Interface Applications Research Articles

Beta-band power classification of go/no-go arm-reaching responses in the human hippocampus

Objective. Can we classify movement execution and inhibition from hippocampal oscillations during arm-reaching tasks? Traditionally associated with memory encoding, spatial navigation, and motor sequence consolidation, the hippocampus has come under scrutiny for its potential role in movement processing. Stereotactic electroencephalography (SEEG) has provided a unique opportunity to study the neurophysiology of the human hippocampus during motor tasks. In this study, we assess the accuracy of discriminant functions, in combination with principal component analysis (PCA), in classifying between ‘Go’ and ‘No-go’ trials in a Go/No-go arm-reaching task. Approach. Our approach centers on capturing the modulation of beta-band (13–30 Hz) power from multiple SEEG contacts in the hippocampus and minimizing the dimensional complexity of channels and frequency bins. This study utilizes SEEG data from the human hippocampus of 10 participants diagnosed with epilepsy. Spectral power was computed during a ‘center-out’ Go/No-go arm-reaching task, where participants reached or withheld their hand based on a colored cue. PCA was used to reduce data dimension and isolate the highest-variance components within the beta band. The Silhouette score was employed to measure the quality of clustering between ‘Go’ and ‘No-go’ trials. The accuracy of five different discriminant functions was evaluated using cross-validation. Main results. The Diagonal-Quadratic model performed best of the 5 classification models, exhibiting the lowest error rate in all participants (median: 9.91%, average: 14.67%). PCA showed that the first two principal components collectively accounted for 54.83% of the total variance explained on average across all participants, ranging from 36.92% to 81.25% among participants. Significance. This study shows that PCA paired with a Diagonal-Quadratic model can be an effective method for classifying between Go/No-go trials from beta-band power in the hippocampus during arm-reaching responses. This emphasizes the significance of hippocampal beta-power modulation in motor control, unveiling its potential implications for brain–computer interface applications.

PUPpy: a primer design pipeline for substrain-level microbial detection and absolute quantification.

Profiling microbial communities at high resolution and with absolute quantification is essential to uncover hidden ecological interactions within microbial ecosystems. Nevertheless, achieving resolved and quantitative investigations has been elusive due to methodological limitations in distinguishing and quantifying highly related microbes. Here, we describe Phylogenetically Unique Primers in python (PUPpy), an automated computational pipeline to design taxon-specific primers within defined microbial communities. Taxon-specific primers can be used to selectively detect and quantify individual microbes and larger taxa within a microbial community. PUPpy achieves substrain-level specificity without the need for computationally intensive databases and prioritizes user-friendliness by enabling both terminal and graphical user interface applications. Altogether, PUPpy enables fast, inexpensive, and highly accurate perspectives into microbial ecosystems, supporting the characterization of bacterial communities in both in vitro and complex microbiota settings.

AttentionCARE: replicability of a BCI for the clinical application of augmented reality-guided EEG-based attention modification for adolescents at high risk for depression.

Affect-biased attention is the phenomenon of prioritizing attention to emotionally salient stimuli and away from goal-directed stimuli. It is thought that affect-biased attention to emotional stimuli is a driving factor in the development of depression. This effect has been well-studied in adults, but research shows that this is also true during adolescence, when the severity of depressive symptoms are correlated with the magnitude of affect-biased attention to negative emotional stimuli. Prior studies have shown that trainings to modify affect-biased attention may ameliorate depression in adults, but this research has also been stymied by concerns about reliability and replicability. This study describes a clinical application of augmented reality-guided EEG-based attention modification ("AttentionCARE") for adolescents who are at highest risk for future depressive disorders (i.e., daughters of depressed mothers). Our results (n = 10) indicated that the AttentionCARE protocol can reliably and accurately provide neurofeedback about adolescent attention to negative emotional distractors that detract from attention to a primary task. Through several within and cross-study replications, our work addresses concerns about the lack of reliability and reproducibility in brain-computer interface applications, offering insights for future interventions to modify affect-biased attention in high-risk adolescents.

Iron Oxide Nanomaterials at Interfaces for Sustainable Environmental Applications

Iron Oxide Nanomaterials at Interfaces for Sustainable Environmental Applications

Hit and run: Forensic vehicle event reconstruction through driver-based cloud data from Progressive's snapshot application

Driving Insurance Applications (DIAs) have emerged as a valuable resource in the ever-evolving digital landscape. Automobile owners are storing extensive data on driving behaviors and patterns. This study pioneers the forensic analysis of Progressive's Snapshot application, focusing on the extraction and potential forensic use of data that remains inaccessible through the mobile application's interface. In our approach we focused on four research questions: How accurate is location and speed data collected by Progressive Snapshot?, What forensically relevant data can we extract from the Progressive Cloud that is unavailable to the user from the mobile application interface?, Can we employ anti-forensics techniques, specifically fake location data, to create false trip details?, Can we reconstruct a hit-and-run scenario from trip event details? To answer these questions, we developed PyShot, a Python-based open-source tool, to extract data from the Progressive cloud. Our tests confirmed Snapshot's accuracy in recording speed and location. Despite efforts to fake the Global Positioning System (GPS) location, the cloud still maintained accurate records. PyShot revealed more detailed driving data, like dangerous maneuvers and distracted driving, compared to the mobile application. This study also explores the forensic reconstruction of hit-and-run incidents, using a mannequin and focusing on Progressive's server data. Analyzing event categories, geographical coordinates, and timestamps provides insights into the capabilities and constraints of this application in forensic investigations. The findings offer valuable insights into the forensic capability of data retained by DIAs, contributing to their potential use in forensic investigations.

Enhancing Archaeological Research Through Immersive Virtual Reality.

Virtual reality (VR) is increasingly employed in archaeology to showcase reconstructions of ancient sites to the general public, yet its utilization for professional purposes by archaeologists remains less common. To address this gap, we introduce a VR application specifically designed to streamline the storage and access of critical data for archaeological studies. This application provides experts with an immersive visualization of excavation sites and related information during the postexcavation analysis phase. The application interface facilitates direct interaction with 3-D models generated through photogrammetry and modeling techniques, enabling detailed examination of collected data and enhancing research activities. We applied this system to the case study of excavations at the Temple of Juno in Agrigento, Italy. In addition, we present the findings of a pilot user study involving archaeologists, which evaluates the effectiveness of immersive technologies for professionals in documenting, preserving, and exploring archaeological sites, while also driving potential future developments.

Implementasi Re-design Application Mobile MRT Jakarta Menggunakan Metode User Centered Design

MRT Mobile Application is used to access information easily and quickly for MRT users, such as schedule information, routes, stations, fares, and other additional services. Based on observations and questionnaires regarding the MRT mobile application, users often experience difficulties or obstacles in interacting with the application interface. Starting with a complex interface, confusing navigation of features to difficulty finding the information you need quickly. This affects the use of the application and reduces the level of user satisfaction. Based on these conditions, it is necessary to redesign the user interface of this application to make it easier to use. This research uses User Centered Design (UCD) method with four phases, which is Understand Context of Use, Specify User Requirements, Design Solution, and Evaluation Against Requirements in analyzing the UI/UX design process of the MRT mobile application. In the design stage, UCD principles are used to integrate insights from user data into UI/UX design process based on results of questionnaire analysis. The final result of this research is a prototype design and user interface design for the MRT mobile application that meets the expectations of application users.

The Research of EEG Headset of Brain–Computer Interface for Artificial Intelligence-Related Applications

Over the past decade, a wide range of brain–computer interface (BCI) applications with artificial intelligence (AI) assistance have emerged. While using a head-mounted electroencephalogram (EEG) device for BCI application, it often requires a user to wear the device close to the scalp so that clear EEG signals can be obtained from the head directly. Those signals can be used to determine a user’s mental state. Due to the head size differences between Chinese and European users, as well as the differences between Chinese users themselves, EEG headsets with fixed-electrode-point will enable some electrodes fail to capture a user’s EEG data accurately. Combined with previous research and related design methodology, the design of a head-mounted EEG device is proposed in this paper. In this study, Chinese youth are regarded as the target user group. After evaluating different designs of device structures, the possible positions and movement methods of electrodes, an EEG headset with movable electrodes for young Chinese users is finally delivered.

КОМПОНЕНТЫ СИСТЕМЫ ПОДБОРА СПЕЦИАЛИСТОВ В СОСТАВ ЭКСПЕРТНЫХ ГРУПП

This study is devoted to one of the stages of developing an automated system for selecting specialists for enterprises in the mechanical engineering sector, namely to the preparatory stage of the application development. At the preparation stage, basic interaction schemes are worked out, the stages of system operation are described, and the tools that will be used for further implementation are determined. The paper describes the components included in the system, which allows one to automate selecting specialists into expert groups, and identifying their main functions, conditions of use, methods of interaction, graphical diagrams, as well as the advantages and disadvantages of the tools applied. A detailed description and analysis of component interactions provide opportunities for further coding of the program and designing the application interface. Detailed descriptions of the terms used to depict the program operation are given. Graphic diagrams make it possible to clearly demonstrate the use of components and the result of the work. The advantages and disadvantages of applying WSGI servers are also stated. The main types of production at machine-building enterprises are shown. Arguments are given that indicate the need to develop software that automates the process of selecting a candidate at machine-building enterprises. The paper objective is to develop an automated sys-tem for selecting specialists. The research methods are analysis, observation. The article contains developments and diagrams, the description of which will help to write code to continued operation of the program. A schematic diagram of the program operation is built, and the sequence of processes required to launch the application is described. The article is one of the stages of developing a web application, which confirms the possibility of creating such a product.

Vintage Vows

Abstract— The “Vintage Vows” is a comprehensive wedding planning project designed to provide a seamless and personalized experience for couples embarking on their journey towards matrimony. In a world where weddings are becoming increasingly complex and time-consuming to organize, Vintage Vows aims to simplify the process by offering a one-stop platform for all wedding-related needs. The project encompasses various aspects of wedding planning, including venue selection, vendor management, budgeting, guest list management, and day-of coordination. Through a user-friendly web interface and mobile application, couples can browse through curated lists of venues and vendors, compare prices and services, and make informed decisions based on their preferences and budget constraints. Vintage Vows also offers innovative features such as personalized wedding websites, RSVP tracking, and task management tools to help couples stay organized and connected throughout the planning process. Additionally, the platform leverages data analytics and machine learning algorithms to provide personalized recommendations and insights tailored to each couple’s unique preferences and requirements. By combining technology with a human touch, Vintage Vows aims to revolutionize the wedding planning industry and redefine the way couples plan and celebrate their special day. With its user-centric approach and attention to detail, Vintage Vows seeks to create unforgettable experiences that reflect the love, personality, and style of each couple, ensuring that their wedding day is nothing short of magical. Keywords – Wedding Planning, Event Management, Venue Selection, Vendor Management, Budgeting, Guest List Management, Day-of Coordination, Personalized Recommendations, User-friendly Interface, Mobile Application, Task Management, RSVP Tracking, Wedding Websites, Data Analytics, Machine Learning Algorithms, Personalized Experiences, User-Centric Approach, Memorable Celebrations, Love and Romance, Magical Moments

BehaviourCoach: Exploring the Use of a Web-Based Serious Game in Health Promotion

Using a multidisciplinary approach, the current study examined the roles of psychological factors and serious games in the promotion of physical activity and wellbeing. The aim was to investigate the use and evaluation of a Web-based application named BehaviourCoach through the following research questions: How do users experience and evaluate this web-application for health promotion? How do elements of serious games and participants’ health status relate to intention to use this web-application? Participants (N = 55) engaged with BehaviourCoach for a duration of 45 minutes. Physical activity, psychological wellbeing, user experience, evaluation and intention to use a digital tool for health as well as demographic information were self-reported. On average, participants were sufficiently active as a group to meet the guidelines of 150 minutes per week of activity. They also reported moderate psychological wellbeing. The evaluation of the web application was positive, with participants expressing enjoyment, reporting that they found the game to support social interaction, and that the web application interface’s navigation was user-friendly. These factors were found to be positively related to intention to use the digital tool for health promotion in the future. In addition, participants’ levels of overall health and subjective wellbeing were predictive of intention to use the web-application for quick results. The study's implications for e-health interventions are discussed, as well as future directions.

A Wearable Device-Based System: The Potential Role in Real-time and Remote EEG Monitoring

Purpose: In recent years, the Electroencephalography (EEG)-based Brain-Computer Interface (BCI) application has been growing rapidly and has emerged as a technology with high translational potential since it allows disabled people to translate human intentions into control signals and to interact with the external environment without any kinesthetic movement. Individuals with significant health problems can benefit from this technology to improve their independence and facilitate participation in activities, thus improving general well-being and preventing impairments. The rapid advances in technology have led to optimal innovation in the context of wearable health monitoring and remote control solutions. Many wearable devices for capturing EEG signals in daily life have recently been released on the market. Our paper aims to present a wearable de-vice-based system for real-time and remote EEG monitoring, to describe the proposed system modules and the signal processing algorithms, to explore the functionalities of this wearable EEG solution, and to suggest its potential application for daily brain data recordings in the home environment. Materials and Methods: The validity of the Emotiv Epoc+ device in the continuous and real-time EEG signals acquisition and monitoring was demonstrated by means of preliminary test measurements during a resting state paradigm performed by a healthy control subject. Results: Our findings confirmed the Epoc+ reliability for event-related brain potential research and in measuring acceptable spectral EEG data. Conclusion: The described approach, focusing on the emerging area of remote monitoring sensors and wearable device applications, might be leveraged to measure complex health outcomes in non-specialist and remote settings.

BaZnF4/Polydimethylsiloxane Composite Film-Based Nanogenerators for Energy Harvesting and Human–Machine Interface Applications

BaZnF₄/Polydimethylsiloxane Composite Film-Based Nanogenerators for Energy Harvesting and Human–Machine Interface Applications

Laser patterned graphene pressure sensor with adjustable sensitivity in an ultrawide response range

Flexible pressure sensors have attracted wide attention because of their applications in wearable electronic, human-computer interface, and healthcare. However, it is still a challenge to design a pressure sensor with adjustable sensitivity in an ultrawide response range to satisfy the requirements of different application scenarios. Here, a laser patterned graphene pressure sensor (LPGPS) is proposed with adjustable sensitivity in an ultrawide response range based on the pre-stretched kirigami structure. Due to the out-of-plane deformation of the pre-stretched kirigami structure, the sensitivity can be easily tuned by simply modifying the pre-stretched level. As a result, it exhibits a maximum sensitivity of 0.243 kPa−1, an ultrawide range up to 1600 kPa, a low detection limit (6 Pa), a short response time (42 ms), and excellent stability with high pressure of 1200 kPa over 500 cycles. Benefiting from its high sensitivity and ultrawide response range, the proposed sensor can be applied to detect physiological and kinematic signals under different pressure intensities. Additionally, taking advantage of laser programmable patterning, it can be easily configured into an array to determine the pressure distribution. Therefore, LPGPS with adjustable sensitivity in an ultrawide response range has potential application in wearable electronic devices.

Abstract PO-003: Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037)

Abstract Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, demonstrated deep and durable clinical responses in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We evaluated the correlation of peripheral blood (PB) and tumor tissue biomarkers with clinical response to epcoritamab. Methods: Pts received priming (0.16 mg), intermediate (0.8 mg) and full epcoritamab doses (48 mg). Absolute lymphocyte count (ALC) was analyzed locally. Blood immunophenotyping was assessed by flow cytometry, plasma cytokines by MSD assay, and %CD20+ in tumors by immunohistochemistry (n=117). Gene expression in baseline tumor biopsies was evaluated using HTG EdgeSeq (n=70). Microenvironment scores were estimated from gene expression as a sum of immune (B/T, NK, dendritic, and myeloid cells) and stromal scores (adipocytes, fibroblasts, and endothelial cells). Best overall response as of April 21, 2023 was assessed by independent review committee using Lugano criteria. P values were based on Wilcoxon rank-sum test. Results: In PB at baseline, significantly higher ALC (P=0.031), CD4+ (P=0.0038), and CD8+ (P=0.043) T-cell levels were observed in responders (R) vs nonresponders (NR). Similarly, CD4+ (P=0.02) and CD8+ (P=0.03) signatures and immune and microenvironment scores were higher in baseline tumor tissue in R vs NR. In PB CD8+ T cells, NR showed higher %PD1+ (P=0.016), %TIM3+ (P=0.048), and %TIM3+TIGIT+ (P=0.045). High tumor %CD20+ (≥90%) was observed in most pts (n=97/117); lower %CD20+ (<50%) was observed only in 6 NRs and 1 R. Epcoritamab treatment caused a rapid decline in circulating B cells irrespective of clinical response. Transient reductions in PB CD4+ and CD8+ T cells (ie, margination) were observed within 24 hours (H) after each dose during cycle (C) 1 and were more pronounced in R vs NR. Magnitude of margination for CD8+ T cells after the priming and intermediate doses was significantly lower in NR (reduced by median 22 & 41%) vs R (57 & 70%), while the difference in CD4+ T cells was not as pronounced in NR vs R, resulting in a substantially lower CD4+/CD8+ ratio in NR vs R. In C1, epcoritamab led to an increase of PB CD4+ and CD8+ T cells expressing activation/proliferation markers, with significantly higher fold change from baseline in R vs NR, especially within 24H post-priming dose. Early cytokine peaks of IFNy and IL-10 were more pronounced 6–24H post-priming dose and 6–14H post-first full dose in complete R vs pts with progressive disease. Epcoritamab also appeared to modulate NK cell numbers (under further investigation). Conclusions: In pts with R/R DLBCL, T-cell abundance and increased margination, activation, proliferation, and modulation of cytokines differed in R vs NR. These findings are consistent with epcoritamab’s mechanism of action and demonstrate the dependency on proper T-cell engagement for clinical benefit. Our findings also revealed differences in the dynamics of CD4+ and CD8+ T-cell margination in R vs NR, warranting further investigation. Previously submitted in part to EHA 2024. Citation Format: Monica Wielgos-Bonvallet, Jimin Zhang, Han Si, Kubra Karagoz, Melih Acar, Yasmin Karimi, Herve Ghesquieres, Michael Roost Clausen, Iş?l Alt?ntaş, Binhuan Wang, Wissam Assaily, Matthew Loya, Gregg Masters, Anantharaman Muthuswamy, Brandon Higgs, Mariana Sacchi, Tahi Ahmadi, Mark Fereshteh, Edith Szafer-Glusman, David Soong, Maria Jure-Kunkel, Andrew J Steele. Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037) [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-003.

Abstract PO-036: Targeting the CBM signalosome with a MALT1 scaffolding inhibitor for treatment of non-Hodgkin lymphomas

Abstract Introduction: The CBM signalosome (CARDs/BCL10/MALT1) is an evolutionarily conserved key regulator of canonical NF-κB signaling. Activating mutations of the CBM signalosome constitutively activate NF-κB, driving tumorigenesis in B-cell Non-Hodgkin Lymphoma (B-NHL). Depletion of individual components of the CBM complex including MALT1 was shown preclinically to suppress NF-κB driven Activated B-Cell Diffuse Large B-Cell Lymphoma (ABC-DLBCL), inspiring many efforts to develop MALT1 inhibitors for therapeutic use. MALT1 is a dual function protein with two independent roles. Primarily, MALT1 is a scaffold protein organizing the CBM complex and directly transducing canonical NF-κB signaling. Secondarily, MALT1 is a paracaspase, fine-tuning multiple signaling pathways, including NF-κB, via substrate cleavage. Research indicates that targeting MALT1 scaffolding activity is likely the preferred approach for effectively suppressing NF-κB activity while minimizing impact on the immune system. Using our Smart AllosteryTM platform, we have developed potentially the first-in-class MALT1 scaffolding inhibitors targeting the CBM signalosome as a more directed approach to specifically block NF-κB signaling. Here, we disclose the distinctive mechanism of action of scaffolding inhibitors. Experiments: The mechanistic studies of MALT1 scaffolding inhibition were explored through comprehensive cellular assays and in vivo analyses. Engineered cell models were utilized to elucidate novel mechanisms of action. Results: We have developed a series of potent MALT1 scaffolding selective inhibitors with cellular IC50 values approximating 250nM for scaffolding activity, 80nM for NF-κB activity, and 590nM for AP-1 activity. Using TR-FRET, NanoBRET, and TurboID assays, we observed scaffolding inhibitors did not interrupt the interaction of MALT1-TRAF6. Rather, they induced a non-productive signalosome blocking NF-κB activity. Scaffolding inhibitors did not inhibit MALT1 protease activity; in fact, inhibition of MALT1 scaffolding activity modestly increased its protease activity, which is consistent with observations in MALT1 scaffolding mutant mice. This distinctive consequence of MALT1 scaffolding inhibition translated to no detrimental effects on T-cell activation or Treg differentiation, both of which are dependent on MALT1 protease activity and cause associated safety concerns with chronic MALT1 protease inhibitor treatment. The distinct and superior mode of action of MALT1 scaffolding inhibitors manifested in a more potent and broad anti-proliferative activity against a panel of B-NHL cell lines dependent on intrinsic BCR or NF-κB activity for growth. Conclusions: The potential first-in-class MALT1 scaffolding inhibitor offers what we believe is a best-in-class approach to targeting CBM-complex-driven NF-κB signaling. Scaffolding inhibitors effectively blocked both NF-κB and AP-1 signaling without impairing protease activity and avoided negative effects on T-cell function. Scaffolding inhibitors offer a promising therapeutic approach for NF-kB driven cancers. Citation Format: Yi Yao, Kevin Ling, Huili Xia, Huadong Sun, Yingzhi Bi, Jun Kuai, Joe Wahle, Wei Liu, Ken Carson, Gerry Harriman, Fang Wang. Targeting the CBM signalosome with a MALT1 scaffolding inhibitor for treatment of non-Hodgkin lymphomas [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-036.

Abstract PO-007: A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies

Abstract Romidepsin, azacitidine and lenalidomide are all active in T-cell malignancies (TCM) demonstrating single agent objective response rates (ORR) of 20 to 30% (Coiffier 2012; Morschhauser 2013; Dupuis 2022). Combinations of these targeted agents improves the rates of complete response (CR) but have significant toxicity due to indefinite schedules. We hypothesized that use of a multi-targeted therapy regimen such as RAdR given in fixed duration cycles would be safe and effective. We tested escalating doses of lenalidomide (5-20mg) with fixed doses of romidepsin, azacitidine and dexamethasone in a phase 1 study. Patients (pts) first received a 7-day window of lenalidomide for cytokine correlative research followed by six cycles of romidepsin (12mg/m2; days 1 and 10), azacitidine (300mg; days 1-10), dexamethasone (40mg; days 1 and 10), and lenalidomide (5-20mg; days 1-10) in 21-day cycles for up to 6 cycles. The primary endpoint was the maximum tolerated dose (MTD) of lenalidomide and the primary objective was the overall safety of the regimen. A 3+3 design was used with an additional 9 pts treated at the MTD. 26 pts were enrolled with a median age of 61 years (range, 28-80) including 31% over 65. Eight (31%) pts had PTCL, NOS, 6 (23%) had mycosis fungoides (MF), 5 (19%) had angioimmunoblastic T-cell lymphoma, and 4 (15%) ATLL. Median prior lines of therapy were 2 (range, 1-8), 31% had received >3 prior lines and 2 patients had received prior allogeneic transplantation. The median number of cycles was 4 (range, <1-6). The most frequent reasons for stopping therapy were progressive disease (38%), completion of planned therapy (27%) and adverse events (23%). The most frequent grade 1-2 non-hematologic adverse events were vomiting (52%), diarrhea (48%) and dysgeusia (48%), and AE grade 3+ included infection (16%) and hypokalemia (16%). Grade 3+ neutropenia occurred in 24% of cycles and both grade 3+ anemia and thrombocytopenia in 12% of cycles. Two DLTs were observed, grade 4 thrombocytopenia at dose level 1 and grade 3 abdominal pain at dose level 2. The MTD of lenalidomide was determined to be 20mg. In evaluable pts (N=21) the ORR was 66% and CR rate was 14%. After a median follow-up of 23 months. Median progression free survival (PFS) and overall survival (OS) were 4 months and not reached, respectively. 2-year OS was 53%. Two pts (PTCL, NOS and MF) completed the planned 6 cycles of therapy and remain in remission without consolidation at 30 months. Five pts were successfully bridged to SCT, all of whom remain alive and without progression. In pts treated at the MTD, the ORR was 89% and the CR rate was 22%. The multi-targeted therapy regimen RAdR is safe and can achieve CR after fixed duration in patients with relapsed refractory TCM. Toxicity is predominantly gastrointestinal and hematologic. Most patients do not achieve durable CR with RAdR alone, but it may be effective bridging therapy to consolidation. This study was supported by the Intramural Research Program of the NIH and was registered at Clinicaltrials.gov [NCT04447027]. Citation Format: Max Gordon, Milos Miljkovic, Samuel Ng, Rahul Lakhotia, Christopher Melani, Kevin Conlon, James Phelan, Bonita Bryant, Stefania Pittaluga, Elaine Jaffe, Louis Staudt, Wyndham Wilson, Mark Roschewski. A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-007.

Abstract PO-020: ZBTB24 is a novel tumor suppressor and cooperates with CDKN2A to suppress B-cell lymphomagenesis

Abstract B-cell lymphoma is the most common hematological malignancy that accounts for the sixth highest mortality among all cancers. Despite recent improvements on combined chemotherapy and immunotherapy, treatments remain challenging due to complex genetic heterogeneity and molecular pathogenesis. To explore novel mechanisms in B-cell lymphomagenesis, we performed a genome-wide CRISPR knockout screen in the murine interleukin-3 (IL-3)-dependent Ba/F3 pro-B cell line and identified Zbtb24 as a putative target whose silencing leads to elevated proliferative signaling and reduced apoptosis, conferring IL-3-independent growth in Ba/F3 cells. Silencing of ZBTB24 also accelerated growth in multiple human B-cell lymphoma cell lines. ZBTB24 is a member of the zinc-finger and BTB domain containing transcription factor that is highly expressed in spleen and bone marrow. While it has been shown that ZBTB24 may play an important role in B-cell development and activation, its involvement in B-cell lymphoma has not been described. Analysis of publicly available datasets found that ZBTB24 copy number deletion occurs in various B-cell lymphomas, which frequently co-occurs with deletion of the tumor suppressor CDKN2A. Hence, we generated B-cell specific Zbtb24 single knockout and Zbtb24/Cdkn2a double knockout mice to explore the role of Zbtb24 in vivo. While Zbtb24 and Cdkn2a single knockout mice remained tumor-free or showed low penetrance of tumorigenesis, the double knockout mice developed lymphadenopathy and splenomegaly accompanied with accelerated mortality. Flow cytometry analysis of bone marrow, spleen, and lymph nodes revealed malignant B-cells. Subsequent transplantation of the splenic cells induced identical malignant B-cell lymphomagenesis and immunophenotype in athymic nude mice, further confirming its malignant identity. These results indicate that ZBTB24 is a novel tumor suppressor in B-cell malignancy. Ongoing studies are being conducted to understand the mechanistic basis for ZBTB24 tumor suppressive function that may involve transcriptional regulation of its target gene expression. This project is supported by the NIH R01CA232246, R01CA129536, and the John Colaizzi Endowment Fund. Citation Format: Rongrong Li, Namratha Sheshadri, Jianliang Shen, Junrong Yan, Jaeyong Jung, Muhammad Usama Tariq, Y Lynn Wang, Ping Xie, Wei-Xing Zong. ZBTB24 is a novel tumor suppressor and cooperates with CDKN2A to suppress B-cell lymphomagenesis [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-020.

Abstract PO-023: CD70 deregulation in follicular lymphoma at diagnosis is associated with relapse and opens new avenues for dual CD19-CD70 CAR-T therapy

Abstract Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. Despite most patients achieve a complete response with first-line treatment, an important fraction of them relapse, which may worsen the prognosis and increase the risk of a histological transformation to aggressive lymphoma. Therefore, there is a need to better stratify the patients at the diagnosis and develop tailored therapies for high-risk patients. Here we have assessed the immune profile (Nanostring® nCounter) in FFPE-derived biopsies in a series of FL patients at diagnosis, homogenously treated with immunochemotherapy regimen (mostly R-CHOP), and followed-up at Hospital Clínic de Barcelona for more than 12 years. By comparing patients who experienced relapse (n=20) with those who did not relapse at any time (NR, n=12), we have found 31 differentially expressed genes, 25 of them up-regulated in the relapse group. Among them, we have further focused on the role of CD70 in FL pathogenesis. mRNA CD70 was higher in those patients who eventually relapsed and correlated with inferior PFS. Moreover, CD70high FL cases bear a limited number of recurrent somatic mutations. We next sought to determine the specific subpopulations expressing CD70 by multiplex immunofluorescence (Vectra Polaris). Interestingly, we have demonstrated it is mainly expressed in tumor cells correlating with inferior PFS. Moreover, a fraction of T cells from the tumor microenvironment also expresses CD70. Intriguingly, higher levels of CD70 were detected in both CD4+ and CD8+ T cells in the relapse group, including T regulatory and T follicular helper cells. CD70 interacts with CD27, its only known ligand, and can be mutually activated. While CD27 RNA levels did not change between groups, CD27 protein was increased in the B cell population in patients who eventually relapse and in TFH cells, while it was down-regulated in CD8+ and CD4+ T helper non-follicular cells. Furthermore, we found an association between the percentage of CD70+ cells within B cell population and CD70+ in CD4+ and CD8+ cells (R=0.51, p < 0.05). To investigate the role of CD70 in FL pathogenesis we generated two CD70 KO cell lines and FL patient derived cells (n=4) using CRISPR/Cas9 technique. By co-culturing T cells from healthy donors with CD70+ or CD70- FL cell lines, we observed CD70+ tumor cells promote CD70 expression in T cells. In primary samples, we have demonstrated that CD70-KO B cells exhibit reduced response to proliferative stimuli. Moreover, RNAseq analysis followed by GSEA pathway assignment indicated that CD70 expression was related to increased angiogenesis, glycolysis and hypoxia. Finally, to advance towards personalized therapies for this high-risk patient and taking advantage of our institution CAR-T program, we have generated a dual CD19-CD70 CAR-T combining an approved academic product, ARI-0001, and a truncated CD27 protein. Finally, we have demonstrated that this novel CAR-T is effective in both cell lines and ex vivo FL spheroids (PDLS, Dobaño-López, Blood Cancer J 2024), while in vivo studies are ongoing. Citation Format: Ferran Araujo-Ayala, Mireia Bachiller, Raluca Alexandru, Pablo Mozas, Salut Colell, María Villalba-Esparza, Judith Mateos-Jaimez, Ferran Nadeu, Andrea Rivero, Maria Ros, Cèlia Dobaño-López, Juan Garcia Valero, Neus Serrat, Marta Gimenez-Alejandre, Ariadna Giro, Daniel Hodson, Armando López-Guillermo, Elias Campo, Dolors Colomer, Alba Maiques-Diaz, José Ignacio Martín-Subero, Sílvia Beà, Laura Magnano, Sonia Guedan, Carlos E. de Andrea, Patricia Pérez-Galan. CD70 deregulation in follicular lymphoma at diagnosis is associated with relapse and opens new avenues for dual CD19-CD70 CAR-T therapy [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-023.

Abstract PO-001: GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance

Abstract Chimeric antigen receptor (CAR)-T cell therapies can be curative for CD19+ hematological malignancies, though are limited by frequent patient relapse and response failures. Here, we identify GPR65 as a tumor-specific determinant of responsiveness to CAR-T cell therapy. In patients and an immune competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) response to CAR-T cell therapy, high GPR65 is associated with a complete tumor response. In mice, GPR65 knockout (GPR65 KO) tumors are resistant to CAR-T cell therapy in vivo, without antigen loss. Single-cell network analyses reveal that GPR65 deficiency remodels tumor interactions with host macrophages, partially through increasing tumor VEGFA. This leads to increased macrophage numbers and preferential M2 macrophage polarization. Either depletion of host macrophages or deletion of VEGFA from GPR65 KO tumors restores responsiveness to CAR-T cell treatment. Anti-VEGFA therapy in combination with CAR-T cell administration also prolongs the survival of GPR65 KO tumor-bearing mice. Our results indicate that tumor GPR65 expression is important for B-ALL responses to CAR-T cell therapy through its impact on the tumor microenvironment and supports new approaches to identify and overcome CAR-T cell resistance. Citation Format: Jayadev Mavuluri. GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-001.