bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4518: Highlighting the prenatal, natal, and early childhood risk factors of cancer: seeking better opportunities for cancer prevention
Authors: Elmoneim Abeer Abd , Roushdy Ayat , Metwally Ehab 
Published: April 2023

Abstract
Background: Fostering new public health approaches to cancer prevention is required to reduce the number of new cases. Early life exposures, to carcinogens may affect different phases of the multi-tage clonal expansion model of carcinogenesis. Critical development periods, in-utero and puberty, exposures may induce permanent changes in tissue differentiation, metabolism, and gene expression that influence cancer risk. Epigenetic modifications are also critical for regulating cellular processes and responses during development that are maintained overtime. Therefore, promising strategies should develop for cancer prevention mainly on environmental approaches. We aim in this study to assess the prevalence of risk factors of childhood cancer in Almadinah City, a local community in Saudi Arabia, and to address cancer prevention opportunities during prenatal, natal and early children life.
Patients and Methods: The study is a cross section observational study. The population includes convenient samples of pregnant mothers, neonates and preschool children. Data regarding natal, prenatal and early childhood risk factors of cancer collected using a predesigned questionnaire.
Results: Early life exposure to cancer risks increases prevalence of cancer. Risk factors like high birth weight, maternal obesity and smoking are the most frequent risks followed by chromosomal anomalies and genetic syndromes. Prenatal use of folic acid, breastfeeding and allergy, respectively, are the most frequent protective factors against cancer development.
conclusions: Strict approaches should be designed for preventing early life exposures and their cumulative effect that can lead to cancer development.
Citation Format: Abeer Abd Elmoneim, Ayat Roushdy, Ehab Metwally. Highlighting the prenatal, natal, and early childhood risk factors of cancer: seeking better opportunities for cancer prevention. [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 4518.
Abstract 4598: Vitamin b1 derivative, benfotamine, prevents VEGF-induced angiogenesis
Authors: Allowitz Kieran V. , Plowman Trevor J. , Ramana Kota V. 
Published: April 2023

Abstract
Several studies have indicated that thiamine, and more specifically its lipid soluble derivative benfotiamine, exerts an anti-oxidative and anti-inflammatory effect on the body. However, its effect in preventing cancer cell proliferation, migration, invasion, and metastasis is not yet clearly understood. It is known that angiogenesis plays a significant role in the growth and spread of many cancers but the role of benfotiamine in neovascularization is not yet known. Therefore, in this study, we hypothesized that benfotiamine would prevent VEGF-induced angiogenesis in vitro and in vivo. To examine this, we have treated human umbilical vein endothelial cells (HUVECs) with VEGF (Vascular Endothelial Growth Factor; 10 ng/ml) in the absence and presence of benfotiamine (0-100 uM) in a time and dose-dependent manner. We then examined the cell viability by MTT assay and apoptosis by Annexin-V staining and found that benfotiamine alone had minimal effect on cell viability and it prevents VEGF-induced cell proliferation. In vitro angiogenesis assay indicates that benfotiamine prevented the VEGF -induced tube formation of HUVECs. Further, benfotiamine regulated the expression of VEGF-induced growth factors such as VEGF, PIGF, IGFBP-1, ECGF, FGF-1 and 2, anti-angiogenic enzymes such as Serpin E1, TIMP-1, MMP-8, TSP-1, PTX3 and uPA and cytokines such as IL-8, Prolactin, ET-1, Endostatin, and CCL3. We will next examine how benfotiamine prevents in vivo angiogenesis by utilizing a rat Matrigel plug model of angiogenesis in rats. The Matrigel sections will be stained with CD36, vWF, and other angiogenic markers to visualize the effect of benfotiamine on VEGF-induced angiogenesis. In conclusion, our current results indicate that benfotiamine has anti-angiogenic potential via inhibition of various pro-angiogenic growth factors and promoting anti-angiogenic factors in vitro and in vivo. Thus, our studies demonstrate that benfotiamine could be further developed as a novel therapeutic agent to prevent cancer growth and metastasis.
Citation Format: Kieran V. Allowitz, Trevor J. Plowman, Kota V. Ramana. Vitamin b1 derivative, benfotamine, prevents VEGF-induced angiogenesis. [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 4598.
Abstract 4668: In-vitro modeling of tumor-associated macrophages in glioblastoma
Authors: Alrefai Hasan , Beierle Andee M. , Schanel Taylor L. , Nassour Lauren C. , Anderson Joshua C. , Hicks Patricia H. , Willey Christopher D. 
Published: April 2023

Abstract
BACKGROUND: The Glioblastoma (GBM) tumor microenvironment (TME) is comprised of a plethora of cancerous and non-cancerous cells that contribute to GBM growth, invasion, and chemo- and radio-resistance. In-vitro models of GBM typically fail to incorporate multiple cell types. Some groups have addressed this problem by employing 3D bioprinting to incorporate macrophages, astrocytes, and other parenchymal cells in an extracellular matrix. However, these models also use serum-containing media, which has been shown to cause GBM brain-tumor initiating cells to lose their stem-like properties, and IL-4/13 polarized macrophages (M2), even though tumor-associated macrophages (TAMs) do not adhere to the traditional M2 phenotype. Taken together, these observations highlight a critical need to develop physiologically accurate in-vitro model systems for GBM.
METHODS: THP-1 monocytes were transitioned from serum-containing RPMI 1640 to serum-free CTS™ AIM V™ SFM and TheraPEAKTM X-VIVOTM-15 Serum-free Hematopoietic Cell Medium. Monocytes were stimulated towards a macrophage-like state with PMA and polarized by co-culturing them with GBM patient-derived xenograft (PDX) lines, using transwell inserts. dPCR, a cytokine array, and a phagocytosis assay were used to characterize macrophages polarized by this method relative to classically polarized resting (M0), pro-inflammatory (M1), and anti-inflammatory (M2) macrophages.
RESULTS: There was no significant difference in proliferation rates up to 48 hours for THP-1 monocytes grown in serum-free CTS AIM V or X-VIVO-15 media compared to serum-containing RPMI 1640. At 72 hours, both serum-free alternatives had slightly decreased proliferation relative to the serum-containing RPMI 1640; however, the X-VIVO-15 had higher proliferation relative to the CTS AIM V (p&lt;0.0001). THP-1 macrophages polarized towards a tumor-supportive phenotype by the GBM PDX cell line, JX39P-RT, did not recapitulate the cytokine expression profile of any other polarization group. M2 macrophages had significantly higher phagocytic capacity (25%) of JX39P-RT relative to M0, M1, and TAMs (&lt;15%, p&lt;0.01).
CONCLUSIONS: We have demonstrated a serum-free method by which we can polarize macrophages towards a GBM-supportive phenotype. This high-fidelity method of modeling TAMs in GBM will aid in the development of innate immunomodulatory therapeutics that may one day enter the clinic in hopes of improving GBM outcomes.
Citation Format: Hasan Alrefai, Andee M. Beierle, Taylor L. Schanel, Lauren C. Nassour, Joshua C. Anderson, Patricia H. Hicks, Christopher D. Willey. In-vitro modeling of tumor-associated macrophages in glioblastoma. [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 4668.
Abstract 4727: RAS and PP2A activities converge on phosphoregulation of epigenetic complexes in cancer
Authors: Sharma Mukund , Aakula Anna , Tabaro Francesco , Honkanen Henrik , Kamila Jesse , Schapira Matthieu , Arrowsmith Cheryl , Nykter Matti , Westermarck Jukka K. 
Published: April 2023

Abstract
RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data, we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. In RAS-driven cancers, PP2A activity is inhibited by nuclear PP2A inhibitor proteins PME-1 and SET. We further demonstrate that these PP2A inhibitors drive oncogenic transcription, but that their transcriptional targets are highly diversified. Whereas PME-1 controls RAS and MYC-driven transcription, SET controls TP53 targets and G2/M checkpoint genes. We further provide evidence that these nuclear PP2A inhibitors significantly differ in their roles in regulating DNA methylation. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, the results provide a rich source for future understanding of phosphorylation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
Citation Format: Mukund Sharma, Anna Aakula, Francesco Tabaro, Henrik Honkanen, Jesse Kamila, Matthieu Schapira, Cheryl Arrowsmith, Matti Nykter, Jukka K. Westermarck. RAS and PP2A activities converge on phosphoregulation of epigenetic complexes in 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 4727.
Abstract 4773: DEAD Box 1 (DDX1) protects its RNA targets in cells exposed to oxidative stress
Authors: Garg Mansi , Godbout Roseline 
Published: April 2023

Abstract
DEAD box 1 (DDX1) belongs to the family of RNA helicases involved in all aspects of RNA metabolism, from transcription to transport, expression, and decay. DDX1 is overexpressed in a subset of retinoblastoma, neuroblastoma, and breast cancers. In breast cancer, the overexpression and cytoplasmic localization of DDX1 is correlated with poor prognosis. Cancer cells often exhibit high metabolic rates which can lead to genomic instability, oxidative stress, and endoplasmic stress. DDX1 is known to play a role in resolving genotoxic stress by participating in DNA double-strand break (DSB) repair. We propose that DDX1 also plays a key role as a stress response regulator in cells undergoing oxidative stress. When cells are exposed to oxidative stress, DDX1 is recruited to cytoplasmic stress granules (SGs). Although the exact function of SGs remains elusive, it is generally believed that tightly controlled SG assembly and disassembly are important for cell survival under stress. We found that while DDX1 is dispensable for SG assembly, depletion of DDX1 leads to impaired SG disassembly and hence, delayed stress recovery. Thus, DDX1 may play a role in stress resolution after the removal of stress conditions. To further understand the role of DDX1 in stress resolution, we performed RNA-immunoprecipitation followed by next-generation sequencing and identified DDX1-bound RNAs under normal and oxidative stress conditions. We found enhanced binding of DDX1 to its RNA targets in the presence of oxidative stress. Furthermore, we observed that DDX1 protects its target RNAs from degradation in the cytoplasm of cells undergoing oxidative stress. This RNA protection after stress exposure was more prominent in DDX1-overexpressing neuroblastoma cells, possibly explaining the faster stress recovery observed in these cells. Taken together, our results suggest that DDX1 plays a role in protecting cells from oxidative stress. This study may shed light on our understanding of cancer cell resistance to anticancer therapies.
Citation Format: Mansi Garg, Roseline Godbout. DEAD Box 1 (DDX1) protects its RNA targets in cells exposed to oxidative stress. [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 4773.
Abstract 4797: β3-AR blockade induces differentiation of malignant leukemia T cells in mature T lymphocytes
Authors: Carrozzo Francesco , Bruno Gennaro , Masi Claudia , Boaretto Alessia , Favre Claudio , Calvani Maura 
Published: April 2023

Abstract
Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous cancer that arises from diverse genetic alterations during early lymphocyte development. About 10-15% of T-cell acute lymphoblastic leukemia (T-ALL) cases occur in childhood; despite having an event-free survival (EFS) rate of 85%, relapse is the main problem of this type of cancer. Mitochondria metabolic reprogramming plays a crucial role in the development of lymphocytes both in physiological and pathological processes such as differentiation and neoplastic transformation respectively. Mitochondria are the main actors of cellular homeostasis. They use glycolysis products exploiting them in the Krebs cycle and in oxidative phosphorylation to produce energy and plays key roles in reactive oxygen species (ROS) generation, Ca2+ signaling, cell death induction, and cellular differentiation. In particular, the increase of ROS is important to reduce tumor cell viability and at the same time is involved in induction of hematopoiesis. β3-adrenoreceptors (β3-Ars) is a class of receptors associated with pro-tumoral signaling in different tumors. In this study, we first have observed the expression of β3-Ars in leukemia T cells and then we studied how the modulation of this receptors affected tumor-related pathways. The treatment with an antagonist of β3-Ars (SR59230A) induced an increase of ROS leading to lymphoblastic cells differentiation, decrease of proliferation and enhanced induction of apoptosis signaling. Overall, these results suggest that β3-Ars could be a possible target for treatment of T-ALL.
Citation Format: Francesco Carrozzo, Gennaro Bruno, Claudia Masi, Alessia Boaretto, Claudio Favre, Maura Calvani. β3-AR blockade induces differentiation of malignant leukemia T cells in mature T lymphocytes. [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 4797.
Abstract 4807: BACH1 proline hydroxylation regulates the hypoxia response and metastasis in triple negative breast cancer
Authors: Nguyen Long Chi , Dann Christopher , Yang Dongbo , Shi Emily , Li Thomas , Wynne Joseph , Stock Letícia , Henn Madeline , Qiao Zeyu , Valdespino Andrea , Watson Raven , Liu Wenchao , Robinson-Mailman Lydia , Khramtsova Galina , Matsumoto Mitsuyo , Moellering Raymond , Olopade Olufunmilayo I. , Igarashi Kazuhiko , Rosner Marsha R. 
Published: April 2023

Abstract
Hypoxia is an important hallmark of aggressive solid tumors. Here we show that the pro-metastatic BTB and CNC homology 1 (BACH1) transcription factor is prolyl-hydroxylated by the HIF Prolyl Hydroxylase 1 (PHD1) in an oxygen-dependent manner. Using mass spectrometry, we identified two major prolyl hydroxylation sites in BACH1 and demonstrate that prolyl hydroxylation increased protein turnover in normoxia. Notably, a clinically relevant BACH1 mutant (BACH1M) resistant to hydroxylation displays enhanced BACH1 DNA binding capacity. Triple-negative breast cancer (TNBC) cells expressing BACH1M showed higher invasion in vitro and increased metastasis in vivo. Loss of BACH1 reduced the cellular transcriptional hypoxic response. Under hypoxia, BACH1 increases chromatin accessibility and gene expression through chromatin remodeling involving direct BACH1 binding and indirect epigenetic regulation. These results indicate that hypoxia stabilizes and enhances the pro-metastatic transcriptional activity of BACH1 through loss of prolyl hydoxylation in TNBC. Our findings identify BACH1 as an oxygen sensitive effector of the hypoxia response and a clinically relevant target for attenuating hypoxia induced, pro-metastatic signaling and therapeutic resistance in cancers.
Citation Format: Long Chi Nguyen, Christopher Dann, Dongbo Yang, Emily Shi, Thomas Li, Joseph Wynne, Letícia Stock, Madeline Henn, Zeyu Qiao, Andrea Valdespino, Raven Watson, Wenchao Liu, Lydia Robinson-Mailman, Galina Khramtsova, Mitsuyo Matsumoto, Raymond Moellering, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 proline hydroxylation regulates the hypoxia response and metastasis in triple negative 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 4807.
Abstract 4864: ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression
Authors: Zhao Wen , Yu Danlei , Zhai Yifan , Sun Shi-Yong 
Published: April 2023

Abstract
The successful treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which were already approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which is supposed to function as a pro-apoptotic protein that transduces TRAIL death signal to trigger apoptosis. Its expression is positively regulated by MEK/ERK signaling and thus can be downregulated by MEK/ERK inhibition. This study thus focused on determining the effects of AKL inhibition on DR4 expression and the underlying mechanisms. ALK-TKIs such as brigatinib and alectinib effectively and preferentially inhibited AKT/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. This was also true to DR4 downregulation, which occurred even at 2 h post treatment. These ALK-TKIs did not affect DR4 protein stability, rather potently decreased DR4 mRNA expression. In parallel, they promoted degradation and decreased the levels of Fra-1 and c-Jun, two critical components of AP-1, and suppressed AP-1 (Fra-1/c-Jun)-dependent transcription/expression of DR4. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation on elucidating the biological significance of DR4 downregulation in ALK-targeted cancer therapy.
Citation Format: Wen Zhao, Danlei Yu, Yifan Zhai, Shi-Yong Sun. ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. [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 4864.
Abstract 4865: Mechanisms of EGFR inhibitor sensitivity and resistance in chordoma
Authors: Punturi Nindo , Dolat Lee , Levy Joan , Sommer Josh , Freed Daniel M. 
Published: April 2023

Abstract
Target discovery studies have identified EGFR inhibition as a promising therapeutic strategy in chordoma, motivating ongoing clinical trials. Yet EGFR is not mutated in chordoma, leaving the mechanisms associated with EGFR inhibitor (EGFRi) sensitivity and resistance unclear. In this study, we profiled a panel of over 10 chordoma cell lines to categorize their sensitivity to afatinib, a second-generation EGFRi with potency against the wild-type receptor. Several cell lines, including U-CHCF365, UM-Chor1, MUG-Chor1, and U-CH1, were highly sensitive to afatinib in cell viability assays, with absolute IC50 values below 50 nanomolar. In contrast, other chordoma cell lines, including UM-Chor5C and U-CHCF359B, exhibited limited response to EGFRi at concentrations exceeding 1 micromolar. Among sensitive cell lines, we found that afatinib promoted cell death in some cases (e.g., U-CH1) whereas in others it induced a profound cell cycle arrest. Moreover, in U-CH1 cells, acute afatinib treatment enriched a population of drug-tolerant persister cells with a fusiform morphology, potentially indicative of an epithelial-mesenchymal transition. Ongoing studies are focused on understanding the mechanisms of afatinib-induced cell death, drug tolerance, and acquired resistance, with a view to designing rational combination strategies capable of enhancing the magnitude and duration of therapeutic response. In cell lines with matched xenograft models, in vitro responses to afatinib were consistent in vivo. In a panel of 12 chordoma patient-derived xenograft (PDX) models treated with afatinib or cetuximab, differential sensitivity to EGFRi was recapitulated - with EGFRi promoting complete or negligent tumor growth inhibition in sensitive or resistant models, respectively. Finally, we combined drug sensitivity profiling of chordoma cell lines and PDXs with whole-exome and whole-transcriptome sequencing to identify genomic and transcriptomic features associated with sensitivity and resistance to EGFRi in chordoma. Collectively, our data identify a striking degree of differential sensitivity to EGFRi in chordoma, and begin to shed light on factors associated with primary and acquired resistance. These results provide a framework for guiding patient selection and identifying potential combination therapy regimens to improve EGFRi efficacy and address resistance.
Citation Format: Nindo Punturi, Lee Dolat, Joan Levy, Josh Sommer, Daniel M. Freed. Mechanisms of EGFR inhibitor sensitivity and resistance in chordoma. [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 4865.