bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-Training Clustering Models to Summarize Vietnamese Texts
Authors: Nguyen Ti-Hon , Do Thanh-Nghi
Published: April 2024

Our investigation aims at pre-training clustering models to summarize Vietnamese texts. For this purpose, we create a large-scale dataset by collecting Vietnamese articles from newspaper websites and extracting the plain text to build the dataset, including 1,101,101 documents. We propose a new single-document extractive text summarization model based on clustering models. Our proposal clusters the documents with the hard clustering k-means algorithm and the soft clustering LDA (Latent Dirichlet Allocation) algorithm. Then, based on the pre-training clustering models, a summary model is used to select the salient sentence in the input text to construct the summary. The empirical results showed that our summary model achieved 51.22% ROUGE-1, 17.62% ROUGE-2 and 29.16% ROUGE-L on the testing set. Besides the traditional word representation such as BoW (Bag-of-Words), we also use the word meaning-based tools like FastText and BERT (Bidirectional Encoder Representations from Transformers) in our model. The additional benefit of our proposed extractive summary model is that the output summary is a long-text, readable document. Furthermore, the model’s architecture is straightforward, easy to understand and runs on cost-efficient resources like arm CPU and GPU too.
MEDUSA: A Dynamic Codec Switching Approach in HTTP Adaptive Streaming
Authors: Lorenzi Daniele , Tashtarian Farzad , Hellwagner Hermann , Timmerer Christian
Published: April 2024

HTTP Adaptive Streaming
(HAS) solutions utilize various Adaptive BitRate (ABR) algorithms to dynamically select appropriate video representations, aiming at adapting to fluctuations in network bandwidth. However, current ABR implementations have a limitation in that they are designed to function with one set of video representations, i.e., the bitrate ladder, which differ in bitrate and resolution, but are encoded with the same video codec. When multiple codecs are available, current ABR algorithms select one of them prior to the streaming session and stick to it throughout the entire streaming session. Although newer codecs are generally preferred over older ones, their compression efficiencies differ depending on the content’s complexity
, which varies over time. Therefore,
it is necessary to select the appropriate codec for each video segment to reduce the requested data while delivering the highest possible quality.
In this article, we first provide a practical example where we compare compression efficiencies of different codecs on a set of video sequences. Based on this analysis, we formulate the optimization problem of selecting the appropriate codec for each user and video segment (on a per-segment basis in the outmost case), refining the selection of the ABR algorithms by exploiting key metrics, such as the perceived segment quality and size. Subsequently, to address the scalability issues of this centralized model, we introduce a novel distributed plug-in ABR algorithm for Video on Demand (VoD) applications called MEDUSA to be deployed on top of existing ABR algorithms. MEDUSA
enhances the user’s Quality of Experience (QoE) by utilizing a multi-objective function that considers the quality and size of video segments when selecting the next representation. Using quality information and segment size from the modified
Media Presentation Description (MPD)
, MEDUSA utilizes buffer occupancy to prioritize quality or size by assigning specific weights in the objective function. To show the impact of MEDUSA, we compare the proposed plug-in approach on top of state-of-the-art techniques with their original implementations and analyze the results for different network traces, video content, and buffer capacities. According to the experimental findings, MEDUSA shows the ability to improve QoE for various test videos and scenarios. The results reveal an impressive improvement in the QoE score of up to 42% according to the ITU-T P.1203 model (mode 0). Additionally, MEDUSA can reduce the transmitted data volume by up to more than 40% achieving a QoE similar to the techniques compared, reducing the burden on streaming service providers for delivery costs.
A Probabilistic Approach to Adaptive Protection in the Smart Grid
Authors: Mohamed Amr S. , Kundur Deepa , Khalaf Mohsen
Published: April 2024

Smart grids are critical cyber-physical systems that are vital to our energy future. Smart grids’ fault resilience is dependent on the use of advanced protection systems that can reliably adapt to changing grid conditions. The vast amount of operational data generated and collected in smart grids can be used to develop these protection systems. However, given the safety-criticality of protection, the algorithms used to analyze this data must be stable, transparent, and easily interpretable to ensure the reliability of the protection decisions. Additionally, the protection decisions must be fast, selective, simple, and reliable. To address these challenges, this article proposes a data-driven protection strategy, based on Gaussian Discriminant Analysis, for fault detection and isolation. This strategy minimizes the communication requirements for time-inverse relays, facilitates their coordination, and optimizes their settings. The interpretability of the protection decisions is a key focus of this article. The method is demonstrated by showing how it can protect the medium-voltage CIGRE network as it transitions between islanded and grid-connected modes and radial and mesh topologies.
Dynamic Effect of Overscreening on Electrochemical and Thermal Properties of EDLC Electrodes during Charging/Discharging Cycles
Authors: Li Jingyu , Hamza Muhammad , Mei Bing-Ang , Feng Huihua , Zuo Zhengxing , Xiong Rui
Published: April 2024

Overscreening was commonly observed during charging/discharging cycles of electric double layer capacitors(EDLCs). This study presented a two-dimensional continuum electrochemical thermal model with a distribution function for concentration considering overscreening to investigate how overscreening affected the dynamic formation of electric double layer (EDL) near electrodes in macroscale. The results indicated that ion distribution was co-affected by EDL formation and overscreening near the electrode. Correspondingly, layered space charge density distribution resulted in a thicker diffuse layer, whose thickness was determined by the sum of co-ion and counter-ion diameters. Additionally, the diffuse layer capacitance was proportional to the reciprocal of counter-ion diameter, while the total capacitance was proportional to a linear combination of counter-ion and the larger ion diameters. Moreover, the shift from endothermic to exothermic for the total heat generation rate was dominated by heat of mixing, and was caused by the local ion mixing due to overscreening, resulting in local entropy increase. The results of this study can be used to further investigate the effect of overscreening on ion transient transport dynamic and heat generation rates.
Electrochemistry of Uranium on Liquid Cadmium Electrode in LiCl-KCl Eutectic
Authors: Novoselova Alena , Smolenski Valeri , Mushnikov Peter
Published: April 2024

This work presents the electrochemical study of LiCl-KCl-UCl3 solutions at the temperature range 673–823 K on inert and reactive electrodes, i.e. W and Cd, respectively. On inert electrode, U(III) ions were reduced to metallic uranium through one step and the mechanism of the cathode reaction was irreversible. The diffusion coefficients of U(III) ions in molten chloride eutectic and liquid cadmium were calculated. On reactive electrode, U(III) ions were reduced with depolarization and were accompanied by the formation of intermetallic compound UCd11. The reactions of the cathodic deposition and anodic dissolution of the U-Cd alloy were studied and the conditions of the alloy formation via galvanostatic electrolysis were found. The solubility and the activity of uranium in liquid cadmium were determined.
Impact of Salts and Linear Carbonates on the Performance of Layered Oxide/Hard Carbon Sodium-Ion Pouch Cells with Alkyl Carbonate Electrolytes
Authors: Ye Ziwei , Hijazi Hussein , Black William , Azam Saad , Dahn J. R. , Metzger Michael
Published: April 2024

This study examines the influence of electrolyte salts and solvents on the performance of O3 layered oxide NaMn0.39Fe0.31Ni0.22Zn0.08O2/hard carbon sodium-ion pouch cells with polyethylene terephthalate (PET) jellyroll tape. A significant enhancement in cell performance between 2.0 and 3.8 V was observed across various temperatures (20, 40, and 55 °C) by substituting NaPF6 with NaFSI, including reduced impedance growth, minimized gas generation, and supressed jellyroll tape decomposition. Ultra-high precision coulometry revealed that the use of NaPF6 resulted in increased unwanted parasitic reactions associated with tape decomposition, e.g., capacity fade and charge endpoint capacity slippage. Teardown of sodium-ion pouch cells after cycling in DMC-based electrolytes revealed a severe decomposition of the PET tape with NaPF6 but not with NaFSI. Gas chromatography shows significantly more electrolyte decomposition products with NaPF6 as opposed to NaFSI. DEC-based electrolyte showed less capacity fade, less electrolyte decomposition products, and less tape decomposition after cycling than DMC-based electrolyte. The electrolyte additive DTD can prevent parasitic reactions in DMC- and NaPF6-based electrolyte. Overall, the choice of salts and linear carbonates in alkyl carbonate electrolytes plays a crucial role in determining the overall cycling performance of the layered oxide/hard carbon sodium-ion cells with PET jellyroll tape.
Synergistic Effect of 3D Electrode Architecture and In Situ Carbon Coating on the Electrochemical Performance of SnO2 Anodes for Sodium-Ion Batteries
Authors: Chakraborty Rupan Das , Bhar Madhushri , Bhowmik Subhajit , Martha Surendra K.
Published: April 2024

SnO2, owing to its high theoretical capacity of 1378 mAh g−1 and low sodium insertion potential, is one of the attractive anode materials for Sodium-ion batteries (SIBs). However, extensive volume expansion (∼300 %), significant capacity loss, particle agglomeration, and low conductivity (1.82 × 10−8 S cm−1) of SnO2 limit its commercial applications. In this work, SnO2 nano-particles have been synthesized via a one-step hydrothermal method. Subsequently, 3D electrode architecture is developed using pitch-coated SnO2 nanomaterial onto carbon fiber (CF) current collector to mitigate the inherent challenges of SnO2 anode. Compared to the conventional SnO2 electrode, the optimized CF-SnO2- carbon composite electrodes show an excellent second-cycle stable capacity of 843 mAh g−1 at 30 mA g−1 with 95 % capacity retention after 100 cycles. This CF-SnO2-carbon composite electrode further delivers a stable capacity of 419 mAh g−1 at 300 mA g−1, having 80 % capacity retention after 200 cycles, and shows excellent C-rate performance. Conductive CF backbone and carbon coating accommodate the volume expansion of the active material, acting as a buffer matrix and reducing the electrode pulverization. This work entails a carbon fiber-based electrode engineering approach to fabricate a binder-less metal current collector-free freestanding electrode as a potential anode for SIBs.
How to Obtain High Load-Bearing Al-Cu Joints by Nanoscale Sculpturing
Authors: Gerngross M.-D. , Baytekin-Gerngross M. , Carstensen J. , Adelung R.
Published: April 2024

The electrochemical formation of high-mechanical-load-bearing Al-Cu joints and their characterization is presented in this paper. These Al-Cu joints rely on the mechanical interlocking between the Al and Cu layer obtained by nanoscale sculpturing of the Al joint partner, resulting in a hierarchical surface structure. The structure consists of cubes of various sizes acting like hooks. When enclosed by Cu the cubic Al hooks establish a rigid connection between the Al and Cu joint partners. In addition, the hierarchical cubic Al structures allow for a gradual transition from Al to Cu in the Al-Cu joint. Therefore, such Al-Cu joints exhibit an extraordinary load carrying ability compared to other Al-Cu joints.
Strategies for inducing and validating zinc deficiency and zinc repletion
Authors: Wenegieme Tara-Yesomi , Elased Dalia , McMichael Kelia E. , Rockwood Jananie , Hasrat Khanzada , Ume Adaku C. , Marshall Andrea G. , Neikirk Kit , Kirabo Annet , Elased Khalid M. , Hinton Antentor , Williams Clintoria R.
Published: April 2024

This methods paper details dietary approaches to alter zinc homeostasis in rodents and qualitative and quantitative methods to ensure the zinc status of experimental animals. The outlined accessible and cost-effective protocol will elevate scientific rigor, ensuring reproducibility in studies exploring the impact of zinc deficiency and repletion on the onset and progression of a multitude of health conditions and diseases.
Ethanol Extract of Ampelopsis brevipedunculata Rhizomes Suppresses IgE-Mediated Mast Cell Activation and Anaphylaxis
Authors: Park Ji-Yeong , Kim Min-Jong , Choi Young-Ae , Lee Seung Woong , Lee Soyoung , Jang Yong Hyun , Kim Sang-Hyun
Published: April 2024

More than 20% of the world’s population suffers from allergic diseases, including allergic asthma, rhinitis, and atopic dermatitis that severely reduce the patient’s quality of life. The treatment of allergy has been developed, but there are still unmet needs. Ampelopsis brevipedunculata (Maxim.) Trautv. is a traditional medicinal herb with beneficial bioactivities, such as antioxidant, anti-hypertension, anti-viral, anti-mutagenic, and skin and liver (anti-hepatotoxic) protective actions. However, its anti-allergic effect has not been addressed. This study designed to investigate the pharmacological effect of an ethanol extract of A. brevipedunculata rhizomes (ABE) on mast cell and anaphylaxis models. For in vivo studies, we used ovalbumin-induced active systemic anaphylaxis (ASA) and immunoglobulin (Ig) E-mediated passive cutaneous anaphylaxis (PCA) models. In ASA model, oral administration of ABE (1, 10, and 100 mg/kg) attenuated the anaphylactic responses, such as hypothermia, serum histamine, and IgE productions. In PCA model, ABE also suppressed the plasma extravasation and swelling. The underlying mechanisms of action were identified in various mast cell types. In vitro, ABE (10, 30, and 60 µg/mL) inhibited the release of essential allergic mediators, such as histamine and β-hexosaminidase, in a concentration-dependent manner. ABE prevented the rapid increase in intracellular calcium levels induced by the DNP-HSA challenge. In addition, ABE downregulated the tumor necrosis factor-α and interleukin-4 by suppressing the activation of nuclear factor-κB. Collectively, this study is the first to identify the anti-allergic effect of ABE, suggesting that ABE is a promising candidate for treating allergic diseases.
Effects of Fuel Flow and Airflow Swirl on Thermal Performance of a Miniature‐Scale Combustor for Direct Energy Conversion Systems
Authors: Sheykhbaglou Soroush , Ghahremani Amirreza , Tabejamaat Sadegh , Sánchez-Sanz Mario
Published: April 2024

Micropower generation and micropropulsion are two emerging fields where micro‐ and miniature‐scale combustors are anticipated to play a significant role. Today, there is a growing interest in combustion‐based direct energy conversion modules such as thermoelectric and thermophotovoltaic micropower generators. In this study, the effects of swirl addition to fuel flow and airflow on combustor operational envelope, flame blowout limit, combustion efficiency, exhaust gas temperature, mean outer wall temperature, emitter efficiency, and normalized temperature standard deviation of a miniature‐scale (mesoscale) combustor are studied under various equivalence ratios. The findings demonstrate that swirling flows improve the flame blowout limit and operational envelope of the combustor; however, this improvement is more significant for airflow swirl. Besides simultaneous swirling flows of fuel and air result in the highest blowout limit. Additionally, it has been shown that swirl addition improves combustion efficiency and causes a significant amount of heat to be generated, which raises the temperature of the exhaust gas, the mean outer wall temperature, and the emitter efficiency. Furthermore, mean outer wall temperature and emitter efficiency have the highest values for simultaneous swirling flows of fuel and air. It is also observed that increasing the fuel flow swirl number generally lessens the normalized temperature standard deviation (NTSD) and consequently improves the combustor wall temperature uniformity, while for the airflow swirl case, a swirler with 30° vane angle for airstream has a lower NTSD than a 45° vane angle swirler. The results obtained in this study provide useful information for designing a combustion‐based direct energy conversion module.
Creation Field Cosmological Model with Variable Cosmological Term (Λ) in Bianchi Type III Space-Time
Authors: Bali Raj , Saraf Seema
Published: April 2024

The paper is devoted to the study of cosmological models with time-varying cosmological term (Λ) in the presence of creation field in the framework of Bianchi type III space-time. To obtain deterministic model of the universe, we have assumed Λ∝1/R3, where R is the scale factor, for steady state cosmology and creation field, and shear (σ) is proportion to expansion (θ) which leads to B=Cn, where B and C are the metric potentials to explain small anisotropic behaviour of the universe and its isotropy. To obtain the results in terms of cosmic time t, we have assumed n=2. The model satisfies conservation equations, and creation field increases with time. The present model is free from singularity, has particle horizon, and provides a natural explanation for inflationary scenario and isotropization. Creation field and Einstein field equations are derived using principle of least action and Lagrangian formulation of variable cosmological term. For illustrative purposes, evolutionary behaviour of some cosmological parameters are shown graphically. The other physical aspects like accelerating behaviour of the model are also discussed. Thus, the model represents not only expanding universe but also accelerating which matches with the results of present-day observations.
Anticolorectal Cancer Activity of Bilobalide in Patient-Derived Colorectal Cancer Organoids and AOM/DSS Mouse Model
Authors: Zhang Heng , Fang Shuhua , Raza Faisal , Cao Nengqi , Fang Xingchao , Lu Xu , Li Ran , Shi Feng , Wang Deqiang , Xu Min
Published: April 2024

Bilobalide has shown strong anti-inflammatory activity. Colorectal cancer (CRC) is closely associated with inflammation. However, no studies have reported on the use of bilobalide for treating CRC. This study aims to evaluate the effect of bilobalide on CRC prevention. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, and immunofluorescence showed that bilobalide significantly inhibits the M2 polarization of macrophages dependent on phorbol 12-myristate 13-acetate (PMA) and interleukin-4 (IL-4). Analysis of signaling pathways showed that the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3) was regulated. In particular, human CRC organoids were established. Western blotting, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL), and analysis of cell viability and morphology further supported the hypothesis that the anti-CRC effects of bilobalide could be explained by its ability to suppress M2 macrophage polarization and promote M1 transformation. C57BL/6 mice treated with azoxymethane (AOM)/dextran sodium sulfate (DSS) were divided into three groups, i.e., control, AOM/DSS, low (2.5 mg/kg), and high (5 mg/kg). High-dose bilobalide markedly inhibited the progression of CRC, as evidenced by the increased body weight, decrease in disease activity index (DAI) death rate, and alleviation of colon length reduction and tumorigenesis. According to the in vivo results, reduced levels of inflammatory cytokines in the serum included tumor necrosis factor (TNF-α), IL-6, IL-1β, and IL-10. Bilobalide reduced oxidative stress indices, lipid peroxide (LPO), and malondialdehyde (MDA) and increased reduced glutathione (GSH). In addition, the expression of proliferating cell nuclear antigen (PCNA), Ki67, cellular Myc (c-Myc), and CD206 was downregulated in the drug-treated groups, as confirmed by the immunohistochemical staining. Collectively, these results indicated that bilobalide administration improve experimental CRC by inhibiting M2 macrophage polarization and oxidative stress. Thus, bilobalide may prevent CRC and serve as a potential therapeutic target for CRC.
Safety and Preliminary Efficacy of Pembrolizumab Following Transarterial Chemoembolization for Hepatocellular Carcinoma: The PETAL Phase Ib Study
Authors: Pinato David J. , D'Alessio Antonio , Fulgenzi Claudia Angela Maria , Schlaak Alexandra Emilia , Celsa Ciro , Killmer Saskia , Blanco Jesus Miguens , Ward Caroline , Stikas Charalampos-Vlasios , Openshaw Mark R. , Acuti Nicole , Nteliopoulos Georgios , Balcells Cristina , Keun Hector C. , Goldin Robert D. , Ross Paul J. , Cortellini Alessio , Thomas Robert , Young Anna-Mary , Danckert Nathan , Tait Paul , Marchesi Julian R. , Bengsch Bertram , Sharma Rohini
Published: April 2024

Purpose:

Transarterial chemoembolization (TACE) may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy.

Patients and Methods:

Patients with liver-confined hepatocellular carcinoma (HCC) were planned to receive up to two rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, with assessment window of 21 days from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumor and host determinants of response.

Results:

Fifteen patients were included in the safety and efficacy population: 73% had nonviral cirrhosis; median age was 72 years. Child-Pugh class was A in 14 patients. Median tumor size was 4 cm. Ten patients (67%) received pembrolizumab after one TACE; 5 patients after two (33%). Pembrolizumab yielded no synergistic toxicity nor dose-limiting toxicities post-TACE. Treatment-related adverse events occurred in 93% of patients, most commonly skin rash (40%), fatigue, and diarrhea (27%). After a median follow-up of 38.5 months, objective response rate 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months [95% confidence interval (CI): 7.30–NE (not estimable)]. Median duration of response was 7.3 months (95% CI: 6.3–8.3). Median overall survival was 33.5 months (95% CI: 11.6–NE). Dynamic changes in peripheral T-cell subsets, circulating tumor DNA, serum metabolites, and in stool bacterial profiles highlight potential mechanisms of action of multimodal therapy.

Conclusions:

TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.
Abstract CT288: Brightline-4: A phase 3 open-label, single-arm, multicenter study to assess the safety and efficacy of brigimadlin (BI 907828) treatment in patients with treatment-naïve or pretreated advanced dedifferentiated liposarcoma
Authors: Schuetze Scott , Jayadeva Girish , Santoro Michael
Published: April 2024

Background Current treatment options for dedifferentiated liposarcoma (DDLPS) are associated with suboptimal efficacy and substantial toxicities.

Purpose Brigimadlin (BI 907828) is a highly potent, orally available MDM2-p53 antagonist that binds to MDM2 and blocks its interaction with p53, thereby restoring p53 function, leading to cell cycle arrest and apoptosis in TP53 wild-type tumors. Brigimadlin has been evaluated in a phase 1a/1b study in patients with solid tumors (NCT03449381) and has shown encouraging preliminary efficacy in patients with DDLPS. Based on these data, brigimadlin is being investigated for the first-line treatment of advanced DDLPS in the randomized phase 2/3 Brightline-1 trial (NCT05218499). The Brightline-4 trial will generate additional safety and efficacy data in a broader DDLPS patient population.

Experimental design Brightline-4 (NCT06058793) is an open-label, single-arm, global, multicenter phase 3 study that aims to assess the safety and efficacy of brigimadlin in patients with treatment-naïve or pretreated advanced DDLPS. Approximately 240 patients with treatment-naïve (Cohort A) or pre-treated (Cohort B) advanced DDLPS will be enrolled. All patients will receive brigimadlin 45 mg orally once every 3 weeks. Key inclusion criteria include: ≥18 years of age; locally advanced/metastatic, unresectable, histologically confirmed DDLPS; tumor MDM2 expression by immunohistochemistry or MDM2 amplification (via fluorescence in situ hybridization or next-generation sequencing); ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. Key exclusion criteria include: prior treatment with an MDM2-p53 antagonist; known mutation in TP53; receiving treatment for brain metastases or leptomeningeal disease. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints are the occurrence of treatment-emergent adverse events (TEAEs) and grade ≥3 TEAEs according to NCI CTCAE v5. Secondary endpoints include objective response, progression-free survival, overall survival, duration of response, disease control and further assessment of safety. All analyses will be descriptive; no hypothesis testing is planned.

Citation Format: Scott Schuetze, Girish Jayadeva, Michael Santoro. Brightline-4: A phase 3 open-label, single-arm, multicenter study to assess the safety and efficacy of brigimadlin (BI 907828) treatment in patients with treatment-naïve or pretreated advanced dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT288.
Abstract LB069: Repurposing anti-mesothelin CAR-NK immunotherapy against colorectal cancer
Authors: Torchiaro Erica , Cortese Marco , D'Andrea Alice , Petti Consalvo , Medico Enzo
Published: April 2024

Colorectal cancer (CRC) is the third most common cancer worldwide, with highly variable prognosis and response to treatment. A large subset of patients does not respond to standard treatments or develops resistance. As an alternative, adoptive immunotherapy based on chimeric antigen receptor (CAR)-transduced immune cells has been proposed, however with significant adverse events. We therefore evaluated alternative CAR targets already tested in other tumour types, and employed the natural killer cell line NK-92 for CAR transduction because of its more favourable toxicity profile.

As an alternative antigen, we considered mesothelin (MSLN), the most represented in CAR-based clinical studies for solid tumours. MSLN RNA expression was analysed in large series of CRC patient-derived xenografts (PDXs, n=500), cell lines (n=150) and tumours (n=640), to evaluate its distribution and to identify MSLN-overexpressing models. NK-92 cells were transduced with anti-MSLN CAR, and subsequently sorted and cloned. Activity of CAR-NK-92 cells against target-expressing ovarian and CRC cells was assessed in vitro and in vivo. Statistical significance of efficacy was evaluated by t-test.

The large-scale expression analysis highlighted that about 10% of CRCs overexpress MSLN at levels comparable to those of ovarian cancer, a typical target of MSLN-CAR-based therapy. Intriguingly, MSLN overexpression is more frequent in the CRIS-B poor prognosis subtype and KRAS/BRAF-mutant CRC. Lentiviral transduction of NK-92 cells with the MSLN-CAR, followed by sorting and cloning, led to the identification of one clone, NK-92cl45, stably expressing the CAR and retaining the NK phenotype. As expected, the clone demonstrated significant in vitro and in vivo activity against ovarian cancer cells. When repurposed against models of CRC expressing high MSLN levels, it displayed comparable efficacy, both in vitro and in vivo. Specificity of NK-92cl45 was confirmed by the absence of activity on control models with low or absent MSLN.

Our results provide preclinical evidence that a subset of colorectal cancers expressing high mesothelin levels can be effectively targeted by MSLN-CAR-based immunotherapy. The potential therapeutic impact of these findings is enhanced by the fact that frequently MSLN-overexpressing CRCs display worse prognosis and resistance to standard care.

Citation Format: Erica Torchiaro, Marco Cortese, Alice D'Andrea, Consalvo Petti, Enzo Medico. Repurposing anti-mesothelin CAR-NK immunotherapy against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB069.
Abstract LB080: iOTarg screening platform reveals novel mechanisms of colorectal cancer evasion from antigen-specific tumor cell killing by T cells
Authors: Michels Tillmann , Volpin Valentina , Amerhauser Carmen , Tschulik Claudia , Majunke Leonie , Weglarz Aleksandra , Baritz Kilian , Sudan Kritika , Bak-Kiss Szilvia , Huth Alina , Strobl Carolin , Turqueti-Neves Adriana , Khandelwal Nisit
Published: April 2024

While immune checkpoint therapies have revolutionized cancer treatment, their efficacy remains limited in colorectal cancer (CRC) and other malignancies. Tumors employ diverse strategies to evade immune-mediated destruction, hindering the success of immunotherapies. We introduce iOTarg, a robust high-throughput screening platform designed to uncover resistance pathways against T cell-mediated tumor killing within the tumor microenvironment. Focusing on CRC, we utilized iOTarg to dissect evasion mechanisms against antigen-specific T cell (TC) killing. In a representative CRC cell line co-culture system (SW480, HCT116 or COLO-678) with various TC sources, we gained key insights of tumor resistance towards killing. Survivin-specific TCs induce strong tumor lysis while tumor-infiltrating lymphocyte 412 (TIL412) represent a weaker basal killing representative of the situation in the tumor. Knockout of β₂-microglobulin abrogated TC-mediated killing, while c-FLIP knockout significantly enhanced tumor lysis. Intriguingly, PD-L1 blockade had no impact on TC activation or killing, underlining its lack of efficacy in CRC. Screening over 6000 druggable genes revealed several critical candidates, including anti-apoptotic BIRC family members (BIRC2, 3), apoptosis regulators (Bcl-xL, XIAP), TNF signaling regulators (TRAF2, MAP3K7), and genes recently described as sensitization mediators (B3GNT3, CHMP4B). Caspase-8 knockout prevented TC-mediated killing of CRC cells, confirming its crucial role in immune-mediated tumor cell clearance. Further validation in secondary screenings reinforced a subset of genes as strong regulators of tumor cell killing, uncovering an array of CRC resistance mechanisms. Our findings present a pioneering platform delineating resistance mechanisms against T cell-mediated colorectal tumor killing. We identify established and novel targets, offering prospects for novel therapeutics and expanding immune oncology treatment options. This platform holds promise for developing first-in-class therapies targeting the tumor microenvironment, potentially transforming CRC treatment paradigms.

Citation Format: Tillmann Michels, Valentina Volpin, Carmen Amerhauser, Claudia Tschulik, Leonie Majunke, Aleksandra Weglarz, Kilian Baritz, Kritika Sudan, Szilvia Bak-Kiss, Alina Huth, Carolin Strobl, Adriana Turqueti-Neves, Nisit Khandelwal. iOTarg screening platform reveals novel mechanisms of colorectal cancer evasion from antigen-specific tumor cell killing by T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB080.
Abstract LB166: Discovery of CT3021, a novel potent adenosine A2a/A2b/A1 receptor triple antagonist
Authors: Han Sandong , Kim Nam Hee , He Hongmei , Chu Zhi Liang
Published: April 2024

In a CD73-positive tumor microenvironment (TME), ATP released from apoptotic tumor cells converts to adenosine, generating an adenosine-rich immunosuppressive environment. Adenosine activates G-protein coupled receptors expressed on immune cells to achieve immune suppression, with a mechanism of action involving 1) dampening antitumor effector cells (T eff and NK cells) via adenosine engagement on A2a receptor, (2) reducing dendritic cell antigen presentation and promoting MDSC differentiation by activating A2b and A2a receptors, and (3) inducing chemotactic migration of immature plasmacytoid dendritic cells to infiltrate tumor tissue via A1 receptor. Furthermore, A1 receptor expression in certain tumors mediates an adenosine-driven tumor cell proliferation, likely through A1 receptor Gi coupling to the Hippo-YAP signal transduction pathway. Thus, pharmacologic inhibition of A2a, A2b, and A1 receptors by a triple antagonist in the context of adenosine-rich TME may represent an attractive strategy to achieve a better outcome in treating solid tumors. We discovered and characterized a novel adenosine receptor antagonist CT3021. CT3021 exhibits high binding affinity to A2a, A2b, and A1, with a Ki value of 0.37 nM, 1.76 nM, and 1.26 nM, respectively, and is selective against the A3 receptor and other 84 pharmacologically and/or toxicologically relevant targets. Schild analysis demonstrated that CT3021 is a competitive antagonist with a calculated KB value of 0.18 nM on A2a receptor in a whole cell cAMP assay in transfected HEK293 cells. In functional antagonist assays, CT3021 maintains its high potency full antagonism under an adenosine-rich TME-like condition (10-100 µM adenosine) both in transfected HEK293 cells and in isolated human T lymphocytes. CT3021 has a high oral bioavailability, a limited CNS exposure, and a favorable ADME profile. CT3021 is well tolerated in rats after repeat dosing. Further toxicology and efficacy studies are underway to explore the potential of CT3021 as a best-in-class adenosine receptor antagonist immunotherapy for the treatment of CD73 positive and A1 receptor positive solid tumors.

Citation Format: Sandong Han, Nam Hee Kim, Hongmei He, Zhi Liang Chu. Discovery of CT3021, a novel potent adenosine A2a/A2b/A1 receptor triple antagonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB166.
Abstract LB175: Discovery of HP567, a highly potent, brain-penetrating, and H1047R-selective PI3Kα inhibitor for the treatment of tumors bearing H1047R mutation
Authors: Li Jing , Fan Lei , Liu Chengcheng , Luo Yao , Chu Xiaohui , Yu Hua , Wang Fei , Li Xinghai
Published: April 2024

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT) is one of the most altered pathways in human cancer and its hyperactivation promotes tumor growth and survival. H1047R increases kinase activity and is the most common PI3Kα mutation with a mutation rate of 7.8% in all cancers, and 21%, 5% and 3% in breast cancer, endometrium, and ovarian cancer, respectively. Alpelisib is an FDA approved PI3Kα inhibitor targeting both wild-type (WT) and mutant PI3Kα, yet its clinical benefit is limited by the toxicities including hyperglycemia and rash (which are considered on target effects of WT- PI3Kα inhibition). Here, we report an allosteric and brain-penetrating PI3Kα inhibitor, HP567 that is 14-fold selective for PI3Kα H1047R over PI3Kα WT and is 80-fold selective over other PI3K isoforms. HP567 strongly inhibits proliferation and p-AKT (S473) in H1047R mutant cell lines with an average IC50 of 138 nM and 8 nM, respectively, and has no activity against PI3Kα WT cell lines. HP567 strongly inhibits growth of tumors bearing H1047R in multiple CDX models including breast cancers (MDA-MB-453, T47D, and CAL-148), ovarian cancer (SK-OV-3), tongue squamous cell carcinoma (CAL-33), and a brain-metastatic breast cancer (MDA-MB-453), without causing hyperglycemia or increases in plasma insulin levels. In conclusion, HP567 is a novel, potent, and brain-penetrating PI3Kα H1047R selective inhibitor. The pre-clinical data supports the clinical development of HP567 for the treatment of tumors bearing PI3Kα H1047R mutations. Structure of HP567 will not be disclosed.

Citation Format: Jing Li, Lei Fan, Chengcheng Liu, Yao Luo, Xiaohui Chu, Hua Yu, Fei Wang, Xinghai Li. Discovery of HP567, a highly potent, brain-penetrating, and H1047R-selective PI3Kα inhibitor for the treatment of tumors bearing H1047R mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB175.
Abstract LB179: Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer
Authors: Du Wu , Tu Zhilin , Qin Dekun , Li Haibo , Duan Jingyi , Liu Shijuan , Zhang Meng , Nie Zhenyan , Yuan Zhihui , Li Jing , Li Xinghai
Published: April 2024

Breast cancer remains an unmet medical need. It has become the most occurring and deadliest cancer for women globally. Estrogen receptor (ER) is expressed in 75% of breast cancers and has the key role in tumorigenesis and progression of ER+ breast cancers. Endocrine treatments that target ER are the mainstay therapies for the ER+ breast cancers, yet drug resistance unavoidably develops due to mutations in the ER gene. The ER-targeting proteolysis targeting chimera (PROTAC) degrader is an emerging new modality that interrupts the ER signaling through degradation of ER and offers unprecedented potential for solving the endocrine resistance. We have discovered HP568, an ER-targeting PROTAC that is highly potent against both the wild-type ER and ER mutants. HP568 has a favorable ADME profile that is superior to known competitor ER-targeting PROTAC. In the head-to-head comparison efficacy studies, HP568 has demonstrated the dose-dependent and superior efficacy that is well consistent with the drug exposure profile and PD biomarkers. HP568 also shows a synergetic effect in combination with a CDK4/6 inhibitor. HP568 is clean in the secondary pharmacology profiling, and well tolerated in animal tox studies. HP568 is under the preclinical development and has the potential to be the best-in-class ER-targeting degrader. HP568 structure will not be disclosed.

Citation Format: Wu Du, Zhilin Tu, Dekun Qin, Haibo Li, Jingyi Duan, Shijuan Liu, Meng Zhang, Zhenyan Nie, Zhihui Yuan, Jing Li, Xinghai Li. Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB179.
Abstract LB212: Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis
Authors: Serresi Michela , Kertalli Sonia , Dramaretska Yuliia , Schmitt Matthias Jürgen , Naumann Heike , Zschummel Maria , Gargiulo Gaetano
Published: April 2024

Metastasis is the endpoint of tumorigenesis and is generally diagnosed at an untreatable stage. The molecular mechanisms underlying metastasis and biomarkers for early intervention are largely unknown. Here, combining a mouse model of aggressive Kras-driven non-small-cell lung cancer with in vivo fate mapping and CRISPR activation screens, we show that transcriptional amplification of oncogenic Kras promotes orthotopic lung cancer lesions growth as well as oligoclonal and polyclonal metastasis to distal organs. Mild Kras transcriptional up-regulation by CRISPRa is sufficient to fuel competitive advantage in vitro and in vivo. Parallel CRISPR activation and transcriptome sequencing show that KrasG12D amplification cooperates with sterile inflammation to drive tumor progression and with the TGFß pathway to promote metastasis. Chromatin profiling of Kras-amplifying cells uncovers transcriptional regulators potentially collaborating with oncogenic Kras to drive lung cancer and metastasis in vivo. Transcriptional modulation of KRAS dosage in mouse cell and pharmacological inhibition in human PDXs affect cell stress and differentiation programs. These observations are corroborated by bulk and single-cell RNA-seq analysis in patients. Collectively, our data on a model oncogene advance our current understanding of how KRAS drives tumor evolution, with implications for prognosis and treatment of patients.

Citation Format: Michela Serresi, Sonia Kertalli, Yuliia Dramaretska, Matthias Jürgen Schmitt, Heike Naumann, Maria Zschummel, Gaetano Gargiulo. Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB212.
Abstract LB319: Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth
Authors: Zhang Baotong , Liu Mingcheng , Mai Fengyi , Xia Siyuan , Dong Jin-Tang
Published: April 2024

Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in the United States. PTEN deficiency is prevalent in patients with prostate cancer. As a tumor suppressor, PTEN is mutated in approximately 20% of primary prostate cancers, and up to 50% of metastatic castration resistant prostate cancer. PTEN inactivation results in high-grade adenocarcinoma with a long latency. The limited tumor progression induced by PTEN deficiency suggests that additional molecular events are activated to constrain tumor progression, and second hits are required. Understanding these secondary genetic hits will provide the rationale for combined therapies in prostate cancer treatment. In this study, we employed a unique genetically knockin mouse model and found that PTEN deficiency induces a KLF5 K369 acetylation-dependent barrier that attenuates FGFR1 signaling and constrains prostate tumor growth. More importantly, we discovered novel microenvironmental crosstalk between prostate cancer cells and cancer associated fibroblasts (CAFs). As suggested by RNA-seq and bioinformatic analyses and further validated by molecular and cellular experiments, we found that interruption of KLF5 acetylation in cancer cells stimulates CAFs to release FGF9 via TNF-α, and FGF9 activating FGFR1 signaling in cancer cells. In addition to this paracrine crosstalk, deacetylated KLF5 induces CX3CR1 and facilitates FGFR1 activation. Our findings provide a proof of concept for posttranslational modifications as essential molecular events induced by PTEN inactivation to stall prostate cancer progression and demonstrate KLF5 acetylation as a key component in a negative feedback loop by which FGFR1 was suppressed by AKT activation. This study reveals a paracrine reciprocal communication between cancer cells and fibroblasts and provides a clinical rationale for combined therapies using FGFR1 inhibitors (or CX3CR1 inhibitors) and p-AKT inhibitors in PTEN-deficient prostate cancer.

Citation Format: Baotong Zhang, Mingcheng Liu, Fengyi Mai, Siyuan Xia, Jin-Tang Dong. Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB319.
Abstract LB339: Transient EZH2 suppression by tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy
Authors: Hou Yingqin , Wu Peng
Published: April 2024

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T cell differentiation, proliferation and function. Previous studies demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and expansion upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we demonstrate that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delays their dysfunctional progression and preserves T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetostat induces T-cell epigenetic reprogramming and increases the expression of the self-renewal T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induce poor tumor control, whereas T cells pretreated with tazemetostat exhibited superior anti-tumor immunity, especially when used in combination with anti-PD-1 blockade after adoptive transfer. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T cell immunotherapy.

Citation Format: Yingqin Hou, Peng Wu. Transient EZH2 suppression by tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB339.