bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimized deep stacked autoencoder for ransomware detection using blockchain network
Authors: Nalinipriya G. , Maram Balajee , Vidyadhari Ch. , Cristin R.
Published: April 2021

The innovation of technologies has become ubiquitous and imperative in day-to-day lives. Malware is the major threat to the network, and Ransomware is a special and harmful type of malware. Ransomware led to huge data losses and induced huge economic costs. Moreover, Ransomware detection is a crucial task to minimize analyst’s workloads. This paper devises a novel deep learning method for detecting Ransomware using the blockchain network. Here, the sequence-based statistical feature extraction is performed, wherein the features are extracted using 2-gram and 3-gram opcodes. Also, the term frequency-inverse document frequency (TF-IDF) is discovered for each feature. Then the Box-Cox transformation is applied to transformation to the data for improved analysis. Also, the feature fusion is progressed using a fractional concept. Finally, the classification of Ransomware is done using Deep stacked Auto-encoder (Deep SAE), wherein the proposed Water wave-based Moth Flame optimization (WMFO) is adapted for generating the optimal weights. The WMFO is designed by integrating Water wave optimization (WWO) and Moth Flame optimization (MFO). The proposed WMFO-Deep SAE outperformed other methods with maximal accuracy of 96.925%, sensitivity of 96.900%, and specificity of 97.920%.
Acylation of electrophilic bicyclo[1.1.0]butanes via Co/Ni-catalyzed reductive cross-coupling
Authors: Wierzba Aleksandra J. , Gryko Daniel T. , Gryko Dorota
Published: April 2021

Cyclobutane scaffold is appreciated in medicinal chemistry for its strained, well-defined three-dimensional structure. Consequently, methods for the synthesis of cyclobutyl derivatives have become highly desired, particularly those offering access to compounds with new patterns of substituents. Herein, an acylation of electrophilic strained molecules at the bridgehead carbon with [Formula: see text]-acyl-glutarimides is reported. For this, the polarity-reversal strategy based on cobalt catalysis that enables the generation of cyclobutyl radicals in a strain release event was harnessed. These nucleophilic species, in the presence of a Ni-complex, couple with [Formula: see text]-acyl-glutarimides to give cyclobutyl ketones in decent yields.
Construction of (n-Fold) EQ-Algebras by Using Fuzzy n-Fold Filters
Authors: Saffar B. Ganji , Muhiuddin G. , Kologani M. Aaly , Borzooei R. A.
Published: April 2021

In this paper, the concept of fuzzy [Formula: see text]-fold (positive implicative, implicative, fantastic) filters in [Formula: see text]-algebras is defined and several results and relation among them are investigated. Then [Formula: see text]-fold (implicative) positive implicative [Formula: see text]-algebras are constructed by using [Formula: see text]-fold fuzzy positive (implicative) filters and suitable congruence relations on [Formula: see text]-algebras.
Adsorption–Desorption Characteristics of ss-DNA on 2D TpTta-COF Studied by Fluorescently Labeled Oligonucleotides
Authors: Han Zhaoyu , Li Sen , Yin Shaoxian , Wang Zhi-Qin , Cai Yanfei , Chen Cheng , Yang Zhaoqi
Published: April 2021

Being the newest member of the 2D materials family, 2D-nanosheet possesses many distinctive physical and chemical properties resulting in a wide range of potential applications. Recently, it was discovered that 2D COF can adsorb single-stranded DNA (ss-DNA) efficiently as well as usefully to quench fluorophores. These properties make it possible to prepare DNA-based optical biosensors using 2D COF. While practical analytical applications are being demonstrated, the fundamental understanding of binding between 2D COF and DNA in solution received relatively less attention. In this work, we carried out a systematic study to understand the adsorption and desorption kinetic, mechanism, and influencing factors of ss-DNA on the surface of 2D COF. We demonstrated that shorter DNAs are adsorbed more rapidly and bind more tightly to the surface of 2D COF. The adsorption is favored by a higher pH. The different buffer types also can affect the adsorption. In Tris-HCl solution, the adsorption reached highest efficiency. By adding the complementary DNA (cDNA), desorption of the absorbed DNA on 2D COF can be achieved. Further, desorption efficiency can also be exchanged by various surfactant in solution. These findings are important for further understanding of the interactions between DNA and COFs and for the optimization of DNA and COF-based devices and sensors.
Evolutionary History of Plant Metabolism
Authors: Maeda Hiroshi A. , Fernie Alisdair R.
Published: April 2021

Tremendous chemical diversity is the hallmark of plants and is supported by highly complex biochemical machinery. Plant metabolic enzymes originated and were transferred from eukaryotic and prokaryotic ancestors and further diversified by the unprecedented rates of gene duplication and functionalization experienced in land plants. Unlike microbes, which have frequent horizontal gene transfer events and multiple inputs of energy and organic carbon, land plants predominantly rely on organic carbon generated from CO2and have experienced very few, if any, gene transfers during their recent evolutionary history. As such, plant metabolic networks have evolved in a stepwise manner and on existing networks under various evolutionary constraints. This review aims to take a broader view of plant metabolic evolution and lay a framework to further explore evolutionary mechanisms of the complex metabolic network. Understanding the underlying metabolic and genetic constraints is also an empirical prerequisite for rational engineering and redesigning of plant metabolic pathways.
A Moving Object Detection Method Using Deep Learning‐Based Wireless Sensor Networks
Authors: Zhao Linghua , Huang Zhihua
Published: April 2021

Aiming at the problem of real‐time detection and location of moving objects, the deep learning algorithm is used to detect moving objects in complex situations. In this paper, based on the deep learning algorithm of wireless sensor networks, a novel target motion detection method is proposed. This method uses the deep learning model to extract visual potential representation features through offline similarity function ranking learning and online model incremental update and uses the hierarchical clustering algorithm to achieve target detection and positioning; the low‐precision histogram and high‐precision histogram cascade the method which determines the correct position of the target and achieves the purpose of detecting the moving target. In order to verify the advantages and disadvantages of the deep learning algorithm compared with traditional moving object detection methods, a large number of comparative experiments are carried out, and the experimental results were analyzed qualitatively and quantitatively from a statistical perspective. The results show that, compared with the traditional methods, the deep learning algorithm based on the wireless sensor network proposed in this paper is more efficient. The detection and positioning method do not produce the error accumulation phenomenon and has significant advantages and robustness. The moving target can be accurately detected with a small computational cost.
Embedding of Besov Spaces and the Volterra Integral Operator
Authors: Qu Dan , Zhu Xiangling , Qian Ruishen
Published: April 2021

The boundedness and compactness of the inclusion mapping from Besov spaces to tent spaces are studied in this paper. Meanwhile, the boundedness, compactness, and essential norm of the Volterra integral operator

T

g

from Besov spaces to a class of general function spaces are also investigated.
Applying the Virtual Input‐Output Method to the Identification of Key Nodes in Busy Traffic Network
Authors: Yang Fan , Yan Fei , Zhang Chikun , Tang Xiaoying , Li Jianchang , Zhang Xindan , Gan Yingxin
Published: April 2021

How to identify the key nodes effectively in urban traffic networks to achieve the equitable resource allocation face to the complex traffic network? This issue needs to be solved in current traffic management. This study considered the urban traffic network topology and network traffic status, put forward an improved model based on the economics of the input‐output method by introducing a virtual node to the selected network set up with the flow of urban traffic network, sensor nodes by Leontief inverse matrix calculation coefficient to determine node importance, according to the node importance to deliberate attack traffic network to analyze its robustness, to test the accuracy and practicability of the method. The results show that this improved method adopted to measure the importance of traffic nodes from the global scope has the advantages of fast calculation and simple process and provides a more reliable basis for rational allocation of transport resources.
Application of Field-of-View Optimized and Constrained Undistorted Single Shot (FOCUS) with Intravoxel Incoherent Motion (IVIM) in 3T in Locally Advanced Rectal Cancer
Authors: Cheng Yipeng , Jiang Huijie , Wang Hui , Tang Qingchao , Liu Tianyi
Published: April 2021

Purpose. To evaluate the efficacy of field-of-view (FOV) optimized and constrained undistorted single shot (FOCUS) with IVIM in 3T MRI in the grading of patients with locally advanced rectal cancer. Methods. From January 1st to December 31st, 2019, patients with locally advanced rectal cancer were retrieved. FOCUS DWI and FOCUS IVIM were obtained. Apparent diffusion coefficient (ADC) and IVIM parameters including mean true diffusion coefficient (

D

), pseudodiffusion coefficient associated with blood flow (

D
∗

), and perfusion fraction (

f

) of the tumor parenchyma and normal rectal wall, as well as the normalized tumor parameters by corresponding normal intestinal wall parameters (ADCNOR,

D

NOR

,

D
∗

NOR

, and

f

NOR

), were compared between the well/moderately differentiated and poorly differentiated groups by Student’s

t

-test. The relationship between the above parameters and the histologic grade was analyzed using Spearman’s correlation test, with the ROC curve generated. Results. Eighty-eight patients (aged 31 to 77 years old,

mean
=
56

) were included for analysis.

D

tumor

and

f

tumor

were positively correlated with the tumor grade (

r
=
0.483

,

p
<
0.001

and

r
=
0.610

,

p
<
0.001

, respectively). All the normalized parameters (ADCNOR,

D

NOR

,

D
∗

NOR

, and

f

NOR

) were positively correlated with the tumor grade (

r
=
0.267

,

p
=
0.007

;

r
=
0.564

,

p
=
0.001

;

r
=
0.414

,

p
=
0.005

; and

r
=
0.605

,

p
<
0.001

, respectively). The best discriminative parameter was the

f

tumor

value, and the area under the ROC curve was 0.927. With a cut-off value of 22.0%,

f

tumor

had a sensitivity of 88.9% and a specificity of 100%. Conclusion. FOCUS IVIM-derived parameters and normalized parameters are useful for predicting the histologic grade in rectal cancer patients.
IOT Medical Device-Assisted Foam Dressing in the Prevention of Pressure Sore during Operation
Authors: Meng Yan , Zhao Hui , Yin Zhigai , Qi Xiaona
Published: April 2021

With the development of the times, people’s living standards are constantly improving, but the medical pressure brought by the aging population is also increasing, and pressure ulcers in elderly patients during hospitalization are also constantly occurring. Of course, the relevant medical equipment is also progressing, especially the emergence of medical-assistant foam dressing on the Internet of Things, which makes people cope with pressure ulcers more handily. In order to test the role of IOT medical devices, especially the application of foam dressings in the prevention of pressure ulcers, this article has carried out a survey of patients in a city hospital, investigated relevant literature, interviewed professionals, collected relevant information, designed experiments, and obtained relevant research data. Research shows that IOT medical devices can improve the efficiency of hospital treatment and improve the efficiency by about 12%; pressure ulcer incidence in different age groups of people is different, and the probability of occurrence in the elderly population is far higher than that of young people; foam dressing has obvious effect on the prevention of pressure sore, and the probability of pressure sore after using foam dressing is lower than that of unused 35%. It indicates that foam dressing can play a key role in the prevention of pressure sore.
Video Stream Session Migration Method Using Deep Reinforcement Learning in Cloud Computing Environment
Authors: Li Lingling , Liu Huixia
Published: April 2021

In the resource scheduling of streaming Media Edge Cloud (MEC), in order to balance the cost and load of migration, this paper proposes a video stream session migration method based on deep reinforcement learning in cloud computing environment. First, combined with the current popular OpenFlow technology, a novel MEC architecture is designed, which separates streaming media service processing in application layer from forwarding path optimization in network layer. Second, taking the state information of the system as the attribute feature, the session migration is calculated, and gradient reinforcement learning is combined with in‐depth learning and deterministic strategy for video stream session migration to solve the user request access problem. The experimental results show that the method has a better request access effect, can effectively improve the request acceptance rate, and can reduce the migration cost, while shortening the running time.
Semantic Optimization of Feature-Based SLAM
Authors: Li Peng , Yin Lili , Gao Jiali , Sun Yuezhongyi
Published: April 2021

The purpose of this paper is to provide reasonable recommendation and removal of inappropriate information for SLAM (Simultaneous Localization and Mapping) technology based on feature method. The methodology is to propose a semantic recognition of environment objects in the natural scene through object detection, which is a kind of bag of word method in SLAM problem between the key frames and object level, the method of establishing key frames, and the relationship between the target object levels, through the practical signiﬁcance of the target object level to judge the merits of the target object level information, and then combined with key frames in the visual SLAM relations with relevant information, so as to get object level targets in each key frame and the relationship between the relevant information, so as to achieve through the object level semantic information to judge the merits of the key frames and screening, as well as to the key frames to judge the merits of the relevant information and screening purpose. The finding of the study is the above method can retain the information of high reliability and good stability for visual SLAM and process the key frames with poor reliability or low stability and the information related to key frames.
Power Spectrum Features of Acupoint Bioelectricity Signal
Authors: Zhang Jingjing , Yu Renhuan , Zhao Enlu , Zhou Quan , Gai Shuping
Published: April 2021

Background. Since the 1950s, many studies have been conducted on the electrical properties of acupuncture points (acupoints), especially their bio-resistance characteristics. Results of such studies have been inconclusive due to factors such as sweat gland density and compounding factors of applying electrical stimulation. In this study, a power spectrum instrument was used to assess the power spectrum and power of acupoints and nonacupoints without electrical stimulation. Using such instrumentation, specificity of electrical signals of acupoints was also explored. Methods. Thirty-six subjects (29 females, 7 males) participated in the study. Stainless steel acupuncture needles (diameter 0.35 mm; length 50 mm) were used. Five acupoints were tested: ST 36, SP 6, GB 39, GB 37, and K I9. Four control sites 0.5–1.0 cm adjacent to each acupoint were chosen. After needle insertion into the acupoint and control sites, the needles were attached to the power spectrum instrument to acquire any electrical signals. Acquire signals were analyzed using self-written software. Results. Power spectrum difference between acupoint and nonacupoint signals was 0–2 Hz. Results of t-test or signed rank sum test (α = 0.05) found that electrical signals between acupoints and nonacupoints were markedly different (

P

 < 0.05). Conclusion. Acupoint bioelectricity signals are higher than adjacent nonacupoints. The most significant difference is distributed between 0 Hz and 2 Hz.
Continuous Spinal Anaesthesia for Intertrochanteric Femur Fracture in a Patient with Skeletal Dysplasia
Authors: Khakurel Sharad , Yadav Rupesh Kumar
Published: April 2021

The practice of continuous spinal anaesthesia is not common. Though underutilised, it offers significant advantage when compared to the single-shot technique nonetheless. Time and again, it has proven its worth in patients with advanced cardiac illness, spinal deformities, and obesity. We here successfully employed this neuraxial anaesthetic technique in a sixty-two-year-old male patient with skeletal dysplasia, who presented for surgical fixation of intertrochanteric fracture of the femur. With short stature, anticipated difficult airway, and poor pulmonary status complicating the anaesthetic plan, we opted for continuous spinal anaesthesia. The procedure was carried out uneventfully with 8 mg of hyperbaric bupivacaine used in titration to anaesthetic needs. Patients with skeletal dysplasia present with wide array of clinical conditions that pose a formidable challenge to anaesthesiologists. Continuous spinal anaesthesia can be safely practiced in such patients as it provides a titratable form of neuraxial blockade with reduced dose of local anaesthesia. This, in turn, ensures a predictable block and, thus, hemodynamic stability.
Epitope-Based Chicken-Derived Novel Anti-PAD2 Monoclonal Antibodies Inhibit Citrullination
Authors: Aosasa Masayoshi , Hossain Md Saddam , Sakata Tomoko , Koga Keita , Shigemitsu Takanari , Shoya Yuji , Yamaguchi Motonori , Saito Kenji , Kim Mujo
Published: April 2021

The aberrant upregulation of protein arginine deiminase 2- (PAD2-) catalyzed citrullination is reported in various autoimmune diseases (rheumatoid arthritis and multiple sclerosis) and several cancers. Currently, there are no anti-PAD2 monoclonal antibodies (mAbs) that can inhibit the citrullination reaction. Here, an epitope 341YLNRGDRWIQDEIEFGY357 was examined as an antigenic site of PAD2. Chickens were immunized with this epitope, and the generated mAbs were screened for its reactivity against the full-length PAD2. Enzyme-linked immunosorbent assay revealed that six mAbs, which were screened from the phage display library, crossreacted with mouse PAD2. Kinetic analysis revealed that mAbs are bound to PAD2 in the nanomolar range, which indicated a strong binding. Results of the in vitro citrullination inhibition assay revealed that the half-maximal effective concentration values of mAbs for the inhibition of histone or benzoyl-L-arginine ethyl ester citrullination were in the range of 6–75 nM which supports strong inhibition capabilities. Alanine scanning of epitope revealed that the peptide fragment 344RGDRWIQDEIEF355 was responsible for generating strong antibody responses that inhibit the PAD2-catalyzed citrullination reaction. These antibodies can aid in understanding the extracellular PAD2 function and treating diseases associated with aberrant citrullination.
Correlations between Left Ventricular and Left Atrial Function Assessed by Speckle Tracking Echocardiography in Patients with Treated Well-Controlled Arterial Hypertension
Authors: Uziębło-Życzkowska Beata , Krzesiński Paweł
Published: April 2021

Introduction. Even in patients with well-controlled arterial hypertension (AH) and without significant comorbidities, left ventricular (LV) and left atrial (LA) strain abnormalities may sometimes be found in speckle-tracking echocardiography. Therefore, the aim of this study was to investigate the correlation between LA strain and LV diastolic and systolic function in a group of patients with treated, well-controlled AH. Material and methods. LA contractile, conduit, and reservoir function, together with echocardiographic signs of LV diastolic function and LV global longitudinal strain (LV GLS), were assessed in 101 patients with treated, well-controlled AH who met the standard criteria of normal LV ejection fraction (LVEF) and normal LV diastolic function. Results. A relevant percentage of study participants presented lower than reference LV (−18.7% for LV GLS) and LA strain (32.9% for LAS during reservoir phase, LASr; −15.9% for LAS during contraction phase, LASct; and −13.9% for LAS during conduit phase, LAScd) values. Moreover, there were statistically significant differences in LA longitudinal strain (LAS) values (LASr (31.43 vs. 36.33;

p

 = 0.0007) and LAS LAScd (−13.09 vs. −15.79;

p

 = 0.008)) between patients with high (>the absolute value of −20%) and lower (≤the absolute value of −20%) LV GLS, confirmed by significant correlations between LASr, LAScd, and GLS. In the correlations analysis between LAS values and LV diastolic function parameters, statistical significance was obtained for the following: LASct (contraction) versus e’avg, LASct versus E/A, LASct versus A, LAScd versus e’avg, LAScd versus E/A, and LAScd versus A. Conclusions. LV and LA strain abnormalities occurred within a significant percentage of patients with treated, well-controlled AH. Impaired LA strain is associated with lower LV strain and reduced LV diastolic function parameters, reflecting both the passive and active properties of the LA.
Study of Massive Floating Solar Panels over Lake Nasser
Authors: Elshafei Moustafa , Ibrahim Abdelrahman , Helmy Amr , Abdallah Mostafa , Eldeib Amgad , Badawy Moustafa , AbdelRazek Sayed
Published: April 2021

Recently, the technology of floating photovoltaic panels has demonstrated several advantages over land installations, including faster deployment, less maintenance cost, and higher efficiency. Lake Nasser is the second largest man-made freshwater lake in the world with a surface area of almost 5000 square km. Being in one of the hottest areas in the world, evaporation of water causes loss of very precious and scarce resources: freshwater. Fortunately, the lake is also located in a very rich area in solar energy. This paper presents a study to utilize Lake Nasser’s surface for massive production of solar energy, while significantly reducing the loss of water by evaporation from the lake surface. The project has the potential to be one of the largest producers of low-cost clean electric energy in the world for Europe and the Middle East and North Africa (MENA) region, especially with the ongoing efforts to connect the North African countries with the European super power grid. The study shows that the first phase of the project is expected to deliver about 16% of European need of electricity and save about 3 billion m3 of freshwater. The subsequent phases will provide low-cost green energy to replace the combustible fuels in Europe by 2045, while saving up to 10-12 billion m3 of freshwater lost by evaporation from Lake Nasser.
Gated Recurrent Unit with RSSIs from Heterogeneous Network for Mobile Positioning
Authors: Wang Junxiang , Guo Canyang , Wu Ling
Published: April 2021

Recently, research studies on Location-Based Services (LBSs) based on networks including cellular network and Wi-Fi network have gradually become popular. Received Signal Strength Indicators (RSSIs) from the network can be detected and collected by mobile devices to estimate the locations without adopting the Global Positioning System (GPS). Previous research studies utilized the RSSIs of only cellular network or only Wi-Fi network to estimate location, which leads to a two-fold predicament involving error limits of cellular network-based methods and environmental constraints of Wi-Fi network-based methods. In addition, accommodating a highly temporal dependence of RSSI series data, this paper proposed a mobile positioning system based on Gated Recurrent Unit (GRU) with RSSIs from the heterogeneous network. GRU learns the temporal correlation of RSSIs and the relationship between RSSIs and GPS coordinates to estimate the locations of mobile devices. A large number of real experiments have been carried out to verify the performance of the proposed method, and experimental results demonstrate that the proposed method has lower errors (i.e., 5.86 m and 75% of errors within 4 m) compared with Neural Network (NN), Recurrent Neural Network (RNN), and Long Short-Term Memory (LSTM).
Performance Enhancement for Multihop Cognitive DF and AF Relaying Protocols under Joint Impact of Interference and Hardware Noises: NOMA for Primary Network and Best‐Path Selection for Secondary Network
Authors: Duy Tran Trung , Ngoc Pham Thi Dan , Tran Phuong T.
Published: April 2021

In this paper, we propose and evaluate performance of multihop multipath underlay cognitive radio networks. In a primary network, an uplink nonorthogonal multiple access method is employed to allow primary transmitters to simultaneously transmit their data to a primary receiver. Using an underlay spectrum‐sharing method, secondary source and secondary relays must adjust their transmit power to guarantee quality of service of the primary network. Under the limited transmit power, cochannel interference from the primary transmitters, and hardware noises caused by impairments, we propose best‐path selection methods to improve the end‐to‐end performance for the secondary network. Moreover, both multihop decode‐and‐forward and amplify‐and‐forward relaying protocols are considered in this paper. We derive expressions of outage probability for the primary and secondary networks and propose an efficient method to calculate the transmit power of the secondary transmitters. Then, computer simulations employing the Monte‐Carlo approach are realized to validate the derivations.
Prenatal Diagnosis of Skeletal Dysplasia and Review of the Literature
Authors: Jimah Bashiru Babatunde , Mensah Teresa Aba , Ulzen-Appiah Kofi , Sarkodie Benjamin Dabo , Anim Dorothea Akosua , Amoako Emmanuella , Gyamfi Evelyn Antwiwaa
Published: April 2021

Introduction. Obstetric ultrasonography is routinely used to screen for fetal anomalies. Thanatophoric dysplasia (TD) is one of the common though rare lethal skeletal dysplasia, detected during routine ultrasound scan. TD is caused by a mutation in FGFR3 gene. Characteristic features include shortening of limbs, macrocephaly and platyspondyly. In our local setting, it is common to miss the diagnosis in the early scans due to lack of expertise of the sonographers. To the best of our knowledge, this is the first publication from Ghana. Case Presentation. We present the case of a 33-year-old woman who was referred to the facility on account of ultrasound scan report suggestive of thanatophoric dysplasia type 1 at 34 weeks of a female baby. The diagnosis was not made despite the mother being a regular antenatal attendant, until a fifth scan done at 34 weeks reported features suggestive of thanatophoric dysplasia. The ultrasound scan features included a biparietal diameter of 37weeks, femur length—24weeks, narrowed thoracic cage with hypoplastic lungs and short ribs. The liquor volume was increased with amniotic fluid index (AFI) of 38.4 cm. The femur, tibia, fibula, humerus, ulna, and radius were shortened (micromelia). The diagnosis of thanatophoric dysplasia type 1 was confirmed on autopsy. Conclusion. This report was aimed to highlight the potential contribution of ultrasound scan in the diagnosis of thanatophoric dysplasia in our setting.
Obinutuzumab in Combination with Chemotherapy Enhances Direct Cell Death in CD20-Positive Obinutuzumab-resistant Non-Hodgkin Lymphoma Cells
Authors: Fujimura Takaaki , Yamashita-Kashima Yoriko , Kawasaki Natsumi , Yoshiura Shigeki , Harada Naoki , Yoshimura Yasushi
Published: April 2021

Follicular lymphoma commonly recurs and is difficult to cure. Obinutuzumab is a humanized glycoengineered type II anti-CD20 antibody with a mode of action that includes induction of antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and direct cell death. There is no evidence on the effectiveness of retreatment with obinutuzumab in patients with prior obinutuzumab treatment. Using obinutuzumab-induced direct-cell-death–resistant cells, we investigated the efficacy of obinutuzumab retreatment in combination with chemotherapeutic agents used in follicular lymphoma treatment. Human non-Hodgkin lymphoma SU-DHL-4 cells were sustainably exposed to obinutuzumab in vitro, and 17 resistant clones expressing CD20 and showing 100-fold higher IC50 of obinutuzumab than parental cells were established. The growth inhibition effect of obinutuzumab in combination with bendamustine, 4-hydroperoxy-cyclophosphamide, doxorubicin, vincristine, or prednisolone was estimated using an interaction index based on the Bliss independence model. For each clone, there were various combinations of obinutuzumab and chemotherapeutic agents that showed supra-additive effects. Obinutuzumab combined with doxorubicin enhanced caspase-dependent apoptosis and growth inhibition effect. Obinutuzumab combined with prednisolone enhanced DNA fragmentation and G0–G1 arrest. These combinations also had an antitumor effect in mouse xenograft models. Our results indicate that retreatment with obinutuzumab, when it is combined with chemotherapeutic agents, is effective in the CD20-positive obinutuzumab-induced direct-cell-death–resistant cells.
Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?
Authors: Lentz Robert W. , Colton Meryl D. , Mitra Siddhartha S. , Messersmith Wells A.
Published: April 2021

While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions (“don't eat me” signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction (“eat me” signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer–cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.
Abstract IA-001: Genomic architecture and targets in hypoxic tumors
Authors: Bristow Robert G.
Published: April 2021

Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localized setting and also identifying novel treatment strategies to prevent progression. Subregions of intratumoral hypoxia are found in all solid tumors and are associated with many biologic drivers of tumor progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity to alter clonal adaption and evolution and driving an aggressive mutator phenotype. More specifically, hypoxic suppression of homologous recombination represents a "contextual lethal" vulnerability in hypoxic prostate tumors which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to prostate and other cancers, and also characterize the role of hypoxia in driving early metastatic spread. Supported by core funding from Cancer Research UK Manchester Institute and grants within the Cancer Research UK Manchester RadNet Unit, NIHR Manchester Biomedical Research Centre and a Prostate Cancer UK-Movember Centre of Excellence award.

Citation Format: Robert G. Bristow. Genomic architecture and targets in hypoxic tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-001.
Abstract IA-003: Oxygen dependent resistance to PARP inhibitors
Authors: Mehibel Manal , Xu Jimmy , Li Grace , Moon Jung , Thakkar Kaushik , Diep Anh , Kim Ryan , Bloomstein Joshua , Xiao Siren , Bacal Julien , Saldivar Joshua , Le Quynh , Cimprich Karlene , Rankin Erinn , Giaccia Amato
Published: April 2021

Severe hypoxia causes resistance to conventional chemotherapy and has been reported to synergize with PARP inhibitors (PARPi) through suppression of homologous recombination (HR). While this synergistic killing is true at oxygen levels less than 0.5%, our study shows that less severe hypoxia (e.g. 2% oxygen) is instead associated with resistance to PARPi in HR proficient cells. Interestingly, we demonstrate that HR deficient hypoxic tumors are significantly less responsive to PARPi, due to limited ROS-induced intrinsic DNA damage. To determine the contribution of hypoxic cells to PARPi, we used the hypoxic cytotoxin Tirapazamine to target hypoxic tumor cells. We found that the elimination of hypoxic tumor cells by Tirapazamine led to a substantial antitumor response with PARPi compared to PARPi treated tumors alone, without enhancing normal tissue toxicity. These studies indicate that tumor hypoxia reduces the efficacy of PARPi to tumor cells and that eliminating hypoxic tumor cells will enhance the efficacy of PARPi therapy.

Citation Format: Manal Mehibel, Jimmy Xu, Grace Li, Jung Moon, Kaushik Thakkar, Anh Diep, Ryan Kim, Joshua Bloomstein, Siren Xiao, Julien Bacal, Joshua Saldivar, Quynh Le, Karlene Cimprich, Erinn Rankin, Amato Giaccia. Oxygen dependent resistance to PARP inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-003.
Abstract IA-010: Deciphering DNA end resection at DSBs
Authors: Chowdhury Dipanjan
Published: April 2021

Double stranded DNA break (DSB)s are repaired by two major mechanistically distinct pathways, homologous recombination (HR) and non-homologous end joining (NHEJ). A decisive factor in the choice between DSB repair pathways is in the competition between DNA end protection (necessary for NHEJ) and DNA end resection (necessary for HR). As the ‘master regulator’ of DSB repair pathway choice, 53BP1, a chromatin-associated reader of epigenetic marks at DSBs, helps channel DSBs into the NHEJ pathway by restricting BRCA1-dependent end resection. 53BP1 nucleates the assembly of a higher order ensemble that includes the Shieldin complex, CST complex, and DNA polymerase (Pol) a-primase complex. Loss of BRCA1 provides a therapeutic opportunity as these tumors are exquisitely sensitive to inhibitors of poly (ADP-ribose) polymerase (PARP), and are also susceptible to platinum-based drugs. Loss of 53BP1 or any of the 53BP1-interacting proteins restores end resection and causes PARPi resistance in BRCA1-mutant tumors. We recently identified Dynein light chain like protein 1 (DYNLL1) as as anti-resection factor. Loss of DYNLL1 allowed DNA end resection and restored HR, thereby inducing resistance to platinum drugs and PARPi in BRCA1-mutant tumors. At the molecular level, DYNLL1 limited the nucleolytic resection of DNA ends by interacting with the resection machinery. Importantly, purified DYNLL1 interacted with MRE11 and inhibited its exonuclease activity in vitro. Now we observe that 53BP1 loss prevents DYNLL1 recruitment to DSBs and more broadly to chromatin. We hypothesize that 53BP1 inhibits MRE11-mediated DNA end resection by recruiting DYNLL1 and that DYNLL1 functions in parallel of Shieldin-CST to regulate DNA end resection and DSB repair pathway choice. We are investigating the crosstalk between the Shieldin-CST and DYNLL1-MRE11 arms of the 53BP1-dependent anti-DNA end resection machinery.

Citation Format: Dipanjan Chowdhury. Deciphering DNA end resection at DSBs [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-010.
Abstract IA-012: Differential immunological effects of carbon-ion versus photon radiation therapy
Authors: Drake Charles G.
Published: April 2021

Radiation therapy (RT) exerts multiple effects on the immune system; in particular RT can serve as an in situ vaccine to either prime new anti-tumor T cell responses, or to induce new responses. We and many others showed that these propitious effects appear to counter-balanced to some degree by immunosuppressive effects, including the expansion of regulatory T cells (Treg), recruitment of myeloid derived suppressive cells (MDSC), and induction of Trex which mitigates the pro-inflammatory effects of STING pathway activation. Carbon-ion radiation therapy (CiRT) is an emerging therapeutic modality based on data showing that heavy ions may improve dosimetry and decrease toxicity to normal tissues. Currently, CiRT is performed at a limited number of centers, thus its immunological effects remain relatively understudied. To address this knowledge gap, we used an orthotopic, syngenic murine model to compare the relative immunological effects of CiRT to conventional photon radiation therapy (PhRT). At short follow-up times post RT, PhRT decreased the prevalence of T cells in the TME at all doses examined, whilst CiRT appeared to be relatively lymphocyte sparing. Higher doses of CiRT increased the secretion of multiple pro-inflammatory cytokines to a greater degree than did PhRT. Consistent with our prior results, both modalities increased Treg infiltration; although this was less apparent with CiRT. Although these are early studies with several caveats, the results support the hypothesis that CiRT may have differential immunological effects than those mediated by PhRT.

Citation Format: Charles G. Drake. Differential immunological effects of carbon-ion versus photon radiation therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-012.
Abstract IA-018: Molecular landmarks of tumor hypoxia across cancer types
Authors: Bhandari Vinayak , Hoey Christianne , Liu Lydia , Lalonde Emilie , Ray Jessica , Livingstone Julie , Lesurf Robert , Shiah Yu-Jia , Vujcic Tina , Huang Xiaoyong , Espiritu Shadrielle M.G. , Heisler Lawrence E. , Yousif Fouad , Huang Vincent , Yamaguchi Takafumi N. , Yao Cindy Q. , Sabelnykova Veronica Y. , Fraser Michael , Chua Melvin L.K. , van der Kwast Theodorus , Liu Stanley K. , Boutros Paul C. , Bristow Robert G.
Published: April 2021

Many primary tumor sub-regions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver mutation signatures. We observed widespread hypoxia-associated dysregulation of miRNAs across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus – an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.

Citation Format: Vinayak Bhandari, Christianne Hoey, Lydia Liu, Emilie Lalonde, Jessica Ray, Julie Livingstone, Robert Lesurf, Yu-Jia Shiah, Tina Vujcic, Xiaoyong Huang, Shadrielle M.G. Espiritu, Lawrence E. Heisler, Fouad Yousif, Vincent Huang, Takafumi N. Yamaguchi, Cindy Q. Yao, Veronica Y. Sabelnykova, Michael Fraser, Melvin L.K. Chua, Theodorus van der Kwast, Stanley K. Liu, Paul C. Boutros, Robert G. Bristow. Molecular landmarks of tumor hypoxia across cancer types [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-018.
Abstract IA-021: Predicting radiotherapy outcomes: Radiogenomics and risk of radiotherapy toxicity
Authors: West Catharine M.L.
Published: April 2021

A key challenge in radiotherapy is to maximize radiation doses to cancer while minimizing damage to surrounding healthy tissues. As toxicity in a minority of patients limits the doses that can be safely given to the majority, there is interest in developing a test to measure an individual’s radiosensitivity before treatment and predict their likelihood of developing toxicity. A biomarker that predicts a cancer patient’s risk of toxicity could be used to personalize dose prescriptions or to offer alternative treatments. Many approaches have been studied to measure radiosensitivity. The development of omics technologies underpinned genome wide association studies (GWAS) attempting to identify genetic variants reported as single nucleotide polymorphisms (SNPs). The advantages of the approach include: a genetic test will be easier to implement clinically than a functional assay; a genetic test will not suffer from the poor reproducibility associated with some radiosensitivity testing methods; and SNPs are the most common type of genetic variation and so easiest to identify. Omics technologies offer promise, but to have an impact on radiotherapy practice research must identify biomarkers that replicate across cohorts. Robust replication needs big data, which is only possible with large collaborative efforts. The need for big data was addressed by establishing an international Radiogenomics Consortium. The latest results from the consortium will be presented including the largest radiogenomics study carried out to date involved ~4,000 men with prostate cancer.

Citation Format: Catharine M.L. West. Predicting radiotherapy outcomes: Radiogenomics and risk of radiotherapy toxicity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-021.
Abstract IA-024: Sirt2: A tumor suppressor or promotor?
Authors: Xia Fen
Published: April 2021

SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine xenograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell activation and proliferation within tumor microenvironment (TME). Furthermore, despite the effect of increased tumor growth rate and tumor volume in wild-type littermate mice, NK cell depletion does not affect that in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses melanoma tumor growth in mice. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which promotes melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.

Citation Format: Fen Xia. Sirt2: A tumor suppressor or promotor? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-024.
Abstract IA-025: Exploiting Redox Biology for Selectively Targeting Cancer Cells
Authors: Spitz Douglas R
Published: April 2021

Relative to normal cells, cancer cells have been shown to demonstrate fundamental alterations in oxidative metabolism leading to increased steady-state levels of superoxide, hydrogen peroxide, and labile iron pools. Alterations in cancer cell oxidative metabolism in turn lead to disruptions in many redox sensitive signaling and gene expression pathways that impact cell growth, differentiation, genomic instability, and cancer progression. Cancer cells adapt to this altered metabolic state by activating many signaling and gene expression pathways that allow them to survive and continue to progress to malignancy. The current talk will discuss how pharmacological ascorbate and superoxide dismutase mimics can be used to target the oxidative metabolic frailties of cancer versus normal cells to enhance therapeutic outcomes to radio-chemo-therapies both in pre-clinical and clinical trials. The long-term goal is to utilize a detailed mechanistic understanding of alterations in cancer versus normal cell oxidative metabolism and redox biology to develop rapidly implementable new strategies that can enhance tumor responses while protecting normal tissues during standard radio-chemo-therapy protocols. (Supported by P01 CA217797, R01 CA182804, T32 CA078586).

Citation Format: Douglas R Spitz. Exploiting Redox Biology for Selectively Targeting Cancer Cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-025.