bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Doping Process Route on LiNiO2 Cathode Material Properties
Authors: Dreyer Sören L. , Kurzhals Philipp , Seiffert Svenja B. , Müller Philipp , Kondrakov Aleksandr , Brezesinski Torsten , Janek Jürgen
Published: June 2023

The pursuit of higher energy density in lithium-ion batteries has driven the increase of the nickel content in lithium nickel cobalt manganese oxide cathode active materials (CAMs), ultimately approaching LiNiO2 (LNO). The downside of the high specific capacity of LNO is more severe degradation of the CAM during battery operation. A common approach to increase structural stability is the introduction of dopants. Various dopants are discussed and compared with each other when integrated into the CAM and tested against undoped materials in the literature, but little attention is given to the role of the process route of their introduction. In this work, we demonstrate with a series of nominally equally Zr-doped LNO samples that effects on various physico- and electrochemical properties are due not to the dopant itself, as one would assume in comparison to an undoped sample, but to the process route and the resulting particle morphology. Dopant, concentration and process routes (co-precipitation, impregnation and co-calcination) were chosen based on their significance for industrial application.
Improved Performance of Silicon-Containing Anodes with Organic Solvent-Solubilized Lithium Nitrate
Authors: Rynearson Leah , Jayawardana Chamithri , Yeddala Munaiah , Lucht Brett L.
Published: June 2023

Three different organic solvents (dimethylacetamide (DMAc), dimethylformamide (DMF), and dimethyl sulfoxide (DMSO)) were used to improve the solubility of LiNO3 in a standard carbonate-based electrolyte with lithium difluoro(oxalato)borate (LiDFOB) as the salt. Together, the LiDFOB and organic-solvent solubilized LiNO3 preferentially reduce on the surface of silicon-containing anodes to create an SEI rich in oxalates, nitrate decomposition species, and B-F species. The improved stability of the SEI throughout the first 100 cycles results in silicon and silicon/graphite composite anodes with better capacity retention than observed with standard electrolytes or fluoroethylene carbonate (FEC) containing electrolytes. This study demonstrates the feasibility of the use of non-traditional electrolyte solvents in the improvement and optimization of lithium ion-battery electrolytes.
Deep Dive into Eutectics: On the Origin of Deep and Elevated Eutectics
Authors: Martin James D. , Shipman Angela M.
Published: June 2023

There is growing interest in deep eutectic solvents (DES) for both chemical synthesis and materials applications. However, there is a general lack of understanding regarding what uniquely defines a system as a deep eutectic, and more importantly, what chemical properties determine unique eutectic behavior. In this work, we identify the thermodynamic basis for ideal eutectics relative to assumptions of ideal solutions. We then articulate the new Solvation Shell-Ionic Liquid (SSIL) and -Liquid Solvate (SSLS) model for solutions which identify the chemical/physical factors that create solution non-ideality and afford the ability to accurately calculate liquiduses, and thus the eutectics, of binary systems. The application of these models is demonstrated using diverse families of materials including aqueous salt solutions (ZnCl2, NaCl, KCl, and NH4NO3), aqueous molecular solutions (sucrose and urea), solutions of naphthalene with aromatic (toluene, benzene, toluene, biphenyl and phenanthrene) and non-aromatic (ethanol, butanol, heptane and acetone) solvents, and the choline chloride:urea system for which the term DES was first introduced. The accurate description of the non-ideal enthalpic and entropic terms affords clear definition and prediction of both deep and elevated eutectics in diverse systems.
Dielectric Characterization of Heterogeneous Composites Using Time Domain Spectroscopy and Microwave Test Benches in Microwave Frequency
Authors: Djouada D. , Bouzit N. , Delfouf R. , Chioukh L. , Martinez Jiménez J. P.
Published: June 2023

Dielectric composite materials made of polymers and ferroelectric ceramics have recently emerged as one of the important components for applications involving the generation, transformation, and storage of sustainable energy. Because there is a trade-off between dielectric permittivity, dielectric loss, and dissipation factor, the end use is the energy storage capacity. In the present study, epoxy resin (RE)/barium titanate (BaTiO3) composite samples are prepared using the mixture cast method with new molds. The dielectric properties, such as dielectric permittivity, dielectric loss, electrical modulus, static conductivity and dissipation factors due to the concentration of barium titanate and frequency effect on the composites, are examined using two characterization methods. The objective of this study is to determine the dielectric permittivity of the material using two microwave methods, the first is time domain spectroscopy (TDS) and the second is on the X-band microwave test bench (MTB). Additionally, different empirical mixture laws are used to estimate the dielectric permittivity of our composites. It is found that an increase in filler concentration (BaTiO3) increases the effective dielectric permittivity, which is confirmed with different empirical mixture models. The findings of this research can be used for electrical devices, including sensors, wave absorbers, resonators, and antennas.
Chemerin is resident to vascular tunicas and contributes to vascular tone
Authors: Wabel Emma , Orr Alexis , Flood Emma D. , Thompson Janice M. , Xie Huirong , Demireva Elena Y. , Abolibdeh Bana , Honke Hulbert Darcy , Mullick Adam E. , Garver Hannah , Fink Gregory D. , Kung Theodore A. , Watts Stephanie W.
Published: June 2023

Vascular tunicas synthesizing chemerin is a new finding. Vascular chemerin is independent of hepatic-derived chemerin. Vasculature from both males and females have resident chemerin. Chemerin1 receptor activity supports vascular tone.
Solving the 0/1 Knapsack Problem Using Metaheuristic and Neural Networks for the Virtual Machine Placement Process in Cloud Computing Environment
Authors: Abid Mohamed , El Kafhali Said , Amzil Abdellah , Hanini Mohamed
Published: June 2023

Virtual machine placement (VMP) is carried out during virtual machine migration to choose the best physical computer to host the virtual machines. It is a crucial task in cloud computing. It directly affects data center performance, resource utilization, and power consumption, and it can help cloud providers save money on data center maintenance. To optimize various characteristics that affect data centers, VMs, and their runs, numerous VMP strategies have been developed in the cloud computing environment. This paper aims to compare the accuracy and efficiency of nine distinct strategies for treating the VMP as a knapsack problem. In the numerical analysis, we test out various conditions to determine how well the system works. We first illustrate the rate of convergence for algorithms, then the rate of execution time growth for a given number of virtual machines, and lastly the rate of development of CPU usage rate supplied by the nine methods throughout the three analyzed conditions. The obtained results reveal that the neural network algorithm performs better than the other eight approaches. The model performed well, as shown by its ability to provide near‐optimal solutions to test cases.
Diffractive Theory Study of Twisted Light’s Evolution during Phase-Only OAM Manipulations
Authors: Zhou Zhi-Yuan , Zhu Zhi-Han , Shi Bao-Sen
Published: June 2023

Twisted light, or orbital angular momentum (OAM) carrying beams or photons, is a pillar of structured photonics, a booming subfield of modern optics. The generation and transformation of twisted light, which lie with coupling topological charges into target light’s wavefunctions, are usually performed by phase-only OAM manipulations. The practical twisted lights, however, obtained by this method are actually noneigen modes of free space, leading to an evolution through the diffractive propagation. Here, we present a general theoretical frame for accurately describing this evolution. Based on the theory, the whole diffractive propagation history in a typical OAM-manipulation loop, converting Gaussian light into a twisted one and then reconverting back, is demonstrated via a set of exact analytical solutions. These results provide a powerful tool for analyzing the transverse profiles of twisted light through the diffractive evolution, as a guideline for studying the science of structured light, which would provide guidelines for research studies in nonlinear optics and high-dimensional quantum information technology based on OAM-degree of freedom.
Identifying Bacteria with Public Health Significance from Farmed Nile Tilapia (Oreochromis niloticus), Zambia
Authors: Chitambo Bertha , Munyeme Musso , Hang’ombe Bernard
Published: June 2023

Zambia has seen rapid development in aquaculture, and in recent years, the industry has experienced disease outbreaks where fish have increasingly become a potential contributor to emerging bacterial zoonotic diseases. The aim of this study was to identify bacterial pathogens with zoonotic potential in apparently healthy fish and water from their habitat. A total of sixty-three fish were sampled, and fifty-nine water samples were collected from the habitats of these fish. Bacteria were cultured from the internal organs of fish and water, and these were identified through standard bacteriological methods comprising morphological characterization, Gram-staining, and a panel of biochemical tests. The following bacterial pathogens with zoonotic potential were identified at a farm prevalence of Aeromonas (13.2%), Bacillus (2.1%), Clostridium (2.1%), Escherichia coli (0.7%), Klebsiella (6.9%), Lactococcus (2.1%), Listeria (0.7%), Staphylococcus (18.1%), and Streptococcus (0.7). Other bacteria with varying significance as fish pathogens identified included Acinetobacter (2.1%), Aequorivita (1.4%), Aerococcus (1.4%), Bordetella (2.1%), Carnobacterium (10.4%), Citrobacter (3.5%), Corynebacterium (1.4%), Dermatophilus (1.4%), Enterococcus (2.1%), Flavobacterium (4.2%), Micrococcus (6.9%), Planococcus (1.4%), Proteus (1.4%), Pseudomonas (6.3%), Rhodococcus (1.4%), Shewanella (1.4%), Streptococcus (0.7%), and Vagococcus (0.7%). The current study provides baseline information for future reference and the implementation of public health guidelines with regard to potential zoonotic diseases in fish.
Magnetic Circuit Optimization and Physical Modeling of Giant Magnetostrictive Actuator
Authors: Li Yuesong
Published: June 2023

Due to the excellent performance, giant magnetostrictive actuator is used in the active vibration isolation control system. However, its hysteresis nonlinear dynamic model is too complex for engineering practical applications, so it is necessary to establish an accurate and easy-to-use model. Based on Simulink/Simcape, a magnetic circuit model and a nonlinear dynamic physical model of the giant magnetostrictive actuator are developed. In the optimization of the magnetic circuit, the uniform distribution and the magnetic energy utilization of the giant magnetostrictive actuator are taken as the optimization objective, and the design criteria of the magnetic circuit are given. The hysteresis performance between the current and the magnetization is analyzed by simulating the magnetic circuit model. From the perspective of energy conservation, a linear magnetostrictive model which can reflect the effects of the frequency doubling and preload is established. Finally, the accuracy of the nonlinear dynamic physical model for the giant magnetostrictive actuator is verified by an experiment. The results show that the physical model agrees well with the experiment results not only under the quasistatic operating conditions but also under dynamic operating conditions. The error of the output displacement of the GMA under step response is less than 0.6 μm.
Thermal Modeling of Oxia Planum: Thermophysical Characterization of the Dark Resistant Unit (DRU) in the Germania Lacus
Authors: Formisano M. , Altieri F. , Frigeri A. , De Sanctis M. C. , Federico C. , Magni G. , Ammannito E. , De Angelis S. , Ferrari M.
Published: June 2023

The aim of this work is to characterize, from a thermophysical perspective, the dark resistant unit (DRU) characterizing Germania Lacus in the Oxia Planum Region, providing new insights to constrain the nature of the materials which compose this unit. We investigated the temperature distribution of the DRU by adopting common values of the thermophysical parameters of the basalt and by exploring several values of porosity. As an additional case, we also explore a composition made of pebbles. The numerical model developed here represents a follow-up of the work recently published by Formisano et al. 2021, and it takes into account a large-scale topography of the site and assumes a diurnal temperature profile for the atmosphere rather than a constant value (unlike Formisano et al. 2021). Comparisons with Mars Pathfinder and Viking data as well as numerical models are also reported. The methodology described here could be useful to characterize as well other sites on Mars’ surface with available small-scale topographic data.
Comparison of Modified Manual Acid-Phenol Chloroform Method and Commercial RNA Extraction Kits for Resource Limited Laboratories
Authors: Sakyi Samuel Asamoah , Effah Alfred , Naturinda Emmanuel , Senu Ebenezer , Opoku Stephen , Amoani Benjamin , Agordzo Samuel Kekeli , Mensah Oscar Simon Olympio , Grant James , Abban Elizabeth , Buckman Tonnies Abeku , Kwarteng Alexander , Ephraim Richard K. Dadzie , Danquah Kwabena Owusu
Published: June 2023

Background and Aim. RNA extraction is a commonly used technique in molecular biology. In recent years, commercially available RNA extraction kits have largely replaced conventional approaches. However, these commercial kits are expensive and are not readily available in many resource-constrained institutions and laboratories. This study therefore compared the performance of the conventional acid guanidinium thiocyanate-phenol-chloroform (AGPC) extraction method to QIAamp® Viral RNA Mini Kit (QIAGEN, Cat. No. 52906) and OxGEn RNA Kit (OxGEn Molecular Solutions, GE-009) to build an in-house RNA extraction technique from blood and oral swab samples. Method. In a comparative experimental cross-sectional study, RNA was extracted from oral swabs and blood samples from 25 healthy individuals at the Department of Molecular Medicine, KNUST. RNA was extracted by the manual AGPC extraction method and commercial RNA extraction kits. The quantity (ng/μl) and purities (260/280 nm) of the extracted RNA were measured spectrophotometrically using the IMPLEN NanoPhotometer® N60. The presence of RNA in the extracts was confirmed using 2% agarose gel electrophoresis. Statistical analyses were conducted using R language. Results. The yield of RNA extracted from blood and oral swab samples using modified AGPC was significantly higher compared to the commercial methods (

p

 < 0.0001). However, the purity of RNA extracted by the manual AGPC method from blood was significantly lower than the commercial methods (

p

 < 0.0001). Moreover, the purity from oral swabs using the manual AGPC method was significantly lower compared to QIAamp (

p

 < 0.0001) and the OxGEn kits method (

p

 < 0.001). Conclusion. The modified manual AGPC method has a very high yield of RNA extracts using blood samples, which could serve as an alternate cost-effective method for RNA extraction in resource-limited laboratories; however, its purity may not be suitable for downstream processes. Moreover, the manual AGPC method may not be suitable for extracting RNA from oral swab samples. Future investigation is needed to improve the purity of the manual AGPC RNA extraction method and also confirmation of the obtained results by PCR amplification and RNA purity verification by sequencing.
Fitting the Distribution of Linear Combinations of
t
−
Variables with more than 2 Degrees of Freedom
Authors: Alcaraz López Onel L. , Garcia Fernández Evelio M. , Latva-aho Matti
Published: June 2023

The linear combination of Student’s

t

random variables (RVs) appears in many statistical applications. Unfortunately, the Student’s

t

distribution is not closed under convolution, thus, deriving an exact and general distribution for the linear combination of

K

Student’s

t

RVs is infeasible, which motivates a fitting/approximation approach. Here, we focus on the scenario where the only constraint is that the number of degrees of freedom of each

t
−

RV is greater than two. Notice that since the odd moments/cumulants of the Student’s

t

distribution are zero and the even moments/cumulants do not exist when their order is greater than the number of degrees of freedom, it becomes impossible to use conventional approaches based on moments/cumulants of order one or higher than two. To circumvent this issue, herein we propose fitting such a distribution to that of a scaled Student’s

t

RV by exploiting the second moment together with either the first absolute moment or the characteristic function (CF). For the fitting based on the absolute moment, we depart from the case of the linear combination of

K
=
2

Student’s

t

RVs and then generalize to

K
≥
2

through a simple iterative procedure. Meanwhile, the CF-based fitting is direct, but its accuracy (measured in terms of the Bhattacharyya distance metric) depends on the CF parameter configuration, for which we propose a simple but accurate approach. We numerically show that the CF-based fitting usually outperforms the absolute moment-based fitting and that both the scale and number of degrees of freedom of the fitting distribution increase almost linearly with

K

.
Elevated EVL Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas
Authors: Yu Ming , Carter Kelly T. , Baker Kelsey K. , Redman Mary W. , Wang Ting , Vickers Kathy , Li Christopher I. , Cohen Stacey A. , Krane Mukta , Ose Jennifer , Gigic Biljana , Figueiredo Jane C. , Toriola Adetunji T. , Siegel Erin M. , Shibata David , Schneider Martin , Ulrich Cornelia M. , Dzubinski Lynda A. , Schoen Robert E. , Grady William M.
Published: June 2023

Background:

Individuals with adenomatous colorectal polyps undergo repeated colonoscopy surveillance to identify and remove metachronous adenomas. However, many patients with adenomas do not develop recurrent adenomas. Better methods to evaluate who benefits from increased surveillance are needed. We evaluated the use of altered EVL methylation as a potential biomarker for risk of recurrent adenomas.

Methods:

Patients with ≥1 colonoscopy had EVL methylation (mEVL) measured with an ultra-accurate methylation-specific droplet digital PCR assay on normal colon mucosa. The association between EVL methylation levels and adenoma or colorectal cancer was evaluated using three case/control definitions in three models: unadjusted (model 1), adjusting for baseline characteristics (model 2), and an adjusted model excluding patients with colorectal cancer at baseline (model 3).

Results:

Between 2001 and 2020, 136 patients were included; 74 healthy patients and 62 patients with a history of colorectal cancer. Older age, never smoking, and baseline colorectal cancer were associated with higher levels of mEVL (P ≤ 0.05). Each log base 10 difference in mEVL was associated with an increased risk of adenoma(s) or cancer at/after baseline for model 1 [OR, 2.64; 95% confidence interval (CI), 1.09–6.36], and adenoma(s) or cancer after baseline for models 1 (OR, 2.01; 95% CI, 1.04–3.90) and model 2 (OR, 3.17; 95% CI, 1.30–7.72).

Conclusions:

Our results suggest that EVL methylation level detected in the normal colon mucosa has the potential to be a biomarker for monitoring the risk for recurrent adenomas.

Impact:

These findings support the potential utility of EVL methylation for improving the accuracy for assigning risk for recurrent colorectal adenomas and cancer.
Data from Identification of 2',4',6'-trihydroxyacetophenone as promising cysteine conjugate beta-lyase inhibitor for preventing cisplatin-induced nephrotoxicity
Authors: Sukeda Nao , Fujigaki Hidetsugu , Ando Tatsuya , Ando Honomi , Yamamoto Yasuko , Saito Kuniaki
Published: June 2023

Abstract
Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. However, irrespective of its potent anticancer properties and efficacy, nephrotoxicity is the dose-limiting factor of cisplatin treatment. Cisplatin infiltrates renal tubular cells in the kidneys and is metabolized by cysteine conjugate-beta lyase 1 (CCBL1) to form highly reactive thiol-cisplatin; this may mediate cisplatin's nephrotoxicity. Therefore, CCBL1 inhibition may prevent cisplatin-induced nephrotoxicity. Using a high-throughput screening assay, we identified 2',4',6'-trihydroxyacetophenone (THA) as an inhibitor of CCBL1. THA inhibited human CCBL1 beta-elimination activity in a concentration-dependent manner. We further investigated the preventive effect of THA on cisplatin-induced nephrotoxicity. THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells (LLC-PK1 cells) but had no effect on cisplatin-induced reduction of proliferation in the tumor cell lines (LLC and MDA-MB-231). THA pre-treatment significantly attenuated cisplatin-induced increases in blood urea nitrogen, creatinine, cell damage score, and apoptosis of renal tubular cells in mice in a dose-dependent manner. Furthermore, THA pre-treatment attenuated cisplatin-induced nephrotoxicity without compromising its anti-tumor activities in mice bearing subcutaneous syngeneic LLC tumors. THA could help prevent cisplatin-induced nephrotoxicity and may provide a new strategy for cisplatin-inclusive cancer treatments.
Abstract 1027: Assessment of tumor mutation burden (TMB) based on whole exome sequencing using extracellular vesicles-derived DNA obtained from bronchoalveolar lavage fluid (BALF) in advanced NSCLC patients treated with pembrolizumab
Authors: Kim Heejoung , Hur Jaeyoung , Kim Wan Seop , Kim In Ae , Park Dong Il , Oh In-Jae , Lee Kye Young
Published: June 2023

Background: Although multiple immune checkpoint inhibitors showed improved outcomes in patients with high tumor mutational burden (TMB) as well as high PD-L1 expression, obtaining adequate tumor tissue for various molecular testing including next-generation sequencing (NGS) is not a simple issue in patients with advanced non-small cell lung cancer (NSCLC). We aimed to assess TMB based on whole exome sequencing (WES) using extracellular vesicles (EV)-derived DNA isolated from bronchoalveolar lavage fluid (BALF) and determine the correlation of TMB between BALF and tissue.

Methods: Patients diagnosed with advanced NSCLC and who were treated with pembrolizumab between December 2018 and December 2021 were included in this multicenter translational cohort study. The correlation of TMB between BALF and tissue measured by WES was evaluated by Spearman’s rank correlation coefficient in matched BALF and tissue samples from 62 patients. We analyzed the association of BALF TMB level with progression-free survival (PFS) and response to pembrolizumab.

Results: Of 62 patients, 47 (75.8%) had evaluable tissue TMB and 57 (91.9%) had evaluable BALF TMB. There were no significant differences between BALF and tissue with regards to DNA amounts, estimated library size, mean depth, and uniformity. Median tissue TMB and BALF TMB were 6.02 and 2.16 mut/Mb, respectively. There was a weak positive correlation between tissue TMB and BALF TMB (r=0.23, p < 0.001), whereas BALF TMB found higher correlations with tissue TMB in patients with squamous cell carcinoma (r=0.77, p < 0.001). Neither tissue TMB nor BALF TMB showed significant differences PFS or ORR benefit for treatment with pembrolizumab, however the BALF TMB of patients who had been treated with pembrolizumab for more than 6 months was higher than that of those who did not (p=0.039).

Conclusions: The findings suggest that NGS using BALF EV DNA is feasible for TMB calculation to overcome the matter of small biopsy issue in advanced NSCLC patients, which may play a supplementary serve as a potential biomarker of clinical benefit in patients with NSCLC treated with pembrolizumab.

Citation Format: Heejoung Kim, Jaeyoung Hur, Wan Seop Kim, In Ae Kim, Dong Il Park, In-Jae Oh, Kye Young Lee. Assessment of tumor mutation burden (TMB) based on whole exome sequencing using extracellular vesicles-derived DNA obtained from bronchoalveolar lavage fluid (BALF) in advanced NSCLC patients treated with pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1027.
Abstract 106: Intratumoral heterogeneity of glioblastoma is attributed to precancerous cells derived from neural stem cells
Authors: Lee Jeong Ho , Kim Hyun Jung , Kang Seok-Gu
Published: June 2023

Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. We and other groups have identified mutation-harboring neural stem cells (NSCs) in the subventricular zone (SVZ) as cells-of-origin carrying driver mutations (Lee et al, Nature 2018). However, little is known about the evolutional process by which mutation-harboring NSCs in the SVZ transform into distant cancer cells with a high degree of molecular heterogeneity. Here, using a spontaneous, somatic mouse model that recapitulates human GBM arising from NSCs that carry driver mutations, we show that mutation-harboring NSCs transform into precancerous cells through oligodendrocyte progenitor cell (OPC) lineage specification during tumor evolution. These precancerous cells show dysregulated translation and/or modification of extracellular matrix (ECM) prior to tumor formation. They subsequently give rise to GBMs with intratumoral heterogeneity exhibiting multiple developmental cell states as in human GBM, and also show activation of additional transcriptional programs, including immune evasion, ECM remodeling, epithelial-mesenchymal transition, and proliferation. Importantly, we further identified precancerous cell populations carrying driver mutations, namely gain of chromosome 7 and loss of chromosome 10 in tumor-free SVZ tissues from GBM patients with intratumoral heterogeneity. These human precancerous cells indeed exhibited OPC and neural progenitor cell-like expression patterns similar to those in our spontaneous GBM mouse model. Thus, our results demonstrate that cell-type specification of precancerous cells with oncogenic transcriptional programs underlie evolution of GBM from mutation-harboring NSCs and intratumoral heterogeneity.

Citation Format: Jeong Ho Lee, Hyun Jung Kim, Seok-Gu Kang. Intratumoral heterogeneity of glioblastoma is attributed to precancerous cells derived from neural stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 106.
Abstract 1198: T cell receptor (TCR) landscape of childhood brain tumors
Authors: Raphael Itay , Nisnboym Michal , Raphael Rebecca A. , Uttam Shikhar , Pollack Ian F. , Chikina Maria , Rajasundaram Dhivyaa , Kohanbash Gary
Published: June 2023

T lymphocytes have a unique ability to recognize a vast array of antigens prompt by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) is key to understand MHC-restricted anti-tumor immunity and for developing T cell-centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNA-Seq data from 997 pediatric brain tumor patients and performed a large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the entire spectrum of pediatric brain tumors. We show that the relative ratio between T cell clonal diversity and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis both within and between tumor types. Interestingly, we show that CEI is strongly associated with molecular subgroups of medulloblastoma but not with known genomic features of these subgroups. Investigation of TCR clonotypes recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals 9 TCR clusters which are tumor-type restricted with defined prognoses and HLA dominance. Using computational immunogenomics and machine learning-based investigations of these clusters we identified novel putative HLA-restricted tumor antigens which could bind and activate the clusters’ specific TCRs. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell-centered immunotherapies. These findings have major implications for understanding the interplay between T cell and tumor genomics, and for developing new immunotherapies for children with brain tumors and other cancers.

Citation Format: Itay Raphael, Michal Nisnboym, Rebecca A. Raphael, Shikhar Uttam, Ian F. Pollack, Maria Chikina, Dhivyaa Rajasundaram, Gary Kohanbash. T cell receptor (TCR) landscape of childhood brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1198.
Abstract 141: Interrogating subclonal mechanisms of immune evasion and immunotherapy resistance in melanoma
Authors: Church Isabella , Gruen Charli , Sassano Antonella , Valencia Julio , Wu Emily , Yang Howard , Needle Gabe , Smith Cari , Chin Sung , Ebersole Jessica , Marcelus Christina , Fon Anyen , Liu Huaitian , Day Chi-Ping , Young Howard , Lee Maxwell , Merlino Glenn , Pérez-Guijarro Eva
Published: June 2023

Immune checkpoint blockade (ICB) therapies are the current first-line melanoma treatments within the clinic; however, their specific mechanisms for combatting tumor progression remain unclear and determinants for efficacious and durable responses within patients remain unknown. Intratumor heterogeneity (ITH) provides cancers with significant adaptability, leading to metastatic progression and resistance to treatment, but its complexity often complicates its study. To understand how ITH contributes to ICB response, we derived 24 clonal sublines from single cells of an ICB-sensitive and genetically and phenotypically heterogenous mouse model of melanoma. Genomic and transcriptomic analyses uncovered the diversity of these sublines and their plasticity while in vivo studies demonstrated a wide range of responses to ICB therapy including resistant, partially sensitive, and fully responsive. Distinct responses to anti-CTLA-4 monotherapy compared to combination (anti-CTLA-4 plus anti-PD-L1) therapy were also observed, and further exploration of untreated tumors revealed correlations between highly inflamed and differentiated phenotypes with response to anti-CTLA-4. To better understand changes in plasticity and immune profile throughout the course of treatment, tumors were harvested from the parental cell line prior to treatment and at several timepoints after treatment with anti-CTLA-4 monotherapy. These samples are undergoing high throughput spatial transcriptomics analysis to map the melanoma phenotypes characterized in the clonal sublines with changes in the immune compartment. Furthermore, blood samples were collected to investigate inflammatory profiles of cytokines and chemokines to describe the evolution of the tumor microenvironment throughout the course of immunotherapy. Further studies will allow us to identify predictive and prognostic biomarkers of resistance and relapse upon ICB therapy, respectively. Overall, the 24 clonal sublines serve as a valuable tool to model tumor dynamics associated with ICB efficacy and understand the complex role melanoma plasticity plays in immune evasion mechanisms.

Citation Format: Isabella Church, Charli Gruen, Antonella Sassano, Julio Valencia, Emily Wu, Howard Yang, Gabe Needle, Cari Smith, Sung Chin, Jessica Ebersole, Christina Marcelus, Anyen Fon, Huaitian Liu, Chi-Ping Day, Howard Young, Maxwell Lee, Glenn Merlino, Eva Pérez-Guijarro. Interrogating subclonal mechanisms of immune evasion and immunotherapy resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 141.
Abstract 1439: In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations
Authors: Fischer John , Bouhana Karyn , Chicarelli Mark , Fell Brad , Fulton Jennifer , Guarnieri Anna , Haygood Leyla , Jalluri Ravi , Johnson Amber , Mclean Brent , Mejia Max , Rieger Rob , Robinson John , Rodriguez Mareli , Sullivan Francis , Wang Yang , Winski Shannon , Zhou YeYun
Published: June 2023

Fibroblast growth factor receptor (FGFR) mutations, fusions, and rearrangements have been linked to the pathogenesis of multiple tumor types. FGFR2 alterations have emerged as oncogenic drivers across a variety of tumor types, including cholangiocarcinoma, lung, endometrial, and uterine cancer. Approved FGFR inhibitors have demonstrated responses in patients that harbor FGFR genetic alterations but show reduced activity in patients with gatekeeper and molecular brake mutations. In addition, pan-FGFR inhibitors are associated with dose-limiting hyperphosphatemia linked to the inhibition of FGFR1. To address these issues, a novel series of reversible FGFR2 inhibitors with activity against clinically relevant mutations and selectivity over FGFR1 has been identified. The inhibition of FGFR2 phosphorylation in engineered cell lines demonstrated activity toward wild-type FGFR2, molecular brake mutations N549H/K, and gatekeeper mutations V564I/F/L. Selectivity of these inhibitors against FGFR1 and the broader kinome could lead to fewer dose limiting toxicities compared to approved FGFR inhibitors. Additionally, maintaining potency against molecular brake and gatekeeper mutations may result in significantly improved clinical response. In vivo characterization to be presented includes dose escalating rodent pharmacokinetics (PK), second species PK, and pharmacodynamics (PD) in tumor bearing mice. Most importantly, efficacy in a mouse tumor xenograft model at a dose that does not show elevated plasma phosphorus levels in the rat hyperphosphatemia model will be presented. Herein, the in vitro and in vivo characterization of a representative selective reversible FGFR2 inhibitor is described.

Citation Format: John Fischer, Karyn Bouhana, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, YeYun Zhou. In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1439.
Abstract 1661: Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers
Authors: Miller Andrew T. , Jin Qihui , Plouffe David , Corpuz Manny , Rodrigo Evelyn , Wu Tom Y.-
Published: June 2023

Transforming growth factor beta (TGFβ) signaling has been implicated in many cancers and fibrotic diseases. Recent pharmacological intervention has shown promising activities in preclinical models and early clinical trials. There are over 15 investigational agents targeting this pathway currently in the clinic, but none have been approved. In particular, small molecule TGFβ inhibitors targeting ALK5 (TGFβ type 1 receptor) have been limited by mechanism-based heart valve toxicity to low dose and intermittent dosing regimens. NEX002 is an oral liver-targeted ALK5 inhibitor with low heart exposure for the treatment of liver cancer and other gastrointestinal cancers with liver metastases. The compound was designed following drug design principles from known liver-specific drugs, such as the statins. In animals, NEX002 exerts preferential distribution (pharmacokinetic) and target inhibition (pharmacodynamic) in liver over the heart. NEX002 has demonstrated activity in several intrahepatic and subcutaneous tumor models, and significantly enhanced the durability of anti-tumor efficacy in combination with lenvatinib, a VEGFR inhibitor approved for the treatment of hepatocellular carcinoma. No heart valve toxicity was observed when benchmarked against galunisertib (systemic ALK5 inhibitor) in toxicity studies with repeated daily dosing. These data suggest that our liver-targeted/heart-sparing approach may allow more robust target engagement compared to systemic ALK5 inhibitors through higher dose or more frequent dosing.

Citation Format: Andrew T. Miller, Qihui Jin, David Plouffe, Manny Corpuz, Evelyn Rodrigo, Tom Y.- Wu. Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1661.
Abstract 1715: SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer
Authors: Sale Matthew J. , Mukherjee Neal , Ruzicka Regina , Jacob Robin , Albrecht Christoph , Zanin Teresa , Madensky Tom , Kostyrko Kaja , Schenk Robyn L. , Baum Anke , Gerlach Daniel , Hofmann Marco H. , McCormick Frank
Published: June 2023

SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates RAS signaling. Mutations in SOS1 are found in 3-5% of non-small cell lung cancers (NSCLC), colorectal cancers (CRC) and melanomas. The recent development of novel SOS1 inhibitors, including BI-3406 and BI-1701963, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers. Here we show that the majority of SOS1 mutations observed in patients enhance RAS guanine nucleotide exchange in cells and activate RAS-MAPK signaling. Of the 11 available SOS1-mutant cancer cell lines without RAS co-mutation, 10 were sensitive to SOS1 inhibition in 2D and/or 3D cell culture, while cells with SOS1 and RAS co-mutations were resistant to SOS1 inhibition. Treatment with a SHP2 inhibitor, which is presumed to inhibit the activity of both SOS1 and SOS2, revealed a subset of SOS1-mutant cell lines that were more sensitive to SHP2 inhibition than SOS1 inhibition. This implied that, in certain settings, SOS2 can compensate for the loss of SOS1 activity. Accordingly, these cells exhibited a rebound in RAS signaling after treatment with SOS1i that was dependent on SOS2. SOS2 knock-down further sensitized these cells to SOS1 inhibition, resulting in responses equivalent to SHP2 inhibition. In addition, we show that, as with SOS1, SOS2 is a target for ERK1/2-dependent feedback phosphorylation. Thus, relief of ERK1/2-dependent negative regulation of SOS2, following SOS1 inhibition, likely contributes to receptor tyrosine kinase (RTK)-SOS2 activation that may mediate SOS1 inhibitor resistance in some contexts. In vivo, SOS1i inhibited tumor growth in xenograft models of SOS1-mutant AML and NSCLC. Tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations.

Citation Format: Matthew J. Sale, Neal Mukherjee, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Tom Madensky, Kaja Kostyrko, Robyn L. Schenk, Anke Baum, Daniel Gerlach, Marco H. Hofmann, Frank McCormick. SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1715.
Abstract 1842: The safety assessment and the pharmacodynamics evaluation of therapeutic cytokine in non-human primates
Authors: Li Wei , Xu Yixuan , Zhou Xin , Zhu Dan , Xiao Meng , Zhou Yulin , Yang Zhijie , Li Haodong , Pang Bo , Song Xinghai , Xiao Yan , Shi Wenting , Qian Qian , Gu Qingyang
Published: June 2023

Cytokines are indispensable regulators of innate and adaptive immunity that transfer signals between cells over short distances. Given their abilities to initiate and activate immune responses, cytokines have long been utilized in cancer therapy, whereas there are limitations, short half-life, pleiotropism, functional redundancy, and side effects, slow down the wide application of cytokine therapy. Thus, evaluating the pharmaceutical properties of cytokines or their translated forms, such as supercytokines, immunocytokines, engager cytokines, and synthetic cytokines, in non-human primates shall be a substantial approach to guide and define clinical trial strategies of cytokine-based therapies. In this study, Interleukin-15 (IL-15) is preferably focused due to its potential in proliferating natural killer cells and cytotoxic T lymphocytes by which host’s immunity was boosted to fight against tumor progression. To evaluate the safety and pharmacodynamics of IL-15 in vivo, rhesus macaques were administered intravenously with recombinant human IL-15 (rhIL-15). We revealed that intravenous administration of rhIL-15 to rhesus macaques caused a slightly weight loss and neutropenia, while no other abnormalities were observed during the whole study. Moreover, the level of C-reactive protein (CRP) was found significantly elevated which was consistent with the increased abundance of MCP1, CCL4, and IL-RA chemokines in serum, suggesting that IL-15 treatment induces acute inflammatory response. Furthermore, flow cytometry analysis showed the activation, proliferation and expansion of memory T and NK cells after receiving IL-15. In conclusion, our study deepens the understanding of T and NK cell homeostasis after IL-15 administration in NHPs and may offer critical clinical strategies for human trials.

Citation Format: Wei Li, Yixuan Xu, Xin Zhou, Dan Zhu, Meng Xiao, Yulin Zhou, Zhijie Yang, Haodong Li, Bo Pang, Xinghai Song, Yan Xiao, Wenting Shi, Qian Qian, Qingyang Gu. The safety assessment and the pharmacodynamics evaluation of therapeutic cytokine in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1842.
Abstract 1849: Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2
Authors: Lotz-Jenne Carina , Cren Sylvaine , Joesch Christoph , Ackerknecht Sabine , Brandes Jennifer , Moebs Claire , Hartl Dominik , Hartrampf Felix , Guerry Philippe , Pothier Julien , Chavanton-Arpel Alexia
Published: June 2023

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) catalyze the oxidation of L-Tryptophan (TRP) leading to the formation of immunosuppressive kynurenine (KYN) pathway metabolites. According to TCGA, a substantial fraction of different tumor types expresses both IDO1 and TDO2. In 82 tumor samples (GBM, hepatocellular carcinoma, NSCLC, and ovarian cancer) analyzed for IDO1/TDO2 RNA expression (RNA sequencing) and TRP metabolite content (LC-MS/MS), we found TDO2 highly expressed in hepatocellular carcinoma and to lower levels in NSCLC and ovarian cancer. IDO1 was found to be expressed in NSCLC and ovarian cancer but at higher levels and its expression was correlating with KYN levels. Immunosuppressive properties of KYN and downstream metabolites are mediated through T cell apoptosis and regulatory T cell (Treg) induction. In our hands, KYN at concentrations ≥ 50uM was shown to be immunosuppressive, notably inducing T cell apoptosis. According to our and published data, such high KYN concentrations (≥ 50uM) can be found in a subset of human tumors. As outlined, both IDO1 and TDO2 can contribute to high KYN levels in tumors. Hence, dual IDO1/TDO2 inhibition should be superior in decreasing tumor KYN levels and levering immunosuppression as compared to IDO1 selective inhibition. In this regard, we have generated potent dual IDO1/TDO2 inhibitors inhibiting IDO1 and TDO2 enzyme activity in cellular assays in vitro. To prove the concept of superiority in vivo, we established a dual IDO1/TDO2 expressing human tumor model (LOVO+IFNg) in the mouse and showed that the oral administration of a dual IDO1/TDO2 inhibitor as compared to an IDO1 selective inhibitor showed enhanced KYN/TRP modulation in the tumor. Lead compounds with favorable drug-like properties are currently investigated for pre-clinical development.

Citation Format: Carina Lotz-Jenne, Sylvaine Cren, Christoph Joesch, Sabine Ackerknecht, Jennifer Brandes, Claire Moebs, Dominik Hartl, Felix Hartrampf, Philippe Guerry, Julien Pothier, Alexia Chavanton-Arpel. Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1849.