bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis
Authors: Gudd Cathrin L C , Mitchell Eoin , Atkinson Stephen R , Mawhin Marie-Anne , Turajlic Samra , Larkin James , Thursz Mark R , Goldin Robert D , Powell Nick , Antoniades Charalambos G , Woollard Kevin J , Possamai Lucia A , Triantafyllou Evangelos
Published: April 2024

Background

Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology.

Methods

C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) (“CPI”) or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements. In vivoinvestigations of CPI-hepatitis were carried out in Rag2−/−and Ccr2rfp/rfptransgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment.

Results

Co-administration of combination CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B+perforin+CD8+T cells and CCR2+monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF-ΚB) and cytokine/chemokine networks (Ifnγ, Cxcl9, Ccl2/Ccr2) as drivers of CPI-hepatitis. Using this model, we show that CD8+T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent on the presence of CCR2+monocytes. The absence of hepatic monocyte recruitment in Ccr2rfp/rfpmice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis.

Conclusion

This newly established mouse model provides a platform forin vivomechanistic studies of CPI-hepatitis. Using this model, we demonstrate the central role of liver infiltrating CCR2+monocyte interaction with tissue-destructive CD8+T cells in the pathogenesis of CPI-hepatitis and highlight CCR2 inhibition as a novel therapeutic target.
The effects of roller crimping direction for termination of fall sown cereal rye (Secale cereale L.)
Authors: Brackenridge Hayley L. , Tardif François J. , Bosveld Kerry , Nurse Robert E.
Published: April 2024

Consensus around the optimal direction of roller crimping a row-planted cover crop has not been established. Several publications report crimping either parallel or perpendicular to the direction of cover crop planting with little to no justification apart from unpublished observations or hypotheses. This study explicitly compared the effects of roller crimping direction on crimping efficacy, weed suppression, and cash crop yield. At Elora, ON in 2020 and 2021, and Harrow, ON in 2021, a cereal rye ( Secale cereale L.) cover crop was planted in three orientations (north-south vs. east-west vs. no rye control) then terminated with a roller crimper parallel or perpendicular to the direction of planting. A sweet corn ( Zea mays L.) cash crop was planted either north–south or east–west in the same direction as roller crimping. A split plot treatment of weediness (weedy vs. weed-free) was applied. It was found that roller crimping direction did not have a consistent effect on rye mortality or number of upright tillers, nor did it affect weed control. However, total marketable sweet corn fresh weight decreased in perpendicular crimped rye compared to parallel crimping, despite equivalent cob counts. We did not find evidence in this study to suggest that perpendicular roller crimping improves ground cover and therefore weed suppression, contrary to other unpublished observations. Given the effect on sweet corn yield, roller crimping perpendicular to the direction of cover crop planting may not be a suitable practice. Alternative methods for improving cover crop-based weed control should be investigated.
The two-photon exchange experiment at DESY
Authors: Alarcon R. , Beck R. , Bernauer J. C. , Broering M. , Christopher A. , Cline E. W. , Dhital S. , Dongwi B. , Fernando I. , Finger M. , Finger M. , Friščić I. , Gautam T. , Grauvogel G. N. , Hasell D. K. , Hen O. , Horn T. , Ihloff E. , Johnston R. , Kelsey J. , Kohl M. , Kutz T. , Lavrukhin I. , Lee S. , Lorenzon W. , Lunkenheimer S. , Maas F. , Milner R. G. , Moran P. , Nazeer J. , Patel T. , Rathnayake M. , Raymond R. , Redwine R. P. , Schmidt A. , Schneekloth U. , Sokhan D. , Suresh M. , Vidal C. , Yang Z.
Published: April 2024

We propose a new measurement of the ratio of positron-proton to electron-proton elastic scattering at DESY. The purpose is to determine the contributions beyond single-photon exchange, which are essential for the Quantum Electrodynamic (QED) description of the most fundamental process in hadronic physics. By utilizing a 20 cm long liquid hydrogen target in conjunction with the extracted beam from the DESY synchrotron, we can achieve an average luminosity of $$2.12\times 10^{35}$$

2.12
×

10
35

 cm$$^{-2}\cdot $$

-
2

·

s$$^{-1}$$

-
1

 ($$\approx 200$$

≈
200

times the luminosity achieved by OLYMPUS). The proposed two-photon exchange experiment (TPEX) entails a commissioning run at a beam energy of 2 GeV, followed by measurements at 3 GeV, thereby providing new data up to $$Q^2=4.6$$

Q
2

=
4.6

 (GeV/c)$$^2$$

2

(twice the range of current measurements). We present and discuss the proposed experimental setup, run plan, and expectations.
Testing χPT with the masses of the Nambu–Goldstone bosons
Authors: Leutwyler H.
Published: April 2024

The spontaneous breakdown of an approximate symmetry implies that the spectrum of the theory contains approximately massless particles. The hidden symmetry very strongly constrains their masses. A numerical evaluation of these constraints on the lattice would allow a more precise determination of the quark mass ratios [Formula: see text] and thereby reduce some of the uncertainties encountered in precision flavour physics.
Space-time entropy, space of singularities and gravity origin: A case study
Authors: Ben Adda Fayçal
Published: April 2024

A new definition of entropy is introduced using a model that simulates an expanding space-time compatible with the fundamental principle of cosmology. The entropy is obtained by mean of a state function that measures the variation of the space-time normal curvature, from a highly compressed space to a lower compressed space. The defined entropy leads to work out a new understanding of the earliest conditions that last for a period estimated to 380,000 years after the Big Bang. It leads to understand via a short period of inflation the process that generates the uniform distribution of matter and energy at the surface of the last scattering. It involves gravitational singularities in a process of gradual decompression propitious to the incubation of matter recombination, and it allows to trace back gravity origin.
Effects of Adding Sorghum Procyanidins on the Structure, Molecular Interactions, and Thermal Properties of Agar-Glycerol-Gelatin Films
Authors: Mendoza-Wilson Ana María , Balandrán-Quintana René Renato , Azamar-Barrios José Antonio , Cabellos José Luis
Published: April 2024

Films made with blends of agar and gelatin are usually unstable in aqueous environments and susceptible to temperature, so modifying these films with the addition of compatible compounds is necessary to improve their structural stability, properties, and potential uses. This work determined the effects of adding sorghum procyanidins on the structure, molecular interactions and thermal properties of agar-glycerol-gelatin films. Films were prepared by solution cast method and characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and computational methods. Adding sorghum procyanidins to agar-gelatin films plasticized with glycerol produced significant modifications compared to control films. They contributed to the amorphous character and roughness of these films and the film’s microstructure, reducing weight loss and enhancing thermal stability. The predominant interactions among the film components were hydrogen bonds, van der Waals, and [Formula: see text]–[Formula: see text] interactions.
SUSTEM: An Improved Rule-based Sundanese Stemmer
Authors: Setiawan Irwan , Kao Hung-Yu
Published: April 2024

Current Sundanese stemmers either ignore reduplication words or define rules to handle only affixes. There is a significant amount of reduplication words in the Sundanese language. Because of that, it is impossible to achieve superior stemming precision in the Sundanese language without addressing reduplication words. This article presents an improved stemmer for the Sundanese language, which handles affixed and reduplicated words. With a Sundanese root word list, we use a rules-based stemming technique. In our approach, all stems produced by the affixes removal or normalization processes are added to the stem list. Using a stem list can help increase stemmer accuracy by reducing stemming errors caused by affix removal sequence errors or morphological issues. The current Sundanese language stemmer, RBSS, was used as a comparison. Two datasets with 8,218 unique affixed words and reduplication words were evaluated. The results show that our stemmer's strength and accuracy have improved noticeably. The use of stem list and word reduplication rules improved our stemmer's affixed type recognition and allowed us to achieve up to 99.30% accuracy.
Design of Cross-Coupled Bandpass Filters with Flexible Coupling via Half-Mode Substrate-Integrated Waveguide
Authors: Liu Qianwen , Zhu Lei
Published: April 2024

In this article, a simple approach for achievement of flexible coupling is presented based on the half-mode substrate-integrated waveguide (HMSIW). Since both electric and magnetic fields vary along the magnetic wall of the HMSIW, there exists mixed coupling between two adjacent HMSIWs. In this context, only by adjusting the width of the coupling slot at specific regions, both coupling property and strength can be conveniently controlled. Besides, as the coupling slot possesses the merits of simple structure and high flexibility, it is also expected to achieve desired couplings between multimode resonators. For demonstration, three cross-coupled bandpass filters (BPFs) with different kinds of frequency responses are constructed based on the typical cascaded trisection coupling topology by mixing one SIW and two HMSIWs, including two single-band and one dual-band designs. All measured results are highly consistent with the simulated ones, validating that the HMSIW not only has the inherent advantage of smaller size than the conventional SIW counterparts but also possesses unique feature in providing flexible coupling without extra circuit.
Promoted Catalytic Activity of CoSx@MoSx/MoOx Supported on Carbon Papers for Electrocatalytic Hydrogen Evolution Reaction
Authors: Hong Sung Hyun , Tekalgne Mahider Asmare , Ryu Sangwoo , Ahn Sang Hyun , Kim Soo Young
Published: April 2024

Developing cost‐effective and stable materials for the electrocatalysis of hydrogen evolution reaction (HER) remains challenging. In this study, efficient catalysts for HER were synthesized by integrating the cobalt and molybdenum oxides via electrodeposition, followed by subsequent sulfurization of the as‐prepared oxides using chemical vapor deposition (CVD). This methodology allowed the incorporation of both cobalt and molybdenum components into the catalyst in a single step. The as‐synthesized CoSx@MoSx/MoOx‐based catalysts exhibited excellent hydrogen production performance in acidic media owing to the presence of Co‐S and Mo‐S bonds in the hybrid structure. Particularly, CoSx@MoSx/MoOx(90@360) and MoSx@CoOx(180@180) displayed the best HER performances with low overpotentials of 80 mV and 150 mV, respectively. The catalysts were highly stable, with their stability preserved for over 1000 cycles with marginal reduction in overall efficiency. Therefore, these findings suggest the potential of CoSx@MoSx/MoOx and MoSx@CoOx composites as ideal candidates for developing low‐cost catalysts for electrochemical hydrogen production.
Predictive Modeling of Environmental Impact on Drone Datalink Communication System
Authors: Bennageh I. , Mahmoudi H. , Hajjaji H. , Laabousse I. , Hamdouchi A.
Published: April 2024

In this study, we introduce an innovative model for evaluating the impact of environmental factors on drone-to-ground control station datalink communications. Our approach integrates both deterministic and stochastic processes to account for small-scale and large-scale fading effects, encompassing propagation attenuation, the Rician fading model, and Gaussian noise to accurately reflect real-world conditions. The model is implemented on signals transmitted using spread spectrum modulation. Through a comparative analysis of the model’s predictions against actual signals received in three distinct environments, the model’s efficacy in diverse scenarios is affirmed. Error metrics obtained from Monte Carlo simulations are employed to validate the theoretical results against experimental data. The proposed approach is pivotal for predicting the transmission range and understanding the electromagnetic susceptibility of the datalink, offering a substantial contribution to the optimization of remote drone control.
The Variation of Oviposition Preference and Host Susceptibility of the Oriental Fruit Fly (Bactrocera dorsalis Hendel) (Diptera: Tephritidae) on Commercial Mango Varieties
Authors: Wijekoon Chandana Dammika , Ganehiarachchi Mangala , Wegiriya Hemantha , Vidanage Shamen
Published: April 2024

The oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae), is a serious fruit pest in South Asia; however, studies of their oviposition behavior on different host fruits in Sri Lanka are insufficient. Thus, the present study was conducted to determine the oviposition preference and host susceptibility of B. dorsalis on four commercial mango varieties (Karutha kolumban (Kc), Willard (Wld), Vellai kolumban (Vc), and Betti amba (Ba)) under controlled laboratory conditions. The comparative preference and host susceptibility of B. dorsalis to four mango varieties were tested by a series of choice and no‐choice experiments. The preference for the oviposition was evaluated by observations, and the host susceptibility was investigated by incubating the above‐tested fruits separately until the pupation and the emergence of adults. The gravid females of B. dorsalis showed a significantly different host preference and susceptibility among the four mango varieties tested. Among four mango varieties, “Kc” showed a significantly high oviposition preference and pupae and adult emergence of B. dorsalis. Study findings are useful to design control measures for B. dorsalis to prevent their damage to the commercial mango varieties in Sri Lanka.
Abstract CT055: Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M mutation
Authors: Wan Rui , Chau Yi Fung , Zhao Jun , Liu Zhe , Zhao Mingfang , Zhao Yanqiu , Dai Xiumei , Pan Yueyin , Zhang Zhihong , Yao Yu , Yang Kunyu , Wu Lin , Xie Yanyan , Chen Bi , Yang Yixuan , Guo Yongqi , Wang Jie , Duan Jianchun
Published: April 2024

In the multicenter, dose-escalation and dose-expansion phase 1 clinical trial (NCT05767866), we evaluated safety and tolerability of YK-029A in various EGFR mutated non-small-cell lung cancer (NSCLC). We have reported efficacy of YK-029A in untreated NSCLC with EGFR ex20ins mutation[1]. This time we report efficacy of YK-029A in patients with acquired EGFR T790M mutation after failure of first or second generation EGFR tyrosine kinase inhibitors (TKIs).

Method: This dose-escalation and dose-expansion phase 1 trial recruited previously treated NSCLC patients with EGFR T790M mutation or patients with EGFR ex20ins or EGFR rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or EGFR rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. Efficacy of YK-029A in EGFR T790M mutated NSCLC was assessed by the investigators.

Results: A total of 114 patients were recruited into the study. Safety profile of the first 108 patients was reported previously[1]. By the cut-off date on Sep 12, 2023, 38 patients harbored EGFR T790M mutation were included in efficacy analysis. All these patients were previously treated with first or second generation EGFR-TKIs. The objective response rate (ORR; RECIST 1.1) was 65.8% (95%CI: 48.6%-80.4%) and disease control rate (DCR) was 84.2% (95%CI: 68.7%-94.0%). With a median follow-up time of 8.2 months,the median progression free survival (PFS) was 11.0 months (95%CI: 7.75-NR). The median overall survival (OS) was not reached. Among the 8 patients with measurable brain metastases, intracranial ORR was 75% (95%CI: 35.6%-95.6%) .

Conclusions: YK-029A has promising activity in previously treated NSCLC patients harboring EGFR T790M mutation.

Reference[1] DUAN J, WU L, YANG K, et al. Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial [J]. J Thorac Oncol, 2023.

Citation Format: Rui Wan, Yi Fung Chau, Jun Zhao, Zhe Liu, Mingfang Zhao, Yanqiu Zhao, Xiumei Dai, Yueyin Pan, Zhihong Zhang, Yu Yao, Kunyu Yang, Lin Wu, Yanyan Xie, Bi Chen, Yixuan Yang, Yongqi Guo, Jie Wang, Jianchun Duan. Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M 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 CT055.
Abstract CT216: Anti-EGFR in combination with paclitaxel as second-line therapy for gastric cancer with EGFR overexpression
Authors: Koo Dong-Hoe , Kim Jin-Young , Kim Jae-Joon , Oh Sung Y. , Ryu Min-Hee , Zang Dae Y. , Kim Hark K.
Published: April 2024

Background: We and other investigators reported that EGFR gene is amplified in 2-4% of gastric cancer with protein overexpression (Gastroenterology 2017 Aug;153(2):536-549; Cancer Cell 2019 Jan 14; 35:1:111:E10), but EGFR-targeted therapy has not entered into clinic.

Patients and Methods: As a subprotocol of the investigator-initated of umbrella trial, patients with metastatic gastric cancer received weekly anti-EGFR monoclonal antibody (GC-1118 (GC Biopharma), 2.5mg/kg) in combination with paclitaxel 80mg/m2 (D1, D8, D15) every 4 weeks as a second-line therapy, if the gastric cancer tissue sample revealed EGFR protein overexpression (NCT04077255). Projected accrual was 19 based on minimax two-stage design (P1=45%; P0=15%; alpha and beta errors, 0.05 and 0.1, respectively).

Results: Among 19 evaluable patients, 6 patients had objective clinical response (RR, 31.6%). Median progression-free survival was 4.7 months (95% CI, 1.8-5.1). Median overall survival was 7.6 months (95% CI, 4.2-11.1). Predictive biomarkers were explored by post hoc correlative analyses.

Conclusion: EGFR inhibition, in combination with paclitaxel, demonstrated modest activity for gastric cancer refractory to first-line 5-FU/platinum-based chemotherapy. (This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HA22C0056.))

Citation Format: Dong-Hoe Koo, Jin-Young Kim, Jae-Joon Kim, Sung Y. Oh, Min-Hee Ryu, Dae Y. Zang, Hark K. Kim. Anti-EGFR in combination with paclitaxel as second-line therapy for gastric cancer with EGFR overexpression [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 CT216.
Abstract CT264: Improved clinical outcomes in patients received treatment beyond tumor progression with AdAPT-001 +/- a checkpoint inhibitor
Authors: Conley Anthony P. , Reid Tony , Larson Chris , Oronsky Bryan , Caroen Scott , Stirn Meaghan , Burbano Erica , Abrouk Nacer , Roland Christina L. , Williams Jeannie , Kennedy Lucy B.
Published: April 2024

Background AdAPT-001 is an oncolytic adenovirus with a TGF-β trap. Pseudoprogression (PsP) or transient tumor enlargement from intense T cell infiltration was commonly observed with AdAPT-001 in immune competent mouse models. We evaluated progression-free survival (PFS) and overall survival (OS) in 36 treatment-resistant patients (pts) that received AdAPT +/- an ICI on a Phase 2 clinical trial.

Methods RECIST1.1 assessment was performed every 8  weeks. PsP was defined as progressive disease (PD) on RECIST 1.1 with subsequent tumor regression during TBP. The decision to TBP was based on investigator-assessed clinical benefit and the potential for late responses with minimal adverse events. Log rank tests were applied to compare PFS between pts with and without PsP and to compare OS between pts with and without TBP.

Results Median (m) PFS was longer in pts with PsP and TBP (3.7, 95% CI: 1.6 - ) than without it (2.0, 95% CI: 1.8 - 3.7, log-rank test p = 0.97). mOS months was significantly longer in pts with TBP (median not reached) vs. no TBP (7.8, 95% CI: 6.1 - log-rank test p = 0.053).

Conclusion A high frequency of PsP occurred on this Phase 2 study likely from infiltration of treatment-activated immune cells. AdAPT-001 mediated PsP and TBP may serve as markers of prolonged clinical benefit. Further validation in larger numbers of future patients is warranted.

Citation Format: Anthony P. Conley, Tony Reid, Chris Larson, Bryan Oronsky, Scott Caroen, Meaghan Stirn, Erica Burbano, Nacer Abrouk, Christina L. Roland, Jeannie Williams, Lucy B. Kennedy. Improved clinical outcomes in patients received treatment beyond tumor progression with AdAPT-001 +/- a checkpoint inhibitor [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 CT264.
Abstract LB015: Differential expression of deubiquitinating enzymes and its related DNA damage response genes in neuroblastoma heterogeneity
Authors: Vaibhav Vaibhav , Nazeerulla Fahika , Paunesku Tatjana , Tripathi Ekta , Woloschak Gayle , Karyala Prashanthi , Papineni Rao V.
Published: April 2024

SK-N-AS and SK-N-DZ are two cell lines of pediatric solid tumors neuroblastomas well characterized to evaluate heterogeneity between different neuroblastomas and are presumed as models for differences between different neuroblastoma. Using this model system, we recently evaluated if radiation could improve efficacy of radiation therapy and to follow these studies later with animal models to determine decrease of tumor burden. Differences between the N-type and S-type neuroblastoma cell lines SK-N-DZ and SK-N-AS, respectively were observed to be high and their responses to radiation stress were equally heterogeneous. Ubiquitin signaling plays a key role during the DNA damage response in protein recruitment and protein interactions. Deubiquitinating enzymes (DUBs) deconjugate ubiquitin from ubiquitylated substrate proteins to control their activity and stability and are shown to regulate various biological processes. DUBs may play a role in regulating the radiosensitivity of cancer cells by modulating DNA damage response and repair pathways. Determination of specific DUBs that are involved in regulating radiosensitivity in cancer cells will provide opportunity for drug targeting and visa-vis enhance the efficacy of radiation therapy in neuroblastoma cancer treatment. Here, using bioinformatic tools, the differentially regulated DUBs were identified. The relationship between DEGs-DUBs with the genes involved in various DNA repair pathways (NHEJ, HR and Fanconi anemia pathway; KEGG pathway database) are described. We identified 32 DEGs (14 upregulated and 18 downregulated) with these neuroblastoma cell lines. USP22 and USP41 DUBs and its differential expression in these cell lines denotes the importance of such analysis. Especially considering USP22 a potentially biomarker for predicting the outcome of patients with neuroblastoma. These DEG-DUBs were likewise correlated with 91 DNA damage response (DDR) genes belonging to three different pathways (NHEJ, HR and Fanconi anemia pathway). Out of which 44 of the DDR genes showed significant correlation with DEG-DUBs. Further studies are needed to determine the mechanisms underlying the complex relationship of these DUBs and to determine the critical DUBs for drug targeting and to enhance the efficacy of radiation therapy in cancer treatment.

Citation Format: Vaibhav Vaibhav, Fahika Nazeerulla, Tatjana Paunesku, Ekta Tripathi, Gayle Woloschak, Prashanthi Karyala, Rao V. Papineni. Differential expression of deubiquitinating enzymes and its related DNA damage response genes in neuroblastoma heterogeneity [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 LB015.
Abstract LB020: Extracellular vesicle-mediated intrinsic induction of ferroptosis causes reversal of chemoresistance in lung cancer
Authors: Srivastava Akhil , Paramananantham Anjugam , Asfiya Rahmat
Published: April 2024

Introduction: Resistance to chemotherapeutic drugs is the major cause of treatment failures and high mortality in lung cancer(LC). Thus, strategies to overcome chemoresistance is the major thrust area of cancer research. Ciplatin (CDDP) is the first line of chemotherapeutic interventions in lung cancer however, the treatment benefit diminishes due to develop resistance against the drug. Dysregulation of apoptosis is the major reason for developing chemoresistance. Ferroptosis is a recently discovered form of non-apoptotic regulated cell death (RCD) that can overcome the apoptosis mediated resistance. To exploit this our laboratory has developed a novel Extracellular Vesicle (EV)-iron oxide nanoparticle (IONP) hybrid system- 'ExoFeR,' that can induce ferroptosis. Experiments conducted on LC cells and patient derived tumoroids (PDTs) have shown reversal of CDDP resistance after ExoFeR treatment. Our study demonstrates the utility of ferroptosis as alternate treatment intervention for treating chemoresistant LC tumors.

Materials and methods: EVs derived from normal lung fibroblast cells (MRC9) were loaded with IONPs. The complex was characterized by Transmission electron microscopy (TEM), Inductively coupled plasma mass spectrometry (ICP-MS) and through Zeta potential measurements. The induction ferroptosis by ExoFeR was confirmed in Non-Small Cell Lung Cancer (NSCLC) A549 cells and NSCLC PDTs by Prussian blue, FerroOrange, and Mito-FerroGreen staining. Further, ferroptosis markers like GPX4 and SCL7A11/xCT were evaluated to examine the induction of ferroptosis. Finally, A549 cells and resistant NSCLC PDTs were tested for sensitivity to chemo drugs.

Results: Physicochemical characterization indicated the successful formulation of ExoFeR. Reduction in the expression level of SLC7A11/xCT- and GPX4 proteins in ExoFeR-treated NSCLC cells and PDTs suggested induction of ferroptosis which also showed sensitization of chemo drug (cisplatin).

Summary/Conclusion: We report here the synthesis of a novel EV-IONP-based system that can intrinsically induce ferroptosis and overcome chemoresistance by circumventing the conventional apoptosis-based resistance. Our finding is expected to develop a potent cancer treatment strategy for efficiently treating resistant NSCLC tumors.

Citation Format: Akhil Srivastava, Anjugam Paramananantham, Rahmat Asfiya. Extracellular vesicle-mediated intrinsic induction of ferroptosis causes reversal of chemoresistance in lung 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 LB020.
Abstract LB021: BAU-243: A novel BCL-2 inhibitor inducing autophagic cell death in glioblastoma, unveiled through multistep virtual screening, comprehensive in vitro and in vivo animal model evaluation
Authors: Calis Seyma , Dogan Berna , Celebi Asuman , Yapicier Ozlem , Kilic Turker , Turanli Eda Tahir , Avsar Timucin , Durdagi Serdar
Published: April 2024

The excessive expression of antiapoptotic members in the B-cell leukemia/lymphoma-2 (BCL-2) family proteins emerges as a noteworthy oncogenic target in cancer cells. Employing a multistep virtual screening and filtering approach that integrates structure and ligand-based drug design, we aimed to identify novel and potent BCL-2 inhibitors from a sizable small molecule database, comprising over 210,000 compounds. Subsequently, seven selected molecules underwent rigorous biological activity tests in human cancer cell lines and Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assays. Four of these compounds exhibited notable inhibitory effects on cancer cell proliferation and led to an increase in apoptotic cell fractions. Among the identified compounds, BAU-243 displayed a substantial affinity for Bcl-2, demonstrating efficacy in reducing glioblastoma (GBM) cell proliferation, including cancer-initiating cells. Notably, in contrast to the selective Bcl-2 inhibitor ABT-199, BAU-243 induced autophagic cell death in GBM cells. In vivo investigations using orthotopic brain tumor models revealed a significant reduction in tumor growth with BAU-243 compared to both the vehicle group and animals treated with ABT-199. Computational modeling simulations, in concordance with in vitro findings, proposed that BAU-243 activates autophagic cell death by disrupting the Beclin 1:Bcl-2 complex. This positions BAU-243 as a promising small molecule for the treatment of GBM.

Citation Format: Seyma Calis, Berna Dogan, Asuman Celebi, Ozlem Yapicier, Turker Kilic, Eda Tahir Turanli, Timucin Avsar, Serdar Durdagi. BAU-243: A novel BCL-2 inhibitor inducing autophagic cell death in glioblastoma, unveiled through multistep virtual screening, comprehensive in vitro and in vivo animal model evaluation [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 LB021.
Abstract LB035: Targeting cytoplasmic condensates in the stress response of cancer cells
Authors: Hsu Ku-Lung , Ciancone Anthony M. , Seo Kyung W. , Chen Miaomiao , Borne Adam L. , Libby Adam H. , Bai Dina L. , Kleiner Ralph E.
Published: April 2024

RNA-binding proteins (RBPs) constitute a large and diverse class of proteins (>1400 human proteins) that control RNA metabolism and function. RBPs bind sequence and/or structural motifs in single- or double-stranded RNA using RNA-binding domains (RBDs) to assemble ribonucleoprotein (RNP) complexes. RNPs regulate gene expression and non-coding RNA (ncRNA) function by organizing RNA-protein networks affecting the biogenesis, transport, translation, and degradation of bound RNAs. RNPs known as processing-bodies (P-bodies) and stress granules (SGs) form cytoplasmic membraneless condensates to compartmentalize cellular processes that facilitate survival of cancer cells in the tumor microenvironment and mediate resistance to anticancer treatments. The composition and dynamic regulation of RNPs and how these molecular features of RNA granules are regulated to promote cancer cell adaptation and progression remains poorly understood. Perturbing RBPs is a viable path towards RNP pharmacology but small molecules for this ‘undruggable’ class of proteins are currently lacking. Here, we described utilization of sulfonyl-triazoles (SuTEx chemistry) for disruption of cytoplasmic condensate through covalent binding of tyrosines to enable pharmacology of RNP function in cancer cells. A chemoproteomics platform founded on SuTEx chemistry was deployed for chemical biology and therapeutic investigation of P-bodies and SGs. Key findings to be presented include: (i) establishing a SuTEx-enabled screening platform for accessing ligandable tyrosine (Y)/lysine (K) residues in stressed cancer cells, (ii) identification of a set of SuTEx ligands capable of preventing or inducing SG and P-body formation in stressed cells, (iii) Discovery of a SuTEx ligand for the hyper-reactive EDC3 Y475 site for P-body modulation and (iv) validation of G3BP1 Y40 as a ligandable site that can disrupt arsenite-induced SG formation in cells. We will also describe unpublished work on efforts to advance discovery of new condensate modulators using global proteomic methods. Collectively, we describe a tractable means to reveal and ultimately target cancer vulnerabilities by disrupting tumor-specific stress coping mechanisms found in dynamic cellular compartments for therapeutic translation.

Citation Format: Ku-Lung Hsu, Anthony M. Ciancone, Kyung W. Seo, Miaomiao Chen, Adam L. Borne, Adam H. Libby, Dina L. Bai, Ralph E. Kleiner. Targeting cytoplasmic condensates in the stress response of cancer 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 LB035.
Abstract LB062: ADT3_A potential first-in-class Vδ1-engager for in situ activation of Vδ1 γδ T cells and enhanced cytotoxicity towards solid tumors
Authors: Freedman Joshua , Stevens Georgia , Hoong Julie Julie , Tuna Mihirban , Shi Yaoyao , Seidl Kathy J. , Galvin Katherine , Hutton Andrew , Banerjee Antara
Published: April 2024

Gamma delta (γδ) T cells are crucial in stress surveillance for infections and cancer. Studies have shown that tumour-infiltrating γδ T cells are a positive prognostic factor in cancer therapy. While γδ T cells share many characteristics with their αβ T cell counterpart, such as cytotoxic effector functions, they express a distinct TCR that is composed of a γ and a δ chain, belong to the HLA-class-I unrestricted immune cell subset with the ability to discriminate and specifically kill tumor cells via recognition of tumor stress ligands. Clinical trials using Vδ1 γδ T cell therapies have demonstrated promising results in Ph 1 trials, with early signs of favorable efficacy and safety profile.ADT3, is a novel bispecific engager that activates tissue-resident Vδ1+ T cells via (Epidermal Growth Factor Receptor) EGFR crosslinking on tumor cells. VD1 T cells isolated from skin biopsies, when activated, enhance the selective killing of EGFR positive tumor cells through innate mechanisms that recognize stress ligands that are otherwise absent on healthy cells. As a bispecific engager, ADT3 preserves high affinity binding to VD1 TCR through the Fab end of the molecule, and binding to two EGFR binding sites via the modified Fc domain. Crosslinking of VD1 and EGFR+ tumor cells with ADT3, mediates a series of events leading to proliferation of VD1 cells, upregulation of activation markers, CD107a degranulation and secretion of chemokines and cytokines (such as TNFa and IFNg) and tumor kill as determined by its potent cytotoxic activity in a T-cell dependent cellular cytotoxicity assay (TDCC). Apart from direct tumor kill, the secretion of such cytokines and chemokines via ADT3 activation are required for induction of immune orchestration of non-Vδ1 immune cells to enhance tumor kill. Preclinical data supports future clinical entry of ADT3, and IND enabling studies are in progress

Citation Format: Joshua Freedman, Georgia Stevens, Julie Julie Hoong, Mihirban Tuna, Yaoyao Shi, Kathy J. Seidl, Katherine Galvin, Andrew Hutton, Antara Banerjee. ADT3_A potential first-in-class Vδ1-engager for in situ activation of Vδ1 γδ T cells and enhanced cytotoxicity towards solid tumors [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 LB062.
Abstract LB071: Weaponizing CAR T-cells to attack PD-L1 presenting cells in solid tumors
Authors: Qie Yaqing , Garavito Emiliano Sanchez , Ulloa Navas Maria J. , Hundal Tanya , Quinones-Hinojosa Alfredo , Qin Hong , Luo Yan
Published: April 2024

Despite its success in treating blood cancers, chimeric antigen receptor (CAR) T-cell therapy has not yielded anticipated clinical outcomes in patients with solid tumors. This discrepancy is primarily attributed to the lack of dependable antigens and the immunosuppressive nature of the tumor microenvironment (TME). A pivotal evasion mechanism employed by tumor to counter antitumor immunity involves the upregulation of programmed death ligand 1 (PD-L1), which interacts with PD1 on T cells, deactivating effector T cells. A variety of immunosuppressive cells within the TME employ similar mechanisms to inhibit T-cell functions. These findings provide a rationale for targeting PD-L1 in both tumors and the immunosuppressive cells. Using a humanized anti-PD-L1 monoclonal antibody, we engineered a second-generation PD-L1 CAR, namely MC9999. MC9999 CAR T-cells exhibited antigen-specific cytotoxicity in vitro and elicited potent in vivo antitumor effects against PD-L1-expressing MDA-MD-232 breast cancer cells. The effectiveness of MC9999 CAR T-cells was confirmed across three other solid tumor models: non-small cell lung cancer, melanoma and glioblastoma (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting the potential to penetrate the blood-brain barrier. In addition to targeting tumor cells, MC9999 CAR T-cells exhibited cytotoxicity against three immunosuppressive cell models, including HMC3 microglia cells, M2 macrophages, and importantly, primary tumor-associated macrophages (TAMs) isolated from GBM. Furthermore, we engineered patient-derived MC9999 CAR T-cells and demonstrated their effectiveness against two primary tumor cell lines derived from GBM tumors and HMC3 cells. Collectively, these proof-of-principle study findings substantiate the viability of targeting PD-L1 against both tumors and their immunosuppressive microenvironment. This prototype MC9999 CAR lays the groundwork for further development of clinically applicable CAR T-cell therapy against solid tumors.

Citation Format: Yaqing Qie, Emiliano Sanchez Garavito, Maria J. Ulloa Navas, Tanya Hundal, Alfredo Quinones-Hinojosa, Hong Qin, Yan Luo. Weaponizing CAR T-cells to attack PD-L1 presenting cells in solid tumors [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 LB071.