bluuebunny/crossref_metadata_2025 huggingface dataset:
Positive regulation of the MarR-type regulator slnO and improvement of salinomycin production by Streptomyces albus by multiple transcriptional regulation
Authors: Zhang Hongrui , Chen Weiwei , Wang Xinyi , Li Yongquan , Zhu Zhenhong
Published: January 2022

The purpose of this study was to explore the function of the MarR family regulator slnO. Additionally, a high-yield strain of salinomycin was constructed using combined regulation strategies. First, the slnO gene overexpression strain (GO) was constructed in Streptomyces albus. Compared to the wild-type (WT) strain, salinomycin production in the GO strain increased by approximately 28%. Electrophoretic mobility gel shift assays (EMSAs) confirmed that the SlnO protein can bind specifically to the intergenic regions of slnN-slnO, slnQ-slnA1, and slnF-slnT. qRT-PCR experiments also showed that slnA1, slnF, and slnT1 were significantly upregulated, whereas the expression level of the slnN gene was downregulated in the GO strain. Second, the slnN gene deletion strain (slnNDM) was used as the starting strain, and the pathway-specific gene slnR in the salinomycin gene cluster was overexpressed in slnNDM. This new strain was named ZJUS01. The yield of salinomycin in the ZJUS01 strain was 25% and 56% higher than those in the slnNDM and WT strains, respectively. The above results indicate that the slnO gene has a positive regulatory effect on the biosynthesis of salinomycin. Meanwhile, the yield of salinomycin can be greatly increased by manipulating multiple transcriptional regulations.
Using Covariant Polarisation Sums in QCD
Authors: Kachelrieß M. , Malmquist M. N.
Published: January 2022

Covariant gauges lead to spurious, non-physical polarisation states of gauge bosons. In QED, the use of the Feynman gauge,$$\sum _{\lambda } \varepsilon _\mu ^{(\lambda )}\varepsilon _\nu ^{(\lambda )*} = -\eta _{\mu \nu }$$∑λεμ(λ)εν(λ)∗=-ημν, is justified by the Ward identity which ensures that the contributions of non-physical polarisation states cancel in physical observables. In contrast, the same replacement can be applied only to a single external gauge boson in squared amplitudes of non-abelian gauge theories like QCD. In general, the use of this replacement requires to include external Faddeev–Popov ghosts. We present a pedagogical derivation of these ghost contributions applying the optical theorem and the Cutkosky cutting rules. We find that the resulting cross terms$$\mathcal {A}(c_1,\bar{c}_1;\ldots )\mathcal {A}(\bar{c}_1,c_1;\ldots )^*$$A(c1,c¯1;…)A(c¯1,c1;…)∗between ghost amplitudes cannot be transformed into$$(-1)^{n/2}|\mathcal {A}(c_1,\bar{c}_1;\ldots )|^2$$(-1)n/2|A(c1,c¯1;…)|2in the case of more than two ghosts. Thus the Feynman rule stated in the literature holds only for two external ghosts, while it is in general incorrect.
Exploring Cognition with Brain–Machine Interfaces
Authors: Andersen Richard A. , Aflalo Tyson , Bashford Luke , Bjånes David , Kellis Spencer
Published: January 2022

Traditional brain–machine interfaces decode cortical motor commands to control external devices. These commands are the product of higher-level cognitive processes, occurring across a network of brain areas, that integrate sensory information, plan upcoming motor actions, and monitor ongoing movements. We review cognitive signals recently discovered in the human posterior parietal cortex during neuroprosthetic clinical trials. These signals are consistent with small regions of cortex having a diverse role in cognitive aspects of movement control and body monitoring, including sensorimotor integration, planning, trajectory representation, somatosensation, action semantics, learning, and decision making. These variables are encoded within the same population of cells using structured representations that bind related sensory and motor variables, an architecture termed partially mixed selectivity. Diverse cognitive signals provide complementary information to traditional motor commands to enable more natural and intuitive control of external devices.
Coupling of 3D Porous Hosts for Li Metal Battery Anodes with Viscous Polymer Electrolytes
Authors: Park Bumjun , Oh Christiana , Yu Sooyoun , Yang Bingxin , Myung Nosang V. , Bohn Paul W. , Schaefer Jennifer L.
Published: January 2022

As the energy storage markets demand increased capacity of rechargeable batteries, Li metal anodes have regained major attention due to their high theoretical specific capacity. However, Li anodes tend to have dendritic growth and constant electrolyte consumption upon cycling, which lead to safety concerns, low Coulombic efficiency, and short battery lifetime. In this work, both conductive and non-conductive 3D porous hosts were coupled with a viscous (melt) polymer electrolyte. The cross-section of the hosts showed good contact between porous hosts and the melt polymer electrolyte before and after extensive cycling, indicating that the viscous electrolyte successfully refilled the space upon Li stripping. Upon deep Li deposition/stripping cycling (5 mAh cm−2), the non-conductive host with the viscous electrolyte successfully cycled, while the conductive host allowed rapid short circuiting. Post-mortem cross-sectional imaging showed that the Li deposition was confined to the top layers of the host. COMSOL simulations indicated that current density was higher and more restricted to the top of the conductive host with the polymer electrolyte than the liquid electrolyte. This resulted in quicker short circuiting of the polymer electrolyte cell during deep cycling. Thus, the non-conductive 3D host is preferred for coupling with the melt polymer electrolyte.
Aqueous Lithium Carboxymethyl Cellulose and Polyacrylic Acid/Acrylate Copolymer Composite Binder for the LiNi0.5Mn0.3Co0.2O2 Cathode of Lithium-Ion Batteries
Authors: Cui Yan , Chen Jiahui , Zhao Jingyang , Ma Zhen , Tan Yuming , Xue Jianjun , Xu Hanliang , Nan Junmin
Published: January 2022

Water-soluble green cathode binders are developed to increase the performance of 18650 type LiNi0.5Mn0.3Co0.2O2 (NMC532) lithium-ion batteries (LIBs). Using four basal substances to prepare the composite binders, it is indicated that the cathode with lithium carboxymethyl cellulose (CMCLi)-polyacrylic acid/acrylate copolymer (type 306 F) composite binder (Marked as Binder C) avoids the corrosion of aluminum substrate, and exhibits stronger adhesive force and better electrolyte adsorption capacity compared to other cathodes with PVDF binder and single aqueous binders. In particular, the electrochemical performance of the batteries with Binder C is also improved, initial specific capacity of 161.5 mAh g−1 at 0.2C and retention capacity of 88.9% at 1C after 1200 cycles are obtained. The batteries with Binder C also exhibit enhanced high-temperature storage performance, there is 97.9% residual capacity when the fully charged batteries are stored in 60 °C for 14 d. The enhanced performance is mainly attributed to the chemical stability and bonding ability of polyacrylic acid/acrylate copolymer and better conduction at the liquid-solid interface caused by CMCLi. These results indicate that Binder C has promising application prospects in the NMC532 cathode, and also provide a reference for the green production of NMC-based LIBs.
High Activity and Selectivity of M-N/C Catalysts toward Two-Electron O2 Electroreduction
Authors: da Cunha Campos Alex , Lopes Thiago
Published: January 2022

Hydrogen Peroxide (H2O2) is a versatile and environmentally friendly chemical oxidant with a remarkably diverse range of applications, including fine chemical synthesis, first aid kits for disinfection, pulp and textile bleaching, wastewater treatment and others. Industrial production of H2O2 is based on the anthraquinone oxidation/reduction process, which consumes a lot of energy, requires complex and large-scale equipment, and mass extraction solvents, generating an enormous waste. There is a general demand for a more decentralised infrastructure, where energy conversion and chemical synthesis are conducted closer to the point of consumption. In this context, developing an electrochemical process to partially reduce O2 to H2O2 (O2 + 2H+/e- → H2O2) in an acidic medium would be an attractive strategy that could be carried out under ambient conditions using renewable energies. However, practical and economic electrocatalysts that exhibit high activity and selectivity for hydrogen peroxide production is to be developed. A series of M-N/C catalysts (M = Fe, Co, and Cu) were prepared in the present study. The performance (activity and selectivity) of these catalysts for the oxygen reduction reaction was investigated in the potential window of 0.2 V to 1.0 V vs. the Reversible Hydrogen Electrode (RHE). Electrochemical measurements demonstrated that the Co-N/C [c] electrocatalyst exhibits high ORR activity and exceptional selectivity for hydrogen peroxide production (92% at 0.5 V vs. RHE).
Asumu Fractional Derivative Applied to Edge Detection on SARS-COV2 Images
Authors: Nchama Gustavo Asumu Mboro , Alfonso Leandro Daniel Lau , Morales Roberto Rodríguez , Aneke Ezekiel Nnamere
Published: January 2022

Edge detection consists of a set of mathematical methods which identifies the points in a digital image where image brightness changes sharply. In the traditional edge detection methods such as the first-order derivative filters, it is easy to lose image information details and the second-order derivative filters are more sensitive to noise. To overcome these problems, the methods based on the fractional differential-order filters have been proposed in the literature. This paper presents the construction and implementation of the Prewitt fractional differential filter in the Asumu definition sense for SARS-COV2 image edge detection. The experiments show that these filters can avoid noise and detect rich edge details. The experimental comparison show that the proposed method outperforms some edge detection methods. In the next paper, we are planning to improve and combine the proposed filters with artificial intelligence algorithm in order to program a training system for SARS-COV2 image classification with the aim of having a supplemental medical diagnostic.
Optimized Query Algorithms for Top-
K
Group Skyline
Authors: Liu Jia , Chen Wei , Chen Ziyang , Liu Lin , Wu Yuhong , Liu Kaiyu , Jain Amar , Elawady Yasser H.
Published: January 2022

Skyline query is a typical multiobjective query and optimization problem, which aims to find out the information that all users may be interested in a multidimensional data set. Multiobjective optimization has been applied in many scientific fields, including engineering, economy, and logistics. It is necessary to make the optimal decision when two or more conflicting objectives are weighed. For example, maximize the service area without changing the number of express points, and in the existing business district distribution, find out the area or target point set whose target attribute is most in line with the user’s interest. Group Skyline is a further extension of the traditional definition of Skyline. It considers not only a single point but a group of points composed of multiple points. These point groups should not be dominated by other point groups. For example, in the previous example of business district selection, a single target point in line with the user’s interest is not the focus of the research, but the overall optimality of all points in the whole target area is the final result that the user wants. This paper focuses on how to efficiently solve top-

k

group Skyline query problem. Firstly, based on the characteristics that the low levels of Skyline dominate the high level points, a group Skyline ranking strategy and the corresponding SLGS algorithm on Skyline layer are proposed according to the number of Skyline layer and vertices in the layer. Secondly, a group Skyline ranking strategy based on vertex coverage is proposed, and corresponding VCGS algorithm and optimized algorithm VCGS+ are proposed. Finally, experiments verify the effectiveness of this method from two aspects: query response time and the quality of returned results.
Maternal and Child Health Services in Rural Settings of The Gambia: Contextual Determinants of Postnatal Care from Mothers’ Perspectives—A Community-Based Analytical Cross-Sectional Study
Authors: Kinteh Bakary , Barrow Amadou , Nget Musa , Touray Ebrima , Touray Jainaba , Kinteh Sambou L. S. , Badjie Mansour , Jatta Solomon P. S.
Published: January 2022

Background. Maternal and child health in The Gambia is a trending public health burden. The postnatal period is critical and vital to the lives and health of the maternal mothers and their newborns, and pieces of evidence deduced that a majority of maternal and newborn deaths occur during this period. Hence, this research aimed to assess the prevalence and determinants of postnatal care utilization across women in rural Gambia. Methods. A community-based cross-sectional design was conducted in January 2020, with 265 women of childbearing age were recruited from the selected households in rural communities across the Upper River Region (URR), Gambia, using multistage sampling technique. A structured-interview questionnaire was developed to elicit contextual sociodemographic characteristics regarding the use of postnatal care. Percentages, chi-square/Fisher’s exact test for variables with

p

value ≤0.15 were considered for inclusion into the logistic regression model. The significance level was set at

p
<
0.05

. The adjusted odds ratios (aOR) with 95% confidence interval (CI) were computed to declare significance. Results. The study revealed that 90% of women utilize postnatal care (PNC) services in the rural settings of URR, Gambia. Factors such as women’s occupation, location, number of pregnancies, attending in last pregnancy, current uptake of family planning, and complication(s) in last labor were found to be associated with PNC utilization. Women who attended antenatal care (ANC) services in their last pregnancy were 10.8 times (aOR = 10.795, 95% CI: 1.025–113.694), current users of FP were 10.7 times (aOR = 10.708, 95% CI: 1.379–83.152), women’s number of pregnancies increases by a factor of 4.6 times (aOR = 4.649, 95% CI: 1.518–14.243) more likely to utilize PNC while women’s number of children alive were less likely by 76.1% (aOR = 0.239, 95% CI: 0.071–0.810) as compared to those who were not utilizing PNC services. Conclusion. The findings showed that attending ANC services, current uptake of FP, women’s number of pregnancies, and number of children alive were associated with PNC. Strengthening women empowerment and designing responsive ANC programs especially for rural women to improve PNC services are required.
Community Environmental Detection and Community Outdoor Space Health Promotion Based on Cloud Resource Scheduling Mechanism
Authors: Pang Chunyu , Guan Zhen
Published: January 2022

In the context of rapid economic growth, people’s living standards are improving day by day, and China’s urbanization process is also gradually accelerating. Urban renewal is a very complex project. The renewal and expansion of most cities in the country usually involve demolishing and rebuilding. This way of urban renewal only pays attention to the renewal efficiency of cities and towns, and ignores the health needs of residents, which will make community residents lack a sense of security, pleasure, comfort, and belonging to the community, and greatly reduce the quality of life and physical fitness of community residents. Building a healthy city is an important goal of today’s society, and community is the basic unit of a city, so it is urgent to build a health-promoting community. We should pay attention to and study the social environment, the external space environment of residential areas, and the interaction between them, so as to make develop them in a healthy direction and create a healthy and positive community. Therefore, it is an urgent task to improve the community residents’ attention to the above problems and build community outdoor space, which has very important practical significance. In this paper, we use the cloud resource scheduling mechanism and the Internet of things to study the healthy role of community outdoor space planning. Through the transplantation of embedded Linux system, the development of communication interface and the external acquisition sensing device, we collect the information of working status and running status, and transmit it to the database built in the cloud through the 4G module on the motherboard. Then, HTML + java script + CSS + JSON + Ajax technology is used to write the display interface and logical relationship, so that the data can be displayed on the mobile terminal and PC, which can provide a useful technical exploration for outdoor space planning. The community Internet of Things technology realizes the intelligent community environment detection, and the community cloud resource scheduling mechanism combined with the community Internet of Things can obtain the residents’ help information in time and allocate the community outdoor resources in real time, which can not only meet the health needs of community members but also be conducive to the sustainable development of a health-promoting community. In addition, the cloud resource scheduling mechanism and the Internet of things also provide new ideas for the study of the health promotion research of community outdoor space planning.
Assembly Quality Inspection of Combine Harvester Based on Whale Algorithm Optimization LSSVM
Authors: Zhao Sixia , Ma Yizhen , Liu Mengnan , Chen Xiaoliang , Xu Liyou
Published: January 2022

In order to detect the assembly quality of the combine harvester accurately and effectively, a method for the assembly quality inspection of the combine harvester based on the improved whale algorithm (IWOA) to optimize the least square support vector machine is proposed. Aiming at the characteristics of whale optimization algorithm’s weak search ability and easy maturity, this paper introduces the cosine control factor and the sine time-varying adaptive weight to improve it and uses the benchmark function to verify the general adaptability of the algorithm. Combined with the local mean decomposition (LMD), the assembly quality inspection model of the combine harvester was established and applied to the Dongfanghong 4LZ-9A2 combine harvester for experimental verification. The experimental results show that the IWOA proposed in this paper has better optimization ability and adaptability. The average accuracy of the IWOA model proposed in this paper reaches 90.5%, which is 4% higher than that of the WOA model, and the standard deviation of the average accuracy is reduced by 0.15%, which indicates that the IWOA model has better stability.
OffFog: An Approach to Support the Definition of Offloading Policies on Fog Computing
Authors: Melo Sávio , Oliveira Felipe , Silva Cícero , Lopes Paulo , Aquino Gibeon
Published: January 2022

IoT devices deployed in Smart Cities usually have significant resource limitations. For this reason, offload tasks or data to other layers such as fog or cloud is regularly adopted to smooth out this issue. Although data offloading is a well-known aspect of fog computing, the specification of offloading policies is still an open issue due to the lack of clear guidelines. Therefore, we propose OffFog—an approach to guide the definition of data offloading policies in the context of fog computing. In order to evaluate OffFog, we extended the well-known simulator iFogSim and conducted an experimental study based on an urban surveillance system. The results demonstrated the benefits of implementing data offloading based on OffFog recommended policies. Furthermore, we identified the best configuration involving design decisions such as data compression, data criticality, and storage thresholds. The best configuration produced at least 76% improvement in network latency and 5% in the average execution time compared to the iFogSim default strategy. We believe these results represent a significant step towards establishing a systematic decision framework for data offloading policies in the context of fog computing.
Designing a Medical Supply Chain Network Considering the Risk of Supply and Flexible Production in Two-Stage Uncertain Conditions
Authors: Hazrati Reza , Samaei Mohamad , Hejri Farkhondeh Mortaz , Haddad Shervin , Amiriyan Sajad
Published: January 2022

In the green supply chain approach, all the links that are put together to provide a product or service are considered, and strategic and operational decisions are made to increase the efficiency and effectiveness of the entire chain. At the same time, the environmental effects should be minimized. In this research, a nonlinear mixed-integer multiobjective model is developed to design a green closed-loop supply chain for medical products. In this supply chain, the echelons include supplier, manufacturer, warehouse, and customer in the forward supply chain and collection centers, repair services, and disposal centers in the reverse supply chain. In the proposed model, four objectives of customer satisfaction, environmental effects, supply risk, and total costs of the supply chain were considered. The developed model is implemented in a supply chain of medical products, and after optimizing the model, the main results including location and capacity of facilities, planning for flexible production, purchase of materials, service and maintenance plan, product transfer, and inventory level are determined and analyzed.
SDTM: A Novel Topic Model Framework for Syndrome Differentiation in Traditional Chinese Medicine
Authors: Ma Jialin , Gong Xiaoqiang , Wang Zhaojun , Xie Qian
Published: January 2022

Syndrome differentiation is the most basic diagnostic method in traditional Chinese medicine (TCM). The process of syndrome differentiation is difficult and challenging due to its complexity, diversity, and vagueness. Recently, artificial intelligent methods have been introduced to discover the regularities of syndrome differentiation from TCM medical records, but the existing DM algorithms failed to consider how a syndrome is generated according to TCM theories. In this paper, we propose a novel topic model framework named syndrome differentiation topic model (SDTM) to dynamically characterize the process of syndrome differentiation. The SDTM framework utilizes latent Dirichlet allocation (LDA) to discover the latent semantic relationship between symptoms and syndromes in mass of Chinese medical records. We also use similarity measurement method to make the uninterpretable topics correspond with the labeled syndromes. Finally, Bayesian method is used in the final differentiated syndromes. Experimental results show the superiority of SDTM over existing topic models for the task of syndrome differentiation.
Experimental Study on Crack Extension Rules of Hydraulic Fracturing Based on Simulated Coal Seam Roof and Floor
Authors: Gao Lu , Kang Xiangtao , Huang Gun , Wang Ziyi , Tang Meng , Shen Xiaoying
Published: January 2022

Hydraulic fracturing can increase the fracture of coal seams, improve the permeability in the coal seam, and reduce the risk of coal and gas outburst. Most of the existing experimental specimens are homogeneous, and the influence of the roof and floor on hydraulic fracture expansion is not considered. Therefore, the hydraulic fracturing test of the simulated combination of the coal seam and the roof and floor under different stress conditions was carried out using the self-developed true triaxial coal mine dynamic disaster large-scale simulation test rig. The results show that (1) under the condition of triaxial unequal pressure, the hydraulic fractures are vertical in the coal seam, and the extension direction of hydraulic fractures in the coal seam will be deflected, with the increase of the ratio of the horizontal maximum principal stress to the horizontal minimum principal stress. The angle between the extension direction of the hydraulic fracture and the horizontal maximum principal stress decreases. (2) Under the condition of triaxial equal confining pressure, the extension of hydraulic fractures in the coal seam are random, and the hydraulic fracture will expand along the dominant fracture surface and form a unilateral expansion fracture when a crack is formed. (3) When the pressure in one direction is unloaded under the condition of the triaxial unequal pressure, the hydraulic fractures in the coal seam will reorientate, and the cracks will expand in the direction of the decreased confining pressure, forming almost mutually perpendicular turning cracks.
Feature Extraction of Ship Radiation Signals Based on Wavelet Packet Decomposition and Energy Entropy
Authors: Li Yuxing , Ning Feiyue , Jiang Xinru , Yi Yingmin
Published: January 2022

The analysis of ship radiation signals to identify ships is an important research content of underwater acoustic signal processing. The traditional fast Fourier transform (FFT) is not suitable for analyzing non-stationary, non-Gaussian, and nonlinear signal processing. In order to realize the feature extraction and accurate classification of ship radiation signals with higher accuracy, a feature extraction method of ship radiation signals based on wavelet packet decomposition and energy entropy is proposed in this paper. According to wavelet packet decomposition, the ship radiation signal is decomposed into different frequency bands, and its energy entropy feature is extracted. As for comparisons, the center frequency and permutation entropy are also used as features to be extracted, then the k-nearest neighbor is applied to classify and recognize the extracted results. Based on the comparisons of wavelet packet decomposition, the center frequency, permutation entropy, and the k-nearest neighbor are used for classification and recognition. The experimental results present that, when comparing with center frequency and permutation entropy, the method based on energy entropy has the best availability, with the highest average recognition rate for four types of ship radiation signals, up to 98%.
Evaluating Slow Pyrolysis of Parthenium hysterophorus Biochar: Perspectives to Acidic Soil Amelioration and Growth of Selected Wheat (Triticum aestivum) Varieties
Authors: Muche Meseret , Molla Eyayu , Mohammed Sultan , Sintie Esubalew , Hassen Ahmed
Published: January 2022

Application of biochar on acidic soils may improve soil fertility and crop productivity. This study aimed to explore the relevance of parthenium biochar-induced changes in the physicochemical properties and agronomic performance of the selected wheat varieties in acidic soils. A pot trial was used in determining the effect of slow pyrolysis parthenium biochar on acidic soils and the agronomic performance of wheat varieties. A general linear model (GLM) of multivariate analysis and principal component analysis (PCA) was used to compare functional variation among soil assayed parameters with biochar dosages and years. Biochar-treated acidic soils did not show significant differences in their physical properties. However, a significant incremental trend was observed in the soil moisture content. The biochar-amended acidic soils showed noticeable differences in the soil pH, available phosphorous, and exchangeable bases (Ca, K, and Na) compared to the control. In all soil samples, a decreasing trend in the soil micronutrients was observed with an increase in the biochar amounts. The analysis also unveiled significant changes in root length, root and shoot dry biomass, and plant height of wheat varieties in response to the biochar amendments. The application of 19.5 t/ha and 23 t/ha dosages of biochar gave the maximum changes in the agronomic performance of Kekeba and Ogolcha varieties, while the minimum was obtained in the 26.5 t/ha and the control. Furthermore, PCA axis 1 accounted for 74.34% of the total variance within a higher eigenvector value (10.4076), and most of the soil parameters were positively correlated with CEC (0.29), available phosphorous (0.29), and soil pH (0.28); however, the micronutrients were negatively correlated. In conclusion, Parthenium hysterophorus biochar has the potential to amend acidic soils, and thus, the application of 16.0, 19.5, and 23 t·ha−1 biochar dosages are considered suitable to reduce the soil acidity level and improve the agronomic performance of wheat varieties. However, extensive research will be needed to determine the effects of biochar on soil properties and crop production in field conditions.
Has the Enemy “MET” Its Match? Subgroup Analysis Results from VISION Study
Authors: Rosner Samuel , Spira Alexander I.
Published: January 2022

Emerging therapies have recently received approval for the treatment of MET exon 14 skipping non–small cell lung cancer (NSCLC). Further characterization of these therapies, such as tepotinib, is needed to identify patient subgroups most likely to derive benefit from these novel agents.

See related article by Le et al., p. 1117
Abstract IA13: Predicting clonal evolution in pancreatic cancer survivors
Authors: Luksza Marta
Published: January 2022

Immune editing of neoantigens is crucial for the success of immunotherapies, but it is still unknown to what extent the immune system naturally edits evolving tumors and what is the fitness cost associated with the presence of neoantigens. Here we develop a biophysically grounded neoantigen quality model, which quantifies the immunogenicity of tumor neoantigens. We use the model to define the fitness of tumor clones as a combination of negative selection due to immune recognition and positive selection due to oncogenic mutations. We investigate how pancreatic cancers – a lowly mutated, poorly immunogenic cancer, largely presumed to not be subject to immunoediting – evolve over 10 years. Our patient cohort includes a set of long-term survivors, who are characterized by high levels of immune infiltration of their primary tumors. With the fitness model, we show that long-term survivors evolve new clones of markedly lower immune fitness cost, to indicate clones with high-quality neoantigens are negatively selected. Importantly, the fitness model predicts the clonal composition of recurrent tumors of the patients. Thus, we submit longitudinal evidence that the human immune system naturally edits neoantigens. Furthermore, we present a model that describes how tumor cell populations evolve under immune pressure over time, with implications for cancer biology and therapy.

Citation Format: Marta Luksza. Predicting clonal evolution in pancreatic cancer survivors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA13.
Abstract P023: Mismatch repair deficiency is not sufficient to increase tumor immunogenicity
Authors: Westcott Peter M. K. , Remolar Francesc M. , Smith Olivia , Hauck Haley , Sacks Nathan J. , Ely Zackery A. , Jaeger Alex M. , Rideout William M. , Bhutkar Arjun , Zhang Daniel , Beytagh Mary C. , Bronson Roderick T. , Canner David A. , Naranjo Santiago , Jin Abbey , Patten J. J. , Cruz Amanda M. , Cortes-Ciriano Isidro , Jacks Tyler
Published: January 2022

Deficient DNA mismatch repair (dMMR) in human cancer is associated with high tumor mutation burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of these tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of dMMR have helped solidify the importance of TMB in immune response, critical questions remain regarding the role of immune surveillance in the evolution of dMMR tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, dMMR in these models did not result in increased immunogenicity or response to ICB, which we showed is driven by profound intratumoral heterogeneity. Studies in animals depleted of T cells further demonstrated that immune surveillance in dMMR tumors has no impact on TMB but shapes the clonal architecture of neoantigens. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

Citation Format: Peter M. K. Westcott, Francesc M. Remolar, Olivia Smith, Haley Hauck, Nathan J. Sacks, Zackery A. Ely, Alex M. Jaeger, William M. Rideout, Arjun Bhutkar, Daniel Zhang, Mary C. Beytagh, Roderick T. Bronson, David A. Canner, Santiago Naranjo, Abbey Jin, J. J. Patten, Amanda M. Cruz, Isidro Cortes-Ciriano, Tyler Jacks. Mismatch repair deficiency is not sufficient to increase tumor immunogenicity [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P023.
Abstract P026: Uncovering mechanisms of immune evasion in a novel immunogenic model of KRAS-mutant lung cancer
Authors: Boumelha Jesse , de Carné Sophie , Romero Pablo , Moliona Miriam , Downward Julian
Published: January 2022

Oncogenic KRAS mutations drive tumorigenesis in 30% of non-small cell lung cancer (NSCLC). Despite much effort, targeted therapies that aim to directly inhibit signaling pathways downstream of KRAS have limited clinical benefits for NSCLC patients, but the recent approval of PD-1/PD-L1 antibodies has led to striking durable responses. However, only a fraction of patients respond and therefore a deeper understanding of the mechanisms that drive immune evasion are required in order to broaden the clinical efficacy of immunotherapy. Increasing evidence suggests that oncogenic signaling pathways greatly influence the tumor immune landscape to impair anti-tumor immune responses. We therefore aim to understand the mechanisms by which KRAS signaling mediates immune evasion in lung cancer. Current mouse models of KRAS-mutant lung cancer are poorly immunogenic, limiting investigations into tumor-immune interactions. To overcome this, we generated a novel transplantable KRAS-mutant lung cancer model, KPAR1.3, which triggers spontaneous anti-tumor immune responses and is sensitive to immune checkpoint blockade. To identify mechanisms of immune evasion we carried out an in vivo pooled CRISPR-Cas9 screen targeting 240 KRAS-regulated genes using this novel immunogenic model. This identified a number of genes that increased sensitivity or caused resistance to anti-tumor immune responses. As an alternative approach we utilized the recently developed class of mutant-specific KRAS-G12C inhibitors to assess the impact of inhibiting KRAS signaling on anti-tumor immune responses in KPAR1.3 tumors. KRAS-inhibition stimulated adaptive immunity in vivo, which contributed to the response of KPAR1.3 tumors in immune-competent mice. Together these data suggest that targeting KRAS, or KRAS-driven mechanisms of immune evasion, could broaden the clinical efficacy of immunotherapy in KRAS-mutant NSCLC.

Citation Format: Jesse Boumelha, Sophie de Carné, Pablo Romero, Miriam Moliona, Julian Downward. Uncovering mechanisms of immune evasion in a novel immunogenic model of KRAS-mutant lung cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P026.
Abstract P034: Tumor-targeted interleukin-12 and Entinostat combination therapy improves cancer survival by reprogramming the tumor immune cell landscape
Authors: Hicks Kristin C. , Chariou Paul L. , Ozawa Yohei , Minnar Christine M. , Knudson Karin M. , Meyer Thomas J. , Bian Jing , Cam Margaret , Schlom Jeffrey , Gameiro Sofia R.
Published: January 2022

Clinical benefit remains elusive for most patients with poorly inflamed carcinomas treated with immune checkpoint blockade. Converting the tumor microenvironment into a functionally inflamed immune hub would increase clinical benefit. By using comprehensive single-cell transcriptome, proteome, and immune cell analysis, we demonstrate here that Entinostat, a class I histone deacetylase inhibitor, facilitates accumulation of the necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon carcinomas and poorly immunogenic breast tumor in which the therapy was curative. Combination therapy reprogrammed the tumor innate and adaptive immune milieu to an inflamed landscape, where the concerted action of highly functional CD8+ T cells and activated neutrophils drove a dramatic macrophage M1-like polarization leading to complete tumor eradication in 41.7%-100% of cases. Biomarker signature of favourable overall survival in multiple human tumor types showed close resemblance to the immune pattern generated by Entinostat/NHS-rmIL12 combination therapy. Collectively, these findings provide a rationale for combining NHS-IL12 with Entinostat in the clinical setting.

Citation Format: Kristin C. Hicks, Paul L. Chariou, Yohei Ozawa, Christine M. Minnar, Karin M. Knudson, Thomas J. Meyer, Jing Bian, Margaret Cam, Jeffrey Schlom, Sofia R. Gameiro. Tumor-targeted interleukin-12 and Entinostat combination therapy improves cancer survival by reprogramming the tumor immune cell landscape [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P034.
Abstract P047: Inactivation of IFN signaling drive immunosuppressive MDSC function and can be therapeutically targeted
Authors: Sanseviero Emilio , Alicea-Torres Kevin , Nefedova Yulia , Fuchs Serge Y. , Gabrilovich Dmitry I.
Published: January 2022

Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity that promote tumor progression and impair the efficacy of anti-tumor therapeutics. Herein we show that type I interferons (IFN1) receptor dampen immune suppressive activity of MDSC. Downregulation of the IFNAR1 is found in MDSC from cancer patients and mouse tumor models. Downregulation of IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype moreover genetic stabilization of IFNAR1 in tumor bearing mice reduces suppressive activity of MDSC and promote antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect that is completely dependent on IFNAR1 expression on MDSC. Thus, inhibition of MDSC immune suppressive function can be exploited therapeutically.

Citation Format: Emilio Sanseviero, Kevin Alicea-Torres, Yulia Nefedova, Serge Y. Fuchs, Dmitry I. Gabrilovich. Inactivation of IFN signaling drive immunosuppressive MDSC function and can be therapeutically targeted [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P047.
Abstract P063: Tumor cell-derived lactic acid inhibit anti-tumor immunity in the immune checkpoint blockade resistant tumor
Authors: Oh Wonkyung , Kim Alyssa Min Jung , Sun Ruoxuan , Lim Seung-Oe
Published: January 2022

Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types. Despite the recent success of PD-1/PD-L1 blockade therapy, acquired resistance, emerging as late relapses or recurrences, has been reported in the long-term follow-up of clinical trials. However, the resistance mechanisms of PD-1/PD-L1 blockade therapy are still unclear. Here we found that tumor cell-derived lactate rendered the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade resistant tumors. Interestingly, increased lactate in the PD-1/PD-L1 blockade resistant tumors enhanced PD-1/PD-L1 interaction. Furthermore, combining a PD-L1-antibody-drug conjugate (ADC) with AZD3965, a MCT inhibitor eradicated the resistant tumor cells synergistically in 4T1 syngeneic murine models. Together, our results suggest a new combination treatment strategy to improve the therapeutic efficacy of immune checkpoint blockade therapies.

Citation Format: Wonkyung Oh, Alyssa Min Jung Kim, Ruoxuan Sun, Seung-Oe Lim. Tumor cell-derived lactic acid inhibit anti-tumor immunity in the immune checkpoint blockade resistant tumor [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P063.
Abstract PR02: The co-expression of VISTA and TIGIT on cytotoxic T cells defines subpopulation with altered immunometabolism
Authors: Gilmour Cassandra , Yoo Seong-Keun (Steve) , Chan Timothy , Wang Lily
Published: January 2022

Cancer immunotherapies, specifically checkpoint blockade therapies, are extremely successful at treating subpopulations of specific cancers long term. The idea is to disrupt the negative regulation of T cells and restore cytotoxic abilities allowing killing of the cancer cells and formation of memory T cells. This provides immunity that has the potential to last a lifetime against recurring cancer. One major limitation to checkpoint blockade is that it is has limited response rate, one theory as to why this is the case, is that there are multiple non-redundant pathways of regulation of T cell activation. In response to the heterogeneous and suppressive tumor microenvironment, the T cell may present many immune checkpoint proteins simultaneously. Thus, it is important to study the immune checkpoint proteins in context of one another with the goal of developing combinatorial therapies. Here we present the co-expression of two immune checkpoint proteins and how their co-expression results in altered metabolism in cytotoxic T cells. V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA) is a protein with many roles that are still largely undefined across a variety of immune cells in which it is expressed. T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a bi-directional receptor that has been reported to have a suppressive intrinsic T cell role when probed with agonistic antibody, the mechanism is yet to be defined. Our data suggest that VISTA and TIGIT are co-expressed in varying amounts across a variety of murine and human cancers and that this co-expression may contribute to an altered metabolic phenotype. Our results give insight to the contribution of multiple checkpoint proteins to the state of the cytotoxic T cell and declare the importance of studying these proteins in context of one another. This data reaffirm the need to study non-redundant pathways of T cell suppression with the goal of developing inhibitors that are more broadly applicable to restore anti-tumor immunity and increase patient survival.

Citation Format: Cassandra Gilmour, Seong-Keun (Steve) Yoo, Timothy Chan, Lily Wang. The co-expression of VISTA and TIGIT on cytotoxic T cells defines subpopulation with altered immunometabolism [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR02.
Is There an Increasing Incidence of Gastroesophageal Junctional Adenocarcinoma and Barrett Esophagus in Asia? A Review of Diagnostic Conundrums
Authors: Tan Phei Oon , Soh Alex Yu Sen , Kusano Chika , Lee Yeong Yeh , Gotoda Takuji
Published: January 2022

Background: Epidemiology data of gastroesophageal junction (GEJ) cancers in Asia are extremely scarce. It is hardly registered by any cancer registry in the region, and only a few reports are available. Based on existing literature works, the overall trend indicates similar or gradually increasing GEJ cancers in Asia but comparably less than the West. The increasing trend in Asia is likely a result of rising risk factors, especially of gastroesophageal reflux disease and obesity. Summary: However, epidemiology data may be misleading due to several contentious diagnostic issues. The diagnostic conundrums are due to inherent complexity of the GEJ as a functional and pathological unit. Challenging diagnostic issues in Asia include the following: nonstandardized landmark of the GEJ, misclassification of Barrett esophagus, targeted versus nontargeted tissue sampling, histopathology disagreement and challenges in screening or surveillance of dysplastic BE and early GEJ cancer. The recent Asian-Pacific survey led by the Asian Barrett Consortium (ABC) has provided useful insights into these contentious issues. A key learning point from these diagnostic limitations is that the awareness of the disease and adherence to existing recommendations or guidelines are poor in the region. Key Messages: Standardization in diagnostic methodology is vital for accurate epidemiology data, and this can only come from better awareness and adherence through educational and international efforts. Last, surveillance strategy may need a paradigm shift from a purely diagnostic approach to a combined targeted surveillance and treatment approach using novel endoscopic techniques.
Statistical modeling and optimal energy distribution of cogeneration units by genetic algorithms
Authors: Maakoul Othmane , El Omari Hamid , Abid Aziza
Published: January 2022

Our main objective is to evaluate the performance of a new method to optimize the energy management of a production system composed of six cogeneration units using artificial intelligence. The optimization criterion is economic and environmental in order to minimize the total fuel cost, as well as the reduction of polluting gas emissions such as COx, NOx and SOx. First, a statistical model has been developed to determine the power that the cogeneration units can provide. Then, an economic model of operation was developed: fuel consumption and pollutant gas emissions as a function of the power produced. Finally, we studied the energy optimization of the system using genetic algorithms (GA), and contribute to the research on improving the efficiency of the studied power system. The GA has a better optimization performance, it can easily choose satisfactory solutions according to the optimization objectives, and compensate for these defects using its own characteristics. These characteristics make GA have outstanding advantages in iterative optimization. The robustness of the proposed algorithm is validated by testing six cogeneration units, and the obtained simulation results of the proposed system prove the value and effectiveness of GA for efficiency improvement as well as operating cost minimization.
Auto tuning of frequency on wireless power transfer for an electric vehicle
Authors: Yamaguchi Kazuya , Iida Kenichi
Published: January 2022

In these days, electric vehicles are enthusiastically researched as a countermeasure to air pollution, although these do not have practicality compared to gasoline-powered vehicles. The aim of this study is to transport energy wirelessly and efficiently to an electric vehicle. To accomplish this, we focused on frequency of an alternating current (AC) power supply, and suggested a method which determined the value of it constantly. In particular, a wireless power transfer circuit and a lithium-ion battery in an electric vehicle were expressed with an equivalent circuit, and efficiency of energy transfer was calculated. Furthermore, the optimal frequency which maximizes efficiency was found, and the behavior of voltage was demonstrated on a secondary circuit. Finally, we could obtain the larger electromotive force at the secondary inductor than an input voltage.