Direct Effect Research Articles

Structural effect of principals change leadership on e-learning effectiveness

<span lang="EN-US">The aim of this research was to investigating the structural effect of the principal change leadership on the effectiveness of online-based learning with teacher work commitment and teacher attitudes towards change as mediator variables, which were approached quantitatively. Multilevel stratified proportional random sampling technique is used in sampling, while inclusion criteria are principals and teachers of primary schools who are still active in Kutai Kartanegara, Samarinda and Balikpapan, East Kalimantan, Indonesia. The structural equation modeling (SEM) analysis technique is used in this research. The results of the study show that the principals’ change leadership has a direct effect on the effectiveness of online-based learning, as well as an indirect effect through teacher work commitment and teacher attitudes towards change. This research contributes both theoretically and practically, where the change leadership demonstrated by the principal can ideally encourage teacher work commitment and teacher attitudes towards change, which in turn can promote the effectiveness of the implementation of online learning, as an effort to meet student learning needs.</span>

Lower Perceived Neighborhood Collective Efficacy Indirectly Influences the Association Between Perceived Maternal Exposure to Community Violence and Household Food Insecurity.

Individuals of color and of low socioeconomic status are at greater risk of experiencing community violence and food insecurity, which are both influenced by neighborhood conditions. We evaluated neighborhood collective efficacy as a linkage between community violence exposure and household food insecurity. Mothers from the Future of Families and Child Wellbeing Study who completed phone surveys when the child was 3 (time 1, T1) and 5 years old (time 2, T2) were included (n = 2068). A covariate-adjusted structural equation model estimated direct and indirect effects of community violence exposure on household food insecurity. A covariate-adjusted multiple mediator model estimated the indirect effects of the 2 neighborhood collective efficacy subscales (informal social control; social cohesion and trust). At T1, 40% of mothers reported community violence exposure; 15% experienced food insecurity at T2. Mean neighborhood collective efficacy (range 1-5) at T1 was 2.44 (SD = 0.94). Neighborhood collective efficacy indirectly influenced the association between community violence exposure and food insecurity (indirect effect = 0.022, 95% CI = 0.007 to 0.040). Only social cohesion and trust contributed independent variance to the indirect effect model (indirect effect = 0.028, 95% CI = 0.001 to 0.056). Community-based efforts to reduce household food insecurity should emphasize building social cohesion and trust in communities experiencing violence.

Early-Life Lead Exposure: Risks and Neurotoxic Consequences.

Lead (Pb) does not have any biological function in a human, and it is likely no safe level of Pb in the human body. The Pb exposure impacts are a global concern for their potential neurotoxic consequences. Despite decreasing both the environmental Pb levels and the average blood Pb levels in the survey populations, the lifetime redistribution from the tissues-stored Pb still poses neurotoxic risks from the low-level exposure in later life. The growing fetus and children hold their innate high-susceptible to these Pb-induced neurodevelopmental and neurobehavioral effects. This article aims to evaluate cumulative studies and insights on the topic of Pb neurotoxicology while assessing the emerging trends in the field. The Pb-induced neurochemical and neuro-immunological mechanisms are likely responsible for the high-level Pb exposure with the neurodevelopmental and neurobehavioral impacts at the initial stages. Early-life Pb exposure can still produce neurodegenerative consequences in later life due to the altered epigenetic imprints and the ongoing endogenous Pb exposure. Several mechanisms contribute to the Pb-induced neurotoxic impacts, including the direct neurochemical effects, the induction of oxidative stress and inflammation through immunologic activations, and epigenetic alterations. Furthermore, the individual nutritional status, such as macro-, micro-, or antioxidant nutrients, can significantly influence the neurotoxic impacts even at low-level exposure to Pb. The prevention of early-life Pb exposure is, therefore, the critical determinant for alleviating various Pb-induced neurotoxic impacts across the different age groups.

How discrimination experiences relate to racial/ethnic identity and mental health across first- and second-generation Vietnamese American adolescents.

Racial/ethnic discrimination has been linked to behavioral and emotional problems in youth from marginalized groups. However, the psychological experience associated with discrimination may differ between immigrant and nonimmigrant youth. Race-based discrimination may impact an adolescent's view of their own group (private regard) and/or their sense of how others view their group (public regard). Owing to differences in racialization, immigrant adolescents may be affected differently by experiences of discrimination than their U.S.-born peers. The present study examined whether nativity moderated the paths from racial/ethnic discrimination to private and public regard to mental health problems among Vietnamese American youth. Surveys were completed by 718 Vietnamese American 10th and 11th graders (Mage = 15.54 years, 61.4% female, 38.6% male). In this sample, 21.2% were first-generation (i.e., born outside of the United States) and 78.8% were second-generation (i.e., born in the United States with at least one parent born outside of the United States). Multigroup path analysis tested the direct and indirect effects of racial/ethnic discrimination on behavioral and emotional problems via private and public regard and whether associations differed for first- versus second-generation youth. Racial/ethnic discrimination was associated with lower public regard, but not private regard, for both first- and second-generation Vietnamese American youth. Public regard was negatively associated with behavioral and emotional problems only among second-generation youth. No indirect effects were significant. Findings suggest differences in racialized experiences, as well as opportunities to support second-generation Vietnamese American and other marginalized youth from immigrant families from the mental health impacts of discrimination. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Pre-service teachers’ mathematics achievement, attitude, and anxiety: The moderative role of pre-service teachers’ interest in the learning process

The aim of the study was meant to investigate the moderative role of pre-service teachers’ interest on mathematics achievement, attitude and anxiety during teaching and learning process. The study was conducted at Akrokerri College of Education Adansi, Ghana on pre-service teachers with a population of 300. A sample of 206 pre-service teachers were involved in the study. Questionnaires were designed with regards to the four main constructs identified in the study. The questionnaires were analyzed using the structural equation model. The findings revealed that pre-service mathematics teachers’ attitude has a direct positive effect on pre-service teachers ‘mathematics achievement. Mathematics anxiety has a positive effect and is statistically insignificant on mathematics achievement. Finally, the moderating effect of mathematics interest on the relationship between mathematics attitude and mathematics achievement result was negative and it is statistically insignificant.

Moderated Mediation Analysis of Structural Stigma and Suicidal Ideation and Behaviors Among Sexual and Gender Minority Adults.

Purpose: This study aimed to conduct a moderated mediation analysis to understand further the complex pathways through which structural stigma in the form of transgender sports bans was associated with suicidal ideation and behaviors among sexual and gender minority (SGM) adults. Methods: A cross-sectional survey of 1033 adults who identified as SGM from across the 50 U.S. states and Washington, DC was conducted between January 28 and February 7, 2022. Distal discrimination distress was the mediation variable; individual resilience and social resources were the moderation variables. Familiarity with transgender sports bans represented structural stigma. The conditional process analysis was applied to build a moderated mediation model. Both conditional direct and indirect effects were computed by estimated coefficients. All models were based on linear regression. Results: Our final model explained nearly half (46%) of the variation in suicidal ideation and behaviors between those SGM adults familiar and those not familiar with transgender sports bans. Social resources significantly moderated the conditional indirect effect of distal discrimination distress (adjusted estimate = -0.23; 95% confidence interval = -0.37 to -0.08). Conclusion: Both discrimination distress and social resources influenced the association between structural stigma as measured by familiarity with transgender sports bans and suicidal ideation and behaviors among SGM adults. Findings support the need for future research examining the pathway between structural stigma and suicidal ideation and behaviors among SGM adults and how minority stress, social safety, and other constructs shape this pathway.

Paths from adverse and benevolent childhood experiences to personal growth after childbirth: The role of psychological distress, social support, and self-compassion.

Dealing with the difficulties and demands of the postpartum period may be distressing for the mother, but it is also an opportunity for her to experience personal growth. One factor that may contribute to this growth is the mother's childhood experiences. Using a prospective study design, and based on Belsky's parenting model and personal growth theory, we examined the direct and indirect contribution of mothers' adverse and benevolent childhood experiences and their current psychological distress, self-compassion, and social support to their personal growth following childbirth and motherhood. A convenience sample of 392 women was recruited through social media and participated in the study about 16 weeks after childbirth (Phase 1) and again 6-10 months postpartum (Phase 2). The direct effects of adverse and benevolent childhood experiences on personal growth were not significant. However, multiple significant paths of indirect associations were found through psychological distress, self-compassion, and social support. To understand the roots of the mother's personal growth, researchers and clinicians alike should not only explore her personal resources, but also the primary processes that contribute to the creation of those resources, that is, childhood experiences. Addressing the mother's childhood experiences may help her to better understand the connections between the past and the present, and to identify the implications of her "ghosts and angels" for her mental state, personal resources, and experience of personal growth. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Методологические предпосылки исследования роботизации промышленности сквозь призму политико-экономического осмысления неолуддизма

The development of the robotization processes of the industry entails a kind of renaissance of research on the phenomena of Luddism and neo-Luddism. Neo-Luddism is considered in the context of an attempt to describe the reaction of a part of society to technological changes, including large-scale robotization of industry, transforming the social and labor landscape of the modern economic system, although it does not represent a complete concept and requires further scientific understanding. The purpose of this article is to identify, by turning to the political and economic features of the phenomena of Luddism and neo-Luddism, the methodological prerequisites for the study of industrial robotization, in particular the development of directions and tools for improving industrial modernization based on robotization. The use of the subject-activity approach (N.V. Gerasimov) and general scientific methods of cognition in the paper enable to describe the essence of Luddism and neo-Luddism through the prism of the clash of interests of individual social groups. A scientific discussion is presented regarding the impact of robotization of the industry on employment, and potential mechanisms for reducing the social costs of this process. The limits of applicability of these mechanisms and the political and economic grounds for their development and application are shown. It has been proven that the features of robotization of industry of specific economic systems, the effectiveness of directions and tools for improving this process, mechanisms for smoothing out socio-economic consequences and appropriating the positive effects of robotization depend on the existing balance of political and economic interests of social subjects and their groups. The obtained results can be useful in developing mechanisms for robotization of industry in the national economy and identifying potential economic and social risks arrising in this process. Further research of the impact of industrial robotization on employment in national economic systems may be of interest

Influencer Marketing Strategies and Brand Image in Boosting Consumer Purchase Intent: The Role of Customer Support Intervention

This research explores the intricate relationships among influencer marketing strategies, brand image, customer support, and consumer purchase intent within the operational framework of PT. Len Industri (Persero) - Jakarta Office. Through path analysis, the study discerns direct and indirect effects, revealing significant findings. Marketing Strategies exhibit a notable direct impact on both Customer Support and Consumer Purchase Intent, underscoring the centrality of effective marketing initiatives in shaping customer interactions and purchase decisions. Conversely, Brand Image reveals a non-significant direct effect on Customer Support but demonstrates a marginally significant impact on Consumer Purchase Intent, indicating a nuanced relationship that warrants further investigation. The indirect effects analysis highlights the substantial influence of Marketing Strategies on Consumer Purchase Intent mediated by Customer Support. These findings underscore the importance of a holistic approach, integrating marketing strategies, brand image cultivation, and effective customer support to enhance overall consumer experiences and drive purchase intent in a competitive market landscape.

The Impact of Personal Financial Management and Emotional Intelligence on Financial Well-being with The Mediation of Risk Management Attitude

This study investigates the intricate relationships among personal financial management, emotional intelligence, risk management attitude, and financial well-being. The study employs a random sampling technique with a sample size of 41 individuals from Bank Mandiri KCP Solo Slamet Riyadi. Path analysis, using the SmartPLS software, is utilized to explore direct and indirect effects. The results reveal a significant positive impact of personal financial management on risk management attitude and financial well-being. However, emotional intelligence is not found to be a significant predictor of risk management attitude or financial well-being. The study concludes that effective personal financial management practices play a crucial role in enhancing financial well-being, both directly and indirectly through influencing risk management attitudes. These findings provide insights for interventions and educational programs aimed at improving individuals' financial resilience and satisfaction by emphasizing responsible financial habits and decision-making.

Team Dynamics in a Hybrid Work Environment: Effective Strategies for Enhancing Employee Performance and Well-being

This study investigates the intricate relationships among team dynamics, employee performance, and well-being in the context of a hybrid work environment, with a specific focus on PT Semen Baturaja (Persero) Tbk. Utilizing path analysis, the study explores both direct and indirect effects to unveil the dynamics shaping organizational practices related to hybrid work. The research reveals a significant direct impact of individual employee performance on both team dynamics and the establishment of a hybrid work environment. Team dynamics are identified as a crucial mediator, emphasizing their pivotal role in translating individual contributions into organizational strategies for hybrid work adaptation. However, the study finds that the direct influence of employee well-being on team dynamics and subsequently on the hybrid work environment may not be statistically significant. These findings offer nuanced insights for organizations aiming to optimize their work environment, suggesting tailored strategies to leverage team dynamics and individual performance for successful hybrid work implementation while considering the multifaceted nature of employee well-being.

Fear of Negative Evaluation, Appearance Distress and Inferiority Complex among University Women Having Acne Problem

This study was designed to investigate the relationship between fear of negative evaluation and inferiority complex in university women with acne problems. Study also explored the mediating role of appearance distress between the variables. A correlational survey research designed was employed to execute the research. Data was collected through purposive sampling and the sample was of university women (n= 220) with acne problem. The tools for the study were ‘Brief Version of the Fear of Negative Evaluation Scale (Leary,1983), Appearance Anxiety Inventory Scale (David Veale, 2011), COMPIN Scale (Djordje Ceklija, 2017) for Inferiority Complex. For data analysis, Partial least square-structural equation modelling (PLS-SEM) was applied via statistical software, i.e. Smart-PLS (version-4 M4). The measurement model showed high reliability and validity and the structural model revealed positive and significant direct and indirect effect of appearance distress between the fear of negative evaluation and inferiority complex among women having acne problem. Practical and societal implications have been discussed for the women having acne, counselors and clinicians.

UNDERSTANDING THE INFLUENCE OF FOOD VALUE ON FAST-FOOD CUSTOMER BEHAVIOR: A STUDY ON THE MEDIATING ROLE OF BLOGGER REVIEWS AND MODERATING EFFECT OF CONTENT CREDIBILITY

This study proposes investigating the effect of food value on food bloggers' reviews (i.e., the direct effect) and the customers' purchase intentions (i.e., the direct and indirect effects) of fast-food restaurants. In addition, this study examines the moderating role of content credibility on food blogger reviews and customers' purchase intention relationships. The quantitative method is used in this study to gather data from fast-food restaurant customers in Cairo, Egypt. Where 450 questionnaires were given out to fast-food restaurant customers, 354 valid questionnaires were gathered for analysis. The data were analyzed using SPSS and Amos software. Food value positively influences food bloggers' reviews and fast-food restaurant customers' purchasing intentions. Additionally, this research found that food blogger reviews mediate a positive relationship between food value and fast-food restaurant customers' intentions to purchase. Importantly, this study discovered that content credibility has a positive moderating impact on the relationship between food blogger reviews and the purchase intention of fast-food restaurant customers. The study contributes to the literature on tourism and hospitality, where we employed food value as a decisive and influencing factor in improving food bloggers' reviews and thus influencing fast-food restaurant customers' intention to purchase. Thus, fast-food restaurant managers should create all the suggested food values because of their impact on food bloggers' reviews and customers' intentions to purchase.

The Mediating Role of Cognitive Flexibility in the Relationship between Intolerance of Uncertainty and Subjective Well-Being in High School Students during the COVID 19 Pandemic

The COVID-19 pandemic brought some uncertain and new changes in life patterns. These changes have had psychological effects on high school students as well as in all age groups. This study aimed to examine the mediating role of cognitive flexibility between intolerance of uncertainty and subjective well-being in high school students during the COVID-19 pandemic. Participants of the study consisted of 437 high school students (234 females and 203 males) in Turkey. They completed measures of intolerance of uncertainty, cognitive flexibility, and adolescent subjective well-being. The hypothetical model developed in order to determine whether cognitive flexibility mediates in the relationship between intolerance of uncertainty and subjective well-being was tested through Structural Equation Modeling. The results of the study revealed that intolerance of uncertainty had a significant direct effect on subjective well-being. Cognitive flexibility partially mediated the association between intolerance of uncertainty and subjective well-being for the high school students during the COVID-19 pandemic. Practitioners can create psychoeducational programs to decrease intolerance of uncertainty and increase the cognitive flexibility levels of the students. The practitioners can apply these programs to high school students.

Mobile phone addiction and suicide behaviors among Chinese adolescents: The mediation of poor sleep quality.

Mobile phone addiction (MPA) is emerging among adolescents, especially during the COVID-19 pandemic. Nevertheless, there is a dearth of knowledge regarding the correlation between MPA and suicide behaviors and its mechanism. The objective of the current study is exploring the direct effect of MPA on suicide behaviors and the indirect effect through poor sleep quality. A total of 18,900 Chinese adolescents aged 12 to 18 were recruited via a multi-stage cluster sampling method. The prevalence of MPA and poor sleep quality was 26.2 and 23.1%, respectively. During the past year, 24.4% participants were involved in suicide behaviors. Specifically, suicide ideators, suicide planners, and suicide attempters were 10.7, 8.4, and 5.3%, respectively. Particularly, rural females had the highest prevalence of suicide behaviors, MPA, and poor sleep quality.Logistic regression analysis showed that MPA was significantly associated with suicide ideators (OR = 1.22, 95% CI: 1.09-1.37, p < 0.001) and planners (OR = 1.18, 95% CI: 1.04-1.34, p < 0.05), but not for suicide attempters (p > 0.05). Structural equation modelling demonstrated that MPA had direct effect on suicide behaviors (β = 0.145, 95% CI = 0.127-0.160), and poor sleep quality partially mediated the relationship (the mediating ratio was 46.7%). The mediating ratio of poor sleep quality was the highest in urban males. MPA has both direct and indirect effects on suicide behaviors. For suicide prevention, limited mobile phone use and improvement sleep quality may be practical for adolescents. Additionally, more efforts of intervention could give priority to rural girls.

The relationship between psychological distress and weight maintenance in weight cycling: mediating role of eating behavior

BackgroundObesity is a global public health concern. The goal of this study was to see if eating habits could mediate the relationship between psychological distress and weight maintenance in a population with a history of weight cycling.MethodsA 3-month outpatient intervention consisting of a diet and exercise program was provided to 153 participants. Psychological distress, appetite, and behavior were assessed at the beginning and end of the study. Anthropometric measurements were taken at baseline and six months.ResultsAfter the structural equation model was developed, it was discovered that the psychological status of people with obesity and weight cycling histories correlated with the weight loss outcome effect (three and six months). This effect was mediated by factors related to eating behavior. Associative psychological factors had a direct effect on eating behavior (three months: β = 0.181, 95% CI: 0.055–0.310; six months: β = 0.182, 95% CI: 0.039–0.332) and appetite had a direct effect on eating behavior (three months: β = 0.600, 95% CI: 0.514–0.717; six months: β = 0.581, 95% CI: 0.457–0.713), both of which were significant (p < 0.01). At three months, psychological distress has a more substantial positive impact on weight change, with eating behavior acting as a partial mediator. At six months, there was no support for appetite’s moderating role in eating behavior.ConclusionsThe findings suggest that psychological interventions should be strengthened to improve weight loss effectiveness, particularly in participants with a history of weight cycling, making weight loss more complicated and prone to rebound.Clinical trial registrationThe study has been registered in Clinical Trials (NCT05311462).

Cloud Computing and firm performance: a SEM microdata analysis for Israeli firms

PurposeThis paper aims to study the economic effects of Cloud Computing for a sample of Israeli firms. The authors propose a framework that considers how this technology affects firm performance also introducing the indirect economic effects that take place through cloud-complementary technologies such as Big Data and Machine Learning.Design/methodology/approachThe model is estimated through structural equation modeling. The data set consists of the microdata of the survey of information and communication technologies uses and cyber protection in business conducted in Israel by the Central Bureau of Statistics.FindingsThe results point to Cloud Computing as a crucial technology to increase firm performance, presenting significant direct and indirect effects as the use of complementary technologies maximizes its impact. Firms that enjoy most direct economic gains from Cloud Computing appear to be the smaller ones, although larger enterprises seem more capable to assimilate complementary technologies, such as Big Data and Machine Learning. The total effects of cloud on firm performance are quite similar among manufacturing and service firms, although the composition of the different effects involved is different.Originality/valueThis paper is one of the very few analyses estimating the impact of Cloud Computing on firm performance based on country microdata and, to the best of the authors’ knowledge, the first one that contemplates the indirect economic effects that take place through cloud-complementary technologies such as Big Data and Machine Learning.

The melano-macrophage: The black leukocyte of fish immunity

Melanin and the process of melanin synthesis or melanogenesis have central roles in the immune system of insects, and production of melanin-synthesizing enzymes from their haemocytes may be induced following activation through danger signals. Melanin-containing macrophage-like cells have been extensively studied in amphibians and they are also present in reptiles. In fish, melano-macrophages are especially recognized with respect to melano-macrophage centres (MMCs), hypothesized to be analogues of germinal centres in secondary lymphoid organs of mammals and some birds. Melano-macrophages are in addition present in several inflammatory conditions, in particular melanised focal changes, or black spots, in the musculature of farmed Atlantic salmon, Salmo salar. Melanins are complex compounds that may be divided into different forms which all have the ability to absorb and scatter light. Other functions include the quenching of free radicals and a direct effect on the immune system. According to the common view held in the pigment cell community, vertebrate melanin synthesis with melanosome formation may only occur in cells of ectodermal origin. However, abundant information suggests that also myeloid cells of ectothermic vertebrates may be classified as melanocytes. Here, we discuss these opposing views and review relevant literature. Finally, we review the current status on the research concerning melanised focal muscle changes that represent the most severe quality problem in Norwegian salmon production, but also other diseases where melano-macrophages play important roles.

Abstract 6528: Integrin ɑvβ6 upregulation as a mechanism of T-cell evasion in head and neck squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) encompasses malignancies of the mucosal epithelium in the oral cavity, pharynx, and larynx. The lack of effective screening strategies and the typically late stage of detection are contributors to a considerable annual death toll of HNSCC. Additionally, the anatomical proximity of the malignancy to delicate structures of the head and neck leads to tremendous treatment-related morbidity. Therefore, there is great interest in developing life-saving therapies and strategies for treatment de-escalation. The immune checkpoint inhibitor pembrolizumab (αPD-1) has been approved for recurrent or metastatic HNSCC and as a frontline therapy for unresectable disease. However, only about a quarter of patients respond to αPD-1 therapy. The immunosuppressive effect of TGFβ has been widely described as relevant to the HNSCC tumor microenvironment. However, attempts to blockade TGFβ have failed mainly due to the widespread side effects of disrupting a highly promiscuous cytokine. Integrin αvβ6 is a major activator of the inert latent TGFβ into the active, immunosuppressive form. With its high relative specificity to HNSCC tissue, inhibition of αvβ6 could offer a safer approach for disrupting TGFβ to overcome resistance to immune checkpoint blockade. After screening ɑvβ6 expression levels of HNSCC cell lines via flow cytometry, cell lines FaDu and CAL27 were selected for further investigation due to high endogenous ITGB6 expression (FaDu 35.57% cells ITGB6+, CAL27 95.69% cells ITGB6+). The cell lines were transduced with a doxycycline-inducible short hairpin RNA (shRNA) knockdown of αvβ6 using a lentiviral system. Both knockdown and control shRNA cell lines were pretreated with 1 μg/mL of doxycycline for five days to induce the shRNA and subsequently co-cultured with TALL-104 T-cells. Quantitative fluorescence microscopy of the co-culture revealed that the knockdown of αvβ6 substantially increased T-cell killing over 24hrs (FaDu CTRL shRNA 6.72%±2.49 dead vs. FaDu ITGB6 shRNA 12.80%±3.16 dead, p&amp;lt;0.001). However, treatment of FaDu and CAL27 cell lines with active-TGFβ showed no change in PD-L1 expression via flow cytometric analysis. To determine whether the T cell evasive effect of αvβ6 is driven by other immune checkpoints on the cancer cells or by the direct effect that TGFβ has on immune cells, we show the generation of relevant mouse αvβ6 shRNA knockdown cells. These syngeneic in vivo studies will facilitate cytokine profiling to uncover the dynamics of tumor-immune cell interactions in response to αvβ6 inhibition. Citation Format: William J. MacDonald, Praveen R. Srinivasan, Maximilian Pinho-Schwermann, Shengliang Zhang, Vida Tajiknia, Connor Purcell, Jillian Strandberg, Nolan Stubbs, Wafik S. El-Deiry. Integrin ɑvβ6 upregulation as a mechanism of T-cell evasion in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6528.

Abstract 3841: Tumor-derived microRNA125a induces CART cell apoptosis and failure in B cell malignancies

Abstract Despite the remarkable efficacy of chimeric antigen receptor T -cell therapy (CART) for the treatment of B-cell malignancies, durable remission remains limited often due to tumor relapse. We have previously demonstrated that tumor-derived extracellular vesicles (EVs) induced CART cell failure in preclinical models. To characterize the impact of tumor EV induced CART cell dysfunction, we assessed microRNA (miRNA) profiles contained within tumor EVs from two independent patient cohorts and studied how they contributed to CART dysfunction. Our first cohort included patients with chronic lymphocytic leukemia (n=50). We previously showed that CLL patient derived EVs induce a state of CART cell dysfunction. To understand this dysfunction, we interrogated the miRNA cargo significantly enriched in CLL EVs and how their coculture impacts CART signaling by RNAseq. Here, we found a significant enrichment in miR-125a within CLL EVs as compared to healthy donor controls (p=.0001). CART cocultured with CLL EVs showed alterations in T cell activation pathways, where miR-125a targets TNFAIP3 and NFkB pathways were activated. These findings implicate miR-125a from CLL EVs in CART dysfunction. Next, we aimed to validate the impact of miRNA on CART cell outcomes in the clinic. We interrogated miRNA profiles from patients with diffuse large B cell lymphoma (DLBCL) treated with CART cell therapy (CART19-28ζ, axicabtagene ciloleucel). EV miRNA cargo was compared between responders (complete remission at 6 months, n=10) and non-responders (no response 1 month post CART19, n=10) to identify differentially enriched miRNAs across groups. miR-125a was again significantly upregulated in EVs of non-responders as compared to responders to CART19 treatment (fold change=3.28, padj=.018). To study the direct effect of miR-125a on CART cell functions, we generated and studied the effector functions of CART19-28z following transfection with miR-125a or negative miR control. CART19 cells transfected with miR-125a showed a dose dependent decrease in killing of lymphoma cells as compared to miR-control (p=.0001). miR-125a also significantly increased the rate of apoptosis in CART19 cells (fold change=1.95, p=.024) and decreased the level of CART proliferation (fold change=.71, p=.013) as compared to controls. Notably, miR-125a did not impact tumor cell growth, further verifying a direct CART effect. In summary, our studies demonstrate the impact of tumor derived miRNAs on CART cell outcomes. They identify that miR-125a is 1) associated with CLL EV induced CART dysfunction, 2) significantly elevated in non-responders to CART therapy in the clinic, and 3) able to decrease CART19 efficacy through reduced CART killing/proliferation and increased apoptosis. These results highlight a novel mechanism of CART19 failure induced through miRNA cargo delivery by tumor-derived EVs and the role of miR-125a in inducing CART19 dysfunction. Citation Format: Olivia Sirpilla, R. Leo Sakemura, Ismail Can, Truc N. Huynh, James H. GIrsch, Claudia Manriquez Roman, Carli M. Stewart, Kun Yun, Ekene J. Ogbodo, Long Mai, Omar Gutierrez Ruiz, Makena Rodriguez, Brooke Kimball, Hong Xia, Jose C. Villasboas, Stephen Ansell, Nora Bennani, Patrick B. Johnston, Jonas Paludo, Januario Castro, Mohamed Kharfandabaja, Sameer Parikh, Neil Kay, Yi Lin, Elizabeth Siegler, Saad Kenderian. Tumor-derived microRNA125a induces CART cell apoptosis and failure in B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3841.