bluuebunny/crossref_metadata_2025 huggingface dataset:
Psicología y Pueblos Indígenas
Authors: González Roberto , Carvacho Héctor , Jiménez-Moya Gloria
Published: January 2022

La pregunta sobre la existencia de características comunes inherentes a la psicología de los pueblos Indígenas de todo el mundo ha sido objeto de mucho debate. Nosotros argumentamos que los pueblos Indígenas comparten la experiencia de la colonización, así como sus consecuencias sociales y psicológicas. Desarrollamos este argumento en cuatro secciones: ( a) La historia global de la colonización y las desigualdades sociales; ( b) aspectos relativos a la identidad y los procesos grupales, incluidas la transmisión intergeneracional de valores compartidos, la conexión con la naturaleza y la promoción del cambio social; ( c) el prejuicio y la discriminación hacia los pueblos Indígenas y el rol que juegan los procesos psicológicos para promover relaciones positivas entre los pueblos Indígenas y no-Indígenas; y ( d) el impacto del trauma histórico y del colonialismo en la cognición, la salud mental y el bienestar de los pueblos Indígenas, así como la base para el desarrollo de intervenciones exitosas que integran los conocimientos Indígenas. Por último, abordamos los desafíos futuros de la investigación sobre estos temas.
Public Health Roles in Addressing Commercial Determinants of Health
Authors: Lee Kelley , Freudenberg Nicholas
Published: January 2022

The shared challenges posed by the production and distribution of health-harming products have led to growing recognition of the need for policy learning and transfer across problems, populations, and social contexts. The commercial determinants of health (CDoH) can serve as a unifying concept to describe the population health consequences arising from for-profit actors and activities, along with the social structures that sustain them. Strategies to mitigate harms from CDoH have focused on behavioral change, regulation, fiscal policies, consumer and citizen activism, and litigation. While there is evidence of effective measures for each strategy, approaches that combine strategies are generally more impactful. Filling gaps in evidence can inform ways of adapting these strategies to specific populations and social contexts. Overall, CDoH are addressed most effectively not through siloed efforts to reduce consumption of health-harming products, but instead as a set of integrated strategies to reduce exposures to health-harming commercial actors and activities.
Continuous Incisional Lidocaine in Pediatric Patients following Open Heart Surgery
Authors: Fernández Sarah Nicole , Toledo Blanca , Cebrián Jesús , Pérez-Caballero Ramón , López-Herce Jesús , Mencía Santiago
Published: January 2022

Continuous incisional lidocaine infusion has been proposed as an adjunctive therapy in the management of postoperative pain in adult patients. The aim of this study was to determine the efficacy and safety of a continuous subcutaneous lidocaine infusion in pediatric patients following open heart surgery. All patients receiving a subcutaneous lidocaine infusion in median sternotomy incisions after open heart surgery during 2 consecutive years were included in the study. A historical cohort of patients was used as a control group. Demographic variables (age, size, and surgical procedure), variables related to sedation and analgesia (COMFORT and analgesia scales, drug doses, and duration), and complications were registered. 106 patients in the lidocaine infusion group and 79 patients in the control group were included. Incisional analgesia was effective for the treatment of pain as it reduced the dose and duration of intravenous fentanyl (odds ratio (OR) 6.26, confidence interval (CI) 95%: 2.48‐15.97, p = 0.001; OR 4.30, CI 95%: 2.09‐8.84, p = 0.001, respectively). The reduction in fentanyl use was more important in children over two years of age. Adverse effects were seen in three children (2.8%): they all had decreased level of consciousness, and one of them presented seizures as well. Two of these three patients had lidocaine levels over 2 mcg/ml. A continuous lidocaine incisional infusion is effective for the treatment of pain after open heart surgery. This procedure reduced intravenous analgesic drug requirements in pediatric patients undergoing a median sternotomy incision. Although the incidence of secondary effects is low, monitoring of neurologic status and lidocaine blood levels are recommended in all patients.
[Retracted] Identification of Potential Key Genes and Molecular Mechanisms of Medulloblastoma Based on Integrated Bioinformatics Approach
Authors: Islam Md. Rakibul , Abdulrazak Lway Faisal , Alam Mohammad Khursheed , Paul Bikash Kumar , Ahmed Kawsar , Bui Francis M. , Moni Mohammad Ali
Published: January 2022

Background. Medulloblastoma (MB) is the most occurring brain cancer that mostly happens in childhood age. This cancer starts in the cerebellum part of the brain. This study is designed to screen novel and significant biomarkers, which may perform as potential prognostic biomarkers and therapeutic targets in MB. Methods. A total of 103 MB‐related samples from three gene expression profiles of GSE22139, GSE37418, and GSE86574 were downloaded from the Gene Expression Omnibus (GEO). Applying the limma package, all three datasets were analyzed, and 1065 mutual DEGs were identified including 408 overexpressed and 657 underexpressed with the minimum cut‐off criteria of ∣log fold change | >1 and P < 0.05. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and WikiPathways enrichment analyses were executed to discover the internal functions of the mutual DEGs. The outcomes of enrichment analysis showed that the common DEGs were significantly connected with MB progression and development. The Search Tool for Retrieval of Interacting Genes (STRING) database was used to construct the interaction network, and the network was displayed using the Cytoscape tool and applying connectivity and stress value methods of cytoHubba plugin 35 hub genes were identified from the whole network. Results. Four key clusters were identified using the PEWCC 1.0 method. Additionally, the survival analysis of hub genes was brought out based on clinical information of 612 MB patients. This bioinformatics analysis may help to define the pathogenesis and originate new treatments for MB.
Numerical Solution of Three-Dimensional Transient Heat Conduction Equation in Cylindrical Coordinates
Authors: Tsega Endalew Getnet
Published: January 2022

Heat equation is a partial differential equation used to describe the temperature distribution in a heat-conducting body. The implementation of a numerical solution method for heat equation can vary with the geometry of the body. In this study, a three-dimensional transient heat conduction equation was solved by approximating second-order spatial derivatives by five-point central differences in cylindrical coordinates. The stability condition of the numerical method was discussed. A MATLAB code was developed to implement the numerical method. An example was provided in order to demonstrate the method. The numerical solution by the method was in a good agreement with the exact solution for the example considered. The accuracy of the five-point central difference method was compared with that of the three-point central difference method in solving the heat equation in cylindrical coordinates. The solutions obtained by the numerical method in cylindrical coordinates were displayed in the Cartesian coordinate system graphically. The method requires relatively very small time steps for a given mesh spacing to avoid computational instability. The result of this study can provide insights to use appropriate coordinates and more accurate computational methods in solving physical problems described by partial differential equations.
Development and Application of Artificial Intelligence Multimedia Technology Based on Big Data
Authors: Zhang Yezi
Published: January 2022

Artificial intelligence is an innovative enterprise theme that combines computer science, physiology, science, and other disciplines, including expert programs, technical experiments, games, native language understanding, cognitive rehabilitation, robotics, engineering, recognition, and other fields. The breakthrough growth made the arrival of the era of big data have a fundamental impact on many traditional industries and has also promoted the transformation of teaching methods and methods in the field of education. In the traditional classroom, due to the limitations of teaching resources, teaching time, and location, students are basically passively accepted by the teacher, and the teaching form is single. This will improve in the age of big data with well-developed network message. Modern distance education uses advanced technology such as computer networks, multimedia, and artificial intelligence to build a virtual teaching environment based on the network. It breaks through the limitations of teachers, teaching materials, experimental equipment, and other resources that exist under the traditional teaching model. Using educational resources of the same scale can expand educational capabilities exponentially and at the same time overcomes the unified progress of traditional teaching methods, single teaching methods, and students’ dissatisfaction. The shortcomings of differences and personalities that are not reflected are conducive to the improvement of the quality of education. It is the original intention of education to offer students special study resources and to stimulate students’ enthusiasm for learning. To enhance the current learning environment, the article builds a personalized multimedia network teaching system based on big data and streaming media technology. By recording the teacher’s class process as a video and uploading it to the multimedia network teaching system, students can watch and download related videos online for learning and also communicate online. The system can also provide personalized and intelligent recommendations for students based on student learning habits. The system is developed based on intelligent multimedia method and has the characteristics of security and stability and has done some help for network teaching of educational institutions.
A Strategy for Screening the Lipid-Lowering Components in Alismatis Rhizoma Decoction Based on Spectrum-Effect Analysis
Authors: Chang Xiao-Yan , Wu Jia-Shuo , Zhang Fang-Qing , Li Zhuang-Zhuang , Jin Wei-Yi , Wang Jing-Xun , Wang Wei-Hua , Shi Yue
Published: January 2022

Alismatis Rhizoma decoction (ARD), comprised of Alisma plantago-aquatica subsp. orientale (Sam.) Sam and Atractylodes macrocephala Koidz. at a ratio of 5 : 2, is a classic traditional Chinese medicine (TCM) formula with successful clinical hypolipidemic effect. This paper aimed to explore the major bioactive compounds and potential mechanism of ARD in the treatment of hyperlipidemia on the basis of spectrum-eﬀect analysis and molecular docking. Nine ARD samples with varying ratios of the constituent herbs were prepared and analyzed by UPLC-Q-TOF/MS to obtain the chemical spectra. Then, the lipid-lowering ability of the nine samples was tested in an oleic acid-induced lipid accumulation model in human hepatoma cells (HepG2). Grey relational analysis and partial least squares regression analysis were then performed to determine the correlation between the chemical spectrums and lipid-lowering efficacies of ARD. The potential mechanisms of the effective compounds were investigated by docking with the farnesoid X receptor (FXR) protein. The results indicated that alisol B 23-acetate, alisol C 23-acetate, and alisol B appeared to be the core eﬀective components on hyperlipidemia in ARD. Molecular docking further demonstrated that all three compounds could bind to FXR and were potential FXR agonists for the treatment of hyperlipidemia. This study elucidated the eﬀective components and potential molecular mechanism of action of ARD for treating hyperlipidemia from a perspective of different compatibility, providing a new and feasible reference for the research of TCM formulas such as ARD.
Role of TRPV4 in the Diagnosis and Treatment of Helicobacter pylori Infection in Children with Duodenal Ulcers
Authors: Li Chuanying , Cheng Rong , Li Lin , Chen Miaomiao , Wu Cheng
Published: January 2022

Duodenal ulcer seriously affects the quality of life and life safety of children, but the pathogenesis of children with duodenal ulcer is still unclear. As an important second messenger in the body, Ca2+ participates in the physiological and pathological processes of various diseases. Therefore, transient receptor potential vanilloid type 4 (TRPV4) as one of the channels that mediate Ca2+ has attracted widespread attention in recent years. Here, we found that TRPV4 is highly expressed in children with duodenal ulcer and has good diagnostic value through specimens of children with duodenal ulcer, and animal experiments have proved that TRPV4 is also highly expressed in duodenal ulcer mice. In addition, TRPV4 can enhance intestinal permeability, thereby promoting further infiltration of inflammatory factors. In summary, these results indicate that TRPV4 is involved in the occurrence and development of duodenal ulcer. Therefore, this study provides the diagnostic and therapeutic value of TRPV4 in children with duodenal ulcer.
Aircraft Target Classification Method for Conventional Narrowband Radar Based on Micro-Doppler Effect
Authors: Xia Saiqiang , Zhang Chaowei , Cai Wanyong , Yang Jun , Hua Liangfa , Wei Xu , Jiang Haiman
Published: January 2022

For a conventional narrowband radar system, its insufficient bandwidth usually leads to the lack of detectable information of the target, and it is difficult for the radar to classify the target types, such as rotor helicopter, propeller aircraft, and jet aircraft. To address the classification problem of three different types of aircraft target, a joint multifeature classification method based on the micro-Doppler effect in the echo caused by the target micromotion is proposed in this paper. Through the characteristics analysis of the target simulation echoes obtained from the target scattering point model, four features with obvious distinguishability are extracted from the time domain and frequency domain, respectively, that is, flicker interval, fractal dimension, modulation bandwidth, and second central moment. Then, a support vector machine model will be applied to the classification of the three different types of aircraft. Compared with the conventional method, the proposed method has better classification performance and can significantly improve the classification probability of aircraft target. The simulations are carried out to validate the effectiveness of the proposed method.
Experimental Study on Thermal Insulation Effect of the Buried Oil-Gas Pipelines in Permafrost Regions
Authors: Liu Deren , Yang Jiale , Wang Xu , Zhao Junming , Xu Shuochang , Zhao Yongchun
Published: January 2022

In permafrost regions, long distance buried pipelines are widely used to transport oil and natural gas resources. However, pipeline problems occur frequently due to the complicated surrounding environment and transportation requirement of positive temperature. In this study, a thermal insulation layer was applied to mitigate permafrost degeneration around the buried oil-gas pipelines. Based on engineering background of the Sebei-Xining-Lanzhou natural gas pipeline in China, an indoor model test was designed and carried out in which many key indices, such as the temperature regime, vertical displacement, pipeline wall stress, and water content, were closely monitored. The test results indicate that the large heat loss of the buried pipeline produces a rapid increase in ground temperatures which seriously reduces the bearing capacity of the permafrost foundation. The buried oil-gas pipelines with a thermal insulation layer can effectively reduce the thawing range and vertical displacement of the permafrost foundation around the buried pipelines, so as to control the stress of the pipeline wall in the normal range and protect the safe and stable operation of the buried oil-gas pipelines. The experimental results can serve as a reference for the construction, operation, and maintenance of buried oil-gas pipelines in permafrost regions.
Study on Aerodynamic Nonlinear Characteristics of Semiclosed Box Deck Based on Variation of Motion Parameters
Authors: Jia Jie , Lu Haoyang , Li Xiaobo , Chen Qian
Published: January 2022

In order to study the nonlinear characteristics of self‐excited aerodynamic forces of bluff body bridge section with the change of motion parameters, a numerical wind tunnel is established by the dynamic mesh technique of computational fluid dynamics (CFD). A state‐by‐state forced vibration method is used to identify the self‐excited aerodynamic forces of single degree‐of‐freedom (DOF) heaving and pitching motion. Fast Fourier transform (FFT) is adopted to obtain frequency‐domain data for analysis. The reliability of the obtained aerodynamic results is verified by wind tunnel tests. The results show that the high‐order harmonic components are found in the self‐excited aerodynamic forces of semiclosed box deck section, which are more significant in aerodynamic lift than in aerodynamic moment. The proportion of aerodynamic nonlinear components increases with amplitude. The effect of amplitude on the nonlinear components of heaving motion is generally higher than that of pitching motion, and aerodynamic moment is highly sensitive to the increase of vertical amplitude. The variation of the nonlinear components of the deck section with frequency is not a simple monotonic relationship, and there is a stationary point at 10 Hz frequency. The existence of wind attack angle makes the proportion of nonlinear components reach more than 30% and greatly increases the proportion of second harmonic. In addition, the high‐order harmonic components, which are not integer multiples, are found at large amplitude and positive angle of attack.
Stability Parameter Range of a Tethered Unmanned Aerial Vehicle
Authors: He Wei , Zhang Suxia
Published: January 2022

In this study, the stability parameter range of a tethered quadrotor unmanned aerial vehicle (UAV) under the action of the transient wind field is numerically analyzed, which can provide a theoretical basis for the design and application of such systems. Three factors affecting the stability of tethered UAV system are determined, namely, cable tension, cable elongation, and UAV vibration velocity, and the corresponding judgment criteria are obtained. Specifically, the priority of the three criteria sequentially decreases. According to these criteria, the stability parameter range of the tethered UAV is examined under the cable parameters such as length, diameter, and elastic modulus and the environmental parameters such as the amplitude and period of the wind field. The results show that for designing the tethered UAV structure, by reducing the length of the tethered cable and increasing its diameter and elastic modulus, the working stability of tethered UAV system can be improved.
The Effects of Hedgehog Signaling Pathway on the Proliferation and Apoptosis of Melanoma Cells
Authors: Peng Zhi-Peng , Huang Shan-Fu , Li Jun-Jun , Tang Xi-Ke , Wang Xi-Yue , Li Hong-Mian
Published: January 2022

Background. Studies have found that the abnormality of the Hedgehog signaling pathway is related to the occurrence and development of a variety of tumors, but the effect of this signaling pathway on melanoma cells is still unclear. Methods. This study aimed to discuss the effect of Hedgehog signaling pathway on the proliferation and apoptosis of human malignant melanoma A375 cells and explore its possible mechanism in the proliferation and apoptosis of melanoma cells. Different concentrations of Hedgehog signaling pathway inhibitor cyclopamine (5, 10, 20 and 40 μM) were used to treat human melanoma A375 cells for 24, 48, and 72 h, and set a blank control group (0 μM). Trypan blue cell counting method was used to detect cell viability. MTT method was used to detect the inhibition rate of cell proliferation. Transwell was used to detect cell invasion, and flow cytometry was used to detect cell apoptosis. Results. Through the trypan blue cell counting method and MTT experiment, it was found that the Hedgehog signaling pathway inhibitor cyclopamine has an inhibitory effect on the proliferation and viability of melanoma A375 cells (

P
<
0.05

), and the proliferation inhibitory effect is enhanced with prolonged action time in a dose- and time-dependent manner. Transwell experiment showed that compared with the blank control group, the invasion and migration ability of the treated melanoma A375 cells are significantly reduced, and the difference is statistically significant (

P
<
0.05

). Cell apoptosis experiment showed that compared with the blank control group, the apoptosis rate of A375 cells is significantly higher after treated by 40 μM cyclopamine for 24 h, and the difference is statistically significant (

P
<
0.05

). Gli1 and Bcl-2 protein are highly expressed in melanoma A375 cells, and their expressions show a downward trend (

P
<
0.05

) after being treated by cyclopamine. Conclusion. Cyclopamine inhibits cell proliferation and induces cell apoptosis by downregulating Gli1. Hedgehog signaling pathway can be used as a new target for the treatment of malignant melanoma, and multiple measures can be used to inhibit the signaling pathway to achieve a therapeutic effect.
NF‐κB‐Related Metabolic Gene Signature Predicts the Prognosis and Immunotherapy Response in Gastric Cancer
Authors: Chen Qiuxiang , Du Xiaojing , Hu Sunkuan , Huang Qingke
Published: January 2022

Background. Sufficient evidence indicated the crucial role of NF‐κB family played in gastric cancer (GC). The novel discovery that NF‐κB could regulate cancer metabolism and immune evasion greatly increased its attraction in cancer research. However, the correlation among NF‐κB, metabolism, and cancer immunity in GC still requires further improvement. Methods. TCGA, hTFtarget, and MSigDB databases were employed to identify NF‐κB‐related metabolic genes (NFMGs). Based on NFMGs, we used consensus clustering to divide GC patients into two subtypes. GSVA was employed to analyze the enriched pathway. ESTIMATE, CIBERSORT, ssGSEA, and MCPcounter algorithms were applied to evaluate immune infiltration in GC. The tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict patients’ response to immunotherapy. We also established a NFMG‐related risk score by using the LASSO regression model and assessed its efficacy in TCGA and GSE62254 datasets. Results. We used 27 NFMGs to conduct an unsupervised clustering on GC samples and classified them into two clusters. Cluster 1 was characterized by high active metabolism, tumor mutant burden, and microsatellite instability, while cluster 2 was featured with high immune infiltration. Compared to cluster 2, cluster 1 had a better prognosis and higher response to immunotherapy. In addition, we constructed a 12‐NFMG (ADCY3, AHCY, CHDH, GUCY1A2, ITPA, MTHFD2, NRP1, POLA1, POLR1A, POLR3A, POLR3K, and SRM) risk score. Followed analysis indicated that this risk score acted as an effectively prognostic factor in GC. Conclusion. Our data suggested that GC subtypes classified by NFMGs may effectively guide prognosis and immunotherapy. Further study of these NFMGs will deepen our understanding of NF‐κB‐mediated cancer metabolism and immunity.
A Novel Homozygous Mutation in the COL4A4 Gene (Gly1436del) Causing Alport Syndrome Exposed by Pregnancy: A Case Report and Review of the Literature
Authors: Jehn Ulrich , Müller-Hofstede Cornelie , Heitplatz Barbara , Van Marck Veerle , Reuter Stefan , Pavenstädt Hermann , George Britta
Published: January 2022

Background. Alport syndrome results from a hereditary defect of collagen IV synthesis. This causes progressive glomerular disease, ocular abnormalities, and inner ear impairment. Case Presentation. Herein, we present a case of Alport syndrome in a 28-year-old woman caused by a novel mutation (Gly1436del) in the COL4A4 gene that was not unveiled until her first pregnancy. Within the 29th pregnancy week, our patient presented with massive proteinuria and nephrotic syndrome. Light microscopic examination of a kidney biopsy showed typical histological features of segmental sclerosis, and electron microscopy revealed extensive podocyte alterations as well as thickness of glomerular basement membranes with splitting of the lamina densa. One and a half years after childbirth, renal function deteriorated to a preterminal stage, whereas nephrotic syndrome subsided quickly after delivery. Conclusion. This case report highlights the awareness of atypical AS courses and emphasizes the importance of genetic testing in such cases.
A Data Organization Method for LSTM and Transformer When Predicting Chinese Banking Stock Prices
Authors: Peng Zong-Yu , Guo Pei-Chang
Published: January 2022

The accurate prediction of stock prices is not an easy task. The long short‐term memory (LSTM) neural network and the transformer are good machine learning models for times series forecasting. In this paper, we use LSTM and transformer to predict prices of banking stocks in China’s A‐share market. It is shown that organizing the input data can help get accurate outcomes of the models. In this paper, we first introduce some basic knowledge about LSTM and present prediction results using a standard LSTM model. Then, we show how to organize the input data during the training period and give the comparison results for not only LSTM but also the transformer model. The numerical results show that the prediction results of LSTM and transformer can be improved after the input data are organized when training.
Evaluation of Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction with Hypertension by Dynamic Electrocardiogram Feature Data
Authors: Wang Guoqiang , Wang Yu , Zhao Ru
Published: January 2022

This work was to study the application value of dynamic electrocardiogram (ECG) feature data in evaluating the curative effect of percutaneous coronary intervention in acute ST-segment elevation myocardial infarction with hypertension, so as to facilitate the early diagnosis and treatment of the disease. In this study, 90 patients with acute ST-segment elevation myocardial infarction accompanied by hypertension were selected as the study subjects and randomly divided into group A (oral aspirin antiplatelet therapy), group B (thrombolytic drug streptokinase (SK) therapy), and group C (percutaneous coronary intervention), with 30 cases in each group. In addition, a P-wave detection algorithm was introduced for automatic detection and analysis of electrocardiograms, and the efficacy of patients was assessed by Holter feature data based on the P-wave detection algorithm. The results showed that the diagnostic error rate, sensitivity, and predictive accuracy of the P-wave detection algorithm for ST-segment elevation myocardial infarction caused by acute occlusion of left main coronary artery (LMCA) were 0.24%, 95.41%, and 92.33%, respectively; the diagnostic error rate, sensitivity, and predictive accuracy for non-LMCA (nLMCA) ST-segment elevation myocardial infarction were 0.28%, 95.32%, and 96.07%, respectively; the proportion of patients with symptom to blood flow patency time <3 h in group C (55.3%) was significantly higher than that in groups A and B (22.1% and 22.6%) (

P

 < 0.05). Compared with group A, the content of B-type natriuretic peptide (pre-proBNP) at 1 week, 2 weeks, and 3 weeks after treatment in groups B and C was significantly lower and group C was significantly lower than group B (

P

 < 0.05). In summary, the P-wave detection algorithm has a high application value in the diagnosis and early prediction of acute ST-segment elevation myocardial infarction. Percutaneous coronary intervention in the treatment of acute ST-segment elevation myocardial infarction with hypertension can shorten the opening time of infarction blood flow, so as to effectively protect the heart function of patients.
Safety of Occlutech Septal Occluder ACCELL Flex II for Transcatheter Closure of Secundum Atrial Septal Defects in Children: A Long-Term Follow-Up
Authors: El-Sisi Amal M. , El-Saiedi Sonia A. , Ammar Rasha , Abdelhameed Asmaa , Hijazi Ziyad M. , Soliman Mohammed M.
Published: January 2022

Objectives. To assess the long-term safety and efficacy of the Occlutech® ACCELL® Flex II device used for atrial septal defect (ASD) closure. This device differs from the regular device by having two very thin patches that are made of polyethylene terephthalate (PET). These patches enhance faster sealing of the defect. Background. Transcatheter closure has become the method of choice to manage most patients with secundum ASDs. There are different types of devices. The regular Occlutech device used to close an ASD is called the Occlutech Figulla Flex II. A newer modification of this device (Occlutech® ACCELL® Flex II) has been designed to eliminate/reduce thrombus formation and to enhance faster sealing. Methods. Thirty patients were followed up after occlusion of secundum ASD using the Occlutech® ACCELL® Flex II Device. The follow-up period ranged from 5.2–5.5 years with median of 5.3 years. Detailed history and full clinical examination, twelve-lead electrocardiogram (ECG), plain chest radiograph, and full 2D transthoracic echocardiography (TTE) were performed at discharge, at one month, six months, and yearly thereafter. Results. The mean age of the study group at the last follow-up was 10.4 ± 4.6 years, with 63.3% (nineteen patients) females. There were no residual shunts or complications encountered immediately after the procedure and at the latest follow-up. Conclusion. This study confirmed the transcatheter closure (TCC) of secundum ASDs using the Occlutech® ACCELL® Flex II device to be safe and effective with no complications detected in children and adolescents.
Abstract IA09: Mapping myeloid programs that control tumor immunity
Authors: Merad Miriam
Published: January 2022

Immune checkpoints blockade established the proof of principle that activating T effector immune function can significantly improve cancer outcome. However, the majority of patients fail to respond to checkpoint blockade therapy, likely because in many patients, suppressive mechanisms cannot be overcome with checkpoint blockade alone. T cells effector programs are instructed and modulated by professional antigen presenting cells (APC) that populate tumor lesions. Yet very little is known about the molecular wiring of APC in the tumor microenvironment. Here we used CITE-Seq to profile 600,000 immune cells in tumor and adjacent tumor-free tissues from 35 patients with lung cancer lesions. We also used CITE-Seq to profile APC that reside in experimental lung cancer lesions. We identified the molecular profile of APC that accumulate in tumors compared to the adjacent tissues and explored the functional relevance of these programs in experimental lung cancers. We show that most APC co-express both immunogenic and suppressive pathways that reduce their functionality in tissues. Specifically, we found that Th2 cytokines produced by tumor cells significantly contribute to limiting APC immunogenicity and to promoting APC -driven immunoregulation of T cell and NK cell effector function in the tumor microenvironment. These data emphasize the benefit of blocking Th2 response in epithelial tumors to enhance APC functionality and promote antitumor immunity.

Citation Format: Miriam Merad. Mapping myeloid programs that control tumor immunity [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 IA09.
Abstract IA20: What does not kill it makes it stronger: Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy
Authors: Obenauf Anna C.
Published: January 2022

Targeted therapies and immunotherapies represent main pillars of cancer treatment, yet how they shape tumours during treatment response and resistance and thereby influence subsequent therapeutic responses is poorly understood. Here, we show in melanoma patients and mouse models that when tumours relapse on targeted MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite their entirely different mode of action. We find that cross-resistance is mediated via a cancer cell-instructed, immune-suppressive tumour microenvironment that lacks functional CD103+ dendritic cells, precluding an effective T cell response. Restoration of CD103+ dendritic cell numbers and functionality can re-sensitize cross-resistant tumours to immunotherapy. Using our lineage tracing method CaTCH, which allows the retrospective isolation of founding clones prior to evolutionary selection, we demonstrate that cross-resistance is acquired during MAPKi treatment. Cross-resistance does not arise from the selective pressure of an immune response during the evolution of resistance, paradoxically it results from the MAPK pathway, which is not only reactivated during the formation of targeted therapy resistance but has gained increased transcriptional output driving immune evasion. Our work provides mechanistic evidence for cross-resistance between unrelated therapies and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy.

Citation Format: Anna C. Obenauf. What does not kill it makes it stronger: Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy [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 IA20.
Abstract P010: Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors
Authors: Burger Megan L. , Cruz Amanda M. , Crossland Grace E. , Gaglia Giorgio , Ritch Cecily C. , Blatt Sarah E. , Bhutkar Arjun , Tavana Sara Z. , Santagata Sandro , Jacks Tyler
Published: January 2022

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet it is unclear whether they interact to potentiate or antagonize the overall anti-tumor response. In a genetically engineered mouse model of lung adenocarcinoma, we find that antigen dominance hierarchies are established in tumors wherein the antigen that most stably binds MHC dominates the CD8 T cell response. This negatively impacts the response to subdominant antigens, suppressing T cell expansion, differentiation and effector function; a phenotype that is reversed when the dominant antigen is removed. Intriguingly, the subdominant response is also enriched for a TCF1+ progenitor cell phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, we find that the subdominant response does not preferentially benefit from ICB due to predominance of a dysfunctional subset of TCF1+ cells marked by CCR6 expression and differentiation to a Tc17 phenotype. CCR6+ TCF1+ cells are also found broadly across human cancers and do not correlate with patient response to ICB. This subset appears to be derived from poor T cell receptor stimulation, due to competition of T cells for good interactions with antigen presenting cells. Vaccination eliminates CCR6+ TCF1+ cells and disrupts the antigen dominance hierarchy, preferentially expanding the subdominant CD8 T cell response in tumors. Overall enrichment of TCF1+ cells is maintained amongst the subdominant response post-vaccination and current studies are exploring whether this promotes more durable tumor control or better response to ICB. These findings provide strong rationale for evaluating the relative response to high versus low pMHC stability antigens in clinical trials of pooled neoantigen vaccines, where low stability, subdominant antigens may contribute more to tumor control than previously realized.

Citation Format: Megan L. Burger, Amanda M. Cruz, Grace E. Crossland, Giorgio Gaglia, Cecily C. Ritch, Sarah E. Blatt, Arjun Bhutkar, Sara Z. Tavana, Sandro Santagata, Tyler Jacks. Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors [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 P010.
Abstract P016: Circulation immune landscape in canonical pathogenesis of colorectal cancer by CyTOF analysis
Authors: Ding Ke-Feng , Kong Xiang-Xing , Xu Jia-Sheng , Jiao Yu-Rong , Hu Ye-Ting , Xiao Qian , Hao Xu-Ran , Gao Zong-Bao , Li Jun
Published: January 2022

Objective: The present study aims to firstly describe the circulation immune landscape in the canonical pathogenesis of colorectal cancer (CRC) by detecting the peripheral white blood cell using mass cytometry by time-of-flight (CyTOF) technology.

Methods: A total of 42 healthy controls (HC), 47 colorectal adenoma (CRA) patients, and 102 CRC patients were enrolled and their pathological information were also collected. A panel of 42 cell surface antigen markers were detected by mass spectrometry flow cytometry after peripheral blood mononuclear cells (PBMC) separated. The expression differences of various cell subsets among the three groups were further compared, and the cell subsets with different expressions were screened out for in-depth analysis.

Results: We annotated the PBMC as T cells, B cells, NK cells and myeloid cells, and performed identification and component comparison of cell subgroups respectively. Compared with HC and CRA, NKT cell subsets were significantly reduced in CRC, while Naïve CD4+ T cells, effector CD8+ T cells and central memory CD8+ T cells were increased. Compared with HC, Treg cells increased in CRA, and central memory CD4+ T increased in CRC; but Naïve CD8+ T cells and Naïve double-negative T (DNT) cells decreased in both CRA and CRC. Compared with HC and CRA, Naïve B cells were significantly decreased in CRC; but switched memory B cells were increased. CD16- NK cells were significantly higher in CRC while CD16+ NK cells were decreased compared with HC. CD16- monocytes were increased, but CD16+ monocytes were decreased in CRC when compared to HC. Basophils and monocytes were significantly increased in CRC compared to CRA. Furthermore, we also found Effector CD4+ T cells and Naïve B cells increased during lymph node metastasis, while unswitched B cells, plasmablast and basophils decreased.

Conclusion: We had successfully described the immune landscape of the canonical pathogenesis of CRC, and we further analyzed the changes in cell subsets related to the occurrence of lymphatic metastasis.

Citation Format: Ke-Feng Ding, Xiang-Xing Kong, Jia-Sheng Xu, Yu-Rong Jiao, Ye-Ting Hu, Qian Xiao, Xu-Ran Hao, Zong-Bao Gao, Jun Li. Circulation immune landscape in canonical pathogenesis of colorectal cancer by CyTOF analysis [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 P016.
Abstract P032: Expression of an IL-15 receptor fusion protein enhances the persistence of TRuC-T cells
Authors: Fleury Michelle , Anderson Courtney , Watt Amy , Horton Holly , Zieba Adam , Ding Jian , Tighe Robert , Hofmeister Robert , McCarthy Derrick , Gutierrez Dario
Published: January 2022

Adoptive cell therapies have shown great promise in hematological malignancies. To realize the potential of T cell therapies in solid tumors, we have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes all TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin-targeting TRuC-T cells (aka TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the effector function and persistence of TRuC-T cells in the hostile tumor microenvironment, we generated TC-210 T cells that express a membrane-tethered IL15Rα-IL15 fusion protein. IL-15 is a common γ chain cytokine that promotes the differentiation, maintenance, and effector function of memory CD8+ T cell subsets and confers resistance to IL-2-mediated activation induced cell death (AICD). In vitro, the co-expression of the IL-15 fusion protein enhances T cell proliferation and persistence upon repeated stimulation with MSLN+ cancer cell lines, while exhaustion marker expression is decreased. Furthermore, IL-15 enhanced TC-210 T cells sustain a significantly higher TCF-1+ population. When tested in a mesothelioma xenograft mouse model, the presence of the IL-15 fusion protein increased tumor infiltration and persistence of TC-210 T cells. Altogether, the presented data support clinical studies that explore the impact of IL-15 enhancement on the persistence of TC-210 T cells and depth of response in patients with MSLN+ malignancies.

Citation Format: Michelle Fleury, Courtney Anderson, Amy Watt, Holly Horton, Adam Zieba, Jian Ding, Robert Tighe, Robert Hofmeister, Derrick McCarthy, Dario Gutierrez. Expression of an IL-15 receptor fusion protein enhances the persistence of TRuC-T cells [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 P032.
Abstract P036: A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs
Authors: Huntington Kelsey E. , Louie Anna , Zhou Lanlan , El-Deiry Wafik S.
Published: January 2022

Inflammatory cytokines, immune stimulants, chemokines, and tumor growth/growth suppressing factors are molecular messengers that circulate and have the capability to modify the tumor microenvironment and impact response to therapeutics. The characterization of soluble mediators as biomarkers for diagnosis and prognosis is of interest in oncology. We utilize the cytokinome to characterize the response of colorectal tumor cell lines to selected small-molecules in oncology as a proof-of-concept dataset with immune synergy heat map rankings of analytes for drug and cell line combinations. We observed overall trends in drug-class effects with MEK-, BRAF-, PARP-inhibitors, and Imipridones in cytokine, chemokine, and growth factor responses that may help guide therapy selection. MEK-inhibitor treatment downregulated analytes VEGF, CXCL9/MIG, and IL-8/CXCL8 and upregulated CXCL14/BRAK, Prolactin, and CCL5/RANTES. BRAF-inhibitor treatment downregulated VEGF and IL-8/CXCL8, while increasing sTRAIL-R2. Treatment with PARP-inhibitors decreased CXCL9/MIG, IL-8/CXCL8, CCL3/MIP-1 alpha, VEGF, and CXCL14/BRAK, while treatment increased sTRAIL-R2 and prolactin. Treatment with Imipridones decreased CCL3/MIP-1 alpha, VEGF, CXCL14/BRAK, IL-8/CXCL8, and Prolactin and increased CXCL5/ENA-78. We also observed differential responses to therapeutics depending on the mutational profile of the cell line. In the future, a similar but larger data-set may be utilized in the clinic to aid in immune synergy prediction of a patient's response to therapy based on tumor genotype.

Citation Format: Kelsey E. Huntington, Anna Louie, Lanlan Zhou, Wafik S. El-Deiry. A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs [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 P036.
Abstract P038: Identification and functional evaluation of monoclonal antibodies specifically targeting human Carbonic Anhydrase IX
Authors: Lenferink Anne E. G. , Baardsnes Jason , Sulea Traian , Wu Cunle , Acchione Maurizio , Jaramillo Maria L. , McDonald Paul C. , Benard Francois , Dedhar Shoukat
Published: January 2022

Poor vascularization of solid tumors leads to inadequate nutrient and oxygen supplies which forces tumor cells to reprogram their metabolism. Consequently, the tumor cell's environment becomes acidic and hypoxic. This triggers signaling cascades involving e.g. heterodimeric hypoxia-inducible factor (HIF). Activation of this hypoxia-induced transcriptional program is crucial for the tumor cell to survive its hostile microenvironment and its ability to metastasize. One of the genes HIF upregulated is carbonic anhydrase (CA)-IX (CAIX, gene G250/MN-encoded transmembrane protein). CA-IX catalyzes carbon dioxide (CO2) thereby generating a proton (H+) and bicarbonate (HCO3−), the latter of which is transported back into the cell and utilized to help safeguard intracellular pH (pHi) stability. Except for the stomach and the gallbladder, CA-IX expression is negligible in normal tissues. In contrast, a broad range of tumors express high levels of CA-IX, where the protein can serve as a biomarker for the early stages of tumor development but also as tumor marker of hypoxia associated with resistance to chemotherapy and radiotherapy. Preclinical and clinical studies have shown that CA-IX is a promising therapeutic target for detection and therapy for several cancer types. To date only a limited number of ant-CAIX monoclonal antibodies (mAbs) have been available for clinical testing as therapeutic and imaging agents. In the current study, we generated and functionally categorized a panel of 51 mouse mAbs that specifically bind to human CA-IX. Characterization of the mAbs revealed that of the mAbs with the best biophysical characteristics, three (3) mAbs are suitable as an antibody-drug conjugate (ADC), two (2) mAbs inhibit the CA-IX enzyme activity, and one (1) mAb that is suitable for CA-IX imaging purposes. These preliminary data presented here could thus form the basis for the development of novel CA-IX targeted immunotherapies and diagnostic tools for the treatment of cancer.

Citation Format: Anne E. G. Lenferink, Jason Baardsnes, Traian Sulea, Cunle Wu, Maurizio Acchione, Maria L. Jaramillo, Paul C. McDonald, Francois Benard, Shoukat Dedhar. Identification and functional evaluation of monoclonal antibodies specifically targeting human Carbonic Anhydrase IX [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 P038.
Abstract P067: Current status of regulatory-approved immunotherapies in Saudi Arabia
Authors: Ajina Reham
Published: January 2022

Immunotherapy has been shown to successfully turn aggressive malignancies in many patients into curable diseases. Thus, immunotherapy has received so much attention internationally, and Saudi Arabia was not an exception. Here, we evaluated the status of regulatory-approved immunotherapies in Saudi Arabia using the Saudi Food and Drug Administration (sFDA) database and the ClinicalTrials.gov website. We found that not all available immunotherapies in the clinic worldwide are approved by the sFDA, and the number of Saudi immunotherapy clinical trials are very limited. In fact, out of the eight regulatory-approved immune checkpoint inhibitors, 5 have received the sFDA approval. These immune check point inhibitors are Yervoy (ipilimumab), Nivolumab (Opdivo), Pembrolizumab (Keytruda), Atezolizumab (Tecentriq) and Avelumab (Bavencio). Also, out of the 5 regulatory approved chimeric antigen receptor (CAR) T cell therapy products, only KYMRIAHTM (tisagenlecleucel) has received the sFDA approval. According to the ClinicalTrials.gov registry (accessed 27 July 2021), only 6 investigational clinical trials have been conducted in Saudi Arabia to evaluate immune check point inhibitors, and only 3 of these studies are currently ongoing. More surprisingly, no Saudi CAR clinical trials have yet been conducted. Taken together, there is an urgent need for a greater accessibility for immunotherapy in the country.

Citation Format: Reham Ajina. Current status of regulatory-approved immunotherapies in Saudi Arabia [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 P067.