bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalized null Cartan helices and principal normal worldsheets in Minkowski 3-space
Authors: Xu Boyuan , Pei Donghe
Published: April 2024

We give a method for constructing generalized null Cartan helices, which may have singularities, by using regular space-like plane curves and smooth functions in Minkowski 3-space. We also study the principle normal worldsheet, which is deeply related to generalized null Cartan helices from the viewpoint of singularity theory.
Generalized vortex flow of nanoparticle shapes over a permeable disc surface with generalized slip conditions
Authors: Rahman Muhammad , Ali Aqib , Turkyilmazoglu Mustafa
Published: April 2024

This paper investigates the generalized vortex flow of nanofluid consisting of titanium dioxide (TiO2) with base fluid (H2O) over a permeable disk surface that generates a heat transfer process in the thermal boundary layer of the disk. Four types of non-spherical shapes of nanoparticles (blade, brick, cylinder and platelet) are considered for the research. The motion is produced when the fluid is far from the disk surface and rotates like a solid body with a constant angular velocity [Formula: see text]. The partial differential equations (PDEs) are obtained using boundary layer approximations and then converted into ordinary differential equations (ODEs) using suitable similarity transformations. These nonlinear ODEs are solved using the bvp4c MATLAB solver. The effect of different parameters (n, A, [Formula: see text], [Formula: see text], R and Pr) on the velocity components and temperature profile is shown graphically and in tabular results. This analysis concludes that for all non-spherical shapes, the velocity spectrum of all nanoparticles decreases when the values of factors such as power-law, suction, volume fraction and slip parameter increase. All non-spherical shapes of a nanofluid experience a decrease in fluid temperature due to the Prandtl number, while radiation numbers have the opposite effect.
Study of lump and periodic waves along with rogue waves and breathers for mathematical modeling of biological dynamical system
Authors: Rizvi Syed T. R. , Seadawy Aly. R. , Khizar Saria , Ahmad Ali
Published: April 2024

Globally, infectious diseases pose a significant threat. Notable cases include influenza, Hepatitis B and HIV. COVID-19, caused by the coronavirus, has been the subject of recent discussion due to its great transmissibility. This study explores the Susceptible–Infectious–Recovered (SIR) epidemic model, explaining several analytical approaches to comprehend the nonlinear incident rates and geographic dispersion. The model investigates phenomena such as M-shaped solitons, homoclinic breather-like solitons, lump waves (LWs), lump solution (LS) with one or two kinks, rogue waves (RWs), periodic waves (PWs) and periodic cross-kink waves. These solutions aid in understanding the disease spread and informing containment strategies by identifying optimal outbreak control methods. This work studies localized wave solutions in nonlinear wave equations, known as soliton solutions including the LS. RWs are characterized by unexpectedly large amplitude and rapid profile changes, drawing attention for their erratic features. PWs exhibit periodic repetitions over time and space. Besides, some type of solitons with special waveforms are the periodic cross-kink, M-shaped and homoclinic breather-like solitons. Graphical representation visualizes the behavior of these effective waves, providing insights into virus spread in specific regions over time. SIR models help identify optimal strategies for controlling outbreaks. The work adds to our understanding of epidemic dynamics by illuminating how the movement of susceptible and infected individuals affects the spread of disease.
CHAOS THEORY, ADVANCED METAHEURISTIC ALGORITHMS AND THEIR NEWFANGLED DEEP LEARNING ARCHITECTURE OPTIMIZATION APPLICATIONS: A REVIEW
Authors: AKGUL AKIF , KARACA YELl̇Z , PALA MUHAMMED ALI , ÇIMEN MURAT ERHAN , BOZ ALI FUAT , YILDIZ MUSTAFA ZAHID
Published: April 2024

Metaheuristic techniques are capable of representing optimization frames with their specific theories as well as objective functions owing to their being adjustable and effective in various applications. Through the optimization of deep learning models, metaheuristic algorithms inspired by nature, imitating the behavior of living and non-living beings, have been used for about four decades to solve challenging, complex, and chaotic problems. These algorithms can be categorized as evolution-based, swarm-based, nature-based, human-based, hybrid, or chaos-based. Chaos theory, as a useful approach to understanding neural network optimization, has the basic idea of viewing the neural network optimization as a dynamical system in which the equation schemes are utilized from the space pertaining to learnable parameters, namely optimization trajectory, to itself, which enables the description of the evolution of the system by understanding the training behavior, which is to say the number of iterations over time. The examination of the recent studies reveals the importance of chaos theory, which is sensitive to initial conditions with randomness and dynamical properties that are principally emerging on the complex multimodal landscape. Chaotic optimization, in this regard, accelerates the speed of the algorithm while also enhancing the variety of movement patterns. The significance of hybrid algorithms developed through their applications in different domains concerning real-world phenomena and well-known benchmark problems in the literature is also evident. Metaheuristic optimization algorithms have also been applied to deep learning or deep neural networks (DNNs), a branch of machine learning. In this respect, the basic features of deep learning and DNNs and the extensive use of metaheuristic algorithms are overviewed and explained. Accordingly, the current review aims at providing new insights into the studies that deal with metaheuristic algorithms, hybrid-based metaheuristics, chaos-based metaheuristics as well as deep learning besides presenting recent information on the development of the essence of this branch of science with emerging opportunities, applicability-based optimization aspects and generation of well-informed decisions.
Anti-van der Waerden Numbers of Some 2-Connected Outerplanar Graphs
Authors: Feng Xinge , Deng Xingchao , Cai Junqing
Published: April 2024

Given a graph [Formula: see text] and a positive integer [Formula: see text], the anti-van der Waerden number [Formula: see text] is defined as the minimum positive integer [Formula: see text] such that every exact [Formula: see text]-coloring of the vertices of [Formula: see text] admits a rainbow [Formula: see text]-AP. In this paper, we determine the exact value of [Formula: see text] if [Formula: see text] is a [Formula: see text]-connected outerplanar graph with diameters [Formula: see text].
An Energy Estimation Benchmark for Quantum Computing Hardware
Authors: Woitzik Andreas J. C. , Hoffmann Lukas , Buchleitner Andreas , Carnio Edoardo G.
Published: April 2024

Certifying the performance of available quantum computing hardware requires standardized tests. We propose a simple energy estimation benchmark to scrutinize actual output against gate and readout errors reported for the IBM Quantum System One platform, where we collected unprecedented amount of data from several devices, mostly from the one in Ehningen, Germany. We observe oscillations of the benchmark data with a characteristic timescale of two hours, as well as outliers. This suggests that current mitigation techniques need to be adapted to account for nontrivial time dependencies of the devices’ output.
WCPNet: Jointly Predicting Wirelength, Congestion and Power for FPGA Using Multi-Task Learning
Authors: Xian Juming , Xing Yan , Cai Shuting , Li Weijun , Xiong Xiaoming , Hu Zhengfa
Published: April 2024

To speed up the design closure and improve the QoR of FPGA, supervised single-task machine learning techniques have been used to predict individual design metric based on placement results. However, the design objective is to achieve optimal performance while considering multiple conflicting metrics. The single-task approaches predict each metric in isolation and neglect the potential correlations or dependencies among them. To address the limitations, this article proposes a multi-task learning approach to jointly predict wirelength, congestion and power. By sharing the common feature representations and adopting the joint optimization strategy, the novel WCPNet models (including WCPNet-HS and WCPNet-SS) cannot only predict the three metrics of different scales simultaneously, but also outperform the majority of single-task models in terms of both prediction performance and time cost, which are demonstrated by the results of the cross design experiment. By adopting the cross-stitch structure in the encoder, WCPNet-SS outperforms WCPNet-HS in prediction performance, but WCPNet-HS is faster because of the simpler parameters sharing structure. The significance of the feature
image
pinUtilization
on predicting power and wirelength are demonstrated by the ablation experiment.
Let's Speak Trajectories: A Vision to Use NLP Models for Trajectory Analysis Tasks
Authors: Musleh Mashaal , Mokbel Mohamed F.
Published: April 2024

The availability of trajectory data combined with various real-life practical applications has sparked the interest of the research community to design a plethora of algorithms for various trajectory analysis techniques. However, there is an apparent lack of full-fledged systems that provide the infrastructure support for trajectory analysis techniques, which hinders the applicability of most of the designed algorithms. Inspired by the tremendous success of the Bidirectional Encoder Representations from Transformers (BERT) deep learning model in solving various Natural Language Processing tasks, our vision is to have a BERT-like system for trajectory analysis tasks. We envision that in a few years, we will have such system where no one needs to worry again about each specific trajectory analysis operation. Whether it is trajectory imputation, similarity, clustering, or whatever, it would be one system that researchers, developers, and practitioners can deploy to get high accuracy for their trajectory operations. Our vision stands on a solid ground that trajectories in a space are highly analogous to statements in a language. We outline the challenges and the road to our vision. Exploratory results confirm the promise and possibility of our vision.
RSUIGM: Realistic Synthetic Underwater Image Generation with Image Formation Model
Authors: Desai Chaitra , Benur Sujay , Patil Ujwala , Mudenagudi Uma
Published: April 2024

In this article, we propose to synthesize realistic underwater images with a novel image formation model, considering both downwelling depth and line of sight (LOS) distance as cue and call it as Realistic Synthetic Underwater Image Generation Model, RSUIGM. The light interaction in the ocean is a complex process and demands specific modeling of direct and backscattering phenomenon to capture the degradations. Most of the image formation models rely on complex radiative transfer models and in-situ measurements for synthesizing and restoration of underwater images. Typical image formation models consider only LOS distance
z
and ignore downwelling depth

d

in the estimation of effect of direct light scattering. We derive the dependencies of downwelling irradiance in direct light estimation for generation of synthetic underwater images unlike state-of-the-art image formation models. We propose to incorporate the derived downwelling irradiance in estimation of direct light scattering for modeling the image formation process and generate realistic synthetic underwater images with the proposed RSUIGM, and name it as
RSUIGM dataset
. We demonstrate the effectiveness of the proposed RSUIGM by using RSUIGM dataset in training deep learning based restoration methods. We compare the quality of restored images with state-of-the-art methods using benchmark real underwater image datasets and achieve improved results. In addition, we validate the distribution of realistic synthetic underwater images versus real underwater images both qualitatively and quantitatively. The proposed RSUIGM dataset is available here.

1
High Fidelity Makeup via 2D and 3D Identity Preservation Net
Authors: Liu Jinliang , Zheng Zhedong , Yang Zongxin , Yang Yi
Published: April 2024

In this article, we address the challenging makeup transfer task, aiming to transfer makeup from a reference image to a source image while preserving facial geometry and background consistency. Existing deep neural network-based methods have shown promising results in aligning facial parts and transferring makeup textures. However, they often neglect the facial geometry of the source image, leading to two adverse effects: (1) alterations in geometrically relevant facial features, causing face flattening and loss of personality, and (2) difficulties in maintaining background consistency, as networks cannot clearly determine the face-background boundary. To jointly tackle these issues, we propose the High Fidelity Makeup via two-dimensional (2D) and 3D Identity Preservation Network (IP23-Net), to the best of our knowledge, a novel framework that leverages facial geometry information to generate more realistic results. Our method comprises a 3D Shape Identity Encoder, which extracts identity and 3D shape features. We incorporate a 3D face reconstruction model to ensure the three-dimensional effect of face makeup, thereby preserving the characters’ depth and natural appearance. To preserve background consistency, our Background Correction Decoder automatically predicts an adaptive mask for the source image, distinguishing the foreground and background. In addition to popular benchmarks, we introduce a new large-scale High Resolution Synthetic Makeup Dataset containing 335,230 diverse high-resolution face images to evaluate our method’s generalization ability. Experiments demonstrate that IP23-Net achieves high-fidelity makeup transfer while effectively preserving background consistency. The code will be made publicly available.
Estimating Future Financial Development of Urban Areas for Deploying Bank Branches: A Local-Regional Interpretable Model
Authors: Li Pei-Xuan , Chang Yu-En , Wei Ming-Chun , Hsieh Hsun-Ping
Published: April 2024

Financial forecasting is an important task for urban development. In this article, we propose a novel deep learning framework to predict the future financial potential of urban spaces. To be more precise, our target is to infer the number of financial institutions in the future for any arbitrary location with environmental and geographical data. We propose a novel local-regional model, the
L
ocal-Regional
I
nterpretable
M
ulti-
A
ttention (LIMA) model, which considers multiple aspects of a location—the place itself and its surroundings. Besides, our model offers three kinds of interpretability, providing a superior way for decision makers to understand how the model determines the prediction: critical rules learned from the tree-based module, surrounding locations that are highly correlated with the prediction, and critical regional features. Our module not only takes advantage of a tree-based model, which can effectively extract cross features, but also leverages convolutional neural networks to obtain more complex and inclusive features around the target location. Experimental results on real-world datasets demonstrate the superiority of our proposed LIMA model against existing state-of-the-art methods. The LIMA model has been deployed as a web system for assisting one of the largest bank companies in Taiwan to select locations for building new branches in major cities since 2020.
Rate Lifting for Stochastic Process Algebra by Transition Context Augmentation
Authors: Soltanieh Amin , Siegle Markus
Published: April 2024

This article presents an algorithm for determining the unknown rates in the sequential processes of a Stochastic Process Algebra (SPA) model, provided that the rates in the combined flat model are given. Such a rate lifting is useful for model reverse engineering and model repair. Technically, the algorithm works by solving systems of nonlinear equations and—if necessary—adjusting the model’s synchronisation structure, without changing its transition system. The adjustments cause an augmentation of a transition’s context and thus enable additional control over the transition rate. The complete pseudo-code of the rate lifting algorithm is included and discussed in the article, and its practical usefulness is demonstrated by two case studies. The approach taken by the algorithm exploits some structural and behavioural properties of SPA systems, which are formulated here for the first time and could be very beneficial also in other contexts, such as compositional system verification.
Performance of Binarization Algorithms on Tamizhi Inscription Images: An Analysis
Authors: Munivel Monisha , Enigo V S Felix
Published: April 2024

Binarization of Tamizhi (Tamil-Brahmi) inscription images are highly challenging, as it is captured from very old stone inscriptions that exists around 3rd century BCE in India. The difficulty is due to the degradation of these inscriptions by environmental factors and human negligence over ages. Though many works have been carried out in the binarization of inscription images, very little research was performed for inscription images and no work has been reported for binarization of inscriptions inscribed on irregular medium. The findings of the analysis hold true to all writings that are carved in irregular background. This article reviews the performance of various binarization techniques on Tamizhi inscription images. Since no previous work was performed, we have applied the existing binarization algorithms on Tamizhi inscription images and analyzed the performance of these algorithms with proper reasoning. In the future, we believe that this reasoning on the results will help a new researcher to adapt or combine or devise new binarization techniques.
Regionalization-Based Collaborative Filtering: Harnessing Geographical Information in Recommenders
Authors: Alves Rodrigo
Published: April 2024

Regionalization, also known as
spatially constrained clustering
, is an unsupervised machine learning technique used to identify and define spatially contiguous regions. In this work, we introduce a methodology to regionalize recommendation systems (RSs) based on a collaborative filtering approach. Two main challenges arise when performing regionalization based on users’ preferences in RSs: (1) unstructured data, as interactions are often scarce and observed on a smaller scale; and (2) the difficulty of evaluation of the quality of the clustering results. To address these challenges, our methodology relies on inductive matrix completion (IMC), a fundamental approach to recover unknown entries of a rating matrix while utilizing region information to extract a region-based feature matrix. With this feature matrix, our method becomes adaptive and seamlessly integrates with various regionalization algorithms to create regionalization candidates. This enables us to derive more accurate recommendations that consider regionalized effects and discover interesting patterns in localized user behavior. We experimentally evaluate our model on synthetic datasets to demonstrate its efficacy in settings where our underlying assumptions are correct. Furthermore, we present a real-world case study illustrating the interpretable information the model can derive in terms of regionalized recommendation relevance.
Impacts of Low Energy Oxygen Irradiation on the Dielectric Properties of PVA/TiO2 Nanocomposite Films
Authors: Altuijri Reem , Abdelhamied M. M. , Atta A. , Abdel-Hamid H. M. , Henaish A. M. A. , El-Aassar M. R.
Published: April 2024

In this work, the cast solutions manufacturing approach was applied to prepare a PVA/TiO2 composite, which is made of titanium dioxide (TiO2) and polyvinyl alcohol (PVA). The energy dispersive X-ray (EDX), atomic force microscope (AFM), and Fourier transform infrared (FTIR) methods were employed to indicated the successful preparations of the composites. Moreover, the XRD and SEM methodologies were employed to investigate the impact of ion bombardment on the structural characteristics and surface morphology of the composite PVA/TiO2. The prepared films were irradiated with oxygen beam at fluencies; 0.3 × 1017, 0.6 × 1017, and 0.9 × 1017 ions cm−2. The ion beam increases the surface roughness of the PVA/TiO2 from 17 nm for the un-bombarded up to 25 nm for highly irradiated one, as indicated and measured by AFM images. The dielectric behavior of the pure and bombarded films were measured at the frequency of 50 Hz–6 MHz. The results reveal that the dielectric properties of PVA/TiO2 films were significantly modified by the oxygen beam bombardment. The results of the research pave the way for potential applications of irradiated PVA/TiO2 nanocomposite sheets in various forms of energy storage as capacitors and batteries.
Time-of-day effects on ex vivo muscle contractility following short-term satellite cell ablation
Authors: Kahn Ryan E. , Lieber Richard L. , Meza Guadalupe , Dinnunhan Fawzan , Lacham-Kaplan Orly , Dayanidhi Sudarshan , Hawley John A.
Published: April 2024

Muscle isometric torque fluctuates according to time-of-day with such variation owed to molecular clock regulation. Satellite cells (SCs) have recently demonstrated diurnal characteristics related to muscle physiology. In our work, force production was reduced in the presence versus absence of SCs in the morning but, not in the afternoon. Morning-SC+ animals, producing lower force, sustained lesser degrees of injury versus SC− counterparts. One potential mechanism underpinning lower forces produced appears to be lower calcium availability.
Damage Identification of Full‐Scale Steel Truss Structure Based on Model Condensation and Mean‐Value Normalization Regularization Techniques
Authors: Chen Huihui , Zhang Haidong , Yuan Xiaojing
Published: April 2024

Structural health monitoring and damage identification aim to detect the internal damage and evaluate the health conditions of the practical engineering structure, which has been the most popular research field for several decades. The sensitivity‐based method incorporated with the regularization techniques is the classical and useful approach, and it can obtain accurate damage detection results. However, with the development of civil engineering structures, this classical method faces two problems: one is it is only applied to simple structures rather than full‐scale structures, and second is the iterative calculation efficiency is lower. Therefore, aiming at these drawbacks, the two improvement strategies have been introduced to the original method for its enhancement in the application potential and computational efficiency. The proposed method has been verified based on two examples, i.e., a numerical steel truss with 144 elements and a full‐scale experimental steel truss with 160 elements. The results prove that the proposed method has better efficiency and good application potential in the practical full‐scale engineering structure.
Sudden Cardiac Arrest in a Youth with Multiple Arrhythmic Substrates
Authors: Ainsworth James , Ionescu Adrian
Published: April 2024

Background. Mitral valve prolapse (MVP) is a common condition with an estimated prevalence of 1‐3%, in which there is systolic displacement of a morphologically redundant mitral valve towards the left atrium. Mitral annular disjunction (MAD) is a separation of the MV attachment with the left ventricle, with hypermobility of the leaflets, and with systolic “curling” of the basal LV (left ventricle) myocardium. It is frequently associated with MVP and may confer an increased arrhythmic risk. Case Description. A 28‐year‐old male had ventricular fibrillation leading to out‐of‐hospital cardiac arrest, which was successfully resuscitated. His coronary arteries were unobstructed on invasive coronary angiography. Transthoracic echocardiogram (TTE) demonstrated MAD, confirmed by cardiac magnetic resonance (CMR) imaging and transoesophageal echocardiogram (TOE). The LV was severely dilated with reduced EF (ejection fraction), and the QTc interval was also prolonged. His father had died suddenly aged 50 years. Conclusions. This report describes the clinical dilemma of identifying and treating a patient with multiple potential causes of cardiac arrest. Despite being relatively common, the clinical significance of MAD is still uncertain and the extent to which it may be linked with complications such as ventricular arrhythmias and sudden cardiac death. MAD appears to confer an increased risk of ventricular arrhythmias, particularly when associated with MVP, particularly nonsustained VT.
Treatment of Open Bite Based on Skeletal Anchorage Using Extrusion Lever Arms and Class III Elastics
Authors: Popov Miodrag , Marinkovic Nemanja , Arsic Ivan , Janosevic Predrag , Nedeljkovic Nenad
Published: April 2024

A 26‐year‐old woman had a masticatory dysfunction, straight profile, retrognathic maxilla and mandible, and Angle’s class I with a tendency to class III malocclusion on both sides, with bilateral posterior crossbites and a 4 mm anterior open bite. Orthognathic surgery and orthodontic camouflage with and without tooth extraction were considered as treatment options. The patient’s preferred method of treatment was orthodontic camouflage without extraction. The transpalatal arch had been placed for the bilateral molars’ derotation. After 3 months, the upper segmented fixed appliance was implanted to address the posterior crossbites in the premolar’s region. One mini‐implant was inserted into the anterior palatum after the transpalatal arch was removed, and a supporting device was attached to the first permanent molars to give indirect skeletal stability. Orthodontic treatment’s active phase lasted 23 months, and all treatment objectives were achieved during that time: the desired facial profile, adequate occlusion, appropriate overbite, and overjet.
Dendritic Cell‐Based Immunotherapy: The Importance of Dendritic Cell Migration
Authors: Song Min-Seon , Nam Ji-Hee , Noh Kyung-Eun , Lim Dae-Seog
Published: April 2024

Dendritic cells (DCs) are specialized antigen‐presenting cells that are crucial for maintaining self‐tolerance, initiating immune responses against pathogens, and patrolling body compartments. Despite promising aspects, DC‐based immunotherapy faces challenges that include limited availability, immune escape in tumors, immunosuppression in the tumor microenvironment, and the need for effective combination therapies. A further limitation in DC‐based immunotherapy is the low population of migratory DC (around 5%–10%) that migrate to lymph nodes (LNs) through afferent lymphatics depending on the LN draining site. By increasing the population of migratory DCs, DC‐based immunotherapy could enhance immunotherapeutic effects on target diseases. This paper reviews the importance of DC migration and current research progress in the context of DC‐based immunotherapy.
The Abundance of Plasmid-Mediated Quinolone Resistance Genes in Enterobacter cloacae Strains Isolated from Clinical Specimens in Kermanshah, Iran
Authors: Afsharian Mandana , Asadi Somayeh , Danesh Camellia , Sedighi Reza , Karimi Kohsar , Miladi Nooshin , Miladi Ronak , Azizi Mohsen , Madadi-Goli Nahid , Ahmadi Kamal , Zamanian Mohammad Hossein
Published: April 2024

Background. Enterobacter cloacae (E. cloacae) is one of the most common Enterobacteriaceae causing nosocomial infections. Plasmid-mediated quinolone resistance (PMQR) determinants have been considered recently. This study evaluated the abundance of PMQR genes in strains of E. cloacae obtained from clinical samples in Kermanshah, Iran. Methods. In this descriptive cross-sectional study, after collecting 113 isolates of E. cloacae, their identity was confirmed using specific biochemical tests. After determining their drug resistance patterns using disc diffusion, the phenotypic frequency of extended-spectrum beta-lactamase (ESBL)-producing isolates was measured by the double-disk synergy test (DDST) method. The isolates were examined for the presence of qnrA, qnrB, qnrS, and aac(6′)-Ib-cr genes by the polymerase chain reaction (PCR) assay. Results. The antibiotic resistance rate of E. cloacae isolates varied from 9.7% to 60.2%; among them, 78% were multidrug-resistant (MDR). The highest quinolone resistance was observed in ESBL-producing strains of E. cloacae. The frequency of positive isolates for PMQR and ESBL was 79.6% and 57.5%, respectively. The genes aac(6′)-ib-cr (70.8%) and qnrB (38.1%) had the highest frequency among other genes. The number of isolates simultaneously carrying 2 and 3 genes was 64 and 5 isolates, respectively. Conclusion. The obtained results indicate a high degree of quinolone resistance among ESBL-producing E. cloacae strains. Nevertheless, there was a significant relationship between the PMQR gene and ESBL-positive isolates. Therefore, special attention should be paid to molecular epidemiological studies on antibiotic resistance to quinolones and beta-lactamases in these strains.
A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors
Authors: Gilmer Tona M. , Lai Chun-Hsiang , Guo Kexiao , Deland Katherine , Ashcraft Kathleen A. , Stewart Amy E. , Wang Yaode , Fu Jianmin , Wood Kris C. , Kirsch David G. , Kastan Michael B.
Published: April 2024

A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiotherapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. In addition, in cells lacking BRCA1/2 XRD-0394 shows single-agent activity and synergy in combination with PARP inhibitors. A phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with radiotherapy has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with radiotherapy, PARP inhibitors, and targeted delivery of topoisomerase I inhibitors.
ETS1, a Target Gene of the EWSR1::FLI1 Fusion Oncoprotein, Regulates the Expression of the Focal Adhesion Protein TENSIN3
Authors: Ebegboni Vernon Justice , Jones Tamara L. , Brownmiller Tayvia , Zhao Patrick X. , Pehrsson Erica C. , Sundara Rajan Soumya , Caplen Natasha J.
Published: April 2024

The mechanistic basis for the metastasis of Ewing sarcomas remains poorly understood, as these tumors harbor few mutations beyond the chromosomal translocation that initiates the disease. Instead, the epigenome of Ewing sarcoma cells reflects the regulatory state of genes associated with the DNA-binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the EWSR1::FLI1/ERG's repression of transcription factor genes, concentrating on those that exhibit a broader range of expression in tumors than in Ewing sarcoma cell lines. Focusing on one of these target genes, ETS1, we detected EWSR1::FLI1 binding and an H3K27me3-repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, substantially altering the transcriptome of Ewing sarcoma cells, including the upregulation of the gene encoding TENSIN3 (TNS3), a focal adhesion protein. Ewing sarcoma cell lines expressing ETS1 (CRISPRa) exhibited increased TNS3 expression and enhanced movement compared with control cells. Visualization of control Ewing sarcoma cells showed a distributed vinculin signal and a network-like organization of F-actin; in contrast, ETS1-activated Ewing sarcoma cells showed an accumulation of vinculin and F-actin toward the plasma membrane. Interestingly, the phenotype of ETS1-activated Ewing sarcoma cell lines depleted of TNS3 resembled the phenotype of the control cells. Critically, these findings have clinical relevance as TNS3 expression in Ewing sarcoma tumors positively correlates with that of ETS1.

Implications: ETS1’s transcriptional regulation of the gene encoding the focal adhesion protein TENSIN3 in Ewing sarcoma cells promotes cell movement, a critical step in the evolution of metastasis.
The Pan-RAF–MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS–MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers
Authors: Ryan Meagan B. , Quade Bradley , Schenk Natasha , Fang Zhong , Zingg Marshall , Cohen Steven E. , Swalm Brooke M. , Li Chun , Özen Ayşegül , Ye Chaoyang , Ritorto Maria Stella , Huang Xin , Dar Arvin C. , Han Yongxin , Hoeflich Klaus P. , Hale Michael , Hagel Margit
Published: April 2024

Alterations in the RAS–MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF–MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS–MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF–MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF–CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF–MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need.

Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.

See first author Meagan B. Ryan discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932606757/4d0bd5aa98
Supplementary Figure S6 from Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R.
Published: April 2024

IHC staining for WT1 (purple) and SMA (brown in top panels; teal in bottom panels) in representative crocidolite-induced and chrysotile-induced MMs from Bap1+/- mice. WT1 stains MM cells, whereas SMA stains CAFs, the latter typically more abundant in chrysotile-induced than crocidolite-induced MMs, as in the examples shown here.
Supplementary Figure S5 from Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R.
Published: April 2024

Expression of arginase and iNOS in a crocidolite-exposed Bap1+/- mouse. Arginase-1 (Arg-1) staining is found mostly in mesothelioma tissue (MM), whereas iNOS staining is present primarily in the granulomatous lesions (G). Arrows indicate crocidolite fibers found in the granuloma.
Supplementary Figure S4 from Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R.
Published: April 2024

Tumor immune microenvironment of chrysotile-induced MM from a Bap1+/- mouse. Serial sections of MM stained with several different immune cell markers: CD3 (T cells), CD45R (B cells), F4/80 (macrophages), and NK1.1 (natural killer cells), clockwise starting from upper left. T, B, and NK cells are depleted in tumor, whereas numerous cells in and around the tumor are stained with the macrophage marker F4/80.
Supplementary Figure S2 from Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R.
Published: April 2024

H&E images of liver fibrosis in Bap1+/- mice chronically injected i.p. with asbestos. A) Interlobular liver fibrosis in a chrysotile-exposed mouse. B) Liver fibrosis in between liver and spleen in chrysotile-injected mouse. C) Fibrosis on surface of liver in a crocidolite-exposed mouse. D) Fibrosis between liver and pancreas of a crocidolite-exposed mouse. All original images are at 200X magnification. Abbreviations: F, fibrosis; L, liver; M, mesothelioma; S, spleen; P, pancreas.
FIGURE 7 from Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R.
Published: April 2024

Preliminary clinical connections of mouse findings based on NCI human MM RNA-seq and germline mutation data (16). A, Comparison of CCL2 mRNA expression levels based on BAP1 germline mutation status in 100 MM samples from the NCI cohort. Statistical analysis was performed using the Student t test. B, Immunoblot analyses of CCL2 in human MM cell lines with or without loss of BAP1 expression. GAPDH was used as a loading control. C, Scatter plots depicting the relationship between CD163 and CCR2, ENTPD1 (CD39), IL10, IL10RA, MRC1 (CD206), and STAT3 mRNA expression levels. Statistical analysis for this correlation study was conducted using Spearman rank-order correlations (r) and P values.
FIGURE 2 from Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R.
Published: April 2024

TIME of crocidolite-induced MMs from Bap1+/− mice. A, Serial sections of a crocidolite-induced MM from Bap1-mutant mouse stained with several different immune cell markers: CD3 (T cells; arrows); CD45R (B cells); F4/80 (macrophages; arrows); and NK1.1 (natural killer cells), clockwise starting from top left. B, Serial sections showing distribution of macrophages in granuloma and TIME of MM from Bap1+/− mouse exposed to crocidolite. Left, Proinflammatory CD11c-positive M1 macrophages. Right, Protumorigenic CD206-positive M2 macrophages. Blue circles, granulomatous lesions; red squares, MM tumor areas. Note numerous crocidolite fibers (yellow block arrows) in granulomatous lesions.
FIGURE 1 from Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R.
Published: April 2024

MM formation induced by crocidolite or chrysotile asbestos in mice with germline Bap1 heterozygous mutation. MM formation induced by minimal exposure to crocidolite (A and B). A,Bap1+/− and Bap1+/+ (WT) littermates injected with a total of 0.8 mg of crocidolite fibers. Left, Kaplan–Meier curves depicting survivals in Bap1+/− and Bap1+/+ groups. Right, Summary of MM incidence and median survival times. B, Results for Bap1+/− and Bap1+/+ mice injected with a total of 0.1 mg of crocidolite. Left, Kaplan–Meier curves. Right, Summary of MM incidence and median survival times. MM formation induced by high (C) and minimal (D) exposure to chrysotile. C,Bap1+/− and Bap1+/+ mice were injected with a total of 3.2 mg of chrysotile. Left, Kaplan–Meier survival curves. Right, MM incidence and median survival times. D,Bap1+/− and Bap1+/+ mice injected with a total of 0.4 mg/mouse of crocidolite. Left, Kaplan–Meier curves. Right, MM incidence and median survival times. For all Kaplan–Meier survival curves, deaths due to all causes are included. Some mice (especially WT animals) succumbed because of adhesion-related intestinal obstructions and/or liver fibrosis.
Endothelial-to-Mesenchymal Transition in Human and Murine Models of Congenital Diaphragmatic Hernia
Authors: Gilley Jamie , Hanneman Sandra K. , Ottosen Madelene J. , Shivanna Binoy , Keswani Sundeep
Published: April 2024

Introduction: Congenital diaphragmatic hernia (CDH) is a complex congenital disorder, characterized by pulmonary hypertension (PH) and hypoplasia. PH secondary to CDH (CDH-PH) features devastating morbidity and mortality (25–30%) among neonates. An unmet need is determining mechanisms triggering CDH-PH to save infants. Prior data suggest abnormal remodeling of the pulmonary vascular extracellular matrix (ECM), presumed to be driven by endothelial-to-mesenchymal transition (EndoMT), hinders postnatal vasodilation and limits anti-PH therapy in CDH. There are limited data on the role of EndoMT in CDH-PH. Methods: The purpose of the study was to investigate how EndoMT contributes to CDH-PH by identifying cells undergoing EndoMT noted by alpha smooth muscle actin (α-SMA) expression in human umbilical vein endothelial cells (HUVECs) and lung tissue obtained from murine pups using the nitrofen model. N = 8 CDH, N = 8 control HUVECs were stained for α-SMA and CD31 after being exposed for 24 h to TGFB, a known EndoMT promoter. N = 8 nitrofen, N = 8 control murine pup lungs were also stained for α-SMA and CD31. α-SMA and CD31 expression was quantified in HUVECs and murine tissue using Fiji imaging software and normalized to the total number of cells per slide noted by DAPI staining. Results: CDH HUVECs demonstrated a 1.1-fold increase in α-SMA expression (p = 0.02). The murine model did not show statistical significance between nitrofen and control pup lungs; however, there was a 0.4-fold increase in α-SMA expression with a 0.8-fold decrease in CD31 expression in the nitrofen pup lungs when compared to controls. Conclusion: These results suggest that EndoMT could potentially play a role in the ECM remodeling seen in CDH-PH.
Translation, Cultural Adaptation, and Content Validation of a Pleural Mesothelioma Questionnaire to Portuguese Context – A Key Tool for Epidemiological Surveillance
Authors: Santos Cátia , Sacadura-Leite Ema , Feijó Salvato , Dixe Maria dos Anjos , Astoul Philippe , Sousa-Uva António
Published: April 2024

Objective: The main objective of this study was to describe the translation, cultural adaptation, and content validation process of the French National Surveillance Programme for Pleural Mesothelioma (FNSPPM) questionnaire for the Portuguese context. Methods: A search was conducted in the PubMed database and Web of Science, in the period from January 1, 1960, to December 31, 2022, to select the questionnaire. Forward and reverse translations, calculation of the content validity index (CVI) by a panel of experts (n = 9), and cognitive interviewing with individuals with at least one exposure to asbestos (n = 10) were performed. Experts rated items on a Likert scale (1-4) based on their relevance. The item-level content validity index (I-CVI), scale-level content validity index based on the average method (S-CVI/Ave), and scale-level content validity index based on the universal agreement method (S-CVI/UA) were calculated. Results: The final version of the FNSPPM questionnaire for the Portuguese context resulted from a translation and content validation process. The panel of experts considered the questionnaire relevant, with an I-CVI of up to 0.78 in 68 of 69 of the questions, an S-CVI/Ave of 0.98, and an S-CVI/UA of 0.90. The participants in the cognitive interviews reported an understanding of the questionnaire. Conclusion: A validated FNSPPM questionnaire for the Portuguese context is now available to study individuals with pleural mesothelioma (PM) and asbestos exposure.
Validation of a Behavioral Activation Model Including Self-Compassion: A Longitudinal Study at Three Time Points
Authors: Takagaki Koki , Yokoyama Satoshi
Published: April 2024

Introduction: Depression is highly prevalent among university students. While behavioral activation has been shown to be an effective psychotherapy for depression, there is a lack of research regarding the behavioral activation mechanism. Furthermore, although self-compassion seems to be a factor in promoting behavioral activation, no studies have attempted to validate a behavioral activation model that includes positive self-compassion. In addition, mechanistic studies have lacked consideration in longitudinal studies of behavioral activation. Thus, in this longitudinal study, we constructed and validated an exploratory model of behavioral activation. Methods: A total of 300 undergraduate students completed online surveys in 2019, 2020, and 2021. We examined the longitudinal effects of five factors (value-based behavior, goal-oriented and scheduled activities, positive reinforcement, self-compassion, and depressive symptoms) using structural equation modeling based on maximum likelihood estimation using bootstrapping. Results: The exploratory model was found to be valid and to have a good fit with the data. The results indicate that value-based behaviors increase the frequency of goal-oriented and scheduled activities, which in turn increases the frequency of positive reinforcement in everyday life. Additionally, when self-compassion, value-based behavior, goal-oriented and scheduled activities, and positive reinforcement are considered together, self-compassion may be indirectly related to activation via value-based behavior. Conclusion: From the perspective of preventing depressive symptoms, it is important to increase the frequency of value-based activities. Furthermore, adding self-compassion is effective in behavioral activation to increase value-based activities. However, to address the limitations of this study, future studies should investigate the relationship among behavioral characteristics during interventions.