Line Model Research Articles

An impedance matching section based on composite right/left‐handed transmission line model in viewpoint of phase shift and noise figure

AbstractIn this paper, a genetic‐based synthesis approach for an impedance matching section based on a composite right‐/left‐handed (CRLH) transmission line model called CRLH transmission line impedance matching section (CRLHTLIMS) in viewpoint of transmission phase shift and noise figure is newly presented. To find the unknown values of right‐/left‐handed inductances and capacitances of a CRLHTLIMS, a type of global optimization algorithm called continuous parameter genetic algorithm is used. The length, transmission phase shift, and noise figure of the CRLHTLIMS are computed by using simple equations. Different examples for a uniform CRLHTLIMS are given. According to the results, this approach is an easy and effective way for the synthesis of transmission line impedance matching sections in viewpoint of transmission phase shift and noise figure.

504 Dihydroxyacetone, a combustion of electronic cigarettes, promotes cardiac-specific injury through metabolic and mitochondrial imbalances

OBJECTIVES/GOALS: Electronic cigarettes have become increasingly popular, with various combustion products generated in the process. Dihydroxyacetone (DHA), a carbohydrate made during the heating process. Exposures may reach high micromolar to low millimolar doses of DHA per day and no studies have been done to understand the effects of DHA in the heart. METHODS/STUDY POPULATION: Here, we examine if DHA contributes to these using rat cardiomyocytes, H9c2 cells, and rat cardiac tissues to DHA evaluating metabolic and mitochondrial effects. Using the cells, we will investigate metabolic and mitochondrial pathways using Seahorse, protein expression changes in nutrient sensing pathways, and understand dose-dependent effects of DHA in the heart. Metabolite pools will also be evaluated to understand the changes promoted by DHA. Oxidative stress as previously observed in other cell models will also be measured. Key findings in the cardiac cells will be investigated in the cardiac tissues exposed to DHA. RESULTS/ANTICIPATED RESULTS: We have previously shown DHA induces oxidative stress, metabolic changes, and mitochondrial dysfunction in various cell line models. Interestingly, these effects are highly cell-type dependent. E-cigarettes are known to have toxic cardiac effects, including arterial stiffness, endothelial dysfunction, vascular injury, and oxidative stress. Changes in glycolytic, fatty acid synthesis, and the citric acid cycle enzymes and metabolites were found in the H9c2 cells. We also observed increased mitochondrial ROS and fuel changes due to DHA exposure. In DHA exposed cardiac tissues, we observed oxidative stress and mitochondrial fission and fusion dynamics altered. DISCUSSION/SIGNIFICANCE: These data suggest further study at physiologically relevant doses is warranted to understand how DHA inhaled impacts the long-term health of vapers. As well as the regulation of DHA in e-cigarettes as it has been deemed as safe for topical applications and warned against inhalation.

Immunomodulatory potential of rapamycin-loaded mesoporous silica nanoparticles: pore size-dependent drug loading, release, and in vitro cellular responses.

Rapamycin is a potent immunosuppressive drug that has been recently proposed for a wide range of applications beyond its current clinical use. For some of these proposed applications, encapsulation in nanoparticles is key to ensure therapeutic efficacy and safety. In this work, we evaluate the effect of pore size on mesoporous silica nanoparticles (MSN) as rapamycin nanocarriers. The successful preparation of MSN with 4 different pore sizes was confirmed by dynamic light scattering, zeta potential, transmission electron microscopy and N2 adsorption. In these materials, rapamycin loading was pore size-dependent, with smaller pore MSN exhibiting greater loading capacity. Release studies showed sustained drug release from all MSN types, with larger pore MSN presenting faster release kinetics. In vitro experiments using the murine dendritic cell (DC) line model DC2.4 showed that pore size influenced the biological performance of MSN. MSN with smaller pore sizes presented larger nanoparticle uptake by DC2.4 cells, but were also associated with slightly larger cytotoxicity. Further evaluation of DC2.4 cells incubated with rapamycin-loaded MSN also demonstrated a significant effect of MSN pore size on their immunological response. Notably, the combination of rapamycin-loaded MSN with an inflammatory stimulus (lipopolysaccharide, LPS) led to changes in the expression of DC activation markers (CD40 and CD83) and in the production of the proinflammatory cytokine TNF-α compared to LPS-treated DC without nanoparticles. Smaller-pored MSN induced more substantial reductions in CD40 expression while eliciting increased CD83 expression, indicating potential immunomodulatory effects. These findings highlight the critical role of MSN pore size in modulating rapamycin loading, release kinetics, cellular uptake, and subsequent immunomodulatory responses.

Method for lightning flashover types identification on transmission lines utilizing OPGW optical polarization state signal characteristics

The Optical Fiber Composite Overhead Ground Wire (OPGW) has undergone rapid development and has been extensively applied in the realm of intelligent power system status monitoring. This article conducts research on lightning signal waveform in optical fibers within the context of lightning fault location using the OPGW optical polarization state method. A transmission line model is simulated employing ATP-EMTP to capture electrical characteristics when lightning strikes the OPGW. Subsequently, by employing the Faraday magneto-optical effect principle, electrical signals are transformed into optical polarization states within the internal fibers of OPGW. Using such data, the optical signal propagation characteristics when lightning strikes OPGW are deduced. Finally, a method for discerning between induced lightning and direct lightning strikes through the analysis of time-frequency domain characteristics in OPGW. This method addresses the limitation of traditional OPGW lightning monitoring, which is unable to deduce electrical signals, thus achieving precise identification of lightning-induced transient faults in transmission lines.

Effects of low-frequency voltage on nonlinear standing wave excitation, plasma uniformity, and ion dynamics in dual-frequency asymmetric capacitive discharges

It is known that in very-high-frequency (VHF) capacitively coupled plasmas, the higher harmonics generated by nonlinear sheath motion can enhance the standing wave effect (SWE), which can lead to center-peaked plasma density profiles. In this work, an improved nonlinear electromagnetic model incorporating a transmission line model, an electron momentum balance model, a bulk plasma model, a collisionless nonlinear numerical sheath model, and an ion Monte-Carlo collision (MCC) model is developed to study the effects of low-frequency (LF) voltage VL on the nonlinear standing wave excitation, plasma uniformity, and ion energy and angular distribution functions (IEDFs and IADFs) in dual-frequency (DF) asymmetric capacitive argon discharges at relatively low pressure of 3 Pa. The plasma diffusion in the radial direction and ion dynamics within the LF oscillating sheath are self-consistently considered. The LF voltage VL at 2 MHz varies from 0 to 700 V while the HF voltage VH at 60 MHz is fixed at 100 V. Simulation results indicate that without the addition of an LF source (i.e. VL= 0 V), there are a considerable number of high-order harmonics with short wavelengths, leading to significant SWE and central peak in the radial plasma density profile. Nevertheless, the high-order harmonic excitations tend to be weakened and merely occur around the phase of the full LF sheath collapse due to a shorter characteristic damping time of the surface waves as VL increases. This, combined with increased surface wavelengths of both the driving frequency and the higher harmonics at a higher VL , leads to suppressed standing waves and improved plasma uniformity. Meanwhile, the simulations show that both the low and the high energy peaks of IEDF move towards higher energies, and the energy peak separation width ΔE becomes wider with the increase of VL . The IEDF at the radial center of the powered electrode exhibits a broader ΔE than that at the edge. For the IADF, an increased VL results in more ions incident on the electrode with a smaller deflection angle. Because of a thinner sheath and a higher sheath voltage at the electrode center, the peak value of IADF at the electrode center is greater than that at the edge.

Fourteen undescribed steroidal saponins from Solanum capsicoides leaves and their neuroprotective effects

A total of 14 previously undescribed steroidal saponins named capsicsaponins A-N were isolated from the leaves of Solanum capsicoides, encompassing various types, including cholesterol derivatives and pseudospirostanol saponins. The structures of all compounds were determined through comprehensive analysis of spectroscopic data (1D NMR and 2D NMR), along with physicochemical analysis methods (acid hydrolysis, OR, and UV). Moreover, in the H2O2-induced pheochromocytoma cell line model, compounds 1-14 were screened for their neuroprotective effects on cells. The bioassay results demonstrated compounds 8-14 were able to revive cell viability compared to the positive control edaravone. The damage neuroprotection of the most active compound was further explored.

Revitalizing Oxygen Reduction Reactivity of Composite Oxide Electrodes via Electrochemically Deposited PrOx Nanocatalysts.

Solid oxide fuel cells that operate at intermediate temperatures require efficient catalysts to enhance the inherently poor electrochemical activity of the composite electrodes. Here, a simple and practical electrochemical deposition method is presented for fabricating a PrOx overlayer on lanthanum strontium manganite-yttria-stabilized zirconia (LSM-YSZ) composite electrodes. The method requires less than four minutes for completion and can be carried out under at ambient temperature and pressure. Crucially, the treatment significantly improves the electrode's performance without requiring heat treatment or other supplementary processes. The PrOx-coated LSM-YSZ electrode exhibits an 89% decrease in polarization resistance at 650°C (compared to an untreated electrode), maintaining a tenfold reduction after ≈400h. Transmission line model analysis using impedance spectra confirms how PrOx coating improved the oxygen reduction reaction activity. Further, tests with anode-supported single cells reveal an outstanding peak power density compared to those of other LSM-YSZ-based cathodes (e.g., 418mWcm-2 at 650°C). Furthermore, it is demonstrated that multicomponent coating, such as (Pr,Ce)Ox, can also be obtained with this method. Overall, the observations offer a promising route for the development of high-performance solid oxide fuel cells.

Design of Energy Efficient & Sustainable Buildings for ISRO Data Centers Using E-Quest

Saving energy is the same as producing new energy. Sustainable development has elevated the importance of energy performance and energy efficiency. Energy efficiency is a crucial part of sustainability, which includes all sectors of the economy from agriculture to manufacturing to services to infrastructure, including buildings used for business and research activities. Developing countries face unique difficulties in achieving sustainability because they must balance two phenomena that are diametrically opposed to one another: rapid economic growth and long-term prosperity. Commercial, information technology (IT), real estate development and construction are important economic drivers. Energy is, of course, a crucial consideration in these fields. In this research, we propose a design strategy for improving energy efficiency in an ISRO Data center by using sustainable green building technology [1]. This paper discusses the initiatives of ISRO in this direction. As maximum operation & maintenance cost of the buildings is due to electrical energy, this study shows how to design the most energy efficient institutional buildings for IMGEOS (Integrated Multi mission Ground Segment for Earth Observation satellites) of ISRO, Hyderabad. The research work discuses about the strategies / techniques to be considered since the planning & designing stage of the building infrastructure itself. This research gives the complete details of the materials with their detailed technical specifications and the methodology to be adopted, for achieving the required energy efficiency level in the data centers / similar IT infrastructure buildings. The research work also explains the process of finding & selecting the most energy efficient model by using different combination of green building materials, with respect to the base line model of ASHRAE using the e-Quest building simulation software and the results obtained thereof. Thus, this detailed research study investigates the process of designing the energy efficient data center buildings for ISRO in the context of emerging countries.

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

Model and experimental analysis of influence of selected parameters of hydraulic line on displacement pump pressure pulsations damping

Among practitioners, the prevailing view is that the use of a discharge line made of an elastic hose allows users not only to isolate the pump unit from the rest of the system for transferred vibrations, but also to obtain the passive damping of pressure pulsation generated by the pump flow rate pulsation. The objective of the model and experimental research described in this article was to confirm or disprove the common opinion that a discharge line with an elastic hose is a sufficient element to damp the pressure pulsation caused by the displacement pump. The article presents experimental studies of the influence of various hydraulic lines on pressure pulsation damping. The research was carried out in the time and frequency domains. A mathematical model of a hydraulic long transmission line is also presented and an analysis of the parameters of hydraulic lines affecting the amplification or damping of pump pressure pulsations was carried out.

The intake port of DI-engine type VIKYNO RV165 desinged using 3D-CAE software

The intake manifold profile in a marine diesel engine profoundly influences engine intake performance, which, in turn, significantly impacts the engine's power characteristics and exhaust emissions which leading to marine polution and challenging the marine sustainable development. Improving the performance of the appropriate geometric design of the intake manifold in order to optimize the study time is a key basis. This research aims to build a parametric model for the 3D profile of the VIKYNO RV165-2 engine intake line. By changing the value of parameter variables in the model through SolidWorks software, it is able to design and change the 3D profile design of the intake manifold. The 3D model of the intake line will be parameterized based on the 2D design drawings of this part provided by VIKYNO. The parameter variables used are upper inclination, lower inclination, curvature, intake valve diameter, input cross-section. Many different 3D models of intakes will be created with respect to the values of parameter variables changed by using SolidWorks software. The results of the study provided a parametric model for the 3D profile of the intake tract, linking the parametric variables of the model with Solidwork software as a basis for speeding up this detailed 3D design process. The 3D design of the intake by the parametric model compared to the 3D design of the intake manifold by direct rendering from the 2D drawing has a difference of no more than 2% in volume. This adaptability and precision are crucial for ensuring air intake efficiency for marine engines operating in diverse and challenging marine conditions.From the platform model, the change of input variables is displayed quickly on new designs, in accordance with the standard, and thereby the model is selected for the stage of researching the efficiency of air intake on the engine. Keywords: CAE, Diesel engine, intake port geometry, numerical design.

Evaluation of disassembly line layouts using an integrated fermatean fuzzy decision-making methodology: An application for refrigerator disassembly line

The layout focusing on the physical arrangement of workstations is an important consideration when designing a disassembly line. The layout of a line has a significant impact on its efficiency. The new problem addressed within this study is evaluating the main disassembly line layout types with respect to a thorough hierarchy of evaluation criteria classifying quantitative and qualitative. The addressed problem is modeled as multi-criteria decision-making (MCDM). To this end, a novel methodology that combines Stepwise Weight Assessment Ratio Analysis (SWARA) and Weighted Aggregated Sum Product Assessment (WASPAS) methods under the Fermatean fuzzy environment is proposed for sustainable waste management. Fermatean fuzzy SWARA (FF-SWARA) is used to find out the weight of criteria consisting of disassembly line balancing characteristics, reconfigurability, working conditions, and end-of-life product characteristics. Fermatean fuzzy WASPAS (FF-WASPAS) is used to rank the alternative disassembly line layouts consisting of straight, U-shaped, two-sided, and parallel lines considering the weight of criteria. The multi-objective mixed integer linear programming (MILP) model for the disassembly line balancing problem (DLBP) of each line layout type is integrated into the proposed methodology. This integration reflects the effect of balancing performance measurements such as the number of stations, removing hazardous parts early, removing high demand parts early, and line lead time. Reconfigurability principles, working conditions, and product characteristics that rely on expert opinions are considered under the qualitative criteria. The developed methodology was applied to a refrigerator disassembly line and verified by sensitivity analysis and comparative studies. The results show that the two-sided disassembly line layout is the best option.

IN VITRO STUDIES ON THE ANTI-INFLAMMATORY EFFECTS OF ESSENTIAL OIL OF Rosmarinus officinalis L. IN MACROPHAGE CELLS

The use of plant-based drugs against various human disorders have attained  &#x0D; global interest. Multicomponent essential oils are used to cure inflammation &#x0D; related disorders. The present study was aimed to assess the anti &#x0D; inflammatory potential of essential oil from Rosmarinus officinalis (EO &#x0D; &#x0D; RO) using in vitro model of LPS-activated RAW macrophage cell lines.  &#x0D; &#x0D; EO-RO was hydro-distilled using Clevenger apparatus and evaluated first  &#x0D; for protein denaturation and proteinase inhibitory activities, followed by  &#x0D; assays for cyclooxygenase (COX) and lipoxygenase (LOX) activities in RAW  &#x0D; 264.7 macrophage cell lines. The data was statistically analysed by one-way  &#x0D; analysis of variance. Dose-dependent inhibition was observed in protein  &#x0D; denaturation with 50 µg mL-1 EO-RO exhibiting a maximum inhibition of  &#x0D; 67.77%. Similarly, proteinase inhibitory assay depicted 72.47% inhibition.  &#x0D; The COX and LOX activities showed increased inhibitions in dose-dependent  &#x0D; manner i.e. 25 to 100 µg mL-1 EO-RO displayed 58.72 and 75.33%; 28.58- &#x0D; 40.86% inhibition, respectively.  

Simulating emission line galaxies for the next generation of large-scale structure surveys

ABSTRACT We investigate emission line galaxies across cosmic time by combining the modified L-Galaxies semi-analytical galaxy formation model with the JiuTian cosmological simulation. We improve the tidal disruption model of satellite galaxies in L-Galaxies to address the time dependence problem. We utilize the public code cloudy to compute emission line ratios for a grid of H ii region models. The emission line models assume the same initial mass function as that used to generate the spectral energy distribution of semi-analytical galaxies, ensuring a coherent treatment for modelling the full galaxy spectrum. By incorporating these emission line ratios with galaxy properties, we reproduce observed luminosity functions for H α, H β, [O ii], and [O iii] in the local Universe and at high redshifts. We also find good agreement between model predictions and observations for autocorrelation and cross-correlation functions of [O ii]-selected galaxies, as well as their luminosity dependence. The bias of emission line galaxies depends on both luminosity and redshift. At lower redshifts, it remains constant with increasing luminosity up to around $\sim 10^{42.5}\, {\rm erg\, s^{-1}}$ and then rises steeply for higher luminosities. The transition luminosity increases with redshift and becomes insignificant above z = 1.5. Generally, galaxy bias shows an increasing trend with redshift. However, for luminous galaxies, the bias is higher at low redshifts, as the strong luminosity dependence observed at low redshifts diminishes at higher redshifts. We provide a fitting formula for the bias of emission line galaxies as a function of luminosity and redshift, which can be utilized for large-scale structure studies with future galaxy surveys.

Abstract 1375: Abundance of KLRB1+ (CD161) T cells in anti-PD1 non responders coupled with enhanced tumor cytotoxicity of anti-CD161 (IMT-009) with anti-PD1 makes it a rational target for combination with anti-PD-(L)1 immunotherapy

Abstract Background: Intra-tumoral CD4+ and CD8+ T cells expressing inhibitory receptor CD161 have an effector memory phenotype with high cytotoxic potential. CD161 inhibits T and NK cell function in the presence of its ligand, CLEC2D. This suppression can be recovered by treatment with IMT-009, a first in class anti-CD161 antibody. Single cell transcriptomic analysis of anti-PD1 refractory microsatellite stable colorectal tumors identified presence of CD161+ CD4+ cytotoxic T cells and CD161+ PD1+ exhausted CD8 T cells suggesting that anti-CD161 treatment may provide benefit in these tumors both as a monotherapy and in combination with anti-PD1. It was also observed that CD161+ CD4/CD8T cells are more abundant in anti-PD1/L1 non responders compared with responders in hepatocellular carcinoma, cutaneous squamous cell carcinoma, clear cell renal carcinoma and breast cancer, providing a rationale for targeting CD161. Using engineered ex-vivo tumor models and dissociated human tumors, we have demonstrated that IMT-009 reverses CLEC2D mediated inhibition and restores primary T cell function. Additionally, co-treatment of IMT-009 with anti-PD1 further enhanced T cell mediated cytotoxicity, providing rationale for studies combining IMT-009 and anti PD1 in the clinic. Methods: Using the Snakemake pipeline developed in house, we processed publicly available scRNAseq data. Cells were clustered by Louvian method followed by cell type annotation by Seurat, and gene expression and gene signature levels per cluster were plotted. For ex-vivo assays, antigen specific CD8 T cells expanded from HLA-A2:01 donors were co-cultured with HLA-A2:01 expressing MDA-MB 231 triple negative breast cancer cell line or Raji Burkitt Lymphoma model with HLA-A2:01 allelic overexpression. Target tumor cells were engineered to express the ligands CLEC2D or PDL1. These cell lines were made to overexpress luciferase for monitoring target cell death using a luminescence readout. Additionally, dissociated tumor cells (DTCs) were cultured in presence of the treatment molecules. Intracellular staining of cytotoxic T cells along with detection of IFNγ, IL-2, TNFα and Granzyme B levels in culture supernatants by MSD/ELISA were used to assess activation profile of tumor infiltrated T cells. Results: Combining anti-PD1 and IMT-009 significantly enhanced cytotoxic benefit compared to individual monotherapy in both Raji and MDA-MB-231 target cell line models. IFNγ levels in supernatants of DTCs treated with this combination were elevated as compared to individual monotherapy. Together with scRNAseq data of increased abundance of KLRB1 (CD161) expressing T cells in anti PD1 non-responder patients, our data provide rationale for testing combination of IMT-009 with anti-PD1 in patients that may not respond to anti PD1 alone. Citation Format: Adwitiya Kar, Tim Nieuwenhuis, Meixue Duan, Siamak Tabrizi, Matthew Huggins, Elizabeth Scanlon, Cynthia Hession, Matthew Bernstein, Michael Ross, Ming Tang, Shruti Malu. Abundance of KLRB1+ (CD161) T cells in anti-PD1 non responders coupled with enhanced tumor cytotoxicity of anti-CD161 (IMT-009) with anti-PD1 makes it a rational target for combination with anti-PD-(L)1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1375.

Abstract 1878: CTPS1: An unexplored vulnerability in breast and ovarian cancer

Abstract Breast and ovarian cancer represent the most common cancer types in women worldwide and are among the top fatal cancers. Despite the use of cytotoxic chemotherapy and targeted agents, recurrence is frequent and survival rates for patients with advanced metastatic disease are dismal. These realities highlight the need to identify novel biomarkers and therapeutic vulnerabilities in such tumors and to develop alternative treatment strategies. We took an unbiased approach to tackle this problem in which we leveraged publically available (DepMap) and in-house generated genome-wide CRISPR screens conducted in over 1000 cancer cell lines. We initially focused on the identification of essential genes that were unique to triple-negative breast cancer (TNBC) cells and whose expression levels were associated with worse patient outcomes. This interrogation revealed six genes (CTPS1, RHOA, PRKRA, RAD9A, HUS1, and RAD1) meeting these initial criteria. The essentiality of these genes was validated using gene-specific siRNAs in a panel of TNBC cells and knockdown of CTPS1 was shown to elicit the most inhibitory effect. CTPS1 depletion resulted in a rapid S-phase cell cycle arrest followed by apoptosis, not only in TNBC cells but also in highly aggressive ovarian cancer cells which share many molecular features with TNBC. CTPS1 converts uridine triphosphate to cytidine triphosphate, forming an essential nucleic acid required for multiple cellular processes. CTPS1 mRNA expression was substantially elevated in tumor vs. normal tissue, for both breast and ovarian cancer. Using over 40 breast and ovarian cancer cell lines, RT-PCR analyses confirmed increased expression of CTPS1 in TNBC and most ovarian cancer cell lines compared to other disease sub-types and “normal” cell line/tissue controls. Interestingly, chemoresistant and PARP inhibitor-resistant models exhibited the highest levels of CTPS1 among all cells analyzed. We subsequently identified and acquired STP938, a first-in-class highly selective CTPS1 inhibitor being developed by Step-Pharma. STP938 was found to elicit potent anti-cancer effects at nM concentrations across many cell line and patient-derived models, in both 2D and 3D culture systems. RNAseq analysis in aggressive cell line models following STP938 treatment or CTPS1 knockdown revealed significant regulation of genes related to DNA replication and the cell cycle pathways suggesting that combinatorial/sequential treatments of STP938 with replication stress/DNA damage response related drugs may be synergistic. STP938 is currently being developed for the treatment of lymphoma, and our findings support the repurposing of STP938 for breast and ovarian cancer, an avenue that we are currently developing. Citation Format: Xiyin Wang, Michael Emch, Lauren Voll, Rebecca Russell, Esther Rodman, Nicole Pearson, Xiaonan Hou, Scott Kaufmann, Saravut Weroha, Philip Beer, John Hawse. CTPS1: An unexplored vulnerability in breast and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1878.

Abstract 4182: Development and evaluation of orthotopically and subcutaneously implanted luciferase-labeled prostate cancer xenograft models for therapeutic assessment

Abstract Introduction: Prostate cancer is the most common male-specific cancer in many western countries including the US and the second most prevalent cause of cancer deaths in American males after lung cancer. The establishment of clinically relevant prostate cancer models is crucial for advancing our understanding of the disease and evaluating potential therapeutic interventions. In this in vivo project we characterize the tumor growth and response to therapy of two luciferase (luc) tagged human prostate cancer xenograft models of metastatic PC3M and non-metastatic DU145 cell lines. These models aim to replicate the variable clinical behavior of prostate cancer to provide valuable pre-clinical platforms to test existing and novel therapies. As a first step, these studies evaluate the effect of standard of care cytotoxic agents paclitaxel and carboplatin and the newer AXL kinase inhibitor bemcentinib alone and in combination on tumor growth kinetics and agent tolerability. Methods: PC3M-luc and DU145-luc cells were implanted subcutaneously on right flank or orthotopically into the prostate of NCG triple immunodeficient mice (Charles River). Subcutaneous tumor progression and treatment responses were monitored using calipers and bioluminescent imaging (BLI), with the capacity to detect developing metastases prior to necropsy. Orthotopic implants were monitored exclusively using BLI. Results: Orthotopic and subcutaneous implants of PC3M-luc demonstrated spontaneous metastasis to lungs and bones, replicating the established behavior of this cell line and effectively modeling metastases observed in prostate cancer patients. In contrast, orthotopic and subcutaneous implants of DU145-luc model did not metastasize. Both PC3M-luc and DU145-luc models independent of the tumor implant placement responded to paclitaxel treatment, with enhanced effects observed when combined with carboplatin. Notably, bemcentinib exhibited no activity as a single agent but showed promise when used in combination with cytotoxic agents. Conclusion: The development of orthotopic and subcutaneous PC3M-luc and DU145-luc prostate cancer models provides a valuable platform for assessing the effectiveness of established and novel therapies. These models mimic various clinical presentations of prostate cancer and promise to offer insights into disease progression and therapeutic strategies. Future studies will focus on durable responses and the assessment of other combination therapies for improved treatment outcomes. Citation Format: Kyle Draheim, Elizabeth Rainbolt, Bincy John, Cara Clouse, Andrew Wong, Brooke Wolff, Justin Avery, Chassidy Hall, Patrick Fadden, Anya Avrutskaya. Development and evaluation of orthotopically and subcutaneously implanted luciferase-labeled prostate cancer xenograft models for therapeutic assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4182.

Abstract 1791: Metabolic rewiring promotes metastatic potential upon glutamine deprivation in STK11 null KRAS-driven lung adenocarcinoma

Abstract Lung adenocarcinoma (LUAD) with concurrent oncogenic KRAS and STK11 loss-of-function mutations define an aggressive subtype characterized, in part, by increased metastasis. Loss of STK11, a tumor suppressor and nutrient sensor, leads to dysregulation of many critical cellular processes, including metabolism. As such, STK11 null cancers are “glutamine addicted” to support proliferative properties and the tumor microenvironment therefore becomes glutamine depleted. We hypothesize that conditions of glutamine stress promote metastatic potential in STK11 null KRAS-driven LUAD due to metabolic rewiring. To test this hypothesis, we utilized a cell culture model of KRAS-driven LUAD cell lines and corresponding STK11 knockout cell lines (∆STK11). Parental and ∆STK11 cells underwent the Seahorse mitochondrial stress test in full and glutamine-deficient media to obtain parameters of mitochondrial respiration at baseline and under conditions reflective of the tumor microenvironment, respectively. At baseline, ∆STK11 cells had a hypermetabolic phenotype associated with enhanced glutamine utilization. Deprivation of glutamine resulted in decreased mitochondrial respiration along with a significant increase in live, detached ∆STK11 cells compared to the parental line. Upon further examination, the detached ∆STK11 cells maintained the ability to re-adhere and proliferate in full media while the detached parental cells did not. Additionally, expression of pro-survival, anti-apoptotic and EMT markers in ∆STK11 cells were increased upon glutamine deprivation. To determine the mechanism(s) underlying this pro-metastatic phenotype, we employed heavy nitrogen labeling which revealed an upregulation of the hexosamine biosynthetic pathway (HBP). The HBP is an offshoot of glycolysis that serves as a central hub to regulate many cancer fitness pathways via O-GlcNAcylation; the addition of a GlcNAc moiety to serine/threonine residues of target proteins. Further assessment of O-GlcNAcylation levels via western and far western blot analysis revealed that parental cells had decreasing HBP flux concordant with decreasing glutamine concentration while ∆STK11 cells, conversely, had enhanced HBP flux upon decreasing glutamine availability. These observations suggest ∆STK11 cells utilize the HBP as a protective shunt under decreased glutamine availability. We are currently characterizing the invasive potential and anchorage-independence of parental and ∆STK11 LUAD cells upon glutamine deprivation. Future studies aim to establish the impact of HBP perturbation, both genetically and pharmacologically, on the described measures of metastatic potential. Overall, this work reveals novel insight into the molecular mechanisms altered downstream of STK11 loss that link glutamine metabolism with metastatic properties in KRAS-driven LUAD. Citation Format: Shannon Prior, Logan Sands, Sean Lenahan, Hailey Sarausky, Melissa Scheiber, David Seward, Paula Deming. Metabolic rewiring promotes metastatic potential upon glutamine deprivation in STK11 null KRAS-driven lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1791.

Abstract 1884: DXC006, Anti-CD56-CPT113 ADC displays favorable anti-tumor efficacy, pharmacokinetic and safety profiles in preclinical studies

Abstract CD56, also known as neural cell adhesion molecule 1 (NCAM1), is a type I plasma membrane glycoprotein involved in cell-cell and cell-matrix adhesion. It is overexpressed in almost all neuroblastomas, 95% of small cell lung cancers and 78% of multiple myeloma patients[1], whereas CD56 is less frequently or less abundantly expressed in normal tissues, making it a potential target for tumor therapy. So far, no CD56-targeting ADCs have entered late-stage clinical trials.DXC006 is an antibody-drug conjugate of a humanized anti-CD56 antibody (DXA006) linked to the topoisomerase I inhibitor CPT113 through a cleavable peptidyl linker and CROSSCONJU™ technology. The pharmacologic activity and mechanism of action of DXC006 were investigated in several human cancer cell lines and xenograft mouse models. Pharmacokinetic and safety profiles were also assessed in rats and cynomolgus monkeys.DXC006 binds specifically to CD56 and internalizes into tumor cells, after intracellular trafficking to lysosome and CPT113 releasing, induces DNA damage. In vitro cell based assays showed that DXC006 remarkably inhibited the cell growth of CD56-positive cell lines of IMR-32 (neuroblastoma), NCI-H526 (small cell lung cancer), and NCI-H929 (multiple myeloma), with IC50 of 0.0046~0.061 nmol/L. Although DXC006 also binds to CD56 expressed NK cells, we found that the inhibition of DXC006 to human NK cells was much less effective, with IC50 higher than 675 nmol/L, which is ten thousand-folds less potent than that of targeted abnormal cells. In vivo, DXC006 demonstrated good durable antitumor activities in three CD56-positive xenograft models of IMR-32, NCI-H526 and NCI-H929 cell lines, with a single dose of 2 mg/Kg, 3 mg/Kg, and 5 mg/Kg, respectively. No animal death or moribund outcome was observed in two months during preclinical safety studies in 150 mg/Kg Q2W dosed rats. For cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) of DXC006 was 20 mg/Kg, in Q2W, four times of administration. PK profiles of both DXC006 the naked antibody DXA006 were comparable in both rats and monkeys. In summary, DXC006 demonstrated strong antitumor activity in various types of cancer cells both in vitro and in vivo, and good pharmacokinetic and safety profiles in rat and monkeys, a potential to be explored in clinical applications. [1] Yang Feng, Yanping Wang, Zhongyu Zhu, et al. Differential killing of CD56-expressing cells by drug-conjugated human antibodies targeting membrane-distal and membrane-proximal nonoverlapping epitopes. mAbs 2016; 799-810. Citation Format: Xiangfei Kong, Huihui Guo, Yong Du, Zhicang Ye, Yongxiang Chen, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Juan Wang, Fang Du, Miaomiao Chen, Qingliang Yang, Robert Y. Zhao. DXC006, Anti-CD56-CPT113 ADC displays favorable anti-tumor efficacy, pharmacokinetic and safety profiles in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1884.

Abstract 3909: PARG inhibitor sensitivity is correlated with accumulation of single strand DNA gaps in preclinical models of ovarian cancer

Abstract Poly (ADP-ribose) glycohydrolase (PARG) is a dePARylating enzyme which promotes DNA repair in conjunction with PARP1 by removal of poly (ADP-ribose) (PAR). Loss or inhibition of PARG results in replication stress and sensitizes cancer cells to DNA damaging agents, suggesting it is a potential therapeutic target for cancer therapy. Indeed, PARG inhibitors are now undergoing clinical development for patients having tumors with homologous recombination deficiency (HRD), such as ovarian and breast cancer patients with BRCA1/2-mutation. In this study, we investigated PARG inhibitor (PARGi)-PDD00017273 activity in preclinical models of ovarian cancer cell lines and primary patient-derived organoids. PARGi exhibited sensitivity in a subset of ovarian cancer cell lines that was distinct from PARP inhibitor sensitivity. Initially, we evaluated a PARGi-sensitive cell line, RMUGS. By gradually increasing the concentration of PARGi, we generated drug resistant cells. PARGi treatment resulted in increased S phase specific PAR, DNA-PARylation, DNA damage, and replication stress in the sensitive cells but not in cells with de novo or acquired resistance. In the sensitive cells, PARGi exposure also increased accumulation of PAR at the replication fork resulting from unligated Okazaki fragment processing. More importantly, PARGi treatment or PARG loss caused accumulation of single strand DNA (ssDNA) gaps in sensitive cells, as detected by the DNA fiber assays combined with S1 nuclease treatment. Regardless of the BRCA-status, the induction of ssDNA gaps in ovarian cancer cells correlated with PARGi sensitivity. Consistent with an increase in ssDNA gaps, PARGi exposure increased p-RPA, a ssDNA surrogate, at the replication fork in sensitive cells. p-RPA sites also colocalized with PAR suggesting that accumulation of PAR occurs at the ssDNA sites, perhaps, leading to the ssDNA gaps. Collectively, these results suggested that toxic accumulation of PAR at the replication fork leads to accumulation of ssDNA gaps due to Okazaki fragment processing defects and ovarian cancer cell killing after PARG inhibition. We further assessed PARG inhibition in patient-derived organoids (PDOs) and patient-derived xenograft (PDX)-derived organoids (PDXOs) as model systems of ovarian cancer. PARGi exhibited monotherapy activity in specific HR-deficient PDOs and PDXOs with BRCA1 or RAD51C mutation and in a HR-proficient PDXO model. Importantly, PARGi exposure resulted in accumulation of ssDNA gaps in organoids of ovarian cancer and this phenotype directly correlated with drug sensitivity. PDOs can therefore be a useful model system for testing PARGi sensitivity. The detection of ssDNA gaps in PDOs may provide a functional biomarker to predict the response to PARG inhibitors in clinical trials. Citation Format: Ramya Ravindranathan, Ozge Somuncu, Yuqing Jiao, Alexandre André B A da Costa, Benjamin P Lamarre, David B Martignetti, Gabriella A Zambrano, Sirisha Mukkavalli, Joyce Liu, Bose Kochupurakkal, Jean-Bernard Lazaro, Kalindi Parmar, Geoffrey I Shapiro, Alan D. D'Andrea. PARG inhibitor sensitivity is correlated with accumulation of single strand DNA gaps in preclinical models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3909.