bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Critical Frequency of the Electrothermal V-Shaped Actuator Using the Particle Swarm Optimization Algorithm
Authors: Hong Pham Phuc , Truong Duc Phuc , Trung Hoang Kien , Bui Ngoc-Tam 
Published: December 2023

This paper presents a thermal transfer model and optimization of a V-beam dimension to improve the critical frequency fC (i.e., expanding the effective working frequency range) of an electrothermal V-shaped actuator (EVA). The obtained results are based on applying the finite difference model, a method for calculating the critical frequency, as well as conditions to ensure the mechanical stability and thermal safety of EVA. The influence of beam dimensions (i.e., length L, width

w

, and incline angle θ of the beam) on the variation of critical frequency fC is investigated and evaluated. Moreover, the particle swarm optimization (PSO) algorithm is used to figure out the optimal beam dimensions aiming to increase the critical frequency while satisfying conditions such as mechanical stability, thermal safety, and suitable displacement of EVA. With the optimal dimensions of V-beam (L = 679 µm,

w

= 4 µm, and θ = 1.8°), the critical frequency of the V-shaped actuator can be achieved up to 136.22 Hz at a voltage of 32 V (average increment of fC is 33.1% with the driving voltage changing from 16 V to 32 V) in comparison with the nonoptimal structure (fC is only 102.34 Hz at 32 V).
Abstract A008: An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors
Authors: Wang Stephanie 
Published: December 2023

Abstract
Tongtong Liu, Feng He, Xuyang Duan, Shuliang Li, Chang Liu, Jingying Ning, Feng Hao* KYinno Biotechnology (Beijing) Co., Ltd. No.3 Building, Yizhuang Biomedical Park, Beijing, China. Correspondence: Feng.hao@kyinno.com Protein kinases have become very popular targets in the treatment of cancer and other diseases, and since 2001, the FDA has approved more than 70 kinase inhibitor drugs. However, due to innate or acquired resistance in tumors, most of these small molecule inhibitors only delay tumor progression. The development of next-generation kinase inhibitors with better specificity and lower resistance is still ongoing. Ba/F3 is a mouse pro-B cell line whose survival and proliferation depend on IL-3. After transduction with driver genes such as kinase genes or their mutants, Ba/F3 cells switch from IL-3 dependence to driver gene dependence, making Ba/F3 cells a powerful tool for discovering new kinase inhibitors. Our group has constructed over 700 Ba/F3 engineered cell lines stably transfected with kinase gene mutants. These Ba/F3 kinase cell lines have been fully validated by sequencing, western blotting, and inhibitor testing, covering many popular kinases including EGFR (&gt;150 cell lines), RAS (80 cell lines), FGFR (55 cell lines), ERBB2 (49 cell lines), MET (41 cell lines), RET (39 cell lines), BCR-ABL (37 cell lines), EML4-ALK (33 cell lines), and FLT3 (26 cell lines), etc. Most of these transformed Ba/F3 cell lines can be used for xenograft models in immunodeficient mice. Based on these Ba/F3 kinase cell line-derived xenograft models, we have established an in vivo screening platform to evaluate the efficacy and toxicity of candidate drugs against specific kinase mutation types, as well as their comparison with previous generation drugs. Overall, our data suggest that xenograft models derived from Ba/F3 kinase cell lines are powerful models for discovering next-generation kinase inhibitors.
Citation Format: Stephanie Wang. An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A008.
Abstract A024: Preclinical profile of novel and potent small molecule inhibitors of KIF18A inhibitors in chromosomally unstable solid tumor lines
Authors: Patra Sukanya , Pothuganti Manoj , Karche Navnath , Gudade Ganesh , Sankeshi Venu , Kummari Githavani , Vishwanadha Srikant 
Published: December 2023

Abstract
Accurate alignment of chromosomes at the equator region and equal chromosome separation during cell division is essential for maintenance of genome integrity. KIF18A belongs to kinesin superfamily of microtubule associated motor proteins and is responsible for maintenance of bipolar spindle fiber integrity during mitotic phase. Cancer cells with chromosomally unstable (CIN+) DNA show synthetic lethal phenotype with genetic ablation of KIF18A. Thus, pharmacological inhibition of KIF18A represents a potential strategy aimed at attenuating growth of CIN +ve tumors. A microtubule dependent ADP Glo kinase assay was used to identify potent KIF18A inhibitors. Mitotic arrest, manifested by an increase in phosphoH3, was determined in cells using fluorescent microscopy. Anti-proliferative activity was confirmed in CIN+ve solid tumor cells with significant selectivity over CIN-ve cancer cells. Compounds inhibited KIF18A at with potencies ranging from 50-80 nM. A dose dependent increase in mitotic index in CIN+ve OVCAR-3 cells (via fluorescence microscopy) was observed in contrast to CIN-ve HCT-116 cells (10-100X selectivity). Translation was evident in an antiproliferation assay using CIN-ve cancer cells with IC50 &lt;10 nM. Selected KIF18A inhibitors demonstrated favorable physicochemical, ADME and PK properties. In Vivo efficacy studies are planned.
Citation Format: Sukanya Patra, Manoj Pothuganti, Navnath Karche, Ganesh Gudade, Venu Sankeshi, Githavani Kummari, Srikant Vishwanadha. Preclinical profile of novel and potent small molecule inhibitors of KIF18A inhibitors in chromosomally unstable solid tumor lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A024.
Abstract A033: Anti-proliferative effects of lentinan, a beta-glucan from shiitake mushroom (lentinula edodes)
Authors: Sombuor Titus , Broughton Kenneth Shane , Bergel Michael 
Published: December 2023

Abstract
Cancer is one of the most significant health challenges worldwide. Lentinan, a β-glucan from shiitake mushroom, Lentinula edodes, has been demonstrated to have an inhibitory effect on selected cancer cells, but results are inconclusive. The aim of the present study was to investigate the anti-proliferative effect of lentinan on breast adenocarcinoma cells (MCF-7), prostate carcinoma (DU-145), and ovarian carcinoma (SKOV3) using MTS (3-(4,5-dimethylthiazol-2-yl)-5—(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and explore possible mechanisms of action of this compound. In the MCF-7 cells that were used as a positive control, lentinan without phenol red resulted in a significant inhibition of cell viability by 96% while in the presence of phenol red, the weak estrogen effect attributable to phenol red eliminated the significant inhibitory effect of lentinan. Treatment of DU-145 cells with different doses of lentinan resulted in up to a 42% inhibition in cell growth. In SKOV3 cells, lentinan induced a biphasic response where doses of 800 µg/ml or less increased cell viability by 76% – 148%; however, a dose of 1.6 mg/ml inhibited cell proliferation significantly by 87%. When SKOV3 cells were co-treated with lentinan (800 µg/ml or less) and laminarin (a Dectin-1 receptor antagonist), the proliferation-promoting effect of lentinan was dominant over the proliferation-inhibiting effect of laminarin. However, when lentinan was presented at significant higher levels (1600 µg/ml), the inhibitory effect of the two agents became additive in suppressing SKOV3 cell proliferation. Lentinan induced a biphasic response in human ovarian surface epithelial cells (HOSEpC) similar to SKOV3 cells, where the highest dose (1600 µg/ml) resulted in the inhibition of cell growth by 53%. Western blots after treatment of SKOV3 cells with 1600 µg/ml of lentinan demonstrated caspase-3 activation and a decreased anti-apoptotic protein Bcl-2 levels. Our findings reveal that lentinan can be considered as a potential anti-cancer drug for effective treatment of breast and prostate cancer.
Citation Format: Titus Sombuor, Kenneth Shane Broughton, Michael Bergel. Anti-proliferative effects of lentinan, a beta-glucan from shiitake mushroom (lentinula edodes) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A033.
Abstract A064: Establishing the cellular and molecular impacts of the dual BRM/BRG1 inhibitor FHD-286 on pre-clinical models of non-small cell lung cancer (NSCLC)
Authors: Wilson Molly M. , Adam Ammar , Amaral Victoria , Mikse Oliver , Elliott GiNell , Lahr David L. , Gartin Ashley K. , Wan Jessica , Johannessen Liv , Ichikawa Kana , Feldman Katharine , Piel Jessica , Sandoval Gabriel J. , Centore Richard C. , Bellon Steven F. , Hentemann Martin 
Published: December 2023

Abstract
The BRG/BRM-associated factor (BAF) complex plays critical roles in chromatin regulation. Within this complex, the two mutually exclusive ATPases BRM and BRG1 (SMARCA2 and SMARCA4, respectively) drive chromatin remodeling activity. Genetic alterations in the SMARCA4 gene, encoding BRG1, are found in approximately 10% of non-small cell lung cancer (NSCLC) patients, leaving this subset of BRG1-deficient tumors highly susceptible to BRM inhibition. In addition, BRG1 has oncogenic activity in NSCLC, rationalizing the use of a dual BRM/BRG1 ATPase inhibitor, such as the highly potent clinical stage compound FHD-286, in NSCLC patients, regardless of SMARCA4 status. Here, we demonstrate that a panel of NSCLC cell lines respond to dual BAF ATPase inhibition in both in vitro and in vivo settings, regardless of SMARCA4 mutation status. Interestingly, dual BRM/BRG1 inhibition in cell lines reduces chromatin accessibility at motifs normally bound by AP-1 transcription factors, which play tumorigenic roles in NSCLC. We also find that expression of the stemness-associated glycoprotein CD44 is decreased by FHD-286, suggesting that dual BRM/BRG1 inhibition impacts the differentiation state of NSCLC. Moreover, transcriptional analyses of NSCLC xenograft models reveal that a basal cell gene expression signature, which is associated with a less differentiated cell state, is downregulated by FHD-286 treatment. Finally, genome-wide CRISPR knockout screening with FHD-286 in 2 NSCLC lines further elucidates mechanisms of action and molecular vulnerabilities induced by dual BAF ATPase inhibition. Collectively, these results indicate a path forward for the development of FHD-286 for the treatment of NSCLC patients.
Citation Format: Molly M. Wilson, Ammar Adam, Victoria Amaral, Oliver Mikse, GiNell Elliott, David L. Lahr, Ashley K. Gartin, Jessica Wan, Liv Johannessen, Kana Ichikawa, Katharine Feldman, Jessica Piel, Gabriel J. Sandoval, Richard C. Centore, Steven F. Bellon, Martin Hentemann. Establishing the cellular and molecular impacts of the dual BRM/BRG1 inhibitor FHD-286 on pre-clinical models of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A064.
Abstract A081: Patient-derived xenograft models from hematological malignancies for preclinical drug development and biomarker research
Authors: Siegert Antje , Brzezicha Bernadette , Fuhrmann Stephan , Janz Martin , Schmitt Clemens , Keller Ulrich , Rupp Christian , Walther Wolfgang , Hoffmann Jens 
Published: December 2023

Abstract
Background: Acute leukemias and lymphomas encompass a diverse group of hematologic malignancies, posing significant challenges in clinical practice. They often exhibit resistance to standard-of-care (SoC) treatments and have a high recurrence rate. Recent advancements in molecular profiling have identified potential drivers for various leukemia and lymphoma subtypes, offering new therapeutic targets. However, the validation of these targets and the development of drugs rely heavily on preclinical models that faithfully represent the different clinical subtypes. These models play a crucial role in refining target selection and facilitating drug development projects.
Methods: AML- and ALL-PDX were derived from bone marrow aspirates or peripheral blood samples, from primary or relapsed acute leukemia patients. Purified cells were transplanted either intravenously (i.v.) and/or subcutaneously (s.c.) into immunodeficient mice. Some mice developed a systemic AML, which was monitored by flow cytometric analysis of blood samples. Non-Hodgkin (NHL) - or Hodgkin lymphoma (HL)-PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, and were usually transplanted subcutaneously into immunodeficient mice.
Results: More than 45 PDX models from AML, ALL, NHL and HL have been successfully established and characterized. Highly individual response rates to SoC and investigational drugs were observed and correlated with mutation and gene expression data. An individual Human Leucocyte Antigen (HLA) profile of each PDX was determined by RNA-seq and a comprehensive HLA matching analysis of the models and peripheral blood mononuclear cell (PBMC) donors was performed to enable personalized, preclinical immuno-oncology studies.
Conclusions: Our extensively characterized PDX models derived from hematologic malignancies serve as valuable tools for evaluating novel targeted and immunological therapies. These models provide an exceptional platform for identifying and validating new targets, as well as preclinical screening of compounds and combinations for translational research projects in this field.
Citation Format: Antje Siegert, Bernadette Brzezicha, Stephan Fuhrmann, Martin Janz, Clemens Schmitt, Ulrich Keller, Christian Rupp, Wolfgang Walther, Jens Hoffmann. Patient-derived xenograft models from hematological malignancies for preclinical drug development and biomarker research [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A081.
Abstract A104: ADAR1-associated metabolic vulnerabilities in triple-negative breast cancer
Authors: Kung Che-Pei , Shriver Leah P , Terzich Nick , Ilagen Ma Xenia G , Prinsen Mike , Ryu Sua , Kladney Raleigh D , Patti Gary J , Maggi Leonard B , Weber Jason D 
Published: December 2023

Abstract
Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. Therefore, the mission to identify actionable targets remains the top priority. We recently demonstrated that an RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), plays important roles in TNBC’s ability to initiate and maintain tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from stresses when otherwise kept in check, contributing to tumorigenesis. By both targeted and unbiased approaches, we identified two metabolic vulnerabilities, 1) iron-dependent cell death pathway, ferroptosis, and 2) serine addiction, associated with ADAR1 in TNBC. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss in TNBC cells increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analysis and phenotypic drug screen using a ferroptosis-focused library were performed to identify underlying mechanisms and drug candidates synergizing with ADAR1 loss through ferroptosis, respectively. Meanwhile, an unbiased screen using a FDA-approved compound library revealed that ADAR1 loss also sensitizes TNBC cell line MDA-MB231 to inhibition of the serine biosynthesis pathway. We showed that ADAR1 knockdown leads to altered serine transport, and a metabolic flux analysis using labeled (U-13C) glucose will be performed to determine if ADAR1 loss affects de novo serine biosynthesis and one-carbon metabolism. By testing the hypothesis that ADAR1 regulates the metabolic fitness of TNBC by desensitizing ferroptosis and serine addiction, we aim to leverage these metabolic vulnerabilities to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC.
Citation Format: Che-Pei Kung, Leah P Shriver, Nick Terzich, Ma Xenia G Ilagen, Mike Prinsen, Sua Ryu, Raleigh D Kladney, Gary J Patti, Leonard B Maggi, Jason D Weber. ADAR1-associated metabolic vulnerabilities in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A104.
Abstract A109: Targeting pyrimidine biosynthesis as a metabolic vulnerability in brain metastasis
Authors: Mobilio Daniel , Singh Sheila K , Chafe Shawn C 
Published: December 2023

Abstract
Metastasis, the spread of cancer cells from one part of the body to another, is the leading cause of death among cancer patients. Lung-to-Brain metastasis remains a largely understudied disease that possesses a dismal prognosis due to the lack of effective therapies. We previously identified purine metabolism as a metabolic vulnerability of brain metastases. Here, we sought to identify whether pyrimidine biosynthesis is also a metabolic dependency of metastatic brain tumours. We identify dihydroorotate dehydrogenase (DHODH) as a cancer-selective targetable vulnerability. DHODH is an essential enzyme that is located within the inner membrane of the mitochondria which has a primary role in producing pyrimidine metabolites through the de novo uridine biosynthesis pathway and also contributes to the proper functioning of the electron transport chain. Knock-out of DHODH with CRISPR-Cas9 or pharmacological inhibition with BAY2402234 decreased cell viability, sphere formation, and proliferation of patient-derived lung-to-brain (LBM) metastasis cells in vitro. Furthermore, suppression of DHODH expression or BAY2402234 treatment reduced growth of intracranial LBM tumours and significantly extended survival. Mechanistically, we identify interfering with DHODH activity abrogates normal mitochondrial function leading to cleavage of gasdermin E and induction of pyroptosis. Taken together, this study highlights the promise of DHODH inhibitors in targeting brain metastasis.
Citation Format: Daniel Mobilio, Sheila K Singh, Shawn C Chafe. Targeting pyrimidine biosynthesis as a metabolic vulnerability in brain metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A109.
Abstract A118: Somatic mutations in the PIK3CA gene and its prognostic implications among Ethiopian breast cancer patients
Authors: Woldesonbet Zelalem Desalegn , Yohannes Meron , Addissie Adamu , Abebe Tamrat , Kantelhardt Eva Johanna , Vetter Martina 
Published: December 2023

Abstract
Purpose: The phosphatidylinositol-4, 5-bisphosphate 3-kinase (PIK3CA), catalytic subunit alpha (c) is frequently mutated in breast cancer (BC). Although the biological impact of PIK3CA mutations in BC has been studied in various parts of the world, limited data is available from sub-Saharan Africa. In this study, the frequency and the prognostic role of PIK3CA mutations were investigated among BC patients from Ethiopia.
Methods: Formalin-fixed paraffin-embedded blocks and fresh frozen BC tissue samples were collected from patients newly diagnosed with BC. Histopathological evaluation was carried out using immunohistochemistry (IHC). PIK3CA mutation profiling was carried out using TaqMan® Mutation detection assay. The association between PIK3CA mutation status and clinical and histopathological features was evaluated. A survival regression (Cox’s model) was employed to assess the effect of PIK3CA mutation and other variables on survival.
Results: The prevalence of the PIK3CA mutations was 20.4%. Mutation of the PIK3CA gene was mainly observed among younger (24%), early pT stage (19.4%), and G1/G2 tumors (22.3%). The proportion of mutation was 24.4%, 27.3% and 20% in ER+, PR+ and HER2- tumors, respectively. A marked difference was observed in the PIK3CA mutation frequency across the four major tumor subgroups. However, most of the mutated tumors were found among HR+/HER2− (24.1%) followed by HR+/HER2+ tumors (27.8%). In his study, only TNBC was negatively associated with the proportion of mutation in the PIK3CA gene (p-value= 0.02) in comparison to HR+/HER2- tumors. In multivariate Cox’s regression analysis, the advanced pT stage and HR−/HER2- IHC group independently predicted worse overall survival. However, PIK3CA mutation status was not associated with survival.
Conclusions: The PIK3CA mutation was relatively high in HR+ tumors. Mutation rates of PIK3CA in Ethiopian BC tumors are similar to those reported for other populations.
Citation Format: Zelalem Desalegn Woldesonbet, Meron Yohannes, Adamu Addissie, Tamrat Abebe, Eva Johanna Kantelhardt, Martina Vetter. Somatic mutations in the PIK3CA gene and its prognostic implications among Ethiopian breast cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A118.