Multimodal Activity Research Articles

The ethnographic museum as a sensitive translation

Abstract This article analyzes the recently renewed, permanent exhibition of the Royal Museum for Central Africa (AfricaMuseum) in Tervuren, Belgium. The museum is seen as a translational space, considering the parallels between, on the one hand, curatorial strategies to represent cultural otherness and, on the other, processes of cultural and interlingual translation (Sturge 2007). We draw on an interdisciplinary mindset of translation as change and choice, as a multimodal and multimedial activity, and as an inevitably meaning-transforming process. Pressured to keep pace with the rapidly evolving public debate on decolonization, the curators-translators of the AfricaMuseum are aware that they are dealing with “sensitive texts” (Simms 1997) and have, accordingly, adopted a set of strategies to reduce perceived “translation risks” (Pym and Matsushita 2018). The article explores these strategies at three levels of translation operating in the museum: cultural, intersemiotic, and interlingual. In particular, we reveal the inherent tensions in the current display by discussing scenographic interventions that undermine the decolonization efforts in a number of galleries. These tensions are conceptualized as incomplete or incoherent forms of translation and illustrate the “work in progress” in the AfricaMuseum.

Network representation of multicellular activity in pancreatic islets: Technical considerations for functional connectivity analysis.

Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect of metabolic homeostasis. Despite the inherent heterogeneity and multimodal activity of individual cells, intercellular coupling acts as a homogenizing force, enabling coordinated responses through the propagation of intercellular waves. Disruptions in this coordination are implicated in irregular insulin secretion, a hallmark of diabetes. Recently, innovative approaches, such as integrating multicellular calcium imaging with network analysis, have emerged for a quantitative assessment of the cellular activity in islets. However, different groups use distinct experimental preparations, microscopic techniques, apply different methods to process the measured signals and use various methods to derive functional connectivity patterns. This makes comparisons between findings and their integration into a bigger picture difficult and has led to disputes in functional connectivity interpretations. To address these issues, we present here a systematic analysis of how different approaches influence the network representation of islet activity. Our findings show that the choice of methods used to construct networks is not crucial, although care is needed when combining data from different islets. Conversely, the conclusions drawn from network analysis can be heavily affected by the pre-processing of the time series, the type of the oscillatory component in the signals, and by the experimental preparation. Our tutorial-like investigation aims to resolve interpretational issues, reconcile conflicting views, advance functional implications, and encourage researchers to adopt connectivity analysis. As we conclude, we outline challenges for future research, emphasizing the broader applicability of our conclusions to other tissues exhibiting complex multicellular dynamics.

Efficacy of the drug maribavir according to clinical studies

Modern medicine has a high demand for new drugs for the prevention and treatment of cytomegalovirus (CMV) infection. This review discusses maribavir — an oral antiviral drug with selective multimodal anti-CMV activity for the treatment of adults and children with post-transplant CMV infection resistant to traditional anti-CMV therapy. Despite numerous clinical trials of maribavir, the results of its effi cacy are ambiguous. Alongside successful studies indicating high effi cacy of the drug under review, there are data from statistically unsuccessful studies. The aim of this review is to examine the mechanism of its action on cytomegalovirus infection, viral sensitivity and cross-resistance mechanisms, as well as to summarize the results of clinical trials of the drug.

Creating more opportunities through multimodal literacy and positioning in online and in-person Chinese heritage language classrooms

The manuscript describes Chinese immigrant children’s literacy and identity in online and in-person Chinese heritage language classrooms. The theoretical perspectives on multimodality and positioning theory are utilized as theoretical perspectives. The data were collected with the same heritage language teacher and the students during the COVID-19 and post-pandemic. Data sources included field notes based on observations, video recordings of class conversations, and interviews with the teacher. The findings present similar and different patterns in relation to multimodal literacy activities in both online and in-person settings. The findings also show that the students’ identities shifted in these settings. Implications include offering more multimodal activities for immigrant children in both settings in the post-pandemic period, providing more digital tools and resources for the children, and calling more attention from funding agencies to support heritage language education.

A multi-objective model for selecting response strategies of primary and secondary project risks under interval-valued fuzzy uncertainty

Risks are uncertain events that can affect criteria such as project cost, quality, and completion time and ultimately lead to project failure. That is why the project risk management process, which is one of the most fundamental parts of project management, must be done properly. In this paper, a new multi-objective fuzzy model is proposed to respond appropriately to the primary and secondary project risks. The contributions, such as risk interdependency, considering the project with multi-mode activities, resource considerations, as well as attention to interval-valued fuzzy uncertainties are regarded simultaneously for the first time. The purpose of the proposed multi-objective mathematical model is to minimize cost, quality reduction, and project completion time. Then, a new two-stage uncertain solution approach is introduced in this paper. In this solution approach, using an equivalent method in the first step and then using an extended multi-choice goal programming method in the second step, for both lower and upper limits of the membership functions for interval-valued fuzzy numbers, the computational processes are performed. To show the application and effectiveness of the proposed model, a case study adapted from the literature is given. Finally, sensitivity analysis is conducted to analyze the behavior of the developed mixed-integer programming model. The analysis of obtained results indicates that the utilization of the proposed model leads to better and more appropriate solutions.

Short communication: Lifetime musical activity and resting-state functional connectivity in cognitive networks.

Participation in multimodal leisure activities, such as playing a musical instrument, may be protective against brain aging and dementia in older adults (OA). Potential neuroprotective correlates underlying musical activity remain unclear. This cross-sectional study investigated the association between lifetime musical activity and resting-state functional connectivity (RSFC) in three higher-order brain networks: the Default Mode, Fronto-Parietal, and Salience networks. We assessed 130 cognitively unimpaired participants (≥ 60 years) from the baseline cohort of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Lifetime musical activity was operationalized by the self-reported participation in musical instrument playing across early, middle, and late life stages using the Lifetime of Experiences Questionnaire (LEQ). Participants who reported musical activity during all life stages (n = 65) were compared to controls who were matched on demographic and reserve characteristics (including education, intelligence, socioeconomic status, self-reported physical activity, age, and sex) and never played a musical instrument (n = 65) in local (seed-to-voxel) and global (within-network and between-network) RSFC patterns using pre-specified network seeds. Older participants with lifetime musical activity showed significantly higher local RSFC between the medial prefrontal cortex (Default Mode Network seed) and temporal as well as frontal regions, namely the right temporal pole and the right precentral gyrus extending into the superior frontal gyrus, compared to matched controls. There were no significant group differences in global RSFC within or between the three networks. We show that playing a musical instrument during life relates to higher RSFC of the medial prefrontal cortex with distant brain regions involved in higher-order cognitive and motor processes. Preserved or enhanced functional connectivity could potentially contribute to better brain health and resilience in OA with a history in musical activity. German Clinical Trials Register (DRKS00007966, 04/05/2015).

Modular multimodal hospital-home chain physical activity rehabilitation programme (3M2H-PARP) in liver cancer: a protocol for a randomised controlled trial

IntroductionPatients with liver cancer are susceptible to experiencing a decline in muscle mass and function, which can lead to physical frailty and have a negative impact on prognosis. However, there...

An open-access simultaneous electrocardiogram and phonocardiogram database

Objective. The EPHNOGRAM project aimed to develop a low-cost, low-power device for simultaneous electrocardiogram (ECG) and phonocardiogram (PCG) recording, with additional channels for environmental audio to enhance PCG through active noise cancellation. The objective was to study multimodal electro-mechanical activities of the heart, offering insights into the differences and synergies between these modalities during various cardiac activity levels. Approach. We developed and tested several hardware prototypes of a simultaneous ECG-PCG acquisition device. Using this technology, we collected simultaneous ECG and PCG data from 24 healthy adults during different physical activities, including resting, walking, running, and stationary biking, in an indoor fitness center. The data were annotated using a robust software that we developed for detecting ECG R-peaks and PCG S1 and S2 components, and overseen by a human expert. We also developed machine learning models using ECG-based, PCG-based, and joint ECG-PCG features, like R–R and S1–S2 intervals, to classify physical activities and analyze electro-mechanical dynamics. Main results. The results show a significant coupling between ECG and PCG components, especially during high-intensity exercise. Notable micro-variations in S2-based heart rate show differences in the heart’s electrical and mechanical functions. The Lomb-Scargle periodogram and approximate entropy analyses confirm the higher volatility of S2-based heart rate compared to ECG-based heart rate. Correlation analysis shows stronger coupling between R–R and R-S1 intervals during high-intensity activities. Hybrid ECG-PCG features, like the R-S2 interval, were identified as more informative for physical activity classification through mRMR feature selection and SHAP value analysis. Significance. The EPHNOGRAM database, is available on PhysioNet. The database enhances our understanding of cardiac function, enabling future studies on the heart’s mechanical and electrical interrelationships. The results of this study can contribute to improved cardiac condition diagnoses. Additionally, the designed hardware has the potential for integration into wearable devices and the development of multimodal stress test technologies.

A high dose KRP203 induces cytoplasmic vacuoles associated with altered phosphoinositide segregation and endosome expansion

In animal cells, vacuoles are absent, but can be induced by diseases and drugs. While phosphoinositides are critical for membrane trafficking, their role in the formation of these vacuoles remains unclear. The immunosuppressive KRP203/Mocravimod, which antagonizes sphingosine-1-phosphate receptors, has been identified as having novel multimodal activity against phosphoinositide kinases. However, the impact of this novel KRP203 activity is unknown. Here, we show that KRP203 disrupts the spatial organization of phosphoinositides and induces extensive vacuolization in tumor cells and immortalized fibroblasts. The KRP203-induced vacuoles are primarily from endosomes, and augmented by inhibition of PIKFYVE and VPS34. Conversely, overexpression of PTEN decreased KRP203-induced vacuole formation. Furthermore, V-ATPase inhibition completely blunted KRP203-induced vacuolization, pointing to a critical requirement of the endosomal maturation process. Importantly, nearly a half of KRP203-induced vacuoles are significantly decorated with PI4P, a phosphoinositide typically enriched at the plasma membrane and Golgi. These results suggest a model that noncanonical spatial reorganization of phosphoinositides by KRP203 alters the endosomal maturation process, leading to vacuolization. Taken together, this study reveals a previously unrecognized bioactivity of KRP203 as a vacuole-inducing agent and its unique mechanism of phosphoinositide modulation, providing a new insight of phosphoinositide regulation into vacuolization-associated diseases and their molecular pathologies.

Modality aware contrastive learning for multimodal human activity recognition

SummaryHuman activity recognition is a well‐established research problem in ubiquitous computing. The increased dependency on various smart devices in our daily lives allows us to investigate the sensor data world produced by multimodal sensors embedded in smart devices. However, the raw sensor data are often unlabeled and annotating this vast amount of data are a costly exercise that can often lead to privacy breaches. Self‐supervised learning‐based approaches are at the forefront of learning semantic representation from unlabeled sensor data, including when applied to human activity recognition tasks. As inferring human activity depends on multimodal sensors, addressing the modality difference and inter‐modality dependencies in a model is an important process. This paper proposes a novel self‐supervised learning approach, modality aware contrastive learning (MACL), for representation learning using multimodal sensor data. The approach uses different sensing modalities to create different views of an input signal. Thus, the model is able to learn the representations by maximizing the similarity among different sensing modalities of the same input signal. Extensive experiments were performed on four publicly available human activity recognition data sets to verify the effectiveness of our proposed MACL method. The experimental evaluation results show that the MACL method attains a comparable performance for human activity recognition to the compared baseline models, directly exceeding the performance of models using standard augmentation transformation strategies.

Levels of Airborne Sound And Substrate-borne Vibration Calling Are Negatively Related Across Neotropical False-leaf Katydids.

Animals often signal in multiple sensory modalities to attract mates, but the level of signaling investment in each modality can differ dramatically between individuals and across species. When functionally overlapping signals are produced in different modalities, their relative use can be influenced by many factors, including differences in signal active space, energetic costs, and predation risk. Characterizing differences in total signal investment across time can shed light on these factors, but requires long focal recordings of signal production. Neotropical pseudophylline katydids produce mate advertisement signals as airborne sound and substrate-borne vibration. Airborne calls, produced via stridulation, are extremely short, high-frequency, and longer-range signals. Conversely, substrate-borne calls produced via abdominal tremulation are longer, low-frequency, relatively more energetically costly, and shorter-range signals. To examine patterns of stridulation and tremulation across species and test hypotheses about the drivers of signal use in each modality, we recorded multimodal signaling activity over 24 hours for males from 10 pseudophylline species from a single Panamanian community. We also collected data on demographic and morphological species characteristics, and acoustic features of airborne calls, such as bandwidth, peak frequency, and duration. Finally, we generated a molecular phylogeny for these species and used phylogenetic generalized least squares models to test for relationships between variables while controlling for evolutionary relationships. We found a negative relationship between sound and vibration calling, indicating that substrate-borne vibrational signaling may compensate for reduced airborne signaling in these species. Sound call bandwidth and the proportion of males collected at lights, a proxy for the amount of male movement, also explained a significant amount of variation in sound calling across species, indicating that the overall relationship between the two types of calling signals may be mediated by the specific characteristics of the signals as well as other species traits.

Exploring Student Agency in Narratives of English Literacy Events across School Subjects

In contemporary academia, English-language reading assignments are prevalent, even in contexts where English is not the primary medium of instruction nor the local language. This presents a challenge for students with English as a foreign language (EFL) who seek to pursue a university education in their home country. This study investigates the presence of English literacy events in Swedish upper secondary schools outside of English classes and explores their implications for university readiness and educational equity. Using survey data from 163 EFL students and qualitative content analysis, students’ written comments revealed a notable absence of English literacy events in non-English subjects, with limited exposure to written English texts and occasional use of multimodal English activities. The findings underscore disparities in students’ opportunities to engage with academic English literacy practices, primarily influenced by individual factors. This paper delves into the interplay between individual dimensions, and institutional and social practices, in shaping student agency in English academic literacy practices.

Multi-terminal pectin/chitosan hybrid electrolyte gated oxide neuromorphic transistor with multi-mode cognitive activities

Multi-terminal pectin/chitosan hybrid electrolyte gated oxide neuromorphic transistor with multi-mode cognitive activities

Piperlongumine and its derivatives against cancer: A recent update and future prospective.

Piperlongumine, or piplartine (PL), is a bioactive alkaloid isolated from Piper longum L. and a potent phytoconstituent in Indian Ayurveda and traditional Chinese medicine with a lot of therapeutic benefits. Apart from all of its biological activities, it demonstrates multimodal anticancer activity by targeting various cancer-associated pathways and being less toxic to normal cells. According to their structure-activity relationship (SAR), the trimethylphenyl ring (cinnamoyl core) and 5,6-dihydropyridin-2-(1H)-one (piperdine core) are responsible for the potent anticancer activity. However, it has poor intrinsic properties (low aqueous solubility, poor bioavailability, etc.). As a result, pharmaceutical researchers have been trying to optimise or modify the structure of PL to improve the drug-likeness profiles. The present review selected 26 eligible research articles on PL derivatives published between 2012 and 2023, followed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) format. We have thoroughly summarised the anticancer potency, mode of action, SAR and drug chemistry of the proposed PL-derivatives against different cancer cells. Overall, SAR analyses with respect to anticancer potency and drug-ability revealed that substitution of methoxy to hydroxyl, attachment of ligustrazine and 4-hydroxycoumarin heterocyclic rings in place of phenyl rings, and attachment of heterocyclic rings like indole at the C7-C8 olefin position in native PL can help to improve anticancer activity, aqueous solubility, cell permeability, and bioavailability, making them potential leads. Hopefully, the large-scale collection and critical drug-chemistry analyses will be helpful to pharmaceutical and academic researchers in developing potential, less-toxic and cost-effective PL-derivatives that can be used against different cancers.

Complex antidepressant therapy with the inclusion of various neuroprotectors in inpatient gerontopsychiatric practice

IntroductionDepressions are the most common mental disorders in elderly and senile patients. In these patients, there is a decrease in neurotrophic potential. Treatment of such patients with antidepressants alone does not always allow to achieve complete normalization of the secretion of neurotrophic factors and complete restoration of neurogenesis processes. In this regard, it is important to expand therapeutic opportunities to develop new therapeutic strategies for pharmacotherapy of late-age depression.ObjectivesComparative evaluation of the effectiveness of two types of complex antidepressant therapy with the inclusion of different neuroprotectors (actovegin or cerebrolysin) in the treatment of late-life depression in the therapeutic regimen.MethodsThe study included 2 groups of patients with mild and moderate depressive episode (DE), comparable in basic demographic and clinical parameters.The 1st group included 21 people, including 7 men (33.3%) and 14 women (66.7%), median age were 69 years [66; 76]. In 10 patients (47.6%), DE was diagnosed as part of recurrent depressive disorder (DDR), in 9 patients (42.9%) - as part of bipolar affective disorder (BAR), and in 2 patients (9.5%) is a single DE. Group 2 included 20 patients, 5 of them men (25%) and 15 women (75%), median age were 64 years [62; 70]. In 11 patients (55%), DE was diagnosed as part of DDR, in 6 patients (30%) - as part of BAR, and in 3 patients (15%) – single DE.The 1st group of patients received complex antidepressant therapy with the inclusion of actovegin for one month, the 2nd group - with the inclusion of cerebrolysin. The effectiveness of the therapy was assessed on the HAMD-17 and HARS scales.ResultsA comparative study demonstrated the effectiveness of both types of complex antidepressant therapy used.A comparative assessment of the effectiveness of the therapeutic response in two groups of patients showed no statistically significant differences in the reduction of depressive disorders after 2 weeks of therapy. Only by the end of the therapeutic course there was a more pronounced reduction of depressive disorders in the 1st therapeutic group (73.6% vs 63.6% (p < 0.05)).Reduction of anxiety disorders, assessed on the HARS scale, was noted both by the 14th and 28th day of therapy in both therapeutic groups. However, it turned out to be more pronounced in the 1st therapeutic group: by the 14th day of therapy, the reduction of anxiety in the 1st and 2nd groups of patients was 36.4% and 30.0%, respectively (p < 0.05), and by the end of therapy - 77.7% and 60.0%, respectively (p < 0.01).ConclusionsThe augmentation of antidepressant therapy with drugs with multimodal activity, actovegin and cerebrolysin, should be considered as effective and it can be recommended for inclusion in the therapeutic regimen for the treatment of late-age depression in a psychiatric hospital.Disclosure of InterestNone Declared

Event detection and classification from multimodal time series with application to neural data

The detection of events in time-series data is a common signal-processing problem. When the data can be modeled as a known template signal with an unknown delay in Gaussian noise, detection of the template signal can be done with a traditional matched filter. However, in many applications, the event of interest is represented in multimodal data consisting of both Gaussian and point-process time series. Neuroscience experiments, for example, can simultaneously record multimodal neural signals such as local field potentials (LFPs), which can be modeled as Gaussian, and neuronal spikes, which can be modeled as point processes. Currently, no method exists for event detection from such multimodal data, and as such our objective in this work is to develop a method to meet this need. Here we address this challenge by developing the multimodal event detector (MED) algorithm which simultaneously estimates event times and classes. To do this, we write a multimodal likelihood function for Gaussian and point-process observations and derive the associated maximum likelihood estimator of simultaneous event times and classes. We additionally introduce a cross-modal scaling parameter to account for model mismatch in real datasets. We validate this method in extensive simulations as well as in a neural spike-LFP dataset recorded during an eye-movement task, where the events of interest are eye movements with unknown times and directions. We show that the MED can successfully detect eye movement onset and classify eye movement direction. Further, the MED successfully combines information across data modalities, with multimodal performance exceeding unimodal performance. This method can facilitate applications such as the discovery of latent events in multimodal neural population activity and the development of brain-computer interfaces for naturalistic settings without constrained tasks or prior knowledge of event times.

Abstract 6554: Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small-cell lung cancer

Abstract Background: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with a very poor prognosis and limited therapeutic options. Repression of the MHC-I and reduced tumor infiltration of cytotoxic T-lymphocytes is often associated with immunotherapy resistance in SCLC. Lurbinectedin is FDA-approved as a second-line treatment for SCLC and we previously showed lurbinectedin as an effective therapeutic strategy in SCLC preclinical models. There are ongoing clinical trials combining immune checkpoint blockade with lurbinectedin in ES-SCLC. However, there is no insight into the effect of lurbinectedin on the immune microenvironment in SCLC. In this study, we evaluated the effect of lurbinectedin on the immune microenvironment and the anti-tumor effect with or without PD-L1 blockade. Results: To determine the effect of lurbinectedin in SCLC models, we treated immunocompetent flank RPP (Rb1, Trp53, and p130) and RPM (Rb1, Trp53, and MYCT58A) tumor-bearing mice with lurbinectedin (0.2 mg/kg, 1/7days) and/or anti-PD-L1 (300µg, 1/7days) for 3 weeks. Mice treated with anti-PD-L1 alone showed no anti-tumor response, and single-agent lurbinectedin caused a delay in tumor growth. However, 6 of the 10 mice treated with the combination of lurbinectedin and anti-PD-L1, had a complete response (100% reduction) and the other 4 had 90% tumor regression. Tumors were resected and analyzed by multicolor flow cytometry for changes in tumor-infiltrating lymphocytes (TILs). Furthermore, analysis of immune cells infiltrating into the tumors post- treatment showed significant induction of cytotoxic T-cells and a reduction of exhausted and regulatory T cells in the combination treatment arm. Similarly, pro-inflammatory M1 type macrophages and dendritic cells were increased, while immunosuppressive M2 type macrophages and MDSC cells were decreased. These effects are consistent with data showing that lurbinectedin treatment leads to an activation of the cGAS/STING pathway, type I/II interferons (IFNα/β), and pro-inflammatory chemokines (CCL5, CXCL10) in tumors. Interestingly, lurbinectedin treatment led to significant upregulation of mRNA and surface expression of MHC class-I genes (HLA-A/B/C) in vitro and in vivo. Finally, bulk RNA sequencing as well as RT-PCR of pre- and post-lurbinectedin treatment demonstrated an increase in DAMPs associated with immunogenic cell death. Conclusion: We provide the first mechanistic insight into the lurbinectedin-induced multimodal immune modulation in SCLC leading to a dramatic anti-tumor activity accompanied by the establishment of a strong anti-tumor immune microenvironment. Since lurbinectedin is already approved as a second-line agent in SCLC, our preclinical data provide a strong rationale for combining this regimen with inhibitors of the PD-L1 pathway and also highlight the immune subsets that the combination targets. Citation Format: Subhamoy Chakraborty, Yazhini Mahendravarman, Utsav Sen, Avisek Banerjee, Charles Coleman, Deniz Demircioglu, Dan Hasson, Triparna Sen. Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small-cell 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 6554.

Abstract 5371: Multimodal CRISPR activation screens reveal new mechanisms to sensitize cancer cells to targeted T cell mediated elimination

Abstract Cell autonomous resistance mechanisms can protect cancer cells from targeted T cell elimination, resulting in resistance to a broad range of immunotherapies. High-throughput gene knockout and gene inhibition screens have been instrumental in identifying key drivers of such mechanisms, yet often uncovering gene activity that is essential but not sufficient for response. Here we set out to leverage gene activation as an orthogonal approach to identify novel regulators of the cancer-immune interface. First, we performed CRISPR activation screens in melanoma cells co-cultured with antigen-specific primary CD8+ T cells. Our findings revealed a collection of novel genes that substantially sensitize melanoma cells to targeted T cell-driven elimination when activated, including DNA damage and unfolded protein response genes (e.g., ETS1, TSPYL2), Wnt ligands (e.g., WNT3A, WNT1), and others that are deleterious only in combination with targeting T cells. Among the resistance genes we found regulators of insulin signaling (e.g., HGF, TCF7L2) and numerous glycoproteins (e.g., PDPN, CD44). Second, we validated top novel hits in 2D and in 3D spheroid models, using optical readouts to investigate their impact on cancer cell elimination and cancer-T-cell spatial dynamics. Third, we performed a Perturb-seq screen to stratify dozens of hits into functional groups based on the transcriptional readouts in the cancer cells. Lastly, we developed an in situ Perturb-Seq method, where we combine high-plex spatial transcriptomic readouts at subcellular resolution with in situ detection of genetically modified cells, and applied it to track the impact of the (de)sensitizing perturbations not only on the cancer cells themselves, but also on T cell recruitment and suppression. Taken together, our study provides a catalog of immune evasion mechanisms and an array of novel targets, demonstrating that synthetic gene activation can diminish immune evasion and open novel avenues for development of agonist-based and RNA-based interventions. Citation Format: Reece V. Akana, Chang Sun, YoungMin Kim, Yuxin Cai, Subin Kim, Jeehyun Yoe, Olivia Laveroni, Livnat Jerby-Arnon. Multimodal CRISPR activation screens reveal new mechanisms to sensitize cancer cells to targeted T cell mediated elimination [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 5371.

Abstract 3181: Immune modulatory activity of radio-sensitizing gold nanoparticle

Abstract Radiation therapy (RT) is frequently used in the neoadjuvant setting in borderline resectable and some resectable pancreatic ductal adenocarcinoma (PDAC) and in the definitive setting in locally advanced PDACs which is third leading cause of cancer associated death. Higher doses of RT improve overall treatment outcomes but increasing the dose significantly above 50Gy in standard 2Gy fractions risks profound gastrointestinal (GI) toxicity. Additionally, genotoxic stress such as RT, can induce CXCL12 secretion by cancer associated fibroblast (CAFs) and overexpression of CXC motif chemokine receptor 4 (CXCR4) in cancer cells. CXCL12-CXCR4 downstream signaling results in immune suppression and consequent enhanced tumor growth and metastasis and poor prognosis in PDAC. To overcome these clinical challenges, we have developed multimodal gold nanoparticle constructs (GNPs) by functionalizing the CXCR4 antagonists to (i) bind to CXCR4 and mediate GNP internalization, (ii) abolish the feedback immune inhibitory signals mediated by CXCR4 overexpression, and (iii) enhance therapeutic benefit of radiation. To achieve these multimodal activities, we have covalently attached the CXCR4 antagonist, AMD070, to thiol-terminated polyethylene glycol (PEG) to synthesize AMD-PEG which was then conjugated with GNPs to produce AMD-PEG-GNP. In our experiment AMD-PEG-GNP has successfully inhibited CXCL12-CXCR4 downstream signalling such as reduction of ERK phosphorylation in PDAC cells. To analyze the radiosensitization role of GNP nanoconjugates, PDAC cells were incubated with AMD-PEG, PEG-GNP and AMD-PEG-GNPs for 4 hours and then treated with increasing doses of radiated, from 1-4Gy. AMD-PEG-GNP demonstrated a systematic enhancement on reactive oxygen species (ROS) production and downregulation of a colony formation. Collectively, the results from in vitro study with PDAC cells confirm that the nanoconjugate with AMD070 enhances radio-cytotoxicity and impair CXCL12-CXCR4 downstream signaling. Hence AMD-PEG-GNP has strong merit to enhance radiation dose locally and simultaneously restrict RT induced immunosuppression in PDAC. Citation Format: Tanmay Kulkarni, Shamit Dutta, Hazel Parent, Karington Perry, Yuri Mackeyev, Santanu Bhattacharya. Immune modulatory activity of radio-sensitizing gold nanoparticle [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 3181.

207P Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small cell lung cancer

207P Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small cell lung cancer