bluuebunny/crossref_metadata_2025 huggingface dataset:
Application and Potential of Drone Technology in Oil Palm Plantation: Potential and Limitations
Authors: Khuzaimah Zailani , Nawi Nazmi Mat , Adam Siti Nooradzah , Kalantar Bahareh , Emeka Okoli Jude , Ueda Naonori
Published: September 2022

Oil palm has become one of the largest plantation industries in Malaysia, but the constraints in terms of manpower and time to monitor the development of this industry have caused many losses in terms of time and expense of oil palm plantation management. The introduction to the use of drone technology will help oil palm industry operators increase the effectiveness in the management of oil palm cultivation and production. In addition, knowledge gaps on drone technology were identified, and suggestions for further improvement could be implemented. Therefore, this study reviews the application and potential of drone technology in oil palm plantation, and the limitation and potential of the methods will be discussed.
Systematic Analysis and Identification of Molecular Subtypes of TRP-Related Genes and Prognosis Prediction in Lung Adenocarcinoma
Authors: Guo Yang , Liu Ning
Published: September 2022

Background. Transient receptor potential channel (TRP) is a superfamily of nonselective cation channels, which is a member of calcium ion channels with a vital role in different calcium ion signal transduction pathways. TRP channel expression is often changed in the tumor, although the role of TRP proteins in lung cancer is unknown. Methods. Molecular Signatures Database (MsigDB) provided the TRP gene set. Univariate Cox regression analysis was performed on The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) data collection set employing the coxph function of R package survival to find prognosis-related genes. The R package ConsumusClusterPlus was employed for doing the consistency cluster analysis of TCGA-LUAD samples according to the prognosis-related TRP gene. The R-package limma was utilized for investigating the differential expression of TRP subtypes. According to the differentially expressed genes between subtypes, the least absolute shrinkage and selection operator (LASSO) regression was employed to find the major genes and develop the risk model. CIBERPORT algorithm, R package maftools, gene set variation analysis (GSVA), and pRRophetic of R-package were employed for measuring the proportion of immune cells among subtypes, genomic mutation difference, pathway enrichment score, and drug sensitivity analysis. Results. A total of 15 TRP-related genes associated with the prognosis of lung adenocarcinoma were found. According to the expression value of 15 genes, lung adenocarcinoma can be sorted into two subcategories. The prognosis of cluster1 is considerably better in comparison with that of cluster2. There were 123 differentially expressed genes between C1 and C2 subtypes, including 6 up- and 117 downregulated genes. There were major variations in the tumor microenvironment between C1 and C2 subtypes. The proportion of CD8 T cells in the C1 subtype was considerably enhanced in comparison with that in the C2 subtype. We further discovered 123 differentially expressed genes among subtypes, and 8 key genes were obtained at the end. The risk score (RS) model developed by the 8-gene signature had good strength in the TCGA validation set, overall set, and Gene Expression Omnibus (GEO) external dataset. There were major variations in immune checkpoint gene expression, patient sensitivity to immunotherapeutic drugs, immune infiltration, and genomic mutations between high and low groups on the basis of RS. Conclusions. The risk model developed on the basis of TRP-related genes can help in predicting the prognosis of patients suffering from lung adenocarcinoma and guide immunotherapy.
Anlotinib Inhibits Tumor Angiogenesis and Promotes the Anticancer Effect of Radiotherapy on Esophageal Cancer through Inhibiting EphA2
Authors: Gu Zhenlin , Zhu Weiguo , Wang Wanwei , Xu Yingying , Jiang Lei , Huang Jiasheng , Huang Jing
Published: September 2022

Background. Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and has antitumor activity in a variety of solid tumors. Given that, our study was designed to unearth the mechanism of anlotinib in radioresistant esophageal cancer (EC) cells. Methods. Radioresistant EC cell lines TE-1R and KYSE-150R were established by multiple fractionated irradiation. Detection of cell proliferation was governed by the MTT assay, angiogenesis by the tube formation assay, and cell migration and invasion by the transwell assay. Lastly, RT-qPCR Western blotting was employed to detect the expression of related genes. Cancerous cells showing tumor growth were then detected by tumor xenografts in mice. Results. Radioresistant EC cell lines TE-1R and KYSE-150R were successfully established. Anlotinib downregulated EphA2 inhibited proliferation, angiogenesis, migration, and invasion of radioresistant EC cells in vitro. The up-regulated expression of EphA2 in both EC cell lines and radioresistant EC cells, along with anlotinib, in turn, inhibited the expression of EphA2 in radioresistant EC cells. Inhibiting EphA2 also enhanced anlotinib-mediated effects on radioresistant EC cells, so as to restrain cell proliferation, angiogenesis, migration, and invasion. Correspondingly, overexpression of EphA2 is capable of reversing the therapeutic effect of anlotinib on radioresistant EC cells. Also, anlotinib enhances the inhibitory effect of irradiation on mice. Conclusion. It is concluded that anlotinib inhibits EphA2 expression, thereby suppressing angiogenesis and resensitizing EC cells to radiotherapy, providing another perspective to overcome radioresistance in EC.
Stability Results for Enriched Contraction Mappings in Convex Metric Spaces
Authors: Panicker Rekha , Shukla Rahul
Published: September 2022

In this paper, we obtain some stability results of fixed point sets for a sequence of enriched contraction mappings in the setting of convex metric spaces. In particular, two types of convergence of mappings, namely,

G

-convergence and

H

-convergence are considered. We also illustrate our results by an application to an initial value problem for an ordinary differential equation.
Construction of Evaluation Index System of Office Sitting Comfort Based on Ergonomics
Authors: Hu Jiadian , Shi Shoudong , Zheng Jiaqing , Fang Zhiyuan
Published: September 2022

People who sit incorrectly can have musculoskeletal disorders like cervical spondylosis and lumbar vertebra disease, but without the guidance of a health care professional, it is difficult for people to evaluate their posture and adopt a more appropriate posture. Therefore, to solve this problem, we established a multilevel sitting posture evaluation system by analyzing the parameters such as joint angle, joint torque, joint force, and muscle force. Use the analytic hierarchy process and entropy comprehensive weighting method to weight evaluation indicators. According to their evaluation standards, each parameter is given weight after quantization and normalization. Firstly, take several sitting postures that often appear in office work as examples and use the lower back analysis and joint and static pressure analysis tools in JACK software for simulation analysis. Then, the weights of various parameters such as joints and muscles of the human body were calculated using the hierarchy analysis and entropy weight method, and the quantitative evaluation system of office sitting comfort was constructed. We recruited 50 subjects for an office simulation experiment to verify the feasibility of the evaluation index. Finally, we classified the sitting posture and selected those commonly used in life for evaluation. The proposed sitting posture evaluation system can objectively and comprehensively reflect the quality of sitting posture and guide people to adopt what kind of sitting posture.
Bortezomib Use for a Critically Ill Patient with Angioimmunoblastic T-Cell Lymphoma
Authors: Shibusawa Motoharu
Published: September 2022

Angioimmunoblastic T-cell lymphoma (AITL) accounts for 18.5% of all peripheral T-cell lymphomas. There is still no gold standard chemotherapy for treating newly diagnosed AITL. This case describes the use of bortezomib in newly diagnosed AITL. A 53-year-old man with no previous illness presented with erythema and swelling in the left neck. A diagnosis of AITL was made based on the results of lymph node biopsies. AITL progression led the patient to a severely deteriorated general condition. Bortezomib was thus administered, which resulted in a reduction in lymphadenopathies, the disappearance of tumor fever, and a decrease in serum lactate dehydrogenase levels. Subsequently, the patient’s general condition gradually improved. Despite the patient’s poor condition, bortezomib was well tolerated. After bortezomib administration, the patient did not require chemotherapy for approximately 10 months. The present case indicates that bortezomib is a possible treatment option for patients with AITL.
Production, Characterization, and Cytotoxicity Effects of Silver Nanoparticles from Brown Alga (Cystoseira myrica)
Authors: Mohamed Rehab M. , Fawzy Eman M. , Shehab Rabea A. , Abdel-Salam M.O. , Salah El Din Rawheya A. , Abd El Fatah Hesham M.
Published: September 2022

A green, eco-friendly approach to biosynthesizing silver nanoparticles has been reported for marine macroalga (Cystoseira myrica) extract as a reducing agent. Different pH and temperature impact the green synthesis of silver nanoparticles suggesting that the synthesis depends greatly on pH and temperature. The structure and characters of synthesized nanoparticles were confirmed using HR-TEM, DLS, XRD, and FTIR. Cytotoxicity was indicated using provided cell lines of breast carcinoma cells (MCF-7) and human hepatocellular carcinoma cells (HepG2). Shape of silver nanoparticles at pH 9 and 75°C for 30 min was found to be suitable for the biosynthesis process and the AgNPs exhibited a characteristic absorption peak at 434 nm. High Resolution Electron Microscope Transmission reported polydisperse and spherical shapes ranging from 8 to 15 nm. High attractive and repulsive forces between each nanoparticle were recorded with an average zeta-potential value of approximately −29.3 mV. The X-ray diffraction study revealed the crystalline structure of silver nanoparticles. FTIR has shown the bioreduction of silver ions to silver nanoparticles through biomolecules found in algal extract. Silver nanoparticles have been found to have anticancer activity. The cytotoxicity assay was studied against MCF-7 and HepG2 at various concentrations (100, 50, 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, and 0.1 μg/mL). By increasing the concentration of AgNPs from 0.1 to 100 μg/mL, the maximum percentage of viability against MCF-7 and HepG2 cell line decreased from 94.55 ± 7.55 to 19.879 ± 0.503 and from 78.56 ± 11.36 to 25.81 ± 2.66 after time exposure, respectively.
Free Vibration Analysis of Bulkhead-Stiffened Functionally Graded Open Shell Using a Meshless Method
Authors: Kwak Songhun , Kim Kwanghun , Pang Kyongjin , Kim Sok , Kim Pyol
Published: September 2022

This paper focuses on the free vibration analysis of bulkhead-stiffened functionally graded open shell (FGOS) by means of the first-order shear deformation theory (FSDT) and the meshless strong form method. The bulkhead-stiffened FGOS is decomposed into several segments without bulkhead, and the equations of motion and boundary conditions for each segment are discretized by meshless strong form method, and the displacement components are approximated using meshfree Legendre–RIPM shape function using the combined basis of multi-quadrics (MQ) radial function and Legendre polynomials. The continuous conditions of displacement are applied at the interfaces between segments. The boundary and continuous conditions are enforced by using the artificial spring technique. The accuracy and reliability of the current method are validated by comparing the present results with those of the kinds of literature and the finite element program ABAQUS. The effects of some geometrical parameters and boundary conditions on the natural frequencies of bulkhead-stiffened FGOS are investigated through numerical examples, which may serve as benchmark data.
Application Based on Artificial Intelligence in Substation Operation and Maintenance Management
Authors: Zheng Xin , Zhang Haihua , Shi Junyi
Published: September 2022

To fulfill state grid Industry’s demands for smart and digitized business growth, traditional technological approaches have fallen short. Artificial intelligence (AI) technology enables coming up with solutions because electricity business types and volumes are constantly expanding and developing. Intelligent automation was a part of China’s smart grid development from the outset, and it continues to grow in the country’s electricity system. Smart substation operations and maintenance could benefit from the use of this system. There are new technological tools and theoretical concepts for the repair and control of power equipment owing to AI’s advancements in performance, accuracy, and self-learning capacity in the detection, forecasting, improvement, and judgment jobs. Substation operations and maintenance management are examined in this research using a new hybridized convolutional neural network and tweaked long short-term memory (HCNN-TLSTM) technique. Normalization is used to gather and preprocess the data immediately. Kernel-based linear discriminant analysis (K-LDA) is used to extract the features. A substation’s functioning and maintenance can then be investigated using the new approach. The genetic algorithm (GA) is used to improve the effectiveness of the proposed method. Finally, the presented technique’s performance is analyzed and compared with specific current models to achieve the largest performance in the proposed method for the management of substation operation and upkeep.
Limit Distributions of Ordered Random Variables in Mixture of Two Gaussian Sequences
Authors: Barakat H. M. , Dwes M. H.
Published: September 2022

In this paper, we study the limit distributions of extreme, intermediate, and central order statistics, as well as record values, of the mixture of two stationary Gaussian sequences under equicorrelated setup.
Realization of the New Situation Based on Reliability Mathematics Application in Public Administration
Authors: Du Jing , Feng Shizhou
Published: September 2022

With the acceleration of social modernization, the level of public management has also been significantly improved compared with previous times. People are more and more aware that a harmonious public life is the basis for realizing a good personal life. As an important guarantee for a harmonious public life, public management occupies an extremely important position. However, the great changes in the economy and society have brought forth new problems in modern public management, and the tasks and burdens of public management have become heavier and heavier, which has had a huge impact on the effectiveness of social governance. On the basis of studying the factors affecting the development of public management and the problems of management, this paper integrates the new situation of reliability mathematics application, and explores and solves the problems of public management. In the experiment, the effectiveness of the method proposed in this paper is tested from two aspects of management analysis and management effect, and the feasibility of this method is verified by comparing with the traditional management method. The final experimental data show that the innovation degree and coordination degree of management work under the traditional management method are 16.6% and 58.4%, respectively. The innovation degree and coordination degree of management work under the method of this paper reach 36.1% and 78.8%, respectively. It shows that the analysis and realization of the new situation of reliability mathematics application in public management have certain operability.
Dynamic Resource Allocation and Task Offloading for NOMA-Enabled IoT Services in MEC
Authors: Xing Hua , Xu Jiajie , Hu Jintao , Chen Ying , Huang Jiwei
Published: September 2022

Integrating nonorthogonal multiple access (NOMA) and edge computing into the Internet of Things (IoT) for resource allocation and computing offloading can effectively reduce delay and energy consumption and improve spectrum efficiency. Computation tasks can be split into several independent subtasks and can be locally processed by IoT devices or offloaded to the MEC servers to process. The limited computing resources deteriorate the system performance. Thus, it is crucial to design the reasonable allocation strategies of computation resource and transmission power resource. In this paper, we jointly determine the CPU-cycle frequency allocation and transmission power allocation and formulate a stochastic optimization to minimize the energy consumption of IoT devices. Based on the Lyapunov optimization theory, we decompose the optimization problem into two deterministic subproblems to solve separately. One of them is obtained by seeking the first derivative, and the other is solved by using the best response idea after establishing the game model. Meanwhile, we propose a dynamic resource allocation and task offloading (DRATO) algorithm. Moreover, the simulation experiments show that the proposed algorithm effectively improves system performance and reduces energy consumption compared to three other benchmark methods.
Quality and Tool Stability Improvement in Turning Operation Using Plastic Compliant Damper
Authors: Sathyapriya G. , Natarajan U. , Sureshkumar B. , Navaneethakrishnan G. , Palanisamy R. , Bajaj Mohit , Sharma Naveen Kumar , Kitmo
Published: September 2022

The major hindrance for any production industry in obtaining higher yield is the lack of achieving full material removal rate in the machine tools. If achieved, the surface quality of the machined works will be compromised. An attempt was made in this work to reduce the compromise of surface finish by integrating a plastic compliant damper that is capable of reducing the effects of unwanted vibrations generated during the machining process. The damper is designed to degenerate the effects of vibration and thereby improve product finish. It is made of acrylonitrile butadiene styrene by fused deposition modelling (an additive manufacturing technique). Measuring the vibration and cutting force is indirectly related to finish in product and tool wear rate. The stability of tool is improved greatly by the new compliant damper possessing displacement resistance. The effect of variation in cutting conditions on the performance of conventional rubber damper and plastic compliant damper was analyzed. The highest speed, feed rate, and depth of cut of 540 rpm, 0.02 mm/s, and 1.5 mm, respectively, found to be cutting condition at which imparted minimum surface roughness values of 2.80 μm and 0.52 μm with conventional rubber damper and plastic compliant damper, respectively. The speed and feed rate and depth of cut are found to be important parameters while studying surface roughness. The peak surface roughness is reduced by 48% by using the proposed compliant damper.
Research on Personalized Recommendation Method of Intangible Social Heritage and Materials in Schools under Double Reduction Policy
Authors: Kun Jiang , Lingchun Shao
Published: September 2022

Individualized recommendation of imperceptible social heritage and materials in schools under the double reduction policy is to evaluate and judge students’ learning interests and specialties and recommend suitable imperceptible social heritage and materials to students. Aiming at the problem that the collaborative filtering recommendation method does not match the individualized needs of primary and secondary school students under the double reduction policy, in this paper, we suggest a personalized recommendation system of imperceptible social heritage and materials in schools under the double reduction policy based on joint template feature matching and interest feature point mining. First, taking the information management platform of imperceptible social heritage and materials in schools as the structural model, the grading model and homomorphic distribution attribute model of imperceptible social heritage and materials for primary and secondary school students under the double reduction policy are constructed. Second, the probability density characteristic analysis method of joint template matching is used to construct the personalized recommendation model of the imperceptible social heritage and materials in schools. Third, then the personalized characteristic distribution and fitness parameter extraction of the imperceptible social heritage and materials in schools under the double reduction policy are carried out, so as to realize the reasonable matching of personalized characteristic requirements and project interest points and realize the personalized recommendation of imperceptible social heritage and materials in schools under the double reduction policy. Finally, a simulation experiment was carried out to test and evaluate the outcomes. The outcomes express that the personalized recommendation items of imperceptible social heritage and materials in schools with this method have higher scores, and the average absolute error and root mean square error are smaller, which improves the quality of dynamic and accurate matching between imperceptible social heritage and materials and students’ hobby characteristics.
Computer-Aided Design Methods in Virtual Reality Product Development
Authors: Guan Shan
Published: September 2022

In order to improve the effectiveness of virtual reality product design, this paper combines the computer-aided design method to construct a virtual reality product development system and analyzes the elements, architecture, and calculation steps of the virtual reality model in detail. Moreover, from the research on the color appearance phenomenon, this paper leads to the improvement direction of improving the virtual reality model. In addition, this paper discusses the advantages of the virtual reality product design model and its feasibility as a PCS link space to undertake the task of color appearance transformation. The experimental research analysis shows that the virtual reality product design system based on computer-aided technology proposed in this paper has good effects and can effectively improve the effect of virtual reality product design.
Trusted Computing and Privacy Protection Method for Computer IoT Nodes Based on Fuzzy Logic Blockchain
Authors: Zhong Beixin , Yang Zilong , Liu Zhonghao , Chen Xiaoyong , Cheng Shi
Published: September 2022

With the continuous growth of the social economy, the trusted computing and privacy protection methods of IoT nodes are constantly innovating and changing, from the traditional single IoT node protection method to the new interactive IoT nodes supplemented by various network resources. That is, the item information server encrypts the detailed information of the item layer by layer with the session key of the adjacent node according to the node sequence of the response path. By completing the complete interactive design and the protection knot in the unique illusory environment, the application and discussion of privacy protection is achieved in the context of Internet of Things, creating a design concept for trusted computing and privacy protection methods for IoT nodes, and discussing the rationality of interactive design in the process of trusted computing and privacy protection methods for IoT nodes. The simulation results show that the application of fuzzy logic blockchain is very extensive, and the trusted computing and privacy protection methods of IoT nodes have a broader platform and a more open environment.
Synthesis of AA8050/B4C/TiB2 Hybrid Nanocomposites and Evaluation of Computer‐Aided Machining Parameters
Authors: Sathish T. , Vinayagam Mohanavel , Raja T. , Seikh A. H. , Siddique M. H. , Subbiah Ram , Hailu Beruk
Published: September 2022

This research focusses on synthesizing the hybrid nanocomposite samples with AA8050 and the reinforcement of B4C and TiB2 nanoparticles at 3 different quality grades. To investigate their machinabilities on the prepared composites in the computer‐aided machining centre, the objectives are maximizing the material removal rate (MRR) and minimizing the surface roughness for a specific application. Stir casting process was employed in synthesizing the hybrid nanocomposite samples. Utilizing CNC turning centre was employed to investigate machinability performance on hybrid nanocomposite samples. The PVD‐coated HSS tool and dry cutting environment were considered. The quality of machining was investigated by observing the surface roughness on the machined surfaces of samples of hybrid nanocomposite. The machining rate was investigated through the response of material removal rate at as per Taguchi design of experiments L27 orthogonal array. The hybrid nanocomposite synthesizing parameter of contribution of nanoparticle reinforcement (8%, 10%, and 12%) and the Turing parameters include spindle speed (800 rpm, 1000 rpm, and 1200 rpm), machining feed (0.05 mm/rev, 0.10 mm/rev, and 0.15 mm/rev) and depth of cut (0.5 mm, 0.75 mm, and 1 mm). The best performing input levels were identified through Taguchi analysis and the involved input variables were analysed and prediction model developed through ANOVA. The maximum material removal rate and the minimum surface roughness were reordered as 1380 mm3/min.
Noninvasive Ventilation in Treatment of Respiratory Failure-Related COVID-19 Infection: Review of the Literature
Authors: Mina Bushra , Newton Alexander , Hadda Vijay
Published: September 2022

The recently diagnosed coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in December 2019 commonly affects the respiratory system. The incidence of acute hypoxic respiratory failure varied among epidemiological studies with high percentage of patients requiring mechanical ventilation with a high mortality. Noninvasive ventilation is an alternative tool for ventilatory support instead of invasive mechanical ventilation, especially with scarce resources and intensive care beds. Initially, there were concerns by the national societies regarding utilization of noninvasive ventilation in acute respiratory failure. Recent publications reflect the gained experience with the safe utilization of noninvasive mechanical ventilation. Noninvasive ventilation has beneficiary role in treatment of acute hypoxic respiratory failure with proper indications, setting, monitoring, and timely escalation of therapy. Patients should be monitored frequently for signs of improvement or deterioration in the clinical status. Awareness of indications, contraindications, and parameters reflecting either success or failure of noninvasive ventilation in the management of acute respiratory failure secondary to COVID-19 is essential for improvement of outcomes.
Abstract IA02: The good and the bad sides of tertiary lymphoid structures in liver cancer
Authors: Pikarsky Eli
Published: September 2022

Tertiary lymphoid structures (TLSs) are formed in chronically inflamed tissues in response to stress. They form an in situ source for adaptive immune responses, and are considered the frontal command posts of the adaptive immune system. In cancer, they were first recognized to be associated with a good prognosis (e.g. in colorectal cancer and melanoma). Later on, we and others noted that in some cancers their presence can be associated with worse prognosis. In particular, we showed that they can form microniches in which tumor cells can proliferate, depending on cues that are derived from TLS residing cells. Recently, several studies showed that TLSs are important in responding to immune checkpoint inhibitors, indicating that T cell exhaustion could play a role in TLS dysfunction. We hypothesized, that similar to single cells, TLSs can also become dysfunctional, explaining why in particular cases they can be associated with a bad outcome in cancer. Using a mouse model of TLS dependent liver cancer we find that T cell exhaustion is prevalent in pro-tumorigenic TLSs in the liver, and dissect the cell types that are responsible for this immunopathologic state. Our studies of human tissues are in line with the notion that TLS dysfunction correlates with T cell exhaustion in TLSs.

Citation Format: Eli Pikarsky. The good and the bad sides of tertiary lymphoid structures in liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA02.
Abstract IA05: Immune mechanisms driving carcinogenesis in NASH
Authors: Heikenwälder Mathias
Published: September 2022

In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multifactorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to the single-cell level. Still, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune checkpoint inhibitors do not work as efficiently. Whereas much effort has been invested in elucidating the role of innate immune response in the hepatic NAFLD microenvironment, only in the past decade have novel critical roles been unraveled for T cells in driving chronic inflammation toward HCC. The metabolic and immune microenvironment interact to recreate a tumor-promoting and immune-suppressive terrain, responsible for resistance to anticancer therapy. Here, I will illustrate the cellular crosstalk with other immune cells, regulatory networks or stimulatory effects of these interactions, and role of the metabolic microenvironment in influencing immune cell functionality in the context of NAFLD and HCC.

Citation Format: Mathias Heikenwälder. Immune mechanisms driving carcinogenesis in NASH [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA05.
Abstract IA09: Role of liquid biopsy in early detection and assessment of response in hepatocellular carcinoma
Authors: Villanueva-Rodriguez Augusto
Published: September 2022

Early hepatocellular carcinoma detection is suboptimal with less than 25% of eligible patients enrolled in surveillance. In addition, recommended tools (biannual abdominal ultrasound with or without AFP) have poor sensitivity (63% for early-stage tumors). This has prompted the development of liquid biopsy approaches to improve performance and increase implementation. Methylation analysis of circulating tumor DNA and RNA sequencing in extracellular vesicles have shown promising performance in case control studies. This technology has also been applied to identify predictor biomarkers of response to systemic therapies. With 9 agents approved and without a clear strategy on how to select patients for therapies, the need to develop minimally-invasive biomarkers in this space cannot be overemphasized.

Citation Format: Augusto Villanueva-Rodriguez. Role of liquid biopsy in early detection and assessment of response in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA09.
Abstract IA14: Lessons learned from phase III trials in HCC: OS, PFS and ORR
Authors: Zhu Andrew X.
Published: September 2022

Through well conducted phase III trials, recent development of molecularly targeted agents, immune checkpoint inhibitors, and combination strategies in advanced hepatocellular carcinoma (HCC) has significantly improved the treatment outcome in this disease. The median overall survival (OS) for patients receiving the new standard treatment, atezolizumab plus bevacizumab, has approached to 20 months in IMbrave150 trial. While OS remains the gold standard and main endpoint for phase III trials in advanced HCC, there is an increasing need to define surrogate endpoints including progression free survival (PFS) and overall response rate (ORR) that can reliably predict the survival benefits. The author will discuss the rationale and current status of using PFS and ORR as surrogate endpoints in HCC, and the strengths and limitations of PFS and ORR as surrogate endpoints to predict survival.

Citation Format: Andrew X. Zhu. Lessons learned from phase III trials in HCC: OS, PFS and ORR [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA14.
Abstract IA16: Trial enrichment and proof of concept studies
Authors: Villanueva-Rodriguez Augusto
Published: September 2022

Identification of oncogene addiction loops has provided new therapeutic targets in oncology. Selective targeting of the ABL-BCR fusion in patients with chronic lymphocytic leukemia using imatinib was a major clinical breakthrough. Similar approaches in other solid tumors led to the approval of additional biomarker-driver molecular therapies (e.g., vemurafenib in BRAF mutated melanoma). Success of this approach was contingent on the identification of biomarkers that could help identify patients most likely to respond to these therapies. This spurred efforts to implement clinical trials able to detect efficacy in specific patient populations, specifically those enriched in the biomarker under evaluation. This has also been applied in hepatocellular carcinoma with mixed results. Approval of ramucirumab in patient with elevated AFP is the first example of successful trial enrichment, while tivantinib is paradigmatic of a negative biomarker enrichment trial. Lack of recurrent druggable mutations makes biomarker-driven clinical trials in HCC more difficult, which underscores the need for predictive biomarkers of immune therapies.

Citation Format: Augusto Villanueva-Rodriguez. Trial enrichment and proof of concept studies [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA16.
Abstract IA17: Assessing response and time-to-event end-points: RECIST and mRECIST
Authors: Lencioni Riccardo
Published: September 2022

In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). mRECIST was intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease. mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches including immunotherapy combination therapies, there is a need to further refine and clarify some concepts around the performance of mRECIST.

Citation Format: Riccardo Lencioni. Assessing response and time-to-event end-points: RECIST and mRECIST [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA17.
Abstract IA18: Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH)
Authors: Yarchoan Mark
Published: September 2022

Hepatocellular carcinoma (HCC) usually arises in the setting of liver cirrhosis from viral or non-viral causes. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is a rising cause of HCC in the United States and many other parts of the world. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD1) or its ligand have improved outcomes for patients with advanced HCC. In general, clinical biomarkers are not currently used to identify patients most likely to benefit from systemic immunotherapy in HCC, and whether etiology has any effect on immunotherapy responses in HCC has been unclear. In this session, we will review recent preclinical data suggesting that NASH may impair immune responses in HCC. We will also review data from The Cancer Genome Atlas (TCGA) comparing the tumor immune microenvironment of viral-associated and non-viral HCC, and review the preponderance of clinical evidence indicating that HBV, HCV, and non-viral HCC all derive clinical benefit from immune checkpoint inhibitor therapy.

Citation Format: Mark Yarchoan. Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH) [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA18.
Abstract IA25: Clinical trials and molecular therapies in iCCA
Authors: Valle Juan W.
Published: September 2022

Cisplatin and gemcitabine (CisGem) has been the stadard of care for patients presenting with advanced iCCA for over a decade. Intensified (triplet) chemotherapy remains investigational except in Japan, where the CisGem and S1 is an option. Robust data has shown that 5FU-based, second-line, combination chemotherapy has modest activity in a molecularly-unselected population. An improved understanding of the biology underpinning iCCA has led to the identification of molecular alterations linked to targeted therapies. The most prominent alterations are mutations in IDH1 and FGFR2 fusions; both of these are addressed later in the session. This presentation will highlight other selected subgroups, including patients whose tumours are harbouring BRAF-V600E mutations, HER2 amplification/over-expression, and NTRK fusions as examples, although additional groups continue to emerge. Cholangiocarcinoma is recognised to have an underlying immune predisposition, in selected cases. Harnessing the immune response has previously provided limited signals of efficacy. However, the TOPAZ-1 study, a randomised phase III study has recently shown an incremental survival benefit in patients with biliary tract cancer with the addition of durvalumab to CisGem chemotherapy, including intrahepatic cholangiocarcinoma. No predictive factors are known to enrich for patients most likely to benefit from immunotherapy to date. Additional analysis of patient subgroups in TOPAZ-1 as well as the results of the KEYNOTE-966 phase III study (CisGem +/- pembrolizumab) are eagerly awaited.

Citation Format: Juan W. Valle. Clinical trials and molecular therapies in iCCA [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA25.
Abstract PO014: Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model
Authors: Yang Jun
Published: September 2022

Lack of relevant animal models and cell lines of hepatoblastoma hampers our understanding pathogenesis of and identifying therapeutic targets for this neoplasm. We report a liver-specific MYC-driven hepatoblastoma murine model that faithfully recapitulates the pathological features of mixed fetal and embryonal hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of human disease. Single-cell RNA-sequencing (scRNA-seq) and spatiotranscriptomics identified distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we mapped the cancer dependency genes using CRISPR-Cas9 screening and identified druggable targets shared with human hepatoblastoma (i.e., CDK7, CDK9, PRMT1, PRMT5). Our screen also revealed oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is the mainstay for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identified modifiers whose loss-of-function synergizes and antagonizes with the effect of chemotherapy. The combination of PRKDC inhibition and chemotherapy greatly enhances therapeutic efficacy. Our studies have provided and characterized useful resources including disease models and identified potential therapeutic targets of high-risk hepatoblastoma.

Citation Format: Jun Yang. Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO014.
Abstract PO029: Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer
Authors: Sanghvi Viraj , Rust Aleksander , Leibold Josef , Lowe Scott , Viale Agnes , Chodera John , Hendrickson Ronald C. , de Stanchina Elisa , Wendel Hans-Guido
Published: September 2022

NRF2 is an “undruggable” oncogenic transcription factor recurrently mutated in solid tumors such as liver and lung cancers. Our recent study demonstrates that NRF2 acts by coordinating the redox and metabolic stress responses as well as drug resistance programs in liver and other cancers. Developing an NRF2 inhibitor is a major goal of cancer drug discovery. Here, we identify the non-canonical Hippo pathway protein serine/threonine kinase 38 (STK38/NDR1) as a new NRF2 kinase that is a requirement for its stability and function. STK38 directly phosphorylates NRF2 at two sites (S33 and T559), and both sites contribute to full NRF2 activation. Loss of STK38 disables the redox response in NRF2 driven cancers and leads to tumor regression in vivo. Conversely, STK38 can also activate NRF2 and promote de novo liver cancer development in mice. This oncogenic effect is reflected in low frequency (3%) genomic amplifications in human liver cancers. Importantly, inhibition of the upstream STK38-activating mammalian Hippo kinases STK3/4 (MST2/1) by XMU-MP-1 inactivates STK38-NRF2 regulatory axis in vitroand in vivo. More importantly, XMU-MP-1 produces single agent activity against NRF2-driven liver and lung cancers in vivo in primary and patient derived xenograft (PDX)-based mouse models. In addition, we performed an in-silicoscreen and identified TAE-684 as an STK38 inhibitor that was subsequently confirmed to block STK38 activity in an in vitro kinase assay. TAE-684 treatment resulted in significant growth impairment of NRF2-mutant PDXs in vivo but no activity was observed in NRF2 wildtype counterparts. Together, these results uncover a surprising role of Hippo-related kinase STK38 in NRF2 activation and point to a paradoxical vulnerability in NRF2-driven cancers.

Citation Format: Viraj Sanghvi, Aleksander Rust, Josef Leibold, Scott Lowe, Agnes Viale, John Chodera, Ronald C. Hendrickson, Elisa de Stanchina, Hans-Guido Wendel. Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO029.
Microbes Contribute to Chemopreventive Efficacy, Intestinal Tumorigenesis, and the Metabolome
Authors: Ferrara Carmen R. , Bai Ji Dong K. , McNally Erin M. , Putzel Gregory G. , Zhou Xi Kathy , Wang Hanhan , Lang Alan , Nagle Deborah , Denoya Paula , Krumsiek Jan , Dannenberg Andrew J. , Montrose David C.
Published: September 2022

Bacteria are believed to play an important role in intestinal tumorigenesis and contribute to both gut luminal and circulating metabolites. Celecoxib, a selective cyclooxygenase-2 inhibitor, alters gut bacteria and metabolites in association with suppressing the development of intestinal polyps in mice. The current study sought to evaluate whether celecoxib exerts its chemopreventive effects, in part, through intestinal bacteria and metabolomic alterations. Using ApcMin/+ mice, we demonstrated that treatment with broad-spectrum antibiotics (ABx) reduced abundance of gut bacteria and attenuated the ability of celecoxib to suppress intestinal tumorigenesis. Use of ABx also impaired celecoxib's ability to shift microbial populations and gut luminal and circulating metabolites. Treatment with ABx alone markedly reduced tumor number and size in ApcMin/+ mice, in conjunction with profoundly altering the metabolite profiles of the intestinal lumen and blood. Many of the metabolite changes in the gut and circulation overlapped and included shifts in microbially derived metabolites. To complement these findings in mice, we evaluated the effects of ABx on circulating metabolites in patients with colon cancer. This showed that ABx treatment led to a shift in blood metabolites, including several that were of bacterial origin. Importantly, changes in metabolites in patients given ABx overlapped with alterations found in mice that also received ABx. Taken together, these findings suggest a potential role for bacterial metabolites in mediating both the chemopreventive effects of celecoxib and intestinal tumor growth.

Prevention Relevance:

This study demonstrates novel mechanisms by which chemopreventive agents exert their effects and gut microbiota impact intestinal tumor development. These findings have the potential to lead to improved cancer prevention strategies by modulating microbes and their metabolites.