Key Determinant Research Articles

CARBON EMISSIONS IN AGRICULTURAL GROWTH: A COMPREHENSIVE ANALYSIS OF FACTORS INFLUENCING ORGANIC CROP PRODUCTION IN KAZAKHSTAN

The article examines the problem of carbon emissions into the atmosphere caused by agricultural activities. She analyzes various aspects of the problem, including the impact of fertilizer use, tillage, and animal husbandry on carbon emissions. The article examines modern methods and technologies that can reduce agriculture’s carbon footprint and improve its environmental sustainability. The authors also discuss the role of renewable energy, effective waste management and sustainable practices in agriculture to reduce its contribution to climate change. This study is anticipated to make significant contributions to both recent literature and policymaking in Kazakhstan across several dimensions. Economic regression analysis was conducted using the panel data models such as Random Effects and Fixed Effects, and two econometric models were assessed. The findings of this study shed light on the intricate relationship between carbon emissions and key determinants within the agricultural sector of Kazakhstan. By employing a comprehensive regression model, incorporating various variables such as oilseed imports and exports, investments in the green economy, fertilizer usage, arable land, and economic indicators, this research delves into the nuanced dynamics influencing carbon emissions

Comparative Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With Blood-Based Biomarkers (Liquid Biopsy) vs Fecal Tests or Colonoscopy

Colorectal cancer (CRC) screening is highly effective but underused. Blood-based biomarkers (liquid biopsy) could improve screening participation. Using our established Markov model, screening every 3 years with a blood-based test that meets minimum Centers for Medicare & Medicaid Services' thresholds (CMSmin) (CRC sensitivity 74%, specificity 90%) was compared with established alternatives. Test attributes were varied in sensitivity analyses. CMSmin reduced CRC incidence by 40% and CRC mortality by 52% vs no screening. These reductions were less profound than the 68%-79% and 73%-81%, respectively, achieved with multi-target stool DNA (Cologuard; Exact Sciences) every 3 years, annual fecal immunochemical testing (FIT), or colonoscopy every 10 years. Assuming the same cost as multi-target stool DNA, CMSmin cost $28,500/quality-adjusted life-year gained vs no screening, but FIT, colonoscopy, and multi-target stool DNA were less costly and more effective. CMSmin would match FIT's clinical outcomes if it achieved 1.4- to 1.8-fold FIT's participation rate. Advanced precancerous lesion (APL) sensitivity was a key determinant of a test's effectiveness. A paradigm-changing blood-based test (sensitivity >90% for CRC and 80% for APL; 90% specificity; cost ≤$120-$140) would be cost-effective vs FIT at comparable participation. CMSmin could contribute to CRC control by achieving screening in those who will not use established methods. Substituting blood-based testing for established effective CRC screening methods will require higher CRC and APL sensitivities that deliver programmatic benefits matching those of FIT. High APL sensitivity, which can result in CRC prevention, should be a top priority for screening test developers. APL detection should not be penalized by a definition of test specificity that focuses on CRC only.

How are you affected? The public’s online information behaviour patterns during the COVID-19 infodemic

PurposeThis paper aims to examine the impact of the COVID-19 infodemic on the public’s online information behaviour, offering insights critical for shaping effective informational responses in future public health emergencies.Design/methodology/approachThis paper uses a structured online survey with 27 targeted questions using a five-point Likert scale to measure eight variables. Data analysis is conducted through structural equation modelling on 307 valid responses to rigorously test the research hypotheses.FindingsThis paper indicates that information quality significantly impacts the public’s capacity to select, share and use online information. Additionally, the comprehensibility of information plays a crucial role in shaping the public’s behaviours in terms of online information exchange and usage. The credibility of information sources emerges as a key determinant influencing the public’s online information selection, exchange and utilization behaviour. Moreover, social influence exerts a substantial effect on the public’s online information selection, acquisition, exchange and utilization behaviour. These findings highlight the presence of universality and sociality, mediation and guidance, as well as the purposefulness and selectivity performed by the public’s online information behaviour during an infodemic.Originality/valueThis paper introduces a novel research model for assessing the influence and identifies the patterns of the public’s online information behaviour during the COVID-19 infodemic. The findings have significant implications for developing strategies to tackle information dissemination challenges in future major public health emergencies.

Exploring mother-daughter communication and social media influence on HPV vaccine refusal for daughters aged 9-17 years in a cross-sectional survey of 11,728 mothers in China

ABSTRACT This study investigated the influences of mother-daughter communication and social media on mothers’ HPV vaccine refusal for their daughters aged 9–17. A cross-sectional online survey among 11,728 mothers of girls aged 9–17 in Shenzhen, China was implemented between July and October 2023. Multi-level logistic regression models were fitted. Among 11,728 participants, 43.2% refused to have their daughters receive an HPV vaccination. In multivariate analysis, more openness in the mother-daughter communication (AOR: 0.99, 95%CI: 0.98, 0.99), perceived more positive outcomes of mother-daughter communication (AOR: 0.77, 95%CI: 0.75, 0.79), higher frequency of exposure to testimonials about daughters’ HPV vaccination (AOR: 0.81, 95%CI: 0.78, 0.85) and information encouraging parents to vaccinate their daughters against HPV on social media (AOR: 0.76, 95%CI: 0.73, 0.79), and thoughtful consideration of the veracity of the information specific to HPV vaccines (AOR: 0.80, 95%CI: 0.77, 0.83) were associated with lower vaccine refusal. Mothers who were not the main decision-makers of daughters’ HPV vaccination (AOR: 1.28 to 1.46), negative outcome expectancies of mother-daughter communication (AOR: 1.06, 95%CI: 1.04, 1.08), and mothers’ HPV vaccine refusal (AOR: 2.81, 95%CI: 2.58, 3.06) were associated with higher vaccine refusal for their daughters. The level of mothers’ HPV vaccine refusal for their daughters was high in China. Openness and outcome expectancies of mother-daughter communication and information exposure on social media were considered key determinants of HPV vaccine refusal for daughters. Future HPV vaccination programs should consider these interpersonal factors.

Tall, large-diameter trees and dense shrub layer as key determinants of the abundance and composition of bird communities in oak-dominated forests

Increasing human activity is altering the structure of forests, which affects the composition of communities, including birds. However, little is known about the key forest structure variables that determine the richness of bird communities in European temperate oak forests. We, therefore, aimed to identify key variables in these habitats that could contribute to the design of management strategies for forest conservation by surveying 11 oak-dominated forest sites throughout the mid-mountain range of Hungary at 86 survey points to reveal the role of different compositional and structural variables for forest stands that influence the breeding bird assemblages in the forests at the functional group and individual species levels. Based on decision tree modelling, our results showed that the density of trees larger than 30 cm DBH was an overall important variable, indicating that large-diameter trees were essential to provide diverse bird communities. The total abundance of birds, the foliage-gleaners, primary and secondary cavity nesters, residents, and five specific bird species were related to the density of high trunk diameter trees. The abundance of shrub nesters was negatively influenced by a high density of trees over 10 cm DBH. The density of the shrub layer positively affected total bird abundance and the abundance of foliage gleaners, secondary cavity nesters and residents. Analysis of the co-dominant tree species showed that the presence of linden, beech, and hornbeam was important in influencing the abundance of various bird species, e.g., Eurasian Treecreeper (Certhia familiaris), Marsh Tit (Poecile palustris) and Wood Warbler (Phylloscopus sibilatrix). Our results indicated that large trees, high tree diversity, and dense shrub layer were essential for forest bird communities and are critical targets for protection to maintain diverse and abundant bird communities in oak-dominated forest habitats.

The Role of County-Level Persistent Poverty in Stroke Mortality in the USA.

Stroke is a major health concern in the USA, disproportionately affecting socioeconomically disadvantaged groups. This study investigates the link between persistent poverty and stroke mortality rates in residents aged 65 and above, positing that sustained economic challenges at the county level correlate with an increase in stroke-related deaths. Persistent poverty refers to a long-term state where a significant portion of a population lives below the poverty threshold for an extended period, typically measured over several decades. It captures the chronic nature of economic hardship faced by a community across multiple generations. Utilizing data from the CDC Wonder database and the American Community Survey, we conducted a comprehensive analysis across US counties, differentiating them by persistent poverty status. Our results indicate a statistically significant link between persistent poverty and increased mortality from ischemic and hemorrhagic strokes; counties afflicted by long-standing poverty were associated with an additional 33.49 ischemic and 8.16 hemorrhagic stroke deaths per 100,000 residents annually compared to their wealthier counterparts. These disparities persisted when controlling for known stroke risk factors and other socioeconomic variables. These results highlight the need for targeted public health strategies and interventions to address the disparities in stroke mortality rates and the broader implications for healthcare equity. The study underscores the vital role of socioeconomic context in health outcomes and the urgency of addressing long-term poverty as a key determinant of public health.

Analysing the Modular Design Strategies to Enhance the Adaptive Capacity of Buildings

In recent years all industries have faced a growing demand for customizable and flexible products that are adaptable to human needs. Buildings being an integral part of our daily lives provide a space to live, work, learn, and socialize and are thus driven to be adaptable according to the dynamic needs of the individuals. New design strategies and technologies are required to make it adaptable without consequences on the economy, ecology, waste generation, and energy consumption. This paper explores the potential application of modular design strategies to address the changing needs and ensure the buildings have enhanced adaptive capacity. To comprehend the nature of these changes and building capacity for adaptation, a thorough analysis of a few chosen case studies based on the type of modular design strategy employed was done. In the cases analyzed, strategies were identified and assessed based on adaptability's key determinants and dimensions. The results of the case studies helped in identifying different modular design strategies that can be employed for different building systems for different purposes to enhance the adaptive capacity of a building. Thus, helping in designing future-proof adaptable structures with a modular approach for a sustainable future. KEYWORDS: adaptability; adaptable building; adaptive capacity; adaptability determinants; modular design; modules

Integrative Dissection of Lignin Composition in Tartary Buckwheat Seed Hulls for Enhanced Dehulling Efficiency.

The rigid hull encasing Tartary buckwheat seeds necessitates a laborious dehulling process before flour milling, resulting in considerable nutrient loss. Investigation of lignin composition is pivotal in understanding the structural properties of tartary buckwheat seeds hulls, as lignin is key determinant of rigidity in plant cell walls, thus directly impacting the dehulling process. Here, the lignin composition of seed hulls from 274 Tartary buckwheat accessions is analyzed, unveiling a unique lignin chemotype primarily consisting of G lignin, a common feature in gymnosperms. Furthermore, the hardness of the seed hull showed a strong negative correlation with the S lignin content. Genome-wide detection of selective sweeps uncovered that genes governing the biosynthesis of S lignin, specifically two caffeic acid O-methyltransferases (COMTs) and one ferulate 5-hydroxylases, are selected during domestication. This likely contributed to the increased S lignin content and decreased hardness of seed hulls from more domesticated varieties. Genome-wide association studies identified robust associations between FtCOMT1 and the accumulation of S lignin in seed hull. Transgenic Arabidopsis comt1 plants expressing FtCOMT1 successfully reinstated S lignin content, confirming its conserved function across plant species. These findings provide valuable metabolic and genetic insights for the potential redesign of Tartary buckwheat seed hulls.

Abstract 136: Determining the genomic basis of PAX3-FOXO1 mediated transformation in rhabdomyosarcoma

Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite rigorous scientific advances and clinical trials, the survival rate for high-risk RMS has not increased above 20% in the last three decades. A deeper understanding of the basic biology driving RMS tumorigenesis is needed to discover novel therapeutic targets. RMS can be divided into two major histologic subtypes: embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS accounts for 20% of pediatric cases and has poorer survival. The majority of ARMS tumors harbor t(2;13)(q35;q14) or t(1;13)(p36;q14) chromosomal translocations resulting in the PAX3-FOXO1 (P3F) and PAX7-FOXO1 (P7F) fusion oncoproteins, respectively. ARMS tumors that lack oncofusions more closely resemble ERMS. Classifying on fusion status more accurately describes the disease and highlights the significance of P3/7F. ARMS tumor genomes only contain an average of 6.4 somatic mutations suggesting the oncofusion protein is the key oncogenic driver and a potential candidate for therapeutic intervention. RMS is commonly thought to arise from skeletal muscle progenitor cells that fail to terminally differentiate. However, RMS occurs throughout the body in sites devoid of skeletal muscle, underscoring the potential for alternative cells of origin. Our lab established that endothelial progenitors are indeed a cell of origin for ARMS by generating a genetically engineered mouse model with endothelial cell specific P3F expression coupled with Cdkn2a loss. We further generated a human model system derived from TP53-null human induced pluripotent stem cells (iPSCs), in which we direct differentiation to endothelial cell fate and then force P3F expression. P3F expression during endothelial cell directed differentiation blocked endothelial maturation and instead reprogrammed cells shifting cell fate to skeletal muscle-like cells that form ARMS tumors in mice. Generation of iPSC-derived ARMS (iARMS) occurs over 15 days and provides a unique model to determine the kinetics and specific genomic contributions facilitated by P3F during RMS transformation. To investigate the genomic changes occurring during iARMS transformation I utilized CUT&RUN for P3F and H3K27ac to assess P3F occupancy and enhancer landscape, ATAC-seq to assess chromatin accessibility, and RNA-seq to assess gene expression changes at timepoints throughout the transformation event. These results define the fundamental genomic changes needed for transformation into FP-RMS by P3F and uncovers the key determinants of ARMS cell identity. The iARMS system provides a unique platform to uncover how P3F establishes and maintains RMS cell state and to dissect the specific dependencies required to maintain the ARMS cell state. Understanding the fundamental mechanism of P3F-driven tumorigenesis could provide greater resolution into the key disease determinants to focus pre-clinical efforts on pivotal targets. Citation Format: Bradley T. Stevens, Yang Zhang, Randolph K. Larsen, Grace E. Adkins, Jack D. Hopkins, Darden W. Kimbrough, Matthew R. Garcia, Brian J. Abraham, Mark E. Hatley. Determining the genomic basis of PAX3-FOXO1 mediated transformation in rhabdomyosarcoma [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 136.

“Coursebook or No Coursebook”? A False Dilemma

The outdated debate over whether an EFL coursebook is necessary or not seems as relevant as ever since it is by no means a self-evident truth to every EFL educator. This paper argues that among the range of factors affecting the assessment of a given textbook is the teacher’s promptness to promote closer collaboration with students through appropriate means. More specifically, a pre-use textbook evaluation through the compilation of an appropriate checklist was put to the test with the aim of checking the serviceability of the new coursebook for the first grade of Greek General Lyceum. The case of an EFL teacher who tried to predict the impact of a textbook on her specific teaching context indicated that the expectation of student inputs to the implementation of learning activities (e.g., participation in activities using technology) was valued as a key determinant in setting priorities for in-use textbook evaluation.

Abstract 5503: Ultrahigh-plex spatial phenotyping of head and neck cancer tissue uncovers multiomic signatures of immunotherapy response

Abstract Background Targeted immune checkpoint inhibitors (ICI) with anti-PD-1/PD-L1 therapy offer durable treatment of mucosal head and neck squamous cell cancer (HNSCC), in both human papillomavirus-positive (HPV+) and negative (HPV-) patients. However, currently available biomarker signatures for targeted ICI therapies have limited predictive value. Our recent ultrahigh-plex profiling of HNSCC tissue with 100+ cancer hallmarks of tumor and immunobiology uncovered distinct spatial domains that serve as defining factors for clinical response and resistance. Methods Our unbiased analysis of whole-slide metastatic HNSCC tumors is from a clinical cohort of patients treated with Pembrolizumab/Nivolumab. The cohort consisted of patients with a range of outcomes from complete vs partial vs progressive disease responses to ICI therapy. We first characterized the tumor microenvironment using our ultrahigh-plex protein panel with 100+ antibodies on the PhenoCycler®-Fusion platform. To expand upon our biomarker discovery, we included multiomic cancer hallmarks with a multimodal protein/RNA detection panel. Targeted spatial RNA detection was performed to complement and augment the microenvironment characterization achieved by our protein panel. To further consolidate the multiomic data, we leveraged MaxFuse, a state-of-the art computational framework that integrates multimodal spatial and single-cell expression data. Results Our multiomic spatial phenotyping uncovered diverse tumor regions, each with distinct biomarker expression that is reflected across modalities including protein, RNA, and metabolic activity, indicating regions likely associated with resistance to immunotherapy. Our multiomic data integration also revealed spatial signatures associated with different tissue compartments, such as the tumor and non-tumor associated tertiary lymphoid structures. Conclusions We demonstrate a multi-pronged approach that incorporated both novel experimental and computational techniques for elucidating tumor microenvironment in HNSCC tissue prior to ICI-based immunotherapy. Our multiomic approach provides deeper characterization of the HNSCC at the transcriptomic and proteomic level incorporating depth across the entire transcriptome and single-cell spatial resolution of key protein determinants for predicting and furthering our understanding of immunotherapy response to ICI therapy. Citation Format: Aditya Pratapa, Lydia Hernandez, Bassem Ben Cheikh, Niyati Jhaveri, Arutha Kulasinghe. Ultrahigh-plex spatial phenotyping of head and neck cancer tissue uncovers multiomic signatures of immunotherapy response [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 5503.

Multimorbidity healthcare expenditure in Belgium: a 4-year analysis (COMORB study)

BackgroundThe complex management of health needs in multimorbid patients, alongside limited cost data, presents challenges in developing cost-effective patient-care pathways. We estimated the costs of managing 171 dyads and 969 triads in Belgium, taking into account the influence of morbidity interactions on costs.MethodsWe followed a retrospective longitudinal study design, using the linked Belgian Health Interview Survey 2018 and the administrative claim database 2017–2020 hosted by the Intermutualistic Agency. We included people aged 15 and older, who had complete profiles (N = 9753). Applying a system costing perspective, the average annual direct cost per person per dyad/triad was presented in 2022 Euro and comprised mainly direct medical costs. We developed mixed models to analyse the impact of single chronic conditions, dyads and triads on healthcare costs, considering two-/three-way interactions within dyads/triads, key cost determinants and clustering at the household level.ResultsPeople with multimorbidity constituted nearly half of the study population and their total healthcare cost constituted around three quarters of the healthcare cost of the study population. The most common dyad, arthropathies + dorsopathies, with a 14% prevalence rate, accounted for 11% of the total national health expenditure. The most frequent triad, arthropathies + dorsopathies + hypertension, with a 5% prevalence rate, contributed 5%. The average annual direct costs per person with dyad and triad were €3515 (95% CI 3093–3937) and €4592 (95% CI 3920–5264), respectively. Dyads and triads associated with cancer, diabetes, chronic fatigue, and genitourinary problems incurred the highest costs. In most cases, the cost associated with multimorbidity was lower or not substantially different from the combined cost of the same conditions observed in separate patients.ConclusionPrevalent morbidity combinations, rather than high-cost ones, made a greater contribution to total national health expenditure. Our study contributes to the sparse evidence on this topic globally and in Europe, with the aim of improving cost-effective care for patients with diverse needs.

Abstract 7558: Novel liquid biopsy based determination of lung cancer histology using a comprehensive epigenomic platform reveals enhancer activity as a key determinant for accurate classification

Abstract BACKGROUND: Accurate molecular characterization of lung cancer including histology classification and therapeutic target profiling is critical for treatment planning and resistance monitoring. For example, detecting lineage transformation from lung adenocarcinoma (LUAD) to small cell lung carcinoma (SCLC) following treatment, an established resistance mechanism, is challenging due to deteriorating patient health and complicated invasive procedures. Here, we describe an accurate lung cancer histological classification using an innovative, multimodal epigenomic liquid biopsy method that comprehensively profiles tumor-specific transcription activation from 1 mL of patient plasma. METHODS: 37 LUAD, 34 SCLC patient plasma samples collected from commercial biobanks, and reference cell lines were profiled for enhancer, promoter and DNA methylation activity to identify epigenomic loci characteristic of LUAD and SCLC. The resulting map of select quantified loci was used as input to a machine learning algorithm that distinguishes SCLC from LUAD, in a cross validated training and testing approach. RESULTS: The epigenomic maps derived from lung cancer patient plasma were highly informative of the regulatory programming of the tumor cells. The enhancers and promoters most strongly linked to lung cancer profiles across the patient population include key, histology-specific driver genes such as NKX2-1, FOXA1, FOXA2, ONECUT2, DLL3, and ASCL1. The resulting classifier was able to accurately predict histology with a cross validated AUC greater than 0.94. In silico simulation results suggest that accurate classification can be achieved with ctDNA content below 1%. Further correlative examination of the SCLC enhancer landscape revealed a partitioning of SCLC patients into molecular subtypes characterized by active enhancer marks at subtype-specific transcripts, including ASCL1, POU2F3, NEUROD1, and YAP1. The transcriptional regulation of ADC targets is apparent through comprehensive epigenomic profiling of plasma in both SCLC and LUAD, with the expression of Claudin 18.2, SEZ6, and others showing a strong dynamic range independent of ctDNA levels. This represents a novel liquid biopsy approach to distinguish LUAD from SCLC and provide simultaneous insight into expression of key targets at clinically relevant ctDNA levels. CONCLUSION: These data demonstrate the feasibility of epigenomic mapping from 1mL of plasma in lung cancer patients to distinguish lung cancer histology. The resulting data is biologically interpretable through the lens of transcriptional activation of key histology specific genes. This liquid-biopsy based approach may provide a non-invasive alternative to invasive and challenging tissue biopsies for biomarker investigation and therapeutic decision making. Citation Format: Jamey Guess, Aparna Gorthi, Anthony D'ippolity, Jonathan Beagan, Travis Clark, Michael Coyne, Tyrone Tamakloe, Baovy Tran, Hyun-Hwan Jeong, Kristian Cibulskis, Hathairat Sawaengsri, Juliann Chmielecki, Corrie A. Painter, J Carl Barrett, Matthew Eaton. Novel liquid biopsy based determination of lung cancer histology using a comprehensive epigenomic platform reveals enhancer activity as a key determinant for accurate classification [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 7558.

Abstract 3968: Class I HLA-independent lysis of cancer cells by tumor-infiltrating CD8 T cells

Abstract T cell-based therapies have transformed cancer treatment, although intrinsic or acquired resistance develops in nearly half of the patients. Tumor-infiltrating CD8+ T lymphocytes (TILs) are key determinants of anti-tumor immunity by secretion of cytotoxic granules, such as granzymes and perforin, and effector cytokines, such as TNFa and IFNg. A deep understanding of how CD8+ TILs eliminate cancer cells will help identify resistance mechanisms and develop new therapeutic strategies. Here, we demonstrate that TILs eliminated matched melanoma cells in a time and dose-dependent manner but in a class I HLA-independent fashion. Specifically, blocking class I HLA-TCR interaction either by the deletion of B2M (resulting in loss of class I HLA surface expression) or TCR genes did not alter the activity of these TILs. We further confirmed that TIL-mediated killing is contact-dependent. After excluding the potential roles of CD1d and MR1-restrictive T cells, gamma delta T cells, and NKG2D in TIL-mediated killing, a whole-genome CRISPR/Cas9 screen was performed in cancer cells. We identified that genes involved in JAK-STAT and cell-extrinsic apoptosis pathways are necessary for TIL-mediated killing. Together, these findings demonstrate that expanded CD8 TILs from melanoma patients are capable of eliminating melanoma cells via a novel, class I MHC-independent mechanism by coactivation of both JAK-STAT and cell-extrinsic apoptosis pathways. Citation Format: Hongyan Xie, Aiping Jiang, Jonathan Perera, Aonkon Dey, Neal Smith, Moshe Sade-Feldman, Robert T. Manguso, Nir Hacohen, Russell W. Jenkins. Class I HLA-independent lysis of cancer cells by tumor-infiltrating CD8 T cells [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 3968.

Abstract 6109: Determinants of generalized self-efficacy and genetic knowledge among Hispanic/Latino colorectal cancer patients participating in ENLACE: A Cancer Moonshot Study

Abstract Background: Colorectal cancer (CRC) is the third most common cancer, and second cause of cancer death in the United States (US). Among US Hispanic/Latino/a/x (H/L) individuals, CRC represents the second and the third most common cancer and the most common cause of cancer death for men and women, respectively. Despite this, the tumor landscape, and key determinants of outcomes in CRC H/L patients are understudied. Methods: To address this need, we launched the ENLACE study, to engage H/L CRC patients in germline and somatic sequencing and identify the optimal approaches for patient participation. Through the Center for Patient Engagement in Cancer Characterization Studies (COPECC) patients were recruited from two healthcare facilities: a safety-net hospital (Los Angeles General Medical Center, LA Gen) and the USC Norris Comprehensive Cancer Center (Norris) a university medical center. Surveys to assess demographics, acculturation, Latino values, health literacy, discrimination, health system distrust, numeracy, and generalized self-efficacy (GSE) were evaluated upon recruitment, and after return-of-results (ROR) for somatic and germline testing. Results: After the first year of the project, a total of 100 H/L CRC patients >18 years of age were included in the ENLACE study, 89 participants completed baseline surveys (49 female, median age 53 (IQR = 16) and 21 completed questionnaires after ROR. A majority self-identified as White (61%), Mexico born (51%), catholic (74%), only spoke Spanish at home (35%) and married (49%). Higher levels of GSE were reported in patients with higher scores for numeracy (p = 0.005) and in males when compared to females (p = 0.016). This association was driven by participants from Norris (n=33) as reported by stratified analyses. In contrast, among participants from LA Gen (n=66) we observed an association with higher median values for the Mexican American acculturation scale and mainstream values and a marginally significant increase in the GSE (p = 0.072 & 0.083, respectively). Additionally, LA Gen participants with a greater than the median score for GSE had a marginally significant higher mean score in the KnowGene scale (p = 0.056) with a reduction in the number of times the “Don’t Know” option was selected (p = 0.045). No statistically significant difference in the generalized self-efficacy score and KnowGene scale were reported after reception of results (p = 0.2386 & 0.1337, respectively) Conclusion: We report differences in GSE and cancer genetic knowledge amongst CRC H/L patients in the ENLACE study that may inform understanding of disparities and social determinants in the populations treated at two different healthcare facilities. Citation Format: Joel Sanchez Mendez, Julie O. Culver, Charité N. Ricker, Natalia Gutierrez, Sandra Algaze, John D. Carpten, Heinz-Josef Lenz, Mariana C. Stern. Determinants of generalized self-efficacy and genetic knowledge among Hispanic/Latino colorectal cancer patients participating in ENLACE: A Cancer Moonshot Study [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 6109.

Abstract 5278: Immunological control by PARP inhibitors for successful immunotherapy in metastatic ovarian carcinoma

Abstract Epithelial ovarian carcinoma (EOC) is among the top five causes of cancer-related death in women. Most women with EOC achieve indeed complete remission after primary or interval cytoreductive surgery combined with chemotherapy based on a platinum-taxane doublet. Homologous recombination (HR) defects imposed by germline or somatic BRCA1 DNA repair-associated (BRCA1) or BRCA2 mutations are not only key determinants of platinum sensitivity in EOC patients but also provide a strong rationale for maintenance therapy based on poly(ADP-ribose) polymerase (PARP) inhibitors, which is generally associated with improved progression-free survival (PFS). Besides direct cytotoxic and cytostatic properties, PARPi have been shown to mediate multipronged immunostimulatory effects, largely reflecting their ability to inhibit DNA repair in malignant cells and indicating the possibility to synergy with immune-check point inhibitors (ICIs). Here, using multiparametric flow cytometry, multiplex immunostaining, single cells transcriptomics and functional studies in experimental syngeneic BR5Brca1-/- mouse model and EOC tumor samples, we discuss PARPi immunomodulatory activity, with a specific focus on molecular and cellular pathways that can be harnessed to develop superior combinatorial regimens for clinical management. Thus, PARPi might enhance the mutational load of EOCs as consequence of unrepaired DNA damage and DAMPs exposure, favoring T cell infiltration, but also appear to drive robust type I IFN secretion downstream of cyclic GMP-AMP synthase and stimulator of IFN response cGAMP interactor 1 activation. In addition, the combination of PARPi with ICIs positively regulate the balance between adaptive anti-tumor immunity and innate myeloid components and significantly improve the cytotoxic T cell profile as shown in both experimental mice model and HGSOC tumor samples. We surmise that rationally designed combinations of PARPi and immunotherapeutic agents might be critical to unlock immunosuppression in the EOC microenvironment in support of clinical efficacy. Citation Format: Peter Holicek, Sarka Vosahlikova, Irena Moserova, Sandra Orsulic, Romana Mikyskova, Michal Hensler, Lenka Kasikova, Tereza Lanickova, Ondrej Novotny, Milan Reinis, Jana Drozenova, Ales Ryska, Jan Laco, Lukas Rob, Michael Halaska, David Cibula, Radek Spisek, Jitka Fucikova. Immunological control by PARP inhibitors for successful immunotherapy in metastatic ovarian 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 5278.

Abstract 5272: APL-1202 enhances anti-tumor immune response through induction of cellular stress signaling and immunogenic cell death pathway in cancer cells

Abstract Introduction: Treatment approach combining cancer cell targeted therapy and immunotherapy is an effective strategy to trigger robust tumor-specific immune responses. The aim of this study is to determine the impact of APL-1202, a clinical-stage drug candidate (NCT04813107), on cellular stress-driven immunogenic outcomes in bladder cancer cells. Methods: RNA-seq analysis was performed using bladder cancer and endothelial cell lines (A56, J82, T24, HUVEC) treated with APL-1202. Key determinants of immunogenic cell death pathway were measured by cell-surface translocation of calreticulin (flow cytometry), extracellular ATP release assay (bioluminescence) and HMGB1 secretion (ELISA) in the supernatants of cancer cells after APL-1202 treatment. Effects on the innate immune effector function was measured by flow cytometry-based phagocytosis assay consisting of Far-Red dye-stained, pre-treated bladder cancer cell lines (UMUC3, T24) in coculture with THP1-derived macrophages/immature dendritic cells or human monocyte-derived dendritic cells. In vivo, tumor end-point immune cell analysis, tumor weight and mouse survival were compared in chemically induced (BBN: N-butyl-N-(4-hydroxybutyl)-nitrosamine) orthotopic bladder cancer mice treated with APL-1202 and anti-PD1 antibody. Results: Pathway analysis of RNA-seq data from APL-1202 treated cells suggested upregulation of cellular stress-related gene signatures (oxidative stress, autophagy, P53) and pro-inflammatory responses (IL-6, IL-8, HMGB1 signaling). Conversely, downregulation of cell cycle (E2F targets, G2-M checkpoint) and IL-10 signaling suggested increased genomic stress and inflammatory switching in the treated cancer cells. Acute exposure to APL-1202 increased cell-surface translocation of calreticulin as well as extracellular release of ATP and HMGB1 in the treated T24 and UMUC3 cells. Higher percentages of phagocytic activities were detected in both THP-1-derived macrophages/immature dendritic cells and human monocyte-derived dendritic cells after coculture with APL-1202 treated T24 and UMUC3 cells compared to coculture with DMSO treated control cells. Immune phenotyping in tumors derived from BBN bladder cancer mouse model revealed increased infiltration of NK cells and CD8+ T cells. Furthermore, APL-1202 enhanced the anti-tumor effects of a therapeutic anti-PD1 antibody in mice as reflected by significantly decreased tumor weights and increased survival in a combination group with APL-1202 treatment compared to the anti-PD-1 antibody alone treatment group. Conclusion: APL-1202 may improve the efficacy of immune-checkpoint blockade therapies in bladder cancer patients by enhancing cancer cell immunogenicity and subsequent anti-tumor effector immune cell processes, particularly in tumors with deficits in antigen-specific immunity. Citation Format: Rakesh BAM, Jingmin Guan, Neetha Nanoth Vellichirammal, Murli Manohar, David Mulholland, John Sfakianos, Qiaoling Sun, Zuoan Yi, Alice Chen. APL-1202 enhances anti-tumor immune response through induction of cellular stress signaling and immunogenic cell death pathway in cancer cells [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 5272.

Abstract 5873: ERα coordinates with squalene synthase to confer statin resistance in lung cancer

Abstract Statins are widely used to treat hypercholesterolemia by inhibiting hydroxymethylglutaryl coenzyme A reductase (HMGCR). Accumulating evidence suggests that statins also have protective effects against cancer recurrence. However, the role of statins in preventing lung cancer and biomarkers for predicting statin treatment response remains lacking. This study analyzes molecular features that dictate statin sensitivity in lung cancer by correlating large-scale statin sensitivity data and basal gene expression in a collection of 125 lung cancer patients. We identified a gene signature associated with lovastatin sensitivity and showed that gene expression in mesenchymal molecular features, the cholesterol biosynthesis pathway, and estrogen receptor alpha (ERα) signaling were key determinants of lovastatin sensitivity in lung cancer cells. To this end, we further discovered that overexpression of a committed step enzyme in cholesterol biosynthesis farnesyl-diphosphate farnesyltransferase 1 (FDFT1), also known as squalene synthase (SQS), is capable of activating ERα and is associated with increased statin tolerance. In clinical specimens, overexpression of SQS positively correlated with nuclear expression of ERα in lung cancer patients, and the combination of SQS and ERα is a powerful prognostic predictor for lung cancer. Activation of the SQS-ERα signaling axis and epithelial-to-mesenchymal transition (EMT) status represents two important features in determining statin sensitivity in lung cancer. Keywords: Statin, cholesterol biosynthesis, squalene synthase, estrogen receptor α, Epithelial-mesenchymal transition Citation Format: Yi-Fang Yang. ERα coordinates with squalene synthase to confer statin resistance in lung cancer [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 5873.

Abstract 5341: Novel FcγR humanized mouse model enables assessment of PK/PD of therapeutic antibodies

Abstract Therapeutic antibodies have revolutionized the way we treat cancer. Enhanced activity of therapeutic IgG can be achieved by the modulation of Fc binding to Fcγ receptors (FcγR), which will consequently modulate the Fc-effector functions triggered upon crosslinking of target and effector cells by these antibodies. Assessment of therapeutic antibodies pharmacodynamic (PD) in preclinical models is challenging, as the FcγR are different from mice to human, as well as their expression pattern. FcRn is involved in the recycling and transport of IgG and is a key determinant of the pharmacokinetics (PK) of IgG. We report here a novel mouse model expressing human FcγR with a human-like expression pattern, in which human FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB are expressed and replace their mouse orthologs. The model was intercrossed with the hSA/hFcRn mouse model (Viuff et al., 2016), which has shown to improve translatability of PK assessment of therapeutics with extended half-life via FcRn recycling and/or HSA binding. Investigation of FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB expression on DC, monocytes, granulocytes, NK, T and B cells shows that expression pattern in hFcγR mice is consistent with their expression on human PBMC, with a few exceptions. These receptors are functional, as a human IgG1 targeting mouse CD20 induces approximately 50% of B-cell depletion in blood and liver, after a single iv administration in hFcγR mice. This depletion is Fc-mediated, as it is abrogated when hFcγR mice are treated with an anti-mouse CD20 human IgG1 with a Fc-null mutation. Assessment of antibody-dependent cell cytotoxicity (ADCC) ex vivo to investigate FcγR functionality in NK cells shows that Rituximab, an anti-human CD20 chimeric IgG1 with regular Fc, induces higher ADCC efficacy in NK cells from hFcγR than in NK cells from WT mice. Obinutuzumab, an anti-human CD20 featuring an optimized Fc portion to enhance binding to FcγRIII, shows higher tumor cell lysis than Rituximab in NK cells from hFcγR mice, suggesting this model enables ranking of antibodies. Moreover, assessment of activity of Fc-engineered anti-influenza IgG antibodies also shows that anti-Flu antibody with enhanced Fc binding outperforms the WT antibody, improves protective activity, and demonstrates effector function in influenza challenge model, following prophylactic treatment. Conversely, hFcγR mice treated with an Fc-null version of the anti-Flu antibody shows reduced protective activity and survival compared with the WT antibody. Therefore, the model reported here is a novel tool for testing efficacy of Fc-engineered therapeutic antibodies. We are currently investigating the PK profile of therapeutic antibodies in the hFcγR/hSA/hFcRn model. This novel tool is being improved to enable tolerability to human IgG1, biodistribution to the central nervous system, and flexibility of test of therapeutics through expression of human immune checkpoints. Citation Format: Fabiane Sonego, Angela Pappalardo, Gaëlle Martin, Rachel Courtois, Séverine Augier, Yacine Cherifi, Ariane Morel, Patricia Isnard-Petit, Kader Thiam. Novel FcγR humanized mouse model enables assessment of PK/PD of therapeutic antibodies [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 5341.

Evaluating COVID-19 vaccine acceptance among parents in Saudi Arabia: a systematic review examining attitudes, hesitancy, and intentions.

The COVID-19 pandemic, affecting adults and children equally, has caused significant disruption to countries worldwide, including Saudi Arabia. In Saudi Arabia, the fast preventative measures and mass vaccine enrollment were vital to contain the devastating impact of the pandemic. However, vaccine hesitancy, especially among parents toward vaccinating their children, was a significant obstacle to vaccine uptake. This systematic review followed PRISMA guidelines to assess parental willingness to vaccinate their children against COVID-19, determine the key determinants influencing such intention and attitudes, and underline the significant concerns and misconceptions regarding the vaccine among parents. The Joanne Briggs Institute (JBI) checklist for prevalence studies was used to assess included studies for risk of bias. Twenty-three studies were included in this systematic review, representing a total of 20,926 participants, with over 66% of them were female. Over 37% of the participants were willing to vaccinate their children against COVID-19. Parents' age, gender, level of education, and income were the main determinants of their intention to vaccinate their children. The parents' main concerns were the potential vaccine side effects, safety, and efficacy. Major misconceptions about the COVID-19 vaccine included it being dangerous to children and that children are at lower risk of severe infection; hence, vaccines were not needed. This seminal review provides insights to public health policymakers, which should be considered and taken together in light of other studies addressing parental vaccine hesitancy.