354: Regulation of TIMPs through MMP dependent cleavage in breast cancer
Authors: Coates-Park Sasha , Gurung Sadeechya , Rich Josh , Stetler-Stevenson William , Peeney David 
Published: April 2023

Abstract
Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) are a broadly expressed family of matrisome proteins that are the primary regulators of matrix metalloproteinases (MMPs). In addition to their originally described function, TIMPs display a broad range of MMP independent biological functions associated with proliferation, apoptosis, migration, and differentiation. MMPs are zinc containing endopeptidases that play an essential role in maintaining the extracellular matrix (ECM) through proteolytic turnover; a balancing act maintained (in part) by the local MMP:TIMP ratio. Disturbances in the balance between MMPs and TIMPs is associated with various disease states, including cancer, heart disease, arthritis, and cognitive dysfunction. While TIMPs are classically characterized as regulators of MMP proteolytic activity, we describe a novel mode of MMP-dependent regulation of TIMP function. We show that active MMP9 (aMMP9) in molar excess can cleave TIMP proteins within their C-terminal domains. As a result of this cleavage, the MMP-dependent and MMP-independent functions of the TIMP proteins are predicted to be altered. MMP9 has been found to contribute to the pathogenesis of many cancer types including breast cancer. Additionally, MMP9 is described as a breast cancer biomarker, with high levels of MMP9 being associated with a worse prognosis. Previous research from our lab has shown recombinant TIMP2 may represent a novel biological therapeutic in triple negative breast cancer models. Utilizing murine models of breast cancer, we describe the prevalence of TIMP cleavage in 4T1 breast tumors as well as the functional outcomes of TIMP cleavage within this model system. Studying the outcomes of TIMP regulation by MMPs may allow researchers to target this model system more effectively in translational studies of breast cancer.
Citation Format: Sasha Coates-Park, Sadeechya Gurung, Josh Rich, William Stetler-Stevenson, David Peeney. Regulation of TIMPs through MMP dependent cleavage in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2354.
Abstract 2416: Uncovering the protective neurological mechanisms of hypofractionated FLASH radiotherapy
Authors: Limoli Charles L. , Allen Barrett D. , Kramár Eniko A. , Alaghband Yasaman , Vozenin Marie-Catherine 
Published: April 2023

Abstract
Implementation of ultra-high dose-rate FLASH radiotherapy (FLASH-RT) is rapidly gaining traction as a unique cancer treatment modality able to dramatically minimize normal tissue toxicity while maintaining anti-tumor efficacy compared to standard of care radiotherapy at conventional dose rate (CONV-RT). The resultant improvements in the therapeutic index have sparked intense investigations in pursuit of the underlying mechanisms. As a preamble to clinical translation, we exposed non-tumor bearing male and female mice to hypofractionated (3x10 Gy) whole brain FLASH- and CONV-RT to evaluate differential neurological responses using a comprehensive panel of functional and molecular outcomes over a 6-month follow up. In each instance, extensive and rigorous behavioral testing showed FLASH-RT to preserve cognitive indices of learning and memory that corresponded to a similar protection of synaptic plasticity as measured by long-term potentiation (LTP). These beneficial functional outcomes were not found after CONV-RT and were linked to a preservation of synaptic integrity at the molecular (synaptophysin) level and to reductions in neuroinflammation (CD68+ microglia) throughout specific brain regions known to be engaged by our selected cognitive tasks (hippocampus, medial prefrontal cortex). Ultra-structural changes in pre/post-synaptic bouton (Bassoon/Homer-1 puncta) within these same regions of the brain were not found to differ in response to dose rate. With this clinically relevant dosing regimen, we provide a mechanistic blueprint from synapse to cognition detailing how FLASH-RT reduces normal tissue complications in the irradiated brain.
Citation Format: Charles L. Limoli, Barrett D. Allen, Eniko A. Kramár, Yasaman Alaghband, Marie-Catherine Vozenin. Uncovering the protective neurological mechanisms of hypofractionated FLASH radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2416.
Abstract 2569: Investigation of the effect of chronic IL-1 exposure on breast cancer cell line response to external signaling factors
Authors: Dhar Roopal , Olaleye Ola M. , Abdelaziz Rana Tarig , Reddy Jyotsna Tera , Delk Nikki 
Published: April 2023

Abstract
As part of our immune response, the body produces anti-tumorigenic inflammatory proteins to kill cancer cells. However, cancer cells can usurp chronic inflammation for their own survival. Interleukin-1 (IL-1) is an inflammatory protein found in breast cancer (BCa) tumors that is elevated in the BCa patient tumors and serum and promotes metastasis, indicating IL-1 is clinically relevant. But the molecular mechanisms underlying the effect of chronic IL-1 on BCa progression remain unknown. We previously discovered that acute exposure to IL-1 represses essential hormone receptors in cancers cells, but concomitantly upregulates other compensatory pro-survival proteins that contribute to tumor progression. To determine if chronic IL-1 inflammation has the same effect, we generated cell subline models using the human breast cancer cell line, T47D, by exposing T47D cells chronically to IL-1 for several months. Notably, we found that the T47D chronic IL-1 sublines stably evolve insensitivity to exogenous IL-1. This result suggests that chronic IL-1 causes stable molecular changes that may affect cancer cell response to exogenous factors.Therapeutic strategies include blocking exogenous hormone or growth factor signals in the tumor microenvironment to attenuate cancer cell growth, proliferation, and survival. Therefore, we grew T47D parental and chronic IL-1 sublines in the absence of serum to determine the effect of chronic IL-1 exposure on BCa cell response to hormone and growth factor inhibition. Preliminarily, we do not observe differences in parental versus subline response to serum starvation, suggesting that differential response to exogenous factors is specific to IL-1 signaling. To better understand how chronic IL-1 -induced molecular changes effect BCa cell response to the tumor microenvironment, we will perform sequencing and bioinformatics analysis to identify IL-1 -dependent and/or independent signaling pathways stably altered in the chronic IL-1 sublines.
Citation Format: Roopal Dhar, Ola M. Olaleye, Rana Tarig Abdelaziz, Jyotsna Tera Reddy, Nikki Delk. Investigation of the effect of chronic IL-1 exposure on breast cancer cell line response to external signaling factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2569.
Abstract 257: CDX model based genome-scale CRISPR KO screens for modulators of KRAS (G12C) inhibitor sensitivity
Authors: Zhao Haixin , Zhai Fangzheng , Li Bin , Fan Qiangqiang , Peng Zhengang 
Published: April 2023

Abstract
KRAS is the most frequently mutated oncogene in human cancers and had long been considered an undruggable target for cancer therapy, until the FDA approval of Sotorasib (AMG 510) for the treatment of patients with non-small cell lung cancer (NSCLC) harboring the KRAS (G12C) mutation. To gain more insights into AMG 510 therapeutic mechanisms, herein we carried out a genome-scale CRISPR Cas9 knock-out screen in a KRAS G12C-harboring NCI-H2122 xenograft model. We first generated a stable NCI-H2122 cell line overexpressing Cas9 and confirmed its Cas9 editing efficiency by a BFP-GFP dual reporter system. Referring to our previous study for in vivo subcutaneous xenograft growth and response to AMG 510 treatment of NCI-H2122 cell line in immunodeficient mice, we decided to conduct the in vivo screens using 10M cell inoculation each mouse. We infected NCI-H2122 Cas9 cells with the genome-wide Brunello guide RNA library. After puromycin selection and two passages of cell recovery, the resultant cells were inoculated into Nu/nu mice subcutaneously, with part of cells collected as baseline. Mice bearing tumors were grouped into three groups at average tumor size of around 200 mm3 for vehicle, 10 or 30 mpk AMG510 treatment. Tumors were collected while the average tumor size of vehicle treatment group reached around 800 mm3. Genomic DNA was extracted from both baseline cell samples and tumor samples followed by Next-generation sequencing. We have performed QC analysis for all the samples and will discuss the hits from the screen and their implication in AMG 510-induced cancer sensitivity and resistance.
Citation Format: Haixin Zhao, Fangzheng Zhai, Bin Li, Qiangqiang Fan, Zhengang Peng. CDX model based genome-scale CRISPR KO screens for modulators of KRAS (G12C) inhibitor sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 257.
Abstract 2940: Use of NK humanized mouse models for the in vivo evaluation of anti-tumor NK-cell therapies
Authors: Rettman Pauline , Meyer Laure-Marie , Rangara Ravi , Ponchet-Lac Anna , Moindrot Nicolas , Biancotto Angélique , Lefranc Céline , Delahaye Fabien , Rabia Emilia , Cesaroni Matteo , Sidhu Sukhvinder , Nicolazzi Céline 
Published: April 2023

Abstract
Novel immunotherapeutic strategies targeting human Natural Killer (huNK) cells using monoclonal or multi-specific antibodies and immune modulator molecules are under development and there is a pressing need to have suitable mouse models for the evaluation of these therapeutics. Existing humanized mouse models have limitations and do not show an optimal development of innate immune cells such as NK, dendritic or other myeloid cells. We previously described the development of robust mouse models that allow the engraftment and maintenance of fully functional huNK cells using several strains of immunodeficient transgenic mice for human cytokines (IL-15). The optimal parameters (source of immune cells, pre-conditioning regimen, route of administration) were identified, and the models were validated by flow cytometry and in vivo efficacy studies using an anti-CD20 Ab.
Here, we report further development and characterization of these models and highlight their value to evaluate a variety of NK based therapeutics. We show that huNK cells can infiltrate a subcutaneous B-cell lymphoma model after treatment with an anti-CD20 Ab. We show that SAR444245 (non-alpha IL2) can activate huNK cells in vivo in all developed huIL-15 transgenic models and confirmed the minimal effective dose by flow-cytometry PD studies. We show the efficacy of both reference and internal ADCC-enhanced antibodies in disseminated tumor models in our humanized huIL-15 transgenic mice. In addition, we performed a deep characterization of huNK cells in huIL-15 transgenic models, using a 28-color flow cytometry panel centered on NK cell biology and profiled them transcriptionally by single cell RNA Seq in a disseminated B-cell lymphoma model.
Overall, we have developed robust models sustaining fully functional huNK cells that can be proficiently recruited in vivo by various NK-based therapeutics and can be used to evaluate the efficacy of combination therapies.
Citation Format: Pauline Rettman, Laure-Marie Meyer, Ravi Rangara, Anna Ponchet-Lac, Nicolas Moindrot, Angélique Biancotto, Céline Lefranc, Fabien Delahaye, Emilia Rabia, Matteo Cesaroni, Sukhvinder Sidhu, Céline Nicolazzi. Use of NK humanized mouse models for the in vivo evaluation of anti-tumor NK-cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2940.