bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal object stitching and video condensation-aided improved YOLOv5-oriented anomaly object detection framework
Authors: Poorni R. , Madhavan P.
Published: April 2024

Recent advances in intelligent surveillance to boost public security have increased interest in anomaly location and identification among computer vision researchers in congested situations. Unrestricted video monitoring is required due to its extensive use in private and public spheres. Particularly, research on finding anomalies in surveillance videos has drawn much interest. Video condensation is an efficient method for quickly scanning and retrieving lengthy surveillance films. Reordering the video events in the spatial or temporal domain seeks to condense large video sequences into their equivalent compact video representation. Additionally, if a delay occurs in anomaly detection, it leads to time consumption for rectifying it. Therefore, the core aim of this task is to reduce the time consumption of detecting the instance of video anomaly detection faster by introducing the optimal object stitching through the deep learning-based video condensation concept. The steps include video condensation and deep learning-based anomaly detection. Initially, the necessary video for anomaly detection is gathered from the datasets. The gathered video is converted into frames and is used for object detection in each frame using Improved YOLOv5 (I-YOLOv5). Then, the optimal frame selection is performed using the hybrid Fitness of Wild Geese and Path Finder (FWGPF) for stitching the detected objects into the selected optimal frames, thus compressing the relevant frames. In the second phase, the condensed (compressed) frames are utilized for determining the anomaly frames with the support of Parameter Tuning in Dilated MobileNet (PTDM), and further, the anomaly objects are detected on the classified condensed frames based on the I-YOLOv5. Here, the tuning of constraint is done in the anomaly detection phase by the same hybrid FWGPF to reduce the time consumption. The experimental analysis of the developed model is performed with baseline algorithms and detection techniques to confirm the developed model’s efficiency.
A Novel Foot Placement Planning of Biped Robots Based on A* Algorithm and Kinematic Manipulability
Authors: Shahbazy Meysam , Fard Behnam Miripour
Published: April 2024

In motion planning of biped robots, the place where the swing foot lands on the ground is crucial. Stability, energy consumption, smoothness of movement as well as naturalness of motion can be depending on the selected foot placement. In this paper, a novel method based on the A* algorithm and kinematic manipulability for foot placement planning is presented. In this method, by calculating the magnitude and direction of the maximum manipulability for the candidate foot placements, one is selected that leads to the most dexterous and agile walking while maintaining stability. The advantage of this approach is avoiding singularities and being ready to create a higher potential for foot velocities. Therefore, the possibility of performing maneuvers to maintain walking stability would be enhanced. The mentioned algorithm has been successfully implemented on a simulated three-dimensional biped robot.
Sampling-Based Global Path Planning Using Convex Polytope Approximation for Narrow Collision-Free Space of Humanoid
Authors: Hiraoka Naoki , Ishida Hirokazu , Hiraoka Takuma , Kojima Kunio , Okada Kei , Inaba Masayuki
Published: April 2024

In this paper, we propose a computationally fast method of sampling-based global path planning for humanoids under Manifold Constraints such as closed kinematic chains and Volume-Reducing Constraints such as collision avoidance. In multi-contact and whole-body manipulation of humanoids, narrow collision-free space causes path planning to take a long computation time (narrow corridor problem). In previous research of constrained planning, Manifold Constraints are locally approximated by tangent plane, and steering motions along Manifold Constraints are found efficiently by projection or continuation methods. In this paper, we applied constrained planning algorithms to collision avoidance. Since tangent plane cannot approximate Volume-Reducing Constraints, we adopted convex polytope instead of tangent plane. Both Manifold Constraints and Volume-Reducing Constraints are locally approximated by convex polytope with linear equality and inequality constraints, and steering motions inside the convex polytope are found efficiently by the SQP-based prioritized inverse kinematics. We developed CP-KPIECE (Convex Polytope approximation-based KPIECE) with this approach. Benchmarks using the humanoid JAXON proved the effectiveness of our approach for fast path planning in narrow collision-free space of humanoids.
Exploring the Drivers and Constraints of Firm Capacity Utilization in the Middle East and North Africa
Authors: Sdiri Hanen
Published: April 2024

This study analyzes the drivers and constraints affecting enterprise capacity utilization (CU) in the Middle East and North Africa (MENA) region. We used data from the World Bank Enterprise Survey and a fractional logit model to examine the impacts of institutional, infrastructural, and sustainability factors on firms’ CU. Our analysis highlights corruption and competition in the informal sector as significant impediments to firms’ CU, alongside complex infrastructure barriers that hinder the optimization. Conversely, environmental responsibility and innovation emerge as critical drivers for enhancing CU. Surprisingly, top managers’ experience introduces a counteractive influence that negatively affects CU. Beyond the empirical findings, this study’s implications extend to various stakeholders, notably policymakers. Emphasizing the need to address corruption, foster an enabling business environment, strategically invest in infrastructure, promote sustainability initiatives, and foster innovation to enhance CU are paramount. Additionally, providing targeted managerial training to mitigate negative managerial influences is crucial. Implementing these recommendations promises to foster an environment conducive to improved CU, driving economic growth, and sustainable development in the MENA region and benefiting stakeholders across sectors.
Recent Progress in Metasurfaces: An Introductory Note from Fundamentals and Design Methods to Applications
Authors: Chen Wei , Shen Jiaqing , Ke Yujie , Hu Yuwei , Wu Lin , Zhu Jinfeng , Dong Zhaogang
Published: April 2024

Metasurfaces refer to the sub-wavelength nanostructures that are capable of manipulating the amplitude, phase, polarization, and other characteristics of light, to enable diverse applications across the ultraviolet, visible, infrared, and terahertz spectra. In this review paper, we aim to provide an introductory note on metasurfaces, from fundamentals and design methods to applications, such as biosensing, environmental monitoring, metalenses, optical cloaking, electromagnetic scattering, structural color, miniaturized devices, and others. Moreover, we also identify the key challenges and limitations of metasurfaces, such as fabrication, integration, optimization, tuning, signal processing, and analysis, and suggest possible directions and solutions for future research. At last, we envision several emerging and promising trends for metasurfaces, such as new materials and structures, new phenomena and mechanisms, machine learning, and artificial intelligence techniques. The review is expected to inspire future development in this exciting and rapidly evolving field of metasurface devices.
Enhancing Unsupervised Outlier Model Selection: A Study on IREOS Algorithms
Authors: Schlieper Philipp , Luft Hermann , Klede Kai , Strohmeyer Christoph , Eskofier Bjoern , Zanca Dario
Published: April 2024

Outlier detection stands as a critical cornerstone in the field of data mining, with a wide range of applications spanning from fraud detection to network security. However, real-world scenarios often lack labeled data for training, necessitating unsupervised outlier detection methods. This study centers on Unsupervised Outlier Model Selection (UOMS), with a specific focus on the family of Internal, Relative Evaluation of Outlier Solutions (IREOS) algorithms. IREOS measures outlier candidate separability by evaluating multiple maximum-margin classifiers and, while effective, it is constrained by its high computational demands. We investigate the impact of several different separation methods in UOMS in terms of ranking quality and runtime. Surprisingly, our findings indicate that different separability measures have minimal impact on IREOS’ effectiveness. However, using linear separation methods within IREOS significantly reduces its computation time. These insights hold significance for real-world applications where efficient outlier detection is critical. In the context of this work, we provide the code for the IREOS algorithm and our separability techniques.
Heterogeneous Fusion and Integrity Learning Network for RGB-D Salient Object Detection
Authors: Gao Haorao , Su Yiming , Wang Fasheng , Li Haojie
Published: April 2024

While significant progress has been made in recent years in the field of salient object detection, there are still limitations in heterogeneous modality fusion and salient feature integrity learning. The former is primarily attributed to a paucity of attention from researchers to the fusion of cross-scale information between different modalities during processing multi-modal heterogeneous data, coupled with an absence of methods for adaptive control of their respective contributions. The latter constraint stems from the shortcomings in existing approaches concerning the prediction of salient region’s integrity. To address these problems, we propose a Heterogeneous Fusion and Integrity Learning Network for RGB-D Salient Object Detection (HFIL-Net). In response to the first challenge, we design an Advanced Semantic Guidance Aggregation (ASGA) module, which utilizes three fusion blocks to achieve the aggregation of three types of information: within-scale cross-modal, within-modal cross-scale, and cross-modal cross-scale. In addition, we embed the local fusion factor matrices in the ASGA module and utilize the global fusion factor matrices in the Multi-modal Information Adaptive Fusion module to control the contributions adaptively from different perspectives during the fusion process. For the second issue, we introduce the Feature Integrity Learning and Refinement Module. It leverages the idea of ”part-whole” relationships from capsule networks to learn feature integrity and further refine the learned features through attention mechanisms. Extensive experimental results demonstrate that our proposed HFIL-Net outperforms over 17 state-of-the-art detection methods in testing across seven challenging standard datasets. Codes and results are available on
https://github.com/BojueGao/HFIL-Net
.
Association between serum estradiol and cardiovascular health among transgender adults using gender-affirming estrogen therapy
Authors: Rytz Chantal L. , Miranda Keila Turino , Ronksley Paul E. , Saad Nathalie , Raj Satish R. , Somayaji Ranjani , Dumanski Sandra M. , Ganshorn Heather , Greene Dina N. , Collister David , Newbert Amelia M. , Peace Lindsay , Ahmed Sofia B.
Published: April 2024

In this systematic review and meta-analysis of 35 studies involving 7,745 participants, high rates of serum estradiol change were associated with small increases in body mass index. Moderate to high rates of change were associated with decreases in low-density lipoprotein. Low rates of change were associated with small decreases in systolic blood pressure. Rate of serum estradiol change in adults using gender-affirming estrogen therapy may influence cardiovascular risk factors, though further research is warranted.
Woody Species Composition, Structure, and Status of Regeneration in Pugnido Forest, Gambella Region, Western Ethiopia
Authors: Masresha Getinet , Melkamu Yirgalem , Mulu Getachew
Published: April 2024

Ethiopia is a biodiversity hotspot area with a high concentration of plant species that play countless roles in ecosystem resilience and mitigating the effects of climate change. However, forest resources are degrading at an alarming rate due to different anthropogenic factors. Pugnido Forest, which is among Ethiopia’s greatest woodland sections, also faced a similar challenge. Thus, this study was intended to assess the composition, structure, and regeneration status of woody plant species in Pugnido Forest, West Ethiopia. Eighty main plots sized 20 × 20 m were sampled systematically on six east-west-oriented line transects, which are parallel to each other and 500 m apart. At the four corners and the center of the main plots, five subplots sized 2 m × 2 m were laid to collect seedling and sapling information. Individual woody species were identified and then recorded per plot. The forest structure and regeneration status data were recorded and analyzed using structural parameters. Communities were identified via cluster analysis. A comparison of diversity and composition among communities was made using the Shannon–Wiener diversity and Sorensen’s similarity coefficients, respectively. A total of 106 woody species included in 40 families were documented. Fabaceae stands first in the species-rich family (23.6%), and Moraceae stands second (8.5%). Overall Shannon–Wiener diversity and evenness of species were 4.41 and 0.93, respectively. Four communities were generated from cluster analysis. Sorensen’s similarity value among communities ranged from 42% to 59%. The forest’s density and basal area were 5298.8 stems·ha−1 and 82.5 m2·ha−1, respectively. The trend in frequency and density classes showed a decreasing number of species towards higher classes. Diameter at breast height (DBH), height, and basal area analyses revealed a normal J-shaped pattern. Several species had a smaller importance value index (IVI) value. Density ratios of juveniles to adult plants indicated good regeneration status. Species with small IVI values and few or no seedlings require conservation priority. Top priority must be given to conserving species with low IVI values and few or no seedlings.
Valsalva Retinopathy Presenting as Subretinal Hemorrhage
Authors: Conci Lívia , Pereira Eliza , Navajas Samia , Neto Epitacio Silva , Pimentel Sérgio , Zacharias Leandro
Published: April 2024

Purpose. To describe a case of subretinal hemorrhage due to the Valsalva maneuver in a patient with no underlying chorioretinal disease. Methods. History and clinical examination, optical coherence tomography (OCT), fluorescein, and indocyanine green angiography. Results. We report a case of a 35-year-old man with a 4-day history of central vision loss in the left eye (OS) after a vomiting episode. His best-corrected visual acuity was 20/200 in OS. Fundus examination revealed a subretinal hemorrhage in the posterior pole, associated with a small preretinal hemorrhage in the superotemporal arcade. OCT confirmed the presence of a thick submacular hemorrhage and a focal hemorrhage beneath the inner limiting membrane along the superotemporal arcade. The patient was submitted to pars plana vitrectomy (PPV), subretinal injection of tissue plasminogen activator (tPA), and air tamponade on the following day. Most of the submacular hemorrhage was displaced, resulting in a satisfactory visual outcome (BCVA=20/30 after 1 month of surgery). Fluorescein and indocyanine green angiography excluded conditions such as retinal arterial macroaneurysm, polypoidal chorioretinopathy, and choroidal neovascularization. Conclusion. Although rare, Valsalva retinopathy may present with submacular hemorrhage in a patient with no underlying chorioretinal disease. PPV and subretinal tPA injection may provide a good visual outcome.
Impact Evaluation of Wastewater Treatment Based on the Anaerobic Digestion of Sewage Sludge Using the Life Cycle Assessment Method
Authors: Rahmati Mohammad , Rasouli Majid , Haji Agha Alizadeh Hossein , Ataeiyan Behnam
Published: April 2024

All the inputs and outputs of a technical system can be interpreted from an environmental point of view. Using the life cycle assessment (LCA) approach, some changes that are less harmful to the environment can be included in the system. This research aims to evaluate the environmental effects of the wastewater treatment plant (WWTP) in South Tehran, and the LCA method was used in this study. Based on the data of qualitative parameters obtained from the measurement of Tehran province’s water and sewage company, the environmental emissions were calculated and analyzed using SimaPro software (9.0.0) and the standards defined under the ReCiPe 2016‐midpoint method. In the ReCiPe 2016 method, the results were expressed in two intermediate levels (including three classes of influence) and final (including 18). The results showed that the treated wastewater and chlorine factors had the most adverse environmental effects. Among the 18 effect classes, the treated wastewater in the class of marine environmental toxicity with the amount of 101.1531 kg 1,4‐DCB had the most environmental impacts among other classes. The power consumed by the biogas‐burning combined heat and power (CHP) unit in the wastewater treatment (WWT) process reduced the environmental effects in most impact classes. The most adverse environmental effects of the WWT process are related to damage to human health and the ecosystem. According to the findings, the use of CHP systems is suggested for energy saving and also for reducing harmful effects on the environment.
The Effect of Mnemonic Learning Strategy on Critical Care Nursing Students’ Tracheal Suction Skill Acquisition
Authors: Elsayed Shimmaa Mohamed , Dogham Rawhia Salah , Ghaly Asmaa Saber , Elcokany Nermine Mohamed
Published: April 2024

Background. The mnemonic learning method is a systematic approach that helps nursing students memorize new information more effectively, productively, and easily by connecting new information with existing information and exploring unfamiliar information through visual images or combinations of letters and words. While mnemonics can help students remember specific information, it is essential to examine how well they facilitate the transfer of learning to real-world nursing practice. Aim. To investigate the effect of the mnemonic learning strategy on critical care nursing students’ tracheal suction skill acquisition and learning satisfaction. Methods. A quasi-experimental research design was used. A total of 280 second-year nursing students enrolled in critical care and emergency nursing courses were recruited. These students were assigned to study and control groups. The study group used a mnemonic learning strategy to recall the steps involved in the tracheal suction procedure, while the control group used the traditional learning strategy. Two tools were used for data collection: the tracheal suction procedure checklist and learning satisfaction scale. Comparisons between both groups regarding their performance and satisfaction scores were done. Results. Performance scores regarding the tracheal suction procedure were significantly higher in the study group than in the control group in the 5th, 6th, and 10th weeks (P<0.001, <0.001, and <0.001). A total of 70.6% of the participants in the study group reported high satisfaction using the mnemonic learning experience. Conclusion. Using a mnemonic learning strategy with critical care nursing students was effective. Participants in the study group exhibited improvement in their tracheal suction procedure scores over time. Critical care nursing students reported higher levels of learning satisfaction with the mnemonic learning method than with the traditional method.
Stabilizing Tumor-Resident Mast Cells Restores T-Cell Infiltration and Sensitizes Sarcomas to PD-L1 Inhibition
Authors: Panagi Myrofora , Mpekris Fotios , Voutouri Chrysovalantis , Hadjigeorgiou Andreas G. , Symeonidou Chloe , Porfyriou Eleni , Michael Christina , Stylianou Andreas , Martin John D. , Cabral Horacio , Constantinidou Anastasia , Stylianopoulos Triantafyllos
Published: April 2024

Purpose:

To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma.

Experimental Design:

We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti–PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial.

Results:

Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen–specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential.

Conclusions:

Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.
Abstract CT155: Trial in progress: A phase Ia/Ib, an open-label, multicenter study of ZL-1310 to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer
Authors: Dowlati Afshin , Spira Alexander , Shen Xiaodong , Fu Yinjia , Pan Yiyuan , Liu Linda , Zhou Renke , Wu Yi-Long
Published: April 2024

Background: ZL-1310, a novel antibody-drug conjugate (ADC) targeting delta-like protein 3 (DLL3) with a camptothecin derivative as its payload via a protease-cleavable linker, employs TMALIN® (Tumor Microenvironment Activable LINker-payload) ADC technology platform. DLL3, an inhibitory Notch pathway ligand and a validated target for directed therapy, is highly expressed in more than 80% of patients with small cell lung cancer (SCLC) and also has variable expression in other neuroendocrine (NE) tumors. There remains an unmet medical need for 2nd-line SCLC, as the standard of care chemotherapy has a modest response rate of ~25%. ZL-1310 is designed to minimize payload toxicity and improve anti-tumor effectiveness.

Methods: This is an open-label, multiple-dose, phase 1 study of ZL-1310 administered to subjects with relapsed/refractory (r/r) metastatic SCLC who have progressed after at least one platinum-based chemotherapy regimen. The study consists of two parts: Part 1 (dose escalation) and Part 2 (dose expansion). In Part 1, the Bayesian optimal interval (BOIN) design is employed for dose escalation, while in Part 2, patients will be randomized into two cohorts with different doses of ZL-1310 to further define safety and preliminary antitumor activity. The major inclusion criteria are as follows: (1) Subjects must have histologically or cytologically confirmed metastatic or extensive-stage SCLC with no more than 3 prior regimens in the r/r setting. (2) Subjects must have at least one measurable target lesion as defined by RECIST v1.1. (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The major exclusion criteria include: (1) Prior exposure to DLL3-targeted therapy. (2) Subjects with symptomatic or uncontrolled brain metastasis requiring concurrent treatment, impaired major organ functions, active autoimmune disease, or active infections.Part 1 Dose Escalation is recruiting subjects in the US and China.

Citation Format: Afshin Dowlati, Alexander Spira, Xiaodong Shen, Yinjia Fu, Yiyuan Pan, Linda Liu, Renke Zhou, Yi-Long Wu. Trial in progress: A phase Ia/Ib, an open-label, multicenter study of ZL-1310 to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT155.
Abstract CT217: First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b-2 trial
Authors: Thibaudin Marion , Fumet Jean-David , Limagne Emeric , Hampe Léa , Daumoine Susy , Derangère Valentin , Laheurte Caroline , Adotevi Olivier , Truntzer Caroline , Ghiringhelli François
Published: April 2024

Metastatic colorectal cancer (mCRC) remains a difficult-to-treat disease. While patients with microsatellite instable metastatic colorectal cancer (mCRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was the primary objective of phase IB; no safety issue was observed. The phase II primary objective of efficacy in terms of 3-month PFS in MSS patients was met, with 3-month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objectives, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9-8.6] and overall survival was not reached in MSS patients. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response, associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758.

Citation Format: Marion Thibaudin, Jean-David Fumet, Emeric Limagne, Léa Hampe, Susy Daumoine, Valentin Derangère, Caroline Laheurte, Olivier Adotevi, Caroline Truntzer, François Ghiringhelli. First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b-2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT217.
Abstract CT252: Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial
Authors: Park Cheol-Kyu , Oh Hyung-Joo , Bae Suk-Chul , Oh In-Jae , Jung Kyoung-Mi , Kim Da-Mi , Lee Jung-Won , Kang Chang Kyun , Park Il Yeong , Kim Young-Chul
Published: April 2024

Background: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-TKIs for patients with stage IV lung cancer carrying EGFR mutations.

Patients and Methods: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively.

Results: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months (95% CI, 10.4-18.3), while the placebo group had a PFS of 10.9 months (9.0-13.2; p = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; p = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (p = 0.01) and never-smokers (p = 0.03) treated with nicotinamide.

Conclusion: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked.

(ClinicalTrials.gov Identifier: NCT02416739)

Citation Format: Cheol-Kyu Park, Hyung-Joo Oh, Suk-Chul Bae, In-Jae Oh, Kyoung-Mi Jung, Da-Mi Kim, Jung-Won Lee, Chang Kyun Kang, Il Yeong Park, Young-Chul Kim. Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT252.
Abstract LB013: Characterizing the role of exosomal miRNAs in metastasis
Authors: Agrawal Piyush , Olgun Gulden , Singh Arashdeep , Gopalan Vishaka , Hannenhalli Sridhar
Published: April 2024

Background: Exosomal microRNAs (Ex-miRs) play a pivotal role in intercellular communication, being transported via extracellular vesicles. In cancer, Ex-miRs influence tumor progression by regulating key cellular processes such as proliferation, angiogenesis, and metastasis. Their role in mediating communication between cancer cells and the tumor microenvironment highlights their significance as potential diagnostic and therapeutic targets.

Methodology: In this study, we aimed to characterize the role of Ex-miRs in influencing the pre-metastatic niche (PMN) across 7 tumor types. We extracted high-confidence Ex-miRs (Log FC >= 2 in exosomes relative to expectation) and their targets (experimentally proven and targeted by at least 2 Ex-miRs) from various studies. Subsequently, we conducted gene ontology analysis to identify enriched pathways and selected the top 100 high-confidence Ex-miR targets based on the frequency of their appearance in the enriched pathways. These top 100 targets were consistently used throughout the analysis.

Results: Pathway enriched among the top Ex-miR targets included common ones such as “wound healing” and “regulation of epithelial cell proliferation”, as well as cancer-specific, like “regulation of angiogenesis in kidney” (KIRC), “ossification” in lung (LUAD), and “positive regulation of cytokine production” in pancreatic cancer (PAAD). Similarly, 'Pathways in cancer' and 'MicroRNAs in cancer' ranked among the top 10 enriched KEGG pathways for all cancer types. Ex-miR targets exhibited cancer-specific downregulation of gene expression in TCGA-Normal Adjacent Tumors (NATs), taken as proxy for PMN, compared to healthy tissue samples in GTEx. We further examined the 3’UTR GC content of these targets and found that Ex-miR targets are GC-rich, consistent with the previous findings stating that Ex-miR bind to the 3’UTR region of the target gene, downregulating their expression. Fisher’s exact test revealed a significant overlap of cancer-specific tumor suppressor genes (TSG) with Ex-miR targets. Cox regression indicated that Ex-miR targets are associated with better survival in certain cancer types, such as BRCA, COAD and KIRC. Lastly, a Support Vector Machine (SVM) model using Ex-miR target gene expression classified responders and non-responders to neoadjuvant chemotherapy with a high AUROC compared to other gene signatures.

Conclusion: Our study unveils the pivotal role of exosomal microRNAs in shaping the PMN in diverse cancers, underscoring the diagnostic and therapeutic potential of Ex-miRs.

Citation Format: Piyush Agrawal, Gulden Olgun, Arashdeep Singh, Vishaka Gopalan, Sridhar Hannenhalli. Characterizing the role of exosomal miRNAs in metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB013.
Abstract LB016: Spatial transcriptomics-based platform for pathological diagnosis and research of colorectal cancer
Authors: Qu Chi , Huang Huaqiang , Quan Yan , He Xuqing , Zhang Weifeng , Duan Tianbi , Zhang Jiajun , Gu Jiang
Published: April 2024

The application of spatial transcriptomic (ST) in contemporary pathology is promising yet rarely validated. We herein established a ST-based platform to analyze colorectal cancers following the logic and workflow of routine histopathological diagnosis. By integrating spatial coordinate traits with in-situ gene expression matrix, we reproduced and extended key diagnostic features for tumor diagnosis and molecular analysis including proliferation evaluation, vasculature identification, immune scoring and dMMR/pMMR molecular subtyping. Meanwhile, spatial and morphological distinction ST co-dominated broadened avenues for targeted cancer therapy and research. In hyperplasia/carcinoma confusion sites, we detected mixed cnv patterns in single crypt with distinct spatial distributions; Meanwhile, RNA-based molecular subtypes prevailed with intratumor heterogeneity and concurrently exhibited uniformed histological characteristics; Moreover, landscape of temporal molecular variation during cancer infiltration stages revealed potential metastatic biomarkers and mechanisms. In conclusion, we have herein established a comprehensive platform to perform and extensely extend assessment for tumor diagnosis. Additionally, by aligning histological features and gene expression profiles, we excavated significant opportunity for pathological investigation and coordination of multimodal molecular pathology dimensions, which is suitable and ideal for scientific discoveries and molecular diagnosis. With improvement in efficiency and cost-effectiveness, we foresee that this de novo platform will significantly advance pathological diagnosis and research of cancer tissue.

Citation Format: Chi Qu, Huaqiang Huang, Yan Quan, Xuqing He, Weifeng Zhang, Tianbi Duan, Jiajun Zhang, Jiang Gu. Spatial transcriptomics-based platform for pathological diagnosis and research of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB016.
Abstract LB029: Degraders of TEAD transcription factors based on interface 3 binders
Authors: Sawant Rajiv , Geitmann Matthis , Gossas Thomas , Emond Wei B. , Bremberg Ulf , Koehler Konrad , Ceribelli Michele , Thomas Craig J. , Brandt Peter
Published: April 2024

TEAD transcription factors have emerged as clinically validated targets for Hippo-altered cancers, e.g. mesothelioma driven by NF2 inactivation/deficiency. We have developed a series of novel small molecule targeted protein degraders of TEAD based on pan-TEAD interface 3 ligands. In cells, the compounds induce degradation of TEAD by formation of a ternary complex with Cereblon, leading to ubiquitination of TEAD and subsequent proteasomal degradation. In a cell-based luciferase reporter assay the degraders show low nanomolar activity. The downstream effects of TEAD degradation were further investigated by qPCR and WB analyses of bona fide YAP-TEAD target genes such as CTGF, Cyr61 and AMOTL2. The effectiveness of the TEAD degraders were compared to other classes of TEAD modulators such as palmitoylation inhibitors and YAP-TEAD protein-protein inhibitors by means of cellular viability assays using various mesothelioma cell lines. Finally, we performed an unbiased, quantitative high-throughput drug combination screening by combining a TEAD degrader with a library of approximately 2,800 oncology-focused drugs. This research was supported in part by the Intramural/Extramural research program of the NCATS, NIH.

Citation Format: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Michele Ceribelli, Craig J. Thomas, Peter Brandt. Degraders of TEAD transcription factors based on interface 3 binders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB029.
Abstract LB060: Engineering KRAS mutation-specific affinity binders: A new frontier in cancer research
Authors: Serrano Ramon , Wallace Ryan , Bibikov Sergei , Weiner Michael , Harvey Kevin J.
Published: April 2024

Cancer is a complex disease involving genetic and proteomic dysregulation. Better understanding of this disease requires precise tools to analyze how cells change from a normal to a diseased state. Among the genes implicated in cancer, the checkpoint inhibitor KRAS is notable for its frequent cancer causing mutations. These mutations, especially in glycine codon 12, are a driving force in several cancers, including those of the pancreas, lung, and colon. Recently, researchers have made significant strides in treating one variant, targeting G12C, using small molecules. However, other mutations, including the G12D and G12V variants, which are more common in disease, still lack targeted treatments. To overcome this challenge, we are using a unique immunization and screening strategy to identify a series of KRAS mutant-specific binders. These affinity binders, targeting the wild-type glycine and variants like G12D, G12S, G12C, G12A, G12R, and G12V, are being designed for research purposes to dissect cancer pathways and understand the spatial organization of cancer cells. They may also hold potential for clinical use as tools for prognosis and therapy. Deep characterization of these and other potentially widely used tools will be critical for advancing their uptake in the laboratory and clinic.

Citation Format: Ramon Serrano, Ryan Wallace, Sergei Bibikov, Michael Weiner, Kevin J. Harvey. Engineering KRAS mutation-specific affinity binders: A new frontier in cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB060.
Abstract LB106: Ultra-short ctDNA: A new paradigm for ctDNA liquid biopsy
Authors: Li Feng , Wei Fang , He Hua-Jun , Lin Chien-Chung , Yang Szu-Chun , Huang Allen Wei-Lun , Tang Cheuk Ying , Kim Yong , Wong David T.
Published: April 2024

Mononucleosomal ctDNA (mnctDNA, 157-bp, double-stranded) spearheads liquid biopsy (LB) for cancer detection, treatment and clinical care. The bottleneck of mnctDNA LB are low copy number of ctDNA and limit of detection of platform technologies. Recent discovery of ultra-short ctDNA (usctDNA, 52-54 nt, single-stranded) that harbors somatic mutations prompted us to explore the quantification and stoichiometry of usctDNA to mnctDNA in plasma and saliva of NSCLC patients.

Paired plasma and saliva from 20 advanced NSCLC patients with tissue genotyped positive for L858R were processed for cfDNA extraction and quantification with Qubit and Tape Station. Digital PCR assays targeting L858R somatic mutation to generate amplicons of 57-bp (usctDNA) and 100-bp (mnctDNA) were performed by UCLA and independently by NIST.

Results in Table 1 revealed that three findings of usctDNA that will have potential to impact ctDNA liquid biopsy. First, the somatic mutation (L858R) is present in usctDNA. Second, The stoichiometric ratio of usctDNA to mnctDNA is similar in plasma and saliva at 1.6X. For the wild-type counterpart, the ratio is 1.1X for plasma and 0.6X for saliva. Third, the copy number of usctDNA and mnctDNA in saliva to plasma is 7.8X and 7.7X.

Conclusion: Detection of tumor-associated/specific EGFR L858R somatic mutations in uscfDNA is translationally impactful, adding 1.6X of the ctDNA targets for molecular detection, effectively cumulating 2.6X of total ctDNA targets, permitting earlier cancer detection, treatment monitoring and therapy prognostication. The finding that saliva harbors 7X of the us- and mnctDNA further raises the prospect of advancing saliva ctDNA liquid biopsy for NSCLC detection as it may effectively allow 15.5X (7.8X+7.7X) ability to detect malignancy-associated ctDNA.

Table 1. Quantification of usctDNA and mnctDNA in Plasma and Saliva Mut usctDNA (L858R) WT cfDNA usctDNA mnctDNA U/M uscfDNA mncfDNA U/M Plasma 1555 ± 326 964 ± 209 1.6X 15201 ± 1509 13261 ± 1424 Saliva 12158 ± 1731 7442 ± 1020 1.6X 340896 ± 27170 601733 ± 71573 1.1X Saliva/Plasma (fold X) 7.8 7.7 1.6X 22.4 45.3 0.6X

Citation Format: Feng Li, Fang Wei, Hua-Jun He, Chien-Chung Lin, Szu-Chun Yang, Allen Wei-Lun Huang, Cheuk Ying Tang, Yong Kim, David T. Wong. Ultra-short ctDNA: A new paradigm for ctDNA liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB106.
Abstract LB143: Environmental assessment of alcohol-related policies and practices at US cancer organizations
Authors: Si Meghan , Martch Stephanie , Shete Sanjay , Hawk Ernest
Published: April 2024

In 1998, the International Agency for Research on Cancer (IARC) declared that the consumption of alcoholic beverages was a class I carcinogen to humans; the designation was reaffirmed in 2007 and 2010. Despite this, approximately 4% of new cancer cases worldwide in 2020 were attributable to alcohol intake. Growing evidence indicates that alcohol use increases the risk of cancers of the upper aerodigestive tract (oral cavity, pharynx, esophagus, and larynx) and lower digestive tract (colon, rectum, and liver). Over half of the 6.3 million cases of these cancers are considered preventable, underscoring notable gaps regarding alcohol consumption and cancer prevention. Despite (1) the longstanding designation of alcohol as an established carcinogen, (2) an increasing and consistent body of data noting alcohol as a leading contributor to the global cancer burden, and (3) the publication of policy statements by authoritative sources, it is unclear whether cancer-focused institutions are aware of these facts or are acting on these data (i.e., implementing evidence-based policies and practices to limit alcohol-related cancer risks for their employees, guests, or the public). Driven by these data and shortfalls, we developed a 22-item survey to inquire about cancer organizations' interpretation of current literature, existing policies, decision-making processes, inclination to act, and perceived responsibility to lead in the realms of public education and policy implementation to mitigate alcohol-related cancer risks in the public’s interest. The survey will be sent to over 100 leading U.S. cancer organizations, including NCI-designated- and other major cancer centers, cancer-oriented professional organizations, and cancer-research organizations. It underwent rigorous testing for clarity, brevity, and expected response time, also drawing upon the expertise of five survey-science professionals. The study is under institutional review board (IRB) review, and we anticipate the survey’s distribution in the first quarter of the calendar year 2024. We expect to share the survey instrument and results during the meeting.

Citation Format: Meghan Si, Stephanie Martch, Sanjay Shete, Ernest Hawk. Environmental assessment of alcohol-related policies and practices at US cancer organizations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB143.
Abstract LB157: Discovery of HP537, a potent and selective p300/CBP inhibitor for the treatment of hematologic malignancies
Authors: Li Jing , Tu Zhilin , Peng Jian , Fan Lei , Yu Hua , Wang Fei , Li Xinghai
Published: April 2024

E1A-binding protein P300 (p300) and its paralog CREB binding protein (CBP) are key acetyl transferases (HAT) and transcriptional co-factors. p300/CBP bromodomain (BRD) inhibition reduces acetylation of H3K27 at enhancers, leading to suppression of enhancer-driven gene expression, such as MYC and IRF4 that are critical for the initiation, progression, and chemoresistance of hematological malignancies. Thus, p300/CBP inhibition is a highly potential therapeutic strategy for the treatment of hematological malignancies, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and leukemia. We have discovered HP537 that competitively inhibits an acetylated peptide substrate to bind BRD of p300/CBP with IC50 < 5 nM. HP537 does not inhibit the enzymatic activity of HAT domain of p300/CBP and HAT1, nor has binding affinity for other BRD containing proteins including BRD4 and BRD9. HP537 inhibits proliferation of a wide range of cell lines derived from MM, leukemia and lymphoma with IC50 values ranged from 0.01 μM to 0.4 μM. Protein expression levels of acetylated H3K27, c-Myc and IRF4 are significantly decreased by HP537 in MM, NHL and acute myelogenous leukemia (AML) cell lines in a dose- and time-dependent manner. HP537 robustly and dose-dependently inhibits tumor growth in OPM-2 (MM), MOLM-16 (AML), and KARPAS-422 (NHL) cell line derived tumor xenograft (CDX) mouse models. Down-regulation of c-Myc and IRF4 are also observed in the tumor samples. In conclusion, HP537 is a novel, potent and selective inhibitor of p300/CBP BRD. The pre-clinical data supports the clinical development of HP537 for the treatment of hematological malignancies. A FIH study of HP537 in cancer patients is planned to start in 2024. HP537 structure will not be disclosed.

Citation Format: Jing Li, Zhilin Tu, Jian Peng, Lei Fan, Hua Yu, Fei Wang, Xinghai Li. Discovery of HP537, a potent and selective p300/CBP inhibitor for the treatment of hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB157.