bluuebunny/crossref_metadata_2025 huggingface dataset:
The Biden Administration’s Indo-Pacific Strategy and its Impacts on Asia-Pacific Order
Authors: Wei Zongyou
Published: April 2023

The Biden administration regards the Indo-Pacific region as the pivot of U.S. global strategy, and China as the primary strategic challenge in the Indo-Pacific region and even the globe. It has implemented forward diplomacy and forward military deployment and promoted Indo-Pacific Economic Framework, attempting to involve allies inside and outside the region in an all-round competition against China and maintain U.S. regional hegemony. Despite the challenges in implementing the Indo-Pacific Strategy, such as U.S. global strategic balance, funding shortage, difficulty in coordinating the allies, and inconsistency of domestic and foreign policy, the Biden administration will continue to promote related policy initiatives, which have and will continue to affect the political, economic, and security order in the Asia-Pacific region and impede the healthy and stable development of U.S.–China relations.
Petrology of the explosive deposits from the April 2021 eruption of La Soufrière volcano, St Vincent: a time-series analysis of microlites
Authors: Frey Holli M. , Manon Matthew R. , Barclay Jenni , Davies Bridie V. , Walters Sydney A. , Cole Paul D. , Christopher Thomas E. , Joseph Erouscilla P.
Published: April 2023

After more than three months of lava dome extrusion, La Soufrière (St Vincent) transitioned to a series of explosive eruptions in April 2021. Here we present a time-series petrologic analysis of the phenocryst and microlite populations during the first
c.
48 h of explosivity to constrain ascent conditions and processes that drove changes in behaviour. Primary eruptive products were crystal-rich (45–50 vol%) basaltic andesites with similar phenocryst phase assemblages and compositions. The change in eruptive style is consistent with overpressurization as a consequence of second boiling from anhydrous microlite crystallization. The microlites display variation between the explosive phases, with two populations: (1) ‘inherited’ − normally zoned high-An plagioclase (>An
70
) + olivine (Fo
62–79
) + clinopyroxene + titanomagnetite, inferred to have crystallized at depths >15 km and high water pressures; (2) ‘juvenile’ − unzoned plagioclase (An
45–65
) + clinopyroxene + orthopyroxene + intermediate pyroxene (Wo
12–38
) + titanomagnetite, inferred to have crystallized upon ascent due to decompression and degassing. Scoria from the first explosions featured extensive groundmass crystallization and a significant ‘inherited’ microlite population. Later explosions had a more abundant ‘juvenile’ microlite population and lower crystallinity, consistent with more rapid ascent from depth, initiated by decompression following initial blasts and destruction of the lava dome.
Hardware/Software Co-Assurance for the Rust Programming Language Applied to Zero Trust Architecture Development
Authors: Hardin David
Published: April 2023

Zero Trust Architecture requirements are of increasing importance in critical systems development. Zero trust tenets hold that no implicit trust be granted to assets based on their physical or network location. Zero Trust development focuses on authentication, authorization, and shrinking implicit trust zones to the most granular level possible, while maintaining availability and minimizing authentication latency. Performant, high-assurance cryptographic primitives are thus central to successfully realizing a Zero Trust Architecture. The Rust programming language has garnered significant interest and use as a modern, type-safe, memory-safe, and potentially formally analyzable programming language. Our interest in Rust particularly stems from its potential as a hardware/software co-assurance language for developing Zero Trust Architectures. We describe a novel environment enabling Rust to be used as a High-Level Synthesis (HLS) language, suitable for secure and performant Zero Trust application development. Many incumbent HLS languages are a subset of C, and inherit many of the well-known security shortcomings of that language. A Rust-based HLS brings a single modern, type-safe, memory-safe, high-assurance development language for both hardware and software. To study the benefits of this approach, we crafted a Rust HLS subset, and developed a frontend to the hardware/software co-assurance toolchain due to Russinoff and colleagues at Arm, used primarily for floating-point hardware formal verification. This allows us to leverage a number of existing hardware/software co-assurance tools with a minimum investment of time and effort. In this paper, we describe our Rust subset, detail our prototype toolchain, and describe the implementation, performance analysis, formal verification and validation of representative Zero Trust algorithms and data structures written in Rust, emphasizing cryptographic primitives and common data structures.
mRNA Regulation by RNA Modifications
Authors: Gilbert Wendy V. , Nachtergaele Sigrid
Published: April 2023

Chemical modifications on mRNA represent a critical layer of gene expression regulation. Research in this area has continued to accelerate over the last decade, as more modifications are being characterized with increasing depth and breadth. mRNA modifications have been demonstrated to influence nearly every step from the early phases of transcript synthesis in the nucleus through to their decay in the cytoplasm, but in many cases, the molecular mechanisms involved in these processes remain mysterious. Here, we highlight recent work that has elucidated the roles of mRNA modifications throughout the mRNA life cycle, describe gaps in our understanding and remaining open questions, and offer some forward-looking perspective on future directions in the field.
Pore-Scale Simulation of Effective Transport Coefficients in the Catalyst Layer of Proton Exchange Membrane Fuel Cells
Authors: He Yusong , Bai Minli , Hao Liang
Published: April 2023

The catalyst layer (CL) of the proton exchange membrane (PEM) fuel cells is reconstructed using the sphere-based simulated annealing (SA) method. By changing carbon phase volume fraction and ionomer loading, the transports of oxygen, water vapor and proton inside the reconstructed CLs are studied using the D3Q7 multiple-relaxation-time (MRT) lattice Boltzmann (LB) method. The results show that Knudsen diffusion has an important role in gas diffusion in CL. The carbon phase distribution influences the gas diffusion process but has little effect on proton conduction. The simulated effective gas diffusivities in CL can fit the experimental data very well if using directly measured porosities, and a fitting formula is proposed to predict the effective diffusivity with porosity. Besides, the simulated effective proton conductivities in CL are in reasonable agreement with the experimental data if considering the ionomer swelling and proton conduction in the condensed water. The influence of the structural randomness of CL during the reconstruction process on the pore-scale simulations is also analyzed. The results show that the relative errors caused by structure randomness for the same structural parameters are not obvious. Therefore, a small number of reconstruction samples are enough to simulate the reasonable transport parameters of CL.
Determination of the Electroactive Surface Area of Supported Ir-Based Oxygen Evolution Catalysts by Impedance Spectroscopy: Observed Anomalies with Respect to Catalyst Loading
Authors: Lončar Anja , Jovanovič Primož , Hodnik Nejc , Gaberšček Miran
Published: April 2023

Recently, several successive papers have proposed a method for determining the actual electrochemically active surface area (ECSA). The method is based on measurements of the impedance response within a suitable potential window and the use of a simple equivalent circuit for the extraction of the so-called adsorption capacity, which is related to the phenomenon of specific adsorption of intermediates in the electrochemical reaction of interest, in particular the oxygen evolution reaction (OER). In this paper, the applicability of the proposed method to the characterization of Ir-based nanostructured electrocatalysts is investigated in more detail. As a model catalyst, we use a commercial sample of Ir nanoparticles dispersed over a high surface area carbon support (Vulcan XC-72). We test the methodology-predicted linear scaling of adsorption capacity with increasing amount (and hence surface area) of catalyst. Systematic experiments are performed with different loadings of the same catalyst. The analysis shows significant deviations from the scaling predicted by the model. To further verify this unexpected result, we extend the analysis to the other model parameters, namely the so-called charge transfer and adsorption resistances and the empirically added double layer capacitance. Interestingly, the analysis shows scaling anomalies only for the first two parameters, which, like the adsorption capacitance, are related to catalytically active sites, but not for the double layer capacitance, which measures the total conductive surface of the studied material. Based on the results, we propose possible reasons for the anomalies and confirm the main hypotheses by impedance simulations using the full physical model - instead of the simplified equivalent circuit.
Potassium Ion Electrolytes Enable High Rate Performance of Li/CFx Primary Batteries
Authors: Li Lei , Zhang Shu , Chen Cheng , Xu Caili , Wang Rui , Wu Mengqiang
Published: April 2023

Combining the cathode and anode materials both possessing the highest theoretical energy density among their category, the Li/CFx primary battery represents advance power sources for versatile applications. However, this technology has long been plagued by poor rate performance and limited the range of its wider applications. Here, the electrochemical behavior of Li/CFx batteries using K-ion electrolyte is systematically investigated and compared with these using Li/Na-ion electrolytes. In comparison with 955 Wh kg−1 (based on the cathode material) and 1104 Wh kg−1 using electrolytes of LiPF6 and NaPF6, respectively, the Li/CFx battery provides superior energy density of 1232 Wh kg−1 at 5C using KPF6, because of the higher discharge voltage and specific capacity. Mechanistic studies reveal that this substantial improvement of the K-ion electrolyte originates from faster ion diffusion coefficient and facile nucleation, in which the initial generation of KF crystals facilitates ion diffusion, as well as changes nucleation and growth of subsequent discharge products. This research provides a new avenue for designing electrolytes to improve electrochemical performance of primary Li metal batteries.
Review—Rational Design of Nitrogen-doped Graphene as Anode Material for Lithium-ion Batteries
Authors: Jauja-Ccana Victor Raúl , La-Torre-Riveros Lyda , Cordova-Huaman Allison , Huayta Giancarlos , Manfredy Luigi , Naupa Alexander , Isaacs Mauricio , La Rosa-Toro Adolfo
Published: April 2023

Nitrogen-doped graphene (N-doped Graphene; includes N-Gr and N-rGO), emerges as an interesting alternative for the development of new anodic materials for the next generation of lithium-ion batteries (LIBs). Due to their characteristics, they can be used both as active materials and in combination with other materials for the formation of composites. As a consequence of the N-Gr synthesis methodology, the physicochemical and structural properties are variable, depending on the number of layers, nitrogen percentage and configuration in the doping product, the presence of oxygenated functional groups, the electroactive area, and the 2D structure or 3D of the material, among others. These properties are closely related to its electrochemical performance, affecting the number of active sites for lithiation, lithium diffusion rate and pathways through a battery system, charge transfer resistance, pseudo capacitive contribution, mechanical stability, among others. In this review, we comprehensively analyze the different characteristics of N-Gr based materials and their relationship with their performance as anodes in LIBs.
Highly Sensitive Electrochemical Detection of ERα Based on AuNPs-SWCNT Composites and Hemin@HKUST-1
Authors: Wang Mengli , Ma Lele , Kang Le , Miao Mingsan , Yang Huaixia
Published: April 2023

Estrogen receptor alpha (ERα) is an important biomarker for breast cancer which is positive in over 75% of breast cancer cases. In this study, an electrochemical biosensor was constructed for sensitive detection of ERα based on the signal amplification of AuNPs-SWCNT nanocomposites and hemin@HKUST-1. AuNPs-SWCNT was served as a conductive substrate, and be used to immobilize the aptamer (Apt) by an Au–S bonding. Then, Apt, ERα and antibody (Ab) formed a sandwich composite structure through specific recognition and immobilized on the electrode. The hemin@HKUST-1 was introduced into the biosensor via an amide bond with Ab and acted as the signal molecule. AuNPs-SWCNT could significantly enhance the conductivity of the electrode and the large specific surface area of HKUST-1 enabled it to load more hemin, and greatly improved the sensitivity of the biosensor. The detection limit (LOD) of the biosensor could reach 27.8 fg·ml−1 after optimization of the conditions, with the current intensity and the logarithm of the ERα concentration exhibited a good linear relationship between 100 fg·ml−1 and 100 ng·ml−1. In addition, the biosensor possessed excellent selectivity, stability, reproducibility and Interference immunity. More importantly, it shows great application potential in practical detection.
Corrosion Susceptibility of Passive Films on 1060, 2024, and 5083 Aluminum Alloys: Experimental Study and First-Principles Calculations
Authors: Ji Yuanyuan , Hu Qian , Xia Da-Hai , Luo Jing-Li
Published: April 2023

The corrosion characteristics of passive films on 1060, 2024 and 5083 aluminum alloys formed in citric acid solution are studied in Cl–-containing solutions by combining scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS). The passive film on 1060 pure Al exhibits the best corrosion resistance while the presence of alloying elements (Cu and Mg) in the passive films reduce the corrosion resistance of the passive films on 2024 and 5083 Al alloys. According to first-principles calculations, Cu/Mg doping γ-Al2O3 surfaces are looser and more reactive than pure γ-Al2O3 (110) surface, and Cl adsorption behavior is changed in Cu/Mg doping γ-Al2O3 surfaces. This illuminates the difference of corrosion resistances of 1060, 2024 and 5083 aluminum alloys from the aspects of the passive film structure and interaction of chlorine ions with the passive films.
Human skeletal muscle methylome after low-carbohydrate energy-balanced exercise
Authors: Gorski Piotr P. , Turner Daniel C. , Iraki Juma , Morton James P. , Sharples Adam P. , Areta José L.
Published: April 2023

We identify novel epigenetically regulated genes associated with train-low sleep-low paradigms. Exercise under low-carbohydrate (CHO) energy-balance (high-fat) conditions elicited a more prominent DNA hypomethylation signature 30 minutes postexercise compared with low-CHO energy-deficit (low-fat) conditions. This was enriched within IL6-JAK-STAT signaling, metabolic processes, p53, cell cycle, oxidative phosphorylation, and fatty acid metabolism. Histone deacetylase (HDAC) family members 2, 4, 10, and 11 demonstrated hypomethylation, with HDAC2 and HDAC11 possessing alternative regulation of gene expression in energy balance versus deficit conditions.
Differential role of oxidative stress in synaptic and nonsynaptic in vitro ictogenesis
Authors: Andreasen Mogens , Nedergaard Steen
Published: April 2023

The main findings of the current study are that area CA3 but not area CA1 can support 2-DG-induced seizure activity, that oxidative stress significantly contributes to 2-DG-induced seizure activity in area CA3, and that the impact of oxidative stress differs between synaptic and nonsynaptic epileptiform activity. In in vitro models where ictogenesis depends on synaptic interactions, oxidative stress lowers the seizure threshold, whereas in nonsynaptic models seizure threshold is unchanged or even increased.
Elevated Gaussian-modeled beta power in the cortex characterizes aging, but not Parkinson’s disease
Authors: Karekal Apoorva , Stuart Samuel , Mancini Martina , Swann Nicole C.
Published: April 2023

Altered sensorimotor beta activity has been shown to be a feature in aging and PD. Using a novel approach, we clarify that resting sensorimotor beta power does not distinguish subjects with PD from healthy younger and older controls. However, beta power was higher in older compared with younger controls in central sensorimotor, frontal, and parietal regions. These results provide a clearer picture of sensorimotor beta power, demonstrating that it is elevated in aging but not PD.
Interindividual variability and individual stability of pain- and touch-related neuronal gamma oscillations
Authors: Valentini Elia , Shindy Alina , Witkovsky Viktor , Stankewitz Anne , Schulz Enrico
Published: April 2023

The interpretation of gamma activity in response to noxious and innocuous somatosensory stimuli has sparked controversy. Here, we show that participants’ gamma oscillations measured through electroencephalography vary. Although some participants do not show a distinct gamma response, others exhibit stable and reliable response patterns in terms of time, frequency, and magnitude.
Preparation, Characteristics, and Application of Biopolymer Materials Reinforced with Lignocellulosic Fibres
Authors: Gurupranes S. V. , Rajendran I. , Gokulkumar S. , Aravindh M. , Sathish S. , Elias Uddin Md.
Published: April 2023

Various environmental concerns motivate scientists and researchers to look out for unique new materials in science and technology. In order to address the demand for polymeric materials with partial biodegradability, the usage of lignocellulosic fibre in the polymer matrix has risen. Lignocellulosic fibres are a cheap, easily renewable resource that is readily available in all regions. Cellulosic plant fibres also have a plethora of possibilities for use in polymer reinforcement because of their properties. Many researchers put their effort into developing a natural polymer with better mechanical properties and thermal stability using nanotechnology and the use of natural polymers to make its composites with lignocellulosic fibres. This study provides a review of the biodegradable composite market, processing methods, matrix-reinforcement phases, morphology, and characteristic improvements. In addition, it provides a concise summary of the findings of significant research on natural fibre polymer composites (NFRCs) that have been published. Indeed, a noticeably brief discussion is provided on the significant issues faced during composite extraction as well as the challenges encountered during the machining. Recent developments in the study of lignocellulosic fibre composites or NFRCs have demonstrated their enormous potential as structural elements in vehicles, aerospace structures, buildings, ballistics, soundproofing, and other structures.
The SARS-CoV-2 UTR’s Intrudes Host RBP’s and Modulates Cellular Splicing
Authors: Singh Anjali , Pandey Kush Kumar , Agrawal Shubham Kumar , Srivastava Rupesh K. , Bhattacharyya Sankar , Verma Bhupendra
Published: April 2023

SARS-CoV-2 is a novel coronavirus that causes a potentially fatal respiratory disease known as coronavirus disease (COVID-19) and is responsible for the ongoing pandemic with increasing mortality. Understanding the host-virus interaction involved in SARS-CoV-2 pathophysiology will enhance our understanding of the mechanistic basis of COVID-19 infection. The characterization of post-transcriptional gene regulatory networks, particularly pre-mRNA splicing, and the identification and characterization of host proteins interacting with the 5′ and 3′UTRs of SARS-CoV-2 will improve our understanding of post-transcriptional gene regulation during SARS-CoV-2 pathogenesis. Here, we demonstrate that either SARS-CoV-2 infection or exogenous overexpression of the 5′ and 3’UTRs of the viral genomic RNAs, results in reduced mRNA levels possibly due to modulation of host cell pre-mRNA splicing. Further, we have investigated the potential RNA-binding proteins interacting with the 5′ and 3′UTRs, using in-silico approaches. Our results suggest that 5′ and 3′UTRs indeed interact with many RNA-binding proteins. Our results provide a primer for further investigations into the UTR-mediated regulation of splicing and related molecular mechanisms in host cells.
Evaluation and Optimization of Air Traffic Complexity Based on Resilience Metrics
Authors: Wang Hongyong , Huang Jiawen , Deng Taotao , Song Ziqi
Published: April 2023

With the rapid growth of civil aviation, the increasing expansion of air traffic flow has brought serious challenges to the service capacity of the current airspace system, making the operation of the control sector increasingly complex. The accurate quantification of sector situational complexity is the basis for improving the service capability of airspace systems. The existing research on complexity ignores the resilience of the air traffic system in case of flight change, which cannot fully describe the dynamic characteristics of the air traffic situation. For this reason, a new air traffic complexity evaluation algorithm based on system resilience is proposed. Firstly, an air traffic situation network based on between-flight interaction is established. Then an overall sector complexity index based on network efficiency, average network failure rate, and average network recovery rate is built. Then, the complexity index is verified by analyzing the real radar number of ZSSSAR01 (sector 1 of Shanghai). By establishing a sector complexity optimization model, the complexity of sector air traffic and its volatility can be greatly reduced by changing the departure time of some flights. Finally, by optimizing the complexity of the sector, the workload of controllers is reduced, and the safety and efficiency of air traffic operations are improved.
ANXA1sp Protects against Sepsis-Induced Myocardial Injury by Inhibiting Ferroptosis-Induced Cardiomyocyte Death via SIRT3-Mediated p53 Deacetylation
Authors: Qin Song , Ren Yingcong , Feng Banghai , Wang Xiaoqin , Liu Junya , Zheng Jie , Li Kang , Chen Miao , Chen Tao , Mei Hong , Fu Xiaoyun
Published: April 2023

Sepsis-induced myocardial injury (SIMI), a common complication of sepsis, may cause significant mortality. Ferroptosis, a cell death associated with oxidative stress and inflammation, has been identified to be involved in SIMI. This study sought to investigate the role of ANXA1 small peptide (ANXA1sp) in SIMI pathogenesis. In this study, the mouse cardiomyocytes (H9C2 cells) were stimulated with lipopolysaccharide (LPS) to imitate SIMI in vitro. It was shown that ANXA1sp treatment substantially abated LPS-triggered H9C2 cell death and excessive secretion of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). ANXA1sp pretreatment also reversed the increase of ROS and MDA generation as well as the decrease of SOD and GSH activity in H9C2 cells caused by LPS treatment. In addition, ANXA1sp considerably eliminated LPS-caused H9C2 cell ferroptosis, as revealed by the suppression of iron accumulation and the increase in GPX4 and FTH1 expression. Furthermore, the ameliorative effects of ANXA1sp on LPS-induced H9C2 cell damage could be partially abolished by erastin, a ferroptosis agonist. ANXA1sp enhanced SIRT3 expression in LPS-challenged H9C2 cells, thereby promoting p53 deacetylation. SIRT3 knockdown diminished ANXA1sp-mediated alleviation of cell death, inflammation, oxidative stress, and ferroptosis of LPS-treated H9C2 cells. Our study demonstrated that ANXA1sp is protected against LPS-induced cardiomyocyte damage by inhibiting ferroptosis-induced cell death via SIRT3-dependent p53 deacetylation, suggesting that ANXA1sp may be a potent therapeutic agent for SIMI.
The Impacts and Vulnerabilities for People Living with Spinal Cord Injury and Their Service Systems of the COVID-19 Pandemic in Queensland, Australia
Authors: Hogan Christy , Burridge Letitia , Foster Michele , Kendall Melissa , Pershouse Kiley , Ungerer Greg , Atresh Sridhar , Morris Charles Phillip , Geraghty Timothy
Published: April 2023

As part of a larger study examining the perceived impacts of health system stress in Queensland, Australia, caused by the COVID-19 pandemic, this study explored the experiences and perspectives of a sample of people with spinal cord injury (SCI) and critical stakeholders to identify secondary complications, access concerns, and potential solutions in the context of the pandemic. This study utilised a multimethods qualitative design. Thirty-four people with SCI completed an online survey between August and November 2021, recruited from an online Spinal Life Australia Peer Support Group. Sixteen SCI expert stakeholders, recruited from the Queensland Spinal Cord Injuries Services, consumer support organisations, and funding agencies, participated in one of two expert stakeholder forums in September 2021, focusing on impacts of the pandemic on the services they provided. Survey and forum results were analysed thematically. Results highlighted service disruption wherein people with SCI faced difficulty accessing health and community services (including rehabilitation) and personal supports. Reduced access led to secondary complications in physical health, psychosocial, and occupational domains. Solutions for safeguarding access to care, including action-ready back-up plans, effective technology and training, collaboration of service networks, and forward planning for system disruption, consumables access, staff support, and advocacy are required to best support vulnerable populations and the supporting staff in times of crisis. In conclusion, COVID-19 disrupted access to specialist SCI and mainstream health, rehabilitation, and social care services, resulting in functional decline and physical and psychosocial complications. While people with SCI and their service providers attempted to innovate and solve problems to overcome service access barriers, this is not possible in all situations. Improved planning and preparation for future system disruptions mitigates risks and better protects vulnerable populations and service providers in times of severe system stress.
Dysbiosis—An Etiological Factor for Cardiovascular Diseases and the Therapeutic Benefits of Gut Microflora
Authors: Singh Taranjit , Kaur Gagandeep , Kaur Ashmeen
Published: April 2023

The human gut is colonized by a variety of microorganisms especially bacteria. There are multiple evidences that gut microflora dysbiosis is a novel risk factor for development of various intestine-related diseases such as irritable bowel syndrome and inflammatory bowel disease as well as nonintestinal diseases including obesity, type II diabetes, and cardiovascular diseases. A mutual relationship among the host’s immune system and the metabolites produced by the gut microflora, including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, is present. Alterations in the host-microbial interaction lead to impaired homeostasis and thus contribute towards the activation of several pathways that causes progression of cardiovascular diseases. This review summarizes the role of gut microflora dysbiosis in the development and progression of atherosclerosis, coronary artery disease, and hypertension. Dysbiosis has been implicated in the pathogenesis of atherosclerosis by TLR activation, intracellular Ca2+ release, FXR-induced signalling, and decreased removal of cholesterol from peripheral macrophages, while in hypertension the mechanism involved is prolonged haemodynamic effects of angiotensin-II and oxLDL-induced hypertension. In fact, CVDs are the leading cause of mortality across the globe; thus, targeting the gut microflora in the treatment of these diseases along with the conventional therapy can markedly reduce the cardiovascular disease burden. The gut microbiota-targeted treatment including prebiotics, probiotics, and postbiotics can be therapeutically beneficial. In future, the heart-gut axis can be presented as a novel and clinically relevant area for research.
Data from Mutated HRAS activates YAP1-AXL signaling to drive metastasis of head and neck cancer
Authors: Jagadeeshan Sankar , Prasad Manu , Badarni Mai , Ben Lulu Talal , Liju Vijayasteltar Belsamma. , Mathukkada Sooraj , Saunders Claire , Shnerb Avital Beeri. , Zorea Jonathan , Yegodayev Ksenia M. , Wainer Monica , Vtorov Liza , Allon Irit , Cohen Ofir , Gausdal Gro , Friedmann-Morvinski Dinorah , Cheong Sok Ching , Ho Alan L. , Rosenberg Ari J. , Kessler Linda , Burrows Francis , Kong Dexin , Grandis Jennifer R. , Gutkind J Silvio , Elkabets Moshe
Published: April 2023

Abstract
The survival rate for head and neck cancer (HNC) patients diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts (PDXs), and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also reduced AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.
Supplementary Figures 1-4 and Tables 1-2 from Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas
Authors: King Amanda R. , Corso Christopher D. , Chen Evan M. , Song Eric , Bongiorni Paul , Chen Zhe , Sundaram Ranjini K. , Bindra Ranjit S. , Saltzman W. Mark
Published: April 2023

Supplementary Figure 1. Encapsulation efficiency (drug loading/theoretical drug encapsulated) of candidate drugs into PLA-PEG NPs as a function of their solubility in DMSO; Supplementary Figure 2. PLA-PEG NP in vitro stability and uptake; Supplementary Figure 3. in vitro dose-dependent response of HR (L) and mNHEJ (R) pathway repair in the U2OS reporter assay to treatment with either free drug (red) or drug-NP (green) for each candidate radiosentizier; Supplementary Figure 4. dsDNA repair pathway activity levels in U2OS reporter cells; Supplementary Table 1. Results of Linear Regression Analysis and Correlation testing between drug properties and release properties; Supplementary Table 2. Summary of NP-drug formulations and established criteria for candidate drug-NP formulation selection.
Abstract 3957: Anticancer effect of novel 1,4-benzodiazepine derivatives through tubulin polymerization inhibition
Authors: Srovnalova Alzbeta , Rehulka Jiri , Gurska Sona , Polyshchuk Pavel , Bachinsky Sergey , Dzubak Petr , Hajduch Marian
Published: April 2023

Benzodiazepines are well known as a key scaffold in medicinal chemistry, providing bioactive compounds for a wide variety of biological targets. Among their primary use as anxiolytics and sedatives, the 1,4-benzodiazepine derivatives and their metabolites play a role as antitumor, antithrombotic, antiviral and antimalarial agents. Recent studies revealed the influence of the benzodiazepine derivatives on microtubule assembly or stability with subsequent mitotic failure. These microtubule-targeting effects were evaluated in novel benzodiazepine derivatives. The antiproliferative activities of novel derivatives were tested against a panel of 10 cancer cell lines and 2 non-cancer cell lines. The compounds with IC50<10 µM were further analyzed for the cell cycle. Flow cytometry and fluorescent cell cycle indicator (FUCCI) assays were performed to evaluate the effects of derivatives on the cell cycle phases. The immunofluorescence alpha-tubulin assay and tubulin polymerization assay were accomplished to detect the changes in the mitosis. Implementation of molecular docking revealed the specific binding site of the derivatives. All tested derivatives reveal the G2/M block in the cell cycle and 3 of them were identified as M-phase blockers. The immunofluorescence alpha-tubulin assay detected the disruption of the cellular microtubule network, and the tubulin polymerization assay uncovered the potential of the tested compounds to inhibit tubulin polymerization. Molecular docking confirms that benzodiazepine derivatives fit the colchicine site best and are partially overlaid with the native colchicine binding pose. This suggests that these compounds may adapt to the tubulin binding site in a conformation induced by colchicine The inhibition of tubulin polymerization by novel derivatives is one of their possible mechanisms of action on antiproliferative effect on cancer cell lines. More rigorous studies will be performed further to establish pose stability and explain structure-activity relationships. This work was supported by European Union - Programme EXCELES, ID Project No. LX22NPO5102, the Czech Ministry of Education, Youth and Sports (CZ-OPENSCREEN - LM2018130, EATRIS-CZ - LM2018133), and by the internal grant of Palacky University Olomouc (IGA_LF_2022_033) and European Regional Development Fund - Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868).

Citation Format: Alzbeta Srovnalova, Jiri Rehulka, Sona Gurska, Pavel Polyshchuk, Sergey Bachinsky, Petr Dzubak, Marian Hajduch. Anticancer effect of novel 1,4-benzodiazepine derivatives through tubulin polymerization inhibition. [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 3957.
Abstract 4: A novel humanized mouse model for study of T cells and NK cells in the tumor microenvironment
Authors: Arora Jyoti , Lemke-Miltner Caitlin D. , Weiner George J.
Published: April 2023

Humanized mouse models can be useful for in vivo preclinical evaluation of mechanisms underlying cancer immunotherapy. Most such models involve systemic engraftment of immunocompromised mice with human lymphoid and hematopoietic cells, often using normal donor peripheral blood mononuclear cells (PBMCs), followed by inoculation with human tumor. The ability to control and modify immune cells within the tumor microenvironment (TME), especially human NK cells, is limited in such models. Here, we report the development of a mouse model designed to control the number of human T cells and NK cells in the TME. 18 mice and pre-validated PBMCs were obtained from Charles River. Six groups of 3 mice each were inoculated with Raji lymphoma cells. Group 1 was inoculated with Raji cells only and received no PBMCs. Raji cells were mixed PBMCs for groups 2-4. Group 5 was systemically engrafted with PBMCs 12 days prior to Raji inoculation and Group 6 was systemically engrafted with PBMCs 10 days after Raji inoculation. All mice developed tumors with similar growth characteristics. Serial fine needle aspirates (FNAs) of the resulting tumors were evaluated by flow cytometry. Results of FNAs are summarized below.

Tumors were harvested at the end of experiment, typically 27 days after tumor inoculation, and evaluated by immunohistochemistry. Both T cells and NK cells were evenly distributed within tumors at the time of harvest. We conclude co-injection of tumor and PBMCs results in engraftment of both T cells and NK cells within the TME for up to 27 days, with T cells and NK cells distributed evenly within the tumor. Mixing higher numbers of PBMCs with tumor cells resulted in increased numbers of T cells and NK cells in the TME throughout the experiment. Matrigel did not improve engraftment or persistence of T or NK cells in the TME. We conclude mixing PBMCs with Raji tumor cells prior to tumor inoculation into immunocompromised mice is an effective approach when a humanized model with human T cells and NK cells within the TME is desired.

Group Description % T cells in tumor at 17 days % NK cells in tumor at 17 days 1 No PBMCs 0 0 2 PBMCs mixed with Raji at 10:1 ratio 8.6 1.5 3 PBMCs mixed with Raji at 2:1 ratio 20.3 2.7 4 PBMCs and Raji in matrigel 9.2 0.6 5 PBMCs systemically engrafted 12 days before Raji inoculation 23.2 0.1 6 PBMCs systemically engrafted 10 days after Raji inoculation 19.6 0.2

Citation Format: Jyoti Arora, Caitlin D. Lemke-Miltner, George J. Weiner. A novel humanized mouse model for study of T cells and NK cells in the tumor microenvironment [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 4.
Abstract 4059: Developing an allogeneic iPSC derived macrophage cell therapy for oncology
Authors: Wang Huafeng , Sumi May , Huh Christine , Parviz Fereshteh , Mastroianni Jessica , Healy Jane , Stevens Nicole , Mitchell Leah , Lang Susanne , Kaufman Dan , Hollingsworth Robert , Rodgers David T.
Published: April 2023

The full potential of cell therapy has yet to be realized in solid tumor indications and new approaches are urgently required. Macrophages are innate immune cells that can kill tumor cells and orchestrate the anti-tumor immune response. Macrophage cell therapy is an exciting new approach to treat cancer with the aim to harness the powerful activity of macrophages to reignite the immune system. Patient derived macrophages, however, are difficult to genetically engineer and do not proliferate, which makes generating high-quality cells at clinically relevant scales challenging. To address this, we have developed an induced pluripotent stem cell (iPSC) approach to macrophage cell therapy. These cells can be genetically engineered at the iPSC stage and then differentiated into billions of highly functional iPSC derived macrophages (iMACs). This allogenic cell therapy product can then be cryopreserved and stored for immediate use in the clinic when the patient is ready.

Here we show that iMACs function like normal macrophages. They migrate towards tumor cells, respond to challenges through innate immune receptors, and produce immune recruiting and activating cytokines and chemokines. iMACs also express high levels of antibody receptors and we show that these cells can be directed to kill tumors in vitro and in vivo via antibody dependent cellular phagocytosis. Furthermore, we have conducted a robust screen to develop a novel CAR that is optimized for use in iMACs. These receptors can be engineered into iMACs at the iPSC stage and trigger robust tumor cell killing. In summary, these data highlight the therapeutic potential of iMACs in oncology and support the further development of this technology for clinical use.

Citation Format: Huafeng Wang, May Sumi, Christine Huh, Fereshteh Parviz, Jessica Mastroianni, Jane Healy, Nicole Stevens, Leah Mitchell, Susanne Lang, Dan Kaufman, Robert Hollingsworth, David T. Rodgers. Developing an allogeneic iPSC derived macrophage cell therapy for oncology. [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 4059.
Abstract 451: AICAR targets oncogenic signaling pathways of MUC1-CT
Authors: Aftab Fareesa , Rodriguez-Fuguet Alice , Silva Luis , Kobayashi Ikei S. , Sun Jiao , Politi Katerina , Levantini Elena , Zhang Wei , Kobayashi Susumu S. , Zhang Wen Cai
Published: April 2023

Lung cancer cells overexpress oncogenic mucin 1 (MUC1), whose C-terminal active subunit (MUC1-CT) is involved in lung tumor formation. Although a specific peptide against MUC1-CT has effectively blocked the MUC1 signaling pathway, intrinsic metabolites targeting MUC1 were not well studied. 5-aminoimidazole-4-carboxamide riboside (AICAR) is a purine biosynthesis intermediate and an analog of adenosine. Our study showed that high AICAR reduced lung tumor cell growth by increasing DNA damage and cell apoptosis. MUC1 was validated as one of the leading AICAR-binding proteins by virtual target screening and thermal stability assay. AICAR treatment dramatically degraded MUC1-CT at protein levels. Whole transcriptome analysis demonstrated that AICAR negatively regulated the Janus kinase (JAK) signaling pathway. Duolink proximity ligation assay revealed that JAK1 interacted with MUC1 directly, and AICAR treatment impaired this protein-protein interaction. Increased epidermal growth factor receptor (EGFR) activity was linked to upregulated expression of MUC1-CT in tissues from an EGFR transgenic mouse lung cancer model. AICAR treatment reduced phosphorylated EGFR, JAK1, and MUC1-CT in lung cancer cells. A mono-treatment with AICAR reduced tumor formation in a mouse lung xenograft model. Combination therapy with AICAR and small-molecule inhibitors against JAK1 or mutant EGFR reduced the growth of lung tissue-derived tumor organoids. Thus, our study has first disclosed a new ligand repressing the MUC1 activity in lung cancer that disrupts protein-protein interactions between MUC1-CT and other oncogenic proteins.

Citation Format: Fareesa Aftab, Alice Rodriguez-Fuguet, Luis Silva, Ikei S. Kobayashi, Jiao Sun, Katerina Politi, Elena Levantini, Wei Zhang, Susumu S. Kobayashi, Wen Cai Zhang. AICAR targets oncogenic signaling pathways of MUC1-CT [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 451.
Abstract 513: Suppressing YBX1 with a small molecule inhibitor sensitizes lung cancer to chemotherapy
Authors: Lee Jee Min , Malhotra Sanjay
Published: April 2023

Y-box binding protein-1 (YBX1) is a multifunctional protein that regulates genes by binding to their DNA and/or RNA. YBX1 is known to contribute to tumorigenesis, disease progression and resistance by stabilizing the mRNAs of genes that are involved in cell growth and survival. High expression of YBX1 has been associated with poor clinical outcomes and decreased overall survival in over 20 cancer types including lung cancer. Given its critical roles in cancer progression and significant correlation with poor cancer prognosis, we hypothesized that inhibition of YBX1 may sensitize the cancer cells to chemotherapeutic agents. To profile the relationship between YBX1 and chemo-response, we aim to investigate the synergistic effect of YBX1 inhibition with standard of care chemotherapy drugs including cisplatin, in lung cancer using animal models and omics analysis. Our studies have found that SU056, a small molecule YBX1 inhibitor, effectively inhibits YBX1 expression in human lung adenocarcinoma cell lines and halts their cell proliferation and clonogenic potential, whereas overexpression of YBX1 promotes cell proliferation. SU056-mediated YBX1 inhibition also led to G2/M cell cycle arrest in these cells followed by apoptotic cell death. These results were further confirmed in A549 lung tumor xenograft model, where inhibitor treatment delayed tumor progression. We will present collective data from in vitro and in vivo studies with YBX1 inhibitor, combination studies with known chemotherapeutic drugs and omics analysis to suggest that targeting YBX1 has therapeutic potential to increase the efficacy of chemotherapeutic agents.

Citation Format: Jee Min Lee, Sanjay Malhotra. Suppressing YBX1 with a small molecule inhibitor sensitizes lung cancer to chemotherapy [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 513.
Abstract 5909: Characterization of the lung cancer microbiome using whole genome sequencing
Authors: McElderry John , Zhang Tongwu , Shi Jianxin , Landi Maria Teresa
Published: April 2023

Microbiome studies have been rapidly increasing over the last decade, providing valuable insights into the commensal bacterial contribution to human physiology and disease, including human cancer. Many studies have demonstrated the important roles of the microbiome in cancer progression, anti-tumor immunity, resistance to therapies, metastasis formation, and in some rare cases even cancer development through the production of genotoxins. However, relatively few studies have analyzed the lung cancer microbiome, and both its composition and role in cancer progression are largely unknown. To characterize the microbiome of tumor and matched normal lung tissues, we performed whole-genome sequencing (WGS) in 872 never smokers using the Kraken pipeline. At the phylum level, WGS analyses of tumor and normal samples showed predominantly Proteobacteria and Actinobacteria (58% and 32%, respectively). Notably, we found overall similar microbiome composition in tumor and normal lung tissue samples. At the genus level, Cutibacterium, Klebsiella, Pseudomonas, Sphingomonas, Staphylococcus, and Acinetobacter genera were among the most abundant bacteria in tumor and normal tissues, alike, and the genera Prevotella, Corynebacterium, and Streptococcus were more abundant in tumor samples compared to normal lung tissue. Comparison of alpha diversity at the genus level between tumors and normal samples showed no substantial difference. We are currently investigating whether the microbiome composition varies by lung tumor anatomical location, sex, histology, study subjects’ geographical location, and immune microenvironment. We will also investigate whether the tumor microbiome composition varies in relation to important genomic features, like cancer driver genes and mutational signatures. Finally, we have 16s rRNA seq data from 771 tumor and normal lung tissues from never smokers and we will compare bacterial microbiome composition and diversity based on WGS and 16s rRNA seq for the same samples. This study, based on the largest analysis of lung microbiome to date, is poised to provide important insights into the role of commensal microbiota in shaping lung tumor development and progression.

Citation Format: John McElderry, Tongwu Zhang, Jianxin Shi, Maria Teresa Landi. Characterization of the lung cancer microbiome using whole genome sequencing [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 5909.