bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5662: PDCD1 and CD48 significantly impact cancer recurrence and survival in pediatric acute lymphoblastic leukemia
Authors: Alotaibi Shatha Fawaz , Abuhadi Lames , Alolyani Noura , Alotaibi Moureq R. , Alhoshani Ali R. , Sobeai Homood As 
Published: March 2024

Abstract
Introduction: Immune checkpoints (ICPs) play a critical role in modulating the immune response, maintaining self-tolerance, and preventing excessive immune system activation. Dysregulation of immune checkpoints has been implicated in cancer progression and treatment resistance. In this study, we aimed to screen for dysregulated immune checkpoint genes that might be associated with cancer recurrence in pediatric acute lymphoblastic leukemia (ALL) following a course of cancer treatment. We hypothesized that certain ICPs would be significantly dysregulated in relapsed ALL patients, potentially providing insights into the underlying mechanisms driving therapy resistance and disease recurrence.
Methods: 51 ICP genomic data (gene expression, copy number alterations (CNAs), and mutation) of133 patients with relapse information [relapse-free (n=29) and relapsed (n=104)] extracted from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were examined in the study. Patient’s t-test (p-value &lt; 0.05) was used to identify significant genetic factors between relapse-free and relapsed patients. Free and overall survival analyses were performed using log-rank test (p-value &lt; 0.05) based on patient gene expression profiles.
Results: Among the 51 genes examined, PDCD1, PVR, CD70, and CD48 were significantly upregulated in relapsed patients compared with relapse-free patients (P &lt; 0.05). No significant CNAs nor mutations were detected in these four genes. Patients with high expression profiles of PDCD1 and CD48 at diagnosis were 1.71 and 1.47 more likely to relapse compared to patients with low expression profiles, respectively (P &lt; 0.05). Furthermore, the upregulation of PDCD1 (P= 0.0004, HR= 1.972) and CD48 (P= 0.0344, HR= 1.533) demonstrated significantly increased mortality rates in patients following treatment, as indicated by overall survival analyses.
Conclusion: The upregulation of PDCD1 and CD48 was significantly associated with relapse and survival of ALL patients. Promisingly, these two ICPs can potentially be used as prognostic biomarkers for relapse risk and rationale for alternative therapeutic strategies. Our study suggests that targeting PDCD1 and CD48 might be beneficial in enhancing the treatment efficiency and thereby reducing the recurrence risk. The study was funded by the Deputyship for Research and Innovation, Ministry of Education, Saudi Arabia (DRI-KSU-1273).
Citation Format: Shatha Fawaz Alotaibi, Lames Abuhadi, Noura Alolyani, Moureq R. Alotaibi, Ali R. Alhoshani, Homood As Sobeai. PDCD1 and CD48 significantly impact cancer recurrence and survival in pediatric acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5662.
Abstract 567: Fisetin sensitizes triple negative breast cancer cells to radiation
Authors: Khozooei Shayan , Veerappan Soundaram , Toulany Mahmoud 
Published: March 2024

Abstract
Triple negative breast cancer (TNBC) represents a highly aggressive subtype, constituting approximately 20% of all breast cancer cases. Y-box binding protein-1 (YB-1) is often overexpressed in various tumor types and has been implicated in conferring resistance to cell death induced by radiotherapy. Fisetin, a flavonoid compound with demonstrated anti-cancer properties, operates in part through inhibiting phosphorylation of YB-1 by p90 ribosomal S6 kinase (RSK). In this study, we investigated the potential synergistic effects of combining fisetin with radiotherapy in TNBC. The activation status of the RSK signaling pathway was assessed in both total cell lysate and subcellular fractions using Western blotting. A standard clonogenic assay was employed to evaluate post-irradiation cell survival. To investigate the frequency of double-strand breaks (DSBs) and chromosomal aberrations, γH2AX foci assay and 3-color fluorescence in situ hybridization analyses were conducted, respectively. The DSB repair pathways targeted by fisetin were examined in cells expressing genomically integrated reporter constructs by quantifying green fluorescence protein expression through flow cytometry. Apoptosis and autophagy were measured using flow cytometric quantification of sub-G1 cells and the assessment of LC3-II protein expression, respectively. Kinase array and phosphoproteomics analyses were carried out to study the potential impact of fisetin on the signaling involved in the DNA damage response (DDR) after irradiation. We demonstrated that fisetin mimics the effects of RSK pharmacological inhibitors in terms of effect on YB-1 phosphorylation. Treatment with fisetin increased frequency of DSB in non-irradiated cells and impaired repair of DSB after irradiation. Fisetin attenuated DSB repair by suppressing the classical non-homologous end-joining and homologous recombination repair pathways. The frequency of chromosomal aberration was enhanced by fisetin treatment. The effect of fisetin on inhibiting DSB repair was partially YB-1 dependent. Phosphoproteomic analysis revealed that fisetin inhibits DDR signaling, which leads to radiosensitization in TNBC cells, as shown in combination with single dose or fractionated doses irradiation. Fisetin neither inhibited DSB repair nor radiosensitized normal human fibroblast HSF7 cells. The radiosensitizing effect of fisetin was not attributed to enhancing apoptosis or modulating autophagy. In summary, combining fisetin with radiotherapy may enhance TNBC radiotherapy outcomes.
-This research was supported by a grant from the German Research Council (DFG,TO 685/2-3).
Citation Format: Shayan Khozooei, Soundaram Veerappan, Mahmoud Toulany. Fisetin sensitizes triple negative breast cancer cells to radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 567.
Abstract 5676: Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples
Authors: Wang Qixuan , Wang Juan , Mathur Radhika , Youngblood Mark W. , Jin Qiushi , Hou Ye , Stasiak Lena A. , Luan Yu , Costello Joseph F. , Yue Feng 
Published: March 2024

Abstract
Glioblastoma (GBM) represents the most prevalent malignant primary brain tumor with highly unfavorable prognosis. Currently, most genomic studies are conducted at a single site of a tumor, which do not reflect the complete genetic or epigenetic information across the whole tumor. Furthermore, the intra-tumoral heterogeneity (ITH) of 3D genome organization has also not been studied yet. To address these gaps, we performed Hi-C experiments in 21 samples obtained from 9 GBM patients, with 15 of them being spatially mapped based on their 3D coordinates from the same patients. We identified extensive inter-tumoral and intra-tumoral heterogeneity in genome compartmentalization and chromatin interactions. Notably, in a patient with 9 spatially mapped samples from both temporal and frontal regions, we accumulated over 6 billion reads and defined high-resolution region-specific chromatin interactions, regulatory networks, and key regulators within the same patient. We detected structural variation (SV) and enhancer hijacking across all the samples, and identified recurrent events that affect known cancer-related genes such as CDKN2A/B. Finally, we introduce the concept of 'enhancer amputation', defined as the loss of enhancers due to SVs which lead to decreased expression of their original target genes. To our knowledge, this study represents the first large-scale exploration of the 3D genome in primary GBM patients and the first investigation of 3D genome organization in multiple regions of the same tumor. Our findings provide unprecedented insights into the ITH of GBM at the 3D genomic level, opening new avenues for understanding and potentially targeting this devastating disease.
Citation Format: Qixuan Wang, Juan Wang, Radhika Mathur, Mark W. Youngblood, Qiushi Jin, Ye Hou, Lena A. Stasiak, Yu Luan, Joseph F. Costello, Feng Yue. Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5676.
Abstract 5683: lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer
Authors: Waiters Kacie D. , Quttina Maram , Khan Ashfia F. , Karami Samaneh , Peidl Anthony S. , Babajide Funmi , Bawa-Khalfe Tasneem 
Published: March 2024

Abstract
Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed BCa type accounting for 70% of all breast cancer cases. A large population of HR+ BCa patients (30-40%) are resistant to mainstay endocrine therapy and develop incurable metastatic disease. Hence, it is imperative to identify viable biomarkers that stratify patients as drug responders or non-responders.
Emerging scientific literature highlights the essential role of long non-coding RNAs (lncRNA) in cancer drug resistance and metastatic transformation; lncRNA include RNAs over 200 nucleotides in length that do not encode protein. Major biological functions of lncRNA rely on association with select protein interactors. As lncRNA equally bind proteins with and without canonical RNA-binding motifs, it is unclear what facilitates this lncRNA-protein interaction. Our recent studies show that SUMO post-translational modification (or SUMOylation) of target proteins potentiates binding with lncRNA, particularly at the chromatin. Using a small-scale screening, we see that SUMO-modification works to enhance association with lncRNAs for proteins with and without a canonical RNA binding domain (RBD). SUMOylation of RBD-expressing heterochromatin protein 1 α (HP1α) drives interaction with multiple chromatin-associated lncRNA both within and outside canonical heterochromatin foci. Interaction with lncRNA supports SUMOylated HP1α’s unconventional function as a transcriptional repressor at select euchromatic loci. We now report an inverse relationship in which SUMOylated HP1α directs the stability of its lncRNA binding partner. Specifically, SUMO-modified HP1α directs cell-cycle dependent recruitment of the RNA degradation machinery to the chromatin and facilitates clearance of chromatin-bound lncRNA. This dynamic lncRNA degradation process is disturbed with cancer onset and instead favors aberrant cancer cell transformation. Consistently, restoring lncRNA degradation homeostasis decreases metastatic properties of HR+ BCa cells and increases sensitivity to targeted therapeutics currently in clinical trials.
Our studies define a fundamental mechanism that dictates lncRNA stability and/or degradation in BCa cells. In addition, we present viable biomarkers that predict sensitivity to ET and alternative targeted therapies.
Citation Format: Kacie D. Waiters, Maram Quttina, Ashfia F. Khan, Samaneh Karami, Anthony S. Peidl, Funmi Babajide, Tasneem Bawa-Khalfe. lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5683.
Abstract 571: CRISPR/Cas9 screening identifies the proteasome subunit PSMC6 as key for the survival of cisplatin-resistant ovarian carcinoma cells
Authors: Costantino Matteo , D'arcy Padraig , Mirra Luca , Corno Cristina , Beretta Giovanni L. , Gubat Johannes , Pratesi Pietro , Ciniselli Chiara M. , Verderio Paolo , Linder Stig , Perego Paola 
Published: March 2024

Abstract
Ovarian carcinoma is a disease with poor prognosis, due to delays in diagnosis and the development of drug resistance. Since deregulation of the ubiquitin proteasome system may contribute to the development of drug resistance, the aim of this study was to investigate the interplay between expression of proteasome subunits and cisplatin resistance by utilizing a CRISPR/Cas9 dropout screen. Paired cisplatin-sensitive and -resistant cells (IGROV-1 and IGROV-1/Pt1) were transfected with Cas9 and transduced with gRNAs against proteasome components. Cells were collected at early (day 4) and late (day 21) time exposure and sequenced to identify genes necessary for survival. Various proteasome subunits were found to be essential for the survival of cisplatin-resistant ovarian carcinoma cells, including PSMA5, PSMC6, PSMD7, PSMD12 and PSMD14. Since PSMC6 knockout produced the greatest growth inhibitory effects, it was selected for functional studies utilizing conventional RNA interference. When IGROV-1 and IGROV-1/Pt1 cells were transfected with small interfering RNAs (siRNAs) targeting PSMC6, efficient down-regulation on the mRNA and protein level was observed. Phenotypic analyses of PSMC6 knockdown cells indicated reduced clonogenicity using both 2D and soft agar assays in parental and resistant cells associated with down-regulation of the canonical MAPK pathway. A slight but not significant increase in sensitivity to cisplatin was observed upon PSMC6 silencing in resistant cells using clonogenic assays. Finally, we carried out a pilot study using ovarian carcinoma specimens (n = 134) obtained through the institutional biobank. The samples were representative of the frequency occurrence of the various histological ovarian carcinoma subtypes. We found that PSMC6 expression, evaluated by qRT-PCR, was associated with tumor stage. These findings suggest that PSMC6 is linked to ovarian carcinoma aggressiveness and that PSMC6 targeting may be an interesting therapeutic strategy.
Citation Format: Matteo Costantino, Padraig D'arcy, Luca Mirra, Cristina Corno, Giovanni L. Beretta, Johannes Gubat, Pietro Pratesi, Chiara M. Ciniselli, Paolo Verderio, Stig Linder, Paola Perego. CRISPR/Cas9 screening identifies the proteasome subunit PSMC6 as key for the survival of cisplatin-resistant ovarian carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 571.
Abstract 5717: CDK4 inhibition suppresses Rab11 mediated collective cell migration in colon cancer cells
Authors: Cheng Chun Pu , Ku Chia-En , Lee Shin-Ru , Wang Yu-Chun , Ching Yu-Chien , Chen Hui-Chun , Chao Wei-Ting 
Published: March 2024

Abstract
In tumor progression, cell proliferation and cell adhesion are critical for tumor growth and metastasis. It has been demonstrated cell division which associated with microtubule organization also has impact on tubulin mediated focal adhesion turnover, however, the mechanism is not clear in the cell cohort migration which is accompanied with both cell proliferation and cell migration. This study is to investigate the effect of cell cycle inhibition in the collective cell migration. HT-29 colon cancer cells were treated with CDK4 inhibitor CINK4, paclitaxel and focal adhesion inhibitor PF573228. The cell proliferation rate was determined by MTT assay, cell migration ability was analyzed by wound healing assay. Rab11, E-cadherin and focal adhesion kinase were revealed by immuno-confocal microscopy. When HT-29 cells were treated with lower dose of CDK4 inhibitor CINK4, cell migration was suppressed. Meanwhile, in the result of immunostaining, the recycling endosomal protein Rab11which is involved in E-cadherin turnover in collective cell migration was not distributed in the cell membrane after CINK4 treatment. Furthermore, when cellular FAK activity were inhibited by PF573228 and tubulin disassembly was inhibited by paclitaxel, the cell area was increased with stable attachment, however, the membrane translocation of Rab11 was not affected. This study demonstrated cell cycle inhibition in G1 phase affected Rab11 mediated collective cell migration through tubulin regulated focal adhesion turnover for cell attachment. Keywords: CDK4, cell cycle, focal adhesion kinase, paclitaxel, colon cancer
Citation Format: Chun Pu Cheng, Chia-En Ku, Shin-Ru Lee, Yu-Chun Wang, Yu-Chien Ching, Hui-Chun Chen, Wei-Ting Chao. CDK4 inhibition suppresses Rab11 mediated collective cell migration in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5717.
Abstract 5771: Utilizing a photoreactive chloroalkane capture tag for target deconvolution
Authors: Uyeda Tetsuo , Hurst Robin , Levin Sergiy , Rosenblatt Mike , Zimmermann Kris , Ohana Rachel F. 
Published: March 2024

Abstract
Identifying the physiologically relevant targets of bioactive compounds is often the rate limiting step toward understanding their mechanism of action. To this end, we developed a streamlined chemical proteomic strategy that utilizes a novel photoreactive cleavable chloroalkane tag, which can be attached to bioactive compounds to isolate their respective cellular targets for identification by mass spectrometry. The tag does not significantly affect compounds potency and membrane permeability, allowing for binding interactions to be established within intact cells under appropriate physiological conditions. UV-induced covalent photo-crosslinking “freezes” the cellular interactions and prevents their dissociation upon cell lysis. Effective enrichment of the cellular targets is achieved through their selective covalent capture onto HaloTag coated particles and subsequent selective release by tag cleavage. Putative targets identified by mass spectrometry can be readily verified using resonance energy transfer. By exchanging the chloroalkane tag for a fluorophore, direct binding to the targets can be revealed through proximity of the fluorophore to a small NanoLuc luciferase genetically fused to the putative target. This approach was used to identify physiologically relevant targets for bioactive compounds including those with low affinity and/or low abundance as well as insoluble targets with multiple trans membrane domains.
Citation Format: Tetsuo Uyeda, Robin Hurst, Sergiy Levin, Mike Rosenblatt, Kris Zimmermann, Rachel F. Ohana. Utilizing a photoreactive chloroalkane capture tag for target deconvolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5771.
Abstract 5811: Ultralong CDR3 engineered interleukin-15 antibody fusion for T and NK cell expansion
Authors: Huang Ruiqi , McGregor Duncan , Smider Vaughn 
Published: March 2024

Abstract
Interleukin (IL)-15 is a promising immunotherapeutic cytokine for cancer treatment because it can stimulate the proliferation and cytotoxicity of CD8+ T lymphocytes and nature killer (NK) cells, similar to the action of IL-2, which has been used to treat metastatic melanoma and renal cancer. IL-15 may have improved pharmacologic properties over IL-2 because it doesn’t cause vascular leak syndrome or stimulate regulatory T cells. However, IL-15 is difficult to express as a stable soluble protein and has a short half-life in vitro and in vivo. To solve the problem, we designed an IL-15 ultralong CDR3 humanized bovine antibody fusion. Bovine ultralong CDR3 antibodies have a unique “stalk and knob” structure in which two antiparallel β-strands support a disulfide bonded knob protruding out of the antibody surface and forms a mini antigen binding domain. By replacing the knob domain with IL-15, we have created a chimeric CDR3-IL-15 IgG which functions as IL-15 in vitro and in vivo but can be easily produced in mammalian cells with increased stability. Thus, the CDR3 can stabilize IL-15 in the absence of its high affinity receptor α (Rα) chain. Furthermore, as IL-15 utilizes Rα for increased trans signaling to the receptor β and γ subunits, one variant candidate (CDR3-IL-15_Rα) was produced by co-expressing Rα sushi domain with the chimeric IgG. Both constructs have been demonstrated to be highly active in stimulating proliferation of NK cells and CD8+ T cells in vitro as well as in stimulating proliferation of NK cells and CD8+ T cells in rats and non-human primates (NHP). Although the CDR3-IL-15_Rα exhibited higher in vitro signaling activity than CDR3-IL-15, both were equally potent in stimulating the proliferation of NK cells and CD4+ and CD8+ T cells in NHP without any immunogenicity detected. Moreover, in vivo studies in NHP indicated that CDR3-IL-15 acted faster than CDR3-IL-15_Rα in stimulating the proliferation of these lymphocytes. CDR3-IL-15 is the first thermodynamically stabilized variant of IL-15 produced in the absence of its Rα chain, is highly active in vivo, and has multiple potential cancer applications as an T and NK cell stimulating agent.
Citation Format: Ruiqi Huang, Duncan McGregor, Vaughn Smider. Ultralong CDR3 engineered interleukin-15 antibody fusion for T and NK cell expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5811.