bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychosocial influences on help-seeking behaviour for cancer in low-income and lower middle-income countries: a mixed-methods systematic review
Authors: McCutchan Grace , Weiss Bahr , Quinn-Scoggins Harriet , Dao Anh , Downs Tom , Deng Yunfeng , Ho Ha , Trung Lam , Emery Jon , Brain Kate
Published: February 2021

Introduction

Starting cancer treatment early can improve outcomes. Psychosocial factors influencing patients’ medical help-seeking decisions may be particularly important in low and lower middle-income countries (LMIC) where cancer outcomes are poor. Comprehensive review evidence is needed to understand the psychosocial influences on medical help-seeking for cancer symptoms, attendance for diagnosis and starting cancer treatment.

Methods

Mixed-methods systematic review registered on PROSPERO (CRD42018099057). Peer-reviewed databases were searched until April 2020 for studies assessing patient-related barriers and facilitators to medical help-seeking for cancer symptoms, diagnosis and treatment in adults (18+ years) living in LMICs. Quality of included studies was assessed using the Critical Appraisal Skills Programme tool. Data were synthesised using meta-analytic techniques, meta-ethnography or narrative synthesis as appropriate.

Results

Of 3963 studies identified, 64 were included. In quantitative studies, use of traditional, complementary and alternative medicine (TCAM) was associated with 3.60 higher odds of prolonged medical help-seeking (95% CI 2.06 to 5.14). Qualitative studies suggested that use of TCAM was a key barrier to medical help-seeking in LMICs, and was influenced by causal beliefs, cultural norms and a preference to avoid biomedical treatment. Women face particular barriers, such as needing family permission for help-seeking, and higher stigma for cancer treatment. Additional psychosocial barriers included: shame and stigma associated with cancer such as fear of social rejection (eg, divorce/disownment); limited knowledge of cancer and associated symptoms; and financial and access barriers associated with travel and appointments.

Conclusion

Due to variable quality of studies, future evaluations would benefit from using validated measures and robust study designs. The use of TCAM and gender influences appear to be important barriers to help-seeking in LMIC. Cancer awareness campaigns developed with LMIC communities need to address cultural influences on medical help-seeking behaviour.
Survey of young people in one region of the UK on accessing COVID-19 information (SOCIAL)
Authors: Lawton Oliver G P , Lawton Sarah A , Dikomitis Lisa , Protheroe Joanne , Smith Joanne , Mallen Christian D
Published: February 2021

COVID-19 has significantly impacted young people’s lives yet little is known about the COVID-19 related sources of information they access. We performed a cross-sectional survey of pupils (11–16 years) in North Staffordshire, UK. 408 (23%) pupils responded to an online survey emailed to them by their school. Descriptive statistics were used to summarise the data. Social media, accessed by 68%, played a significant role in the provision of information, despite it not being considered trustworthy. 89% felt that COVID-19 had negatively affected their education. Gaps in the provision of information on COVID-19 have been identified.
Development of a poly-axial platen for testing true-triaxial behavior of rocks
Authors: Garg Prasoon , Pandit Bhardwaj , Mishra Brijes , Sivakumar Babu G.L.
Published: February 2021

Mining at greater depths can lead to stress-induced failure, especially in areas of high horizontal in situ stress. The induced stresses around the opening are known to be in a poly-axial stress state where, σ1 ≠ σ2 ≠ σ3 with special case of σ3 = 0 and σ1, σ2 ≠ 0 at its boundary, where σ1, σ2, σ3 are major, intermediate, minor principal stress, respectively. The conventional triaxial testing does not represent the actual in situ strength of the rock in regions of high horizontal stress, as it ignores the influence of intermediate principal stress (σ2). The typical poly-axial testing (biaxial and true-triaxial tests) of intact rock mostly requires sophisticated and expensive loading systems. This study investigated the mechanical behavior of intact rock under a poly-axial stress state using a simple and cost-effective design. The apparatus consists of a biaxial frame and a confining device. The biaxial frame has two platens that apply equal stress in both directions (σ1 = σ2) on a 50.8 mm cubical specimen when placed inside the uniaxial loading device. The confining device performed separate biaxial tests under constant intermediate principal stress (σ2 = constant) and true-triaxial tests when used along with the biaxial frame. This study then compared the failure modes and peak strength of Berea sandstone specimens with other biaxial–triaxial devices to validate the design of the poly-axial apparatus. We also performed uniaxial tests on both standard cylindrical samples and prismatic specimens of different slenderness ratios. These tests provided a complete understanding of the failure mode transition from standard uniaxial compressive tests to triaxial stress conditions on cubical specimens. Additionally, this study determined best-fitted strength envelopes for biaxial and triaxial stress state. Based on regression analysis, we found a quadratic polynomial to be a good fit to biaxial strength envelope. For the true-triaxial strength envelope, we found the three-dimensional (3D) failure criterion to be a good fit with R2 of 0.964.
Experimental testing of slender load-bearing masonry walls with realistic support conditions
Authors: Pettit Clayton , Mohsin Erum , Cruz-Noguez Carlos , Elwi Alaa
Published: February 2021

Slender, load-bearing masonry walls with slenderness ratios (h/t) greater than 30 are required to be designed as pinned-pinned elements according to North American provisions for masonry, CSA S304-14 and TMS 402-16. This provision neglects the contribution of the reactive stiffness of the foundation to the strength of the wall and its effect on the redistribution of bending moments along its height. Eight full-scale masonry walls were built with different degrees of base stiffness and tested under an eccentric axial load. The results of the tests showed an increased load-bearing capacity and decreased deflections with increased rotational base stiffness. Experimental data were used to determine key design parameters, including the effective flexural rigidity and moment distribution along the height of the walls. Comparing the values of effective flexural rigidity determined from experimental results to code provisions, it was found that both codes tend to underestimate the effective flexural rigidity of the walls.
Euler–Heisenberg waves propagating in a magnetic background
Authors: Guzman-Herrera Elda , Breton Nora
Published: February 2021

We derive the Euler–Heisenberg solutions that describe electromagnetic waves propagating through very intense uniform magnetic or electric background, with the effective metric approach. We first explore the case of a magnetic background: as a result of the interaction between the wave and the background there is birefringence and a longitudinal electric field component arises. The two phase velocities depend on the intensity of the external magnetic field and on the polarization of the wave; phase velocities can be slowed down up to the order of hundred thousandths for fields $$B/B_\mathrm{cr}<< 1$$

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cr

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1

. The analogous study is done when the wave propagates through a uniform electric field. We then consider the situation when the background is in movement by means of a Lorentz boost, modeling then a magnetized flowing medium. We determined how this motion affects the speed of propagation of the electromagnetic wave, in this case the phase velocities depend on both the magnetic background and the direction and velocity of the boost.
Weak gravitational lensing Schwarzschild-MOG black hole in plasma
Authors: Atamurotov Farruh , Abdujabbarov Ahmadjon , Rayimbaev Javlon
Published: February 2021

This paper is devoted to study weak gravitational lensing properties around black hole surrounded plasma medium in modified gravity (MOG). We have investigated the effects of the MOG-parametr and plasma medium on the deflection angle and total magnification of the images. we have presented the comparisons of the effects of the uniform plasma, singular isothermal sphere and non-singular isothermal sphere. We have also shown that the uniform plasma effects significantly stronger than the other models of plasma medium.Through the studies of the total magnifications of images of a remote source we have shown that the effects of the MOG parameter and plasma medium are similar and the increase of the MOG parameter and plasma frequency cause to increase the total magnification. Moreover, we have explored and analyzed how the MOG effects can reflect the plasma medium providing the same values of the total magnification of images.
Effects of extended uncertainty principle on the relativistic Coulomb potential
Authors: Hamil B. , Merad M. , Birkandan T.
Published: February 2021

The relativistic bound-state energy spectrum and the wave functions for the Coulomb potential are studied for de Sitter and anti-de Sitter spaces in the context of the extended uncertainty principle. Klein–Gordon and Dirac equations are solved analytically to obtain the results. The electron energies of hydrogen-like atoms are studied numerically.
Magnetic and electric properties of multiferroic LiFeP2O7. Comparison with LiCrP2O7
Authors: Apostolov A. T. , Apostolova I. N. , Wesselinowa J. M.
Published: February 2021

The temperature and magnetic field dependence of the magnetic and electric properties of LiFeP2O7 (LFPO) and LiCrP2O7 (LCPO) are studied using a microscopic model and the Green’s function technique. We have shown that LFPO is antiferromagnetic, but shows a weak ferromagnetism along the [Formula: see text] axis which originates from the canted antiferromagnetic order. For LCPO, such a ferromagnetic order along the [Formula: see text] axis is not observed. In the temperature dependence of the electrical polarization [Formula: see text] along the [Formula: see text] axis there is a kink at [Formula: see text] K which is an indirect evidence for the intrinsic magnetoelectric effect in LFPO. Applying an external magnetic field [Formula: see text], the polarization [Formula: see text] increases, stronger for small temperatures and the kink at [Formula: see text] disappears. For LCPO, we do not obtain a kink at [Formula: see text] K. LCPO is polar, but not ferroelectric. We can conclude that the missing magnetoelectric properties in LCPO could be due to the differences in the magnetic orders between LFPO and LCPO.
Internet of Things (IoT) for MC-CDMA-Based Cognitive Radio Network (CRN) in 5G: Performance Results
Authors: Khan M. R. H. , Hoque M. A. , Rahman M. Saifur
Published: February 2021

Both the internet-connected devices, i.e. IoT and Cognitive Radio Network (CRN) are considered to be the future technologies for the fifth generation of cellular wireless standards (5G). On the one hand, Internet of Things (IoT) focuses primarily on how to allow general objects to see, hear, and smell their own physical environment and make them connected to share the observations. On the other hand, a CRN is based on a complex spectrum allocation system, and licenced primary users (PUs) or unlicenced secondary users (SUs) are allowed to share the spectrum, provided they do not cause significant interference. The IoTs are meaningless if IoT objects are not equipped with cognitive radio capability. In cognitive radio, it is important to control the transmission power of SUs so that the interference should not be harmful to the quality of service of PUs. In this paper, the authors addressed the effects of imperfect power control between primary users (PUs) and the secondary users (SUs) of an IoT-based CRN. The effect of the co-channel interference (CCI) and adjacent channel interferences (ACIs) occurring in CRN using MC-CDMA system is also analysed. A new expression of the signal-to-interference-noise ratio (SINR) for CRN-based MC-CDMA system over a Nakagami-[Formula: see text] fading channel with imperfect power control condition is derived and investigated. The performance of IoT-based CRN using MC-CDMA system over the frequency selective multipath fading channel is examined with varying the number of users, the SINR per bit, number of fading path and number of sub-carriers. From the simulation results, we have seen that the SINR performance is affected by these parameters. The result of the analysis will provide relevant information to design the physical layer protocol for high-speed IoT-based CRN system for 5G.
Local well-posedness of the two-dimensional Dirac–Klein–Gordon equations in Fourier–Lebesgue spaces
Authors: Pecher Hartmut
Published: February 2021

The local well-posedness problem is considered for the Dirac–Klein–Gordon system in two space dimensions for data in Fourier–Lebesgue spaces [Formula: see text], where [Formula: see text] and [Formula: see text] and [Formula: see text] denote dual exponents. We lower the regularity assumptions on the data with respect to scaling improving the results of d’Ancona et al. in the classical case [Formula: see text]. Crucial is the fact that the nonlinearities fulfill a null condition as detected by these authors.
A Nitroxide Containing Organic Molecule in a Deep Eutectic Solvent for Flow Battery Applications
Authors: Sinclair Nicholas S. , Poe Derrick , Savinell Robert F. , Maginn Edward J. , Wainright Jesse S.
Published: February 2021

The nitroxide radical redox organic molecule, 2-phenyl-4,4,5,5-tetrame- thylimidazoline-1-oxyl-3-oxide (PTIO), was investigated for the first time in a deep eutectic solvent (DES)-like system consisting of a 1:4 molar ratio of choline chloride and ethylene glycol (Ch1EG4) as a redox flow battery electrolyte. PTIO is a single molecule with three oxidation states, and can provide both positive and negative redox couples for a flow battery. A flow battery using the PTIO/Ch1EG4 electrolyte demonstrated nearly 50% round trip efficiency with an approximately 1 V open circuit potential. Inefficiencies were primarily due to membrane resistance which can be significantly lowered with increased temperature. While PTIO appears stable over short periods (hours), the oxidized form is not stable in the DES-like electrolyte over longer times. Molecular modeling was performed to investigate the relative stability of PTIO in DES as compared to the previously studied 4-hydroxy-TEMPO (4HT). It was found that the oxoammonium cation 4HT+ exhibits a noticeably larger nucleophilic reactive cloud as compared to PTIO+, indicating a higher reactivity. This method to predict stability of the oxoammonium cation shows promise to inform the design and synthesis of promising redox systems based on nitroxide radicals in DES electrolytes to identify new chemistries for large scale energy storage.
Synthesis of ZnS Nanorods Coated by MoS2/N-Doped Carbon Nanosheets with Enhanced Sodium Storage Properties
Authors: Liu Yuan , Cai Shu , Shen Kaier , Li Qianqian , Xie Yao , Zuo You , Sun Xiaohong
Published: February 2021

In order to obtain an excellent ZnS-based anode material for sodium-ion batteries (SIBs), a designed hierarchical nanostructure formed by ZnS hollow nanorods and uniform nanosheets was synthesized via hydrothermal method in the presence of carboxymethyl chitosan. The nanosheets were composed of amorphous nitrogen doped carbon and molybdenum disulfide (MoS2-NC). Notably, the one-dimensional tubular framework possessed low impedance characteristics. Through the way of combining it with nanosheets which had abundant defects, it could boost the charge transfer and improve the sodium storage performance effectively. When tested as the anode material of SIBs, this ZnS@MoS2-NC composite exhibited excellent cycling and rate performance. Moreover, it was further assembled into sodium-ion full batteries and showed good cyclic stability. This work provides a valuable option for preparing promising SIBs anode materials by combining structural design with multi-component coordination, which can be extended to other metal sulfide electrode materials.
Revealing the Nanostructure of Mesoporous Fuel Cell Catalyst Supports for Durable, High-Power Performance
Authors: Ko Matthew , Padgett Elliot , Yarlagadda Venkata , Kongkanand Anusorn , Muller David A.
Published: February 2021

Achieving high power performance and durability with low Pt loadings are critical challenges for proton exchange membrane fuel cells. PtCo catalysts developed on new carbon black supports show promise by simultaneously providing good oxygen reduction kinetics and local oxygen transport. We investigate the role of nanoscale morphology in the performance of these catalysts supported on accessible (HSC-e and HSC-f) and conventional (Ketjen Black) porous carbons using 3D electron tomography, nitrogen sorption, and electrochemical performance measurements. We find that the accessible porous carbons have hollow interiors with mesopores that are larger and more numerous than conventional porous carbons. However, mesopore-sized openings (>2 nm width) are too rare to account for significant oxygen transport. Instead we propose the primary oxygen transport pathway into the interior is through 1–2 nm microporous channels permeating the carbon. The increased mesoporosity in the accessible porous carbons results in a shorter diffusion pathlength through constrictive, tortuous micropores in the support shell leading to lower local oxygen transport resistance. In durability testing, the accessible porous carbons show faster rates of electrochemical surface area loss, likely from fewer constrictive pores that would mitigate coarsening, but maintain superior high current density performance at end of test from the improved local oxygen transport.
Analysis of Three-Dimensional Vibration Characteristics of Single-Circle Double-Track Subway Tunnel under Moving Load
Authors: Dai Chunquan , Yang Mengying , Wang Quanlei , Yang Tingzhi , Jiang Kun
Published: February 2021

With the development of urban rail transit, subway lines are becoming more and more denser, the departure time interval is short, and the probability of subway trains meeting is high. The impact of vibration caused by double-line subway meeting on the surrounding environment cannot be ignored. Taking the typical cross-section of a single-circle double-track subway tunnel as an example, a single running scenario and three typical meeting scenarios, namely, 4 s meeting, 6 s meeting, and 8 s meeting scenarios were considered, and a track-tunnel-foundation three-dimensional ABAQUS finite element model was established. The dynamic response of monitoring points at different distances between the center of the track bed and the center line of the track was analyzed. Results showed that due to the consistent load action period, the center acceleration of the track bed increases significantly during the meeting, the main frequency of vibration and the peak value of the 1/3 octave spectrum were increased by about 5 Hz, and the vibration level at the dominant frequency was increased by about 7 dB. The center displacement of the track bed and the peak compressive strain increased significantly under the 4 s meeting and 6 s meeting working scenarios; while the 8 s meeting and 4 s single running scenarios were basically the same, only the action time was doubled. The dynamic response of the 4 working scenarios decreases with the increase of distance, and the attenuation rate gradually decreases and has gradually stabilized within 15–19 m above the vault.
A Framework for Interpreting Lateral Swelling Pressure in Unsaturated Expansive Soils
Authors: Li Mingyu , Wei Yanqing , Liu Yunlong , Jin Junwei
Published: February 2021

Lateral swelling pressure (LSP) develops when expansive soil volume increment associated with water infiltration is restrained in a confined domain, for example, due to construction of civil infrastructure. In this paper, initially a flowchart is developed to highlight various key factors that influence the LSP mobilization according to lab and field studies collected from previous literature studies. Then extending unsaturated soil mechanics, a theoretical framework is proposed for illustrating the LSP mobilization in the field against retaining structures and pile foundations under different boundary conditions, respectively. An example problem for a basement wall and a pile foundation constructed in a typical expansive soil from Regina, Canada, is presented to illustrate the proposed theoretical framework. The framework and corresponding analysis presented in this paper can facilitate to provide rational designs of geotechnical infrastructures in expansive soils.
Modeling the Relationship between Rice Yield and Climate Variables Using Statistical and Machine Learning Techniques
Authors: Wickramasinghe Lasini , Weliwatta Rukmal , Ekanayake Piyal , Jayasinghe Jeevani
Published: February 2021

This paper presents the application of a multiple number of statistical methods and machine learning techniques to model the relationship between rice yield and climate variables of a major region in Sri Lanka, which contributes significantly to the country’s paddy harvest. Rainfall, temperature (minimum and maximum), evaporation, average wind speed (morning and evening), and sunshine hours are the climatic factors considered for modeling. Rice harvest and yield data over the last three decades and monthly climatic data were used to develop the prediction model by applying artificial neural networks (ANNs), support vector machine regression (SVMR), multiple linear regression (MLR), Gaussian process regression (GPR), power regression (PR), and robust regression (RR). The performance of each model was assessed in terms of the mean squared error (MSE), correlation coefficient (R), mean absolute percentage error (MAPE), root mean squared error ratio (RSR), BIAS value, and the Nash number, and it was found that the GPR-based model is the most accurate among them. Climate data collected until early 2019 (Maha season of year 2018) were used to develop the model, and an independent validation was performed by applying data of the Yala season of year 2019. The developed model can be used to forecast the future rice yield with very high accuracy.
Protecting the Moving User’s Locations by Combining Differential Privacy and k‐Anonymity under Temporal Correlations in Wireless Networks
Authors: Zhang Weiqi , Yin Guisheng , Sha Yuhai , Yang Jishen
Published: February 2021

The rapid development of the Global Positioning System (GPS) devices and location‐based services (LBSs) facilitates the collection of huge amounts of personal information for the untrusted/unknown LBS providers. This phenomenon raises serious privacy concerns. However, most of the existing solutions aim at locating interference in the static scenes or in a single timestamp without considering the correlation between location transfer and time of moving users. In this way, the solutions are vulnerable to various inference attacks. Traditional privacy protection methods rely on trusted third‐party service providers, but in reality, we are not sure whether the third party is trustable. In this paper, we propose a systematic solution to preserve location information. The protection provides a rigorous privacy guarantee without the assumption of the credibility of the third parties. The user’s historical trajectory information is used as the basis of the hidden Markov model prediction, and the user’s possible prospective location is used as the model output result to protect the user’s trajectory privacy. To formalize the privacy‐protecting guarantee, we propose a new definition, L&A‐location region, based on k‐anonymity and differential privacy. Based on the proposed privacy definition, we design a novel mechanism to provide a privacy protection guarantee for the users’ identity trajectory. We simulate the proposed mechanism based on a dataset collected in real practice. The result of the simulation shows that the proposed algorithm can provide privacy protection to a high standard.
An Efficient ECC-Based Authentication Scheme against Clock Asynchronous for Spatial Information Network
Authors: Huang Huihui , Miao Xuyang , Wu Zehui , Wei Qiang
Published: February 2021

With the rapid development of mobile communication technology, the spatial information networks (SIN) have been used for various space tasks’ coverage in commercial, meteorology, emergency, and military scenarios. In SIN, one basic issue is to achieve mutual authentication and secret communication among the participants. Although many researches have designed authentication schemes for SIN, they have not considered the situation where the clock is not synchronized as the broad coverage space in wireless environment. In this paper, we disclose several flaws of Altaf et al.’s scheme (2020), in which the main weakness is that a malicious user can easily obtain the master key of the network control center after launching the offline password-guessing attack. Then, we design an authentication scheme against clock asynchronous for SIN by utilizing elliptic curve cryptosystem (ECC) and identity-based cryptography (IBC). Based on a brief introduction to the main design ideas of our scheme, the security protocol analysis tools of Scyther and AVISPA are used to prove that the scheme can resist various existing active and passive attacks. We further discuss our scheme that provides five essential requirements of security properties to design a robust scheme for SIN and is superior in terms of resistance to security functionality and computational performance by comparison with two other representative schemes. As a result, our scheme will be workable and efficient security for mobile users in the actual environment.
Comprehensive Evaluation of Operating Speeds for High-Speed Railway: A Case Study of China High-Speed Railway
Authors: Zhang Jiamin , Zhang Jiarui
Published: February 2021

This paper proposes the indicator systems and integrated desirability framework for comprehensive evaluation towards the operating speeds of high-speed railway (HSR). Speed is a crucial piece in the characterization of the HSR system. The debate about what is the most appropriate operating speed continues. The established indicator systems and integrated desirability framework can comprehensively evaluate the HSR operating speeds from stand points of the economic efficiency, operational efficiency, track capacity, operational security, and environment impact. Moreover, the integrated desirability framework, which is a combination of entropy-analytical hierarchy procedure (EAHP) and technique for order preference by similarity to ideal solution (TOPSIS), can output some references for selecting the most suitable speed regimes of HSR. The application of the desirability framework to the case of China high-speed railway (CHSR) is demonstrated concretely. Based on the case study of CHSR, the comprehensive analysis of the effectiveness of the indicator systems on HSR operating speeds is carried out. The case study shows that the proposed indicator systems and integrated desirability framework can be used to evaluate comprehensively the HSR operating speeds under various conditions.
Gross and Histopathology of Goats Feeding on Opuntia stricta in Laikipia County, Kenya
Authors: Ncebere Jackson M. , Mbuthia Paul G. , Waruiru Robert M. , Gathumbi Peter K.
Published: February 2021

Various plant species such as Opuntia stricta have developed defensive measures, namely, spines, thorns, and other sharp pointed structures to protect themselves from herbivores and other animals feeding on them. Opuntia stricta has invaded the northern part of Laikipia County, Kenya, and its fruits are protected by small spines called glochids. This study determined the pathology in goats feeding on this plant in Laikipia County. Eighteen goats that had eaten the plant and six others that were raised in a ranch without O. stricta were purchased for the study. All study animals were clinically examined for lesions and euthanized for necropsy examination. Clinically, goats affected by O. stricta had poor body condition, wounds on various body parts, and diarrhea. Variable numbers of O. stricta spines occurred externally on the skin throughout the body and elicited pain, swelling, and ulcerative wounds on affected parts. Internal lesions were observed in subcutaneous tissues (100%), together with stomatitis, cheilitis, gingivitis, glossitis, abomasitis (100%), rumen, reticulum, omasum thinning and loss of papillae (72.2%), esophagitis, and duodenitis (5.6%). Carcasses had gelatinous fat and muscular atrophy. Other gross lesions were generalized viscera atrophy, edema, subcutaneous emphysema, lymphadenopathy, abscesses, ascites, hydrothorax, and hydropericardium. The abomasum wall and its mucosal folds were swollen with edema, haemorrhages, and scattered foci of abscesses. Histopathology confirmed the main lesions in all affected goats were foreign-body granulomas which were located in all organs with gross lesions. Goats from O. stricta-free ranches had no spines or lesions. The pathological effects caused by O. stricta resulted in emaciated goats due to pain, inability to masticate and assimilate food, and stress, resulting in poor carcass and organs quality and possible condemnation and death. This could affect the socioeconomics and livelihoods of communities in the study area, and therefore, the spread of this plant needs to be controlled.
Targeting the platelet-derived growth factor receptor α with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: Implications as a potential therapeutic target
Authors: Loizos Nick , Xu Yan , Huber Jim , Liu Meilin , Lu Dan , Finnerty Bridget , Rolser Robin , Malikzay Asra , Persaud Anita , Corcoran Erik , Deevi Dhanvanthri S. , Balderes Paul , Bassi Rajiv , Jimenez Xenia , Joynes Christopher J. , Mangalampalli Venkata R.M. , Steiner Philipp , Tonra James R. , Wu Yan , Pereira Daniel S. , Zhu Zhenping , Ludwig Dale L. , Hicklin Daniel J. , Bohlen Peter , Witte Larry , Kussie Paul
Published: February 2021

Platelet-derived growth factor receptor α (PDGFRα) is a type III receptor tyrosine kinase that is expressed on a variety of tumor types. A neutralizing monoclonal antibody to human PDGFRα, which did not cross-react with the β form of the receptor, was generated. The fully human antibody, termed 3G3, has a Kd of 40 pmol/L and blocks both PDGF-AA and PDGF-BB ligands from binding to PDGFRα. In addition to blocking ligand-induced cell mitogenesis and receptor autophosphorylation, 3G3 inhibited phosphorylation of the downstream signaling molecules Akt and mitogen-activated protein kinase. This inhibition was seen in both transfected and tumor cell lines expressing PDGFRα. The in vivo antitumor activity of 3G3 was tested in human glioblastoma (U118) and leiomyosarcoma (SKLMS-1) xenograft tumor models in athymic nude mice. Antibody 3G3 significantly inhibited the growth of U118 (P = 0.0004) and SKLMS-1 (P < 0.0001) tumors relative to control. These data suggest that 3G3 may be useful for the treatment of tumors that express PDGFRα.
The conventional nonsteroidal anti-inflammatory drug sulindac sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15
Authors: Kim Jong-Sik , Baek Seung Joon , Sali Tina , Eling Thomas E.
Published: February 2021

Although the chemopreventive and antitumorigenic activities of nonsteroidal anti-inflammatory drug (NSAID) against colorectal cancer are well established, the molecular mechanisms responsible for these properties in ovarian cancer have not been elucidated. Therefore, there is an urgent need to develop mechanism-based approaches for the management of ovarian cancer. To this end, the effect of several NSAIDs on ovarian cancer cells was investigated as assessed by the induction of NAG-1/MIC-1/GDF-15, a proapoptotic gene belonging to the transforming growth factor-β superfamily. Sulindac sulfide was the most significant NSAID activated gene 1 (NAG-1) inducer and its expression was inversely associated with cell viability as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. This growth suppression by sulindac sulfide was recovered by transfection of NAG-1 small interfering RNA. These results indicate that NAG-1 is one of the genes responsible for growth suppression by sulindac sulfide. Furthermore, we observed down-regulation of p21 WAF1/CIP1 by introduction of NAG-1 small interfering RNA into sulindac sulfide–treated cells. In addition, to elucidate other potential molecular mechanisms involved in sulindac sulfide treatment of ovarian cancer cells, we did a membrane-based microarray experiment. We found that cyclin D1, MMP-1, PI3KR1, and uPA were down-regulated by sulindac sulfide. In conclusion, a novel molecular mechanism is proposed to explain the experimental results and provide a rationale for the chemopreventive activity of NSAIDs in ovarian cancer.
Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16
Authors: Fuller Gregory N. , Su Xiaohua , Price Roger E. , Cohen Zvi R. , Lang Frederick F. , Sawaya Raymond , Majumder Sadhan
Published: February 2021

Medulloblastoma, one of the most malignant pediatric brain tumors, is believed to arise from the undifferentiated external granule-layer cells in the cerebellum. It is a heterogeneous cancer, and the mechanism of tumorigenesis for the majority of types is unknown. Repressor element-1 silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional repressor that can block transcription of a battery of neuronal differentiation genes by binding to a specific consensus DNA sequence present in their regulatory region. Previously, we found that some medulloblastoma cell lines express REST/NRSF at high levels compared with either neuronal progenitor cells or fully differentiated neurons. However, it is not known if REST/NRSF is indeed overexpressed in human medulloblastoma tumor specimens and in what frequency. Here, we did an immunohistochemical analysis of such tumor specimens using an anti-REST antibody. We show that among 21 human medulloblastoma tumors, 17 expressed REST/NRSF (6 strongly and 11 weakly). In contrast, adjacent normal cerebellum tissue sections and four of the tumor specimens did not express REST/NRSF, indicating that abnormal expression of REST/NRSF is observed in the majority of human medulloblastoma tumors. To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma cells through agents, such as REST-VP16, can interfere with their tumorigenicity.
Chemosensitivity profile of cancer cell lines and identification of genes determining chemosensitivity by an integrated bioinformatical approach using cDNA arrays
Authors: Nakatsu Noriyuki , Yoshida Yoko , Yamazaki Kanami , Nakamura Tomoki , Dan Shingo , Fukui Yasuhisa , Yamori Takao
Published: February 2021

We have established a panel of 45 human cancer cell lines (JFCR-45) to explore genes that determine the chemosensitivity of these cell lines to anticancer drugs. JFCR-45 comprises cancer cell lines derived from tumors of three different organs: breast, liver, and stomach. The inclusion of cell lines derived from gastric and hepatic cancers is a major point of novelty of this study. We determined the concentration of 53 anticancer drugs that could induce 50% growth inhibition (GI50) in each cell line. Cluster analysis using the GI50s indicated that JFCR-45 could allow classification of the drugs based on their modes of action, which coincides with previous findings in NCI-60 and JFCR-39. We next investigated gene expression in JFCR-45 and developed an integrated database of chemosensitivity and gene expression in this panel of cell lines. We applied a correlation analysis between gene expression profiles and chemosensitivity profiles, which revealed many candidate genes related to the sensitivity of cancer cells to anticancer drugs. To identify genes that directly determine chemosensitivity, we further tested the ability of these candidate genes to alter sensitivity to anticancer drugs after individually overexpressing each gene in human fibrosarcoma HT1080. We observed that transfection of HT1080 cells with the HSPA1A and JUN genes actually enhanced the sensitivity to mitomycin C, suggesting the direct participation of these genes in mitomycin C sensitivity. These results suggest that an integrated bioinformatical approach using chemosensitivity and gene expression profiling is useful for the identification of genes determining chemosensitivity of cancer cells.
Imatinib and gastrointestinal stromal tumors: Where do we go from here?
Authors: De Giorgi Ugo , Verweij Jaap
Published: February 2021

Imatinib has tremendously changed the treatment of gastrointestinal stromal tumor (GIST). Research is currently focusing on its optimal use and the mechanisms of resistance that may emerge. A multidisciplinary approach including medical oncologists, surgeons, radiologists, and pathologists is crucial for the optimal management of these patients. Moreover, imatinib treatment in GIST represents an extraordinary model to expand our knowledge on the molecular mechanisms that are basic to the effects of molecularly targeted therapies. This review summarizes the existing knowledge of the imatinib treatment in GIST and describes directions for further development.
Abstract IA02: A case for priming, not checkpoint
Authors: Vonderheide Robert H.
Published: February 2021

Most tumors are unresponsive to immune checkpoint blockade, especially if deep immunosuppression in the tumor develops prior to and prevents T cell immunosurveillance. Failed or frustrated T cell priming often needs repair before successful sensitization to PD-1/PD-L1 blockade. CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot. In preclinical studies, agonistic CD40 antibodies demonstrate T cell-dependent anti-tumor activity, especially in combination with chemotherapy, checkpoint inhibitory antibodies, and other immune modulators. With the advent of multiple CD40 agonists with acceptable single-agent toxicity, clinical evaluation of CD40 combinations has accelerated.

Citation Format: Robert H. Vonderheide. A case for priming, not checkpoint [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA02.
Abstract IA05: Innate immune defenses against cancer: Potential for mobilizing NK cells for cancer immunotherapy
Authors: Raulet David H.
Published: February 2021

Immunotherapies that mobilize CD8 T cells have revolutionized cancer therapy in recent years. A likely limitation of CD8 T cells in immunotherapy is that many tumors display few neoantigens and/or lack MHC I expression. Natural killer cells have emerged as exciting targets for new generations of immunotherapeutics. We investigated innate cues necessary for mobilizing spontaneous anti-tumor responses against tumors in mice and identified the cGAS-STING pathway as a critical pathway that is activated by cancer cells and mobilizes both NK cell and T cell mediated tumor rejection. Cyclic dinucleotides (CDNs) are STING agonists that, when injected into tumors, superactivate cellular immunity. We investigated the efficacy of CDNs in mobilizing anti-tumor activity in 6 independent gene edited models of MHC I-deficient tumors. Due to the absence of MHC I, CD8 T cells played no role in these responses. When transplanted syngeneic tumors of all 6 models were established and then treated intratumorally with CDNs (a single treatment, or in some cases 3 early treatments), tumor rejection rapidly ensued, which was NK-dependent and independent of CD8 T cells. In 5 of 6 MHC I-deficient tumor models tested, CDN therapy resulted in the indefinite survival of between 30% and 100% of the animals, with no evidence of residual tumors, suggesting the animals were cured. In one model (MHC I-deficient B16 melanoma cells) early rejection of the tumors was followed by relapse in all of the animals. Tumor rejection induced by CDNs was IFN-I-dependent, and conditional knockout experiments indicated that IFN-I acted directly on NK cells but also indirectly on DCs. After CDN therapy, DCs in the draining lymph nodes upregulated IL-15/IL-15R complexes on the membrane, and tumor rejection was blocked by neutralizing IL-15/IL15R. These data suggested that CDNs induce trans-presentation of IL15 by DCs to NK cells to support the tumor rejection response. CDN-induced tumor rejection was markedly enhanced by combining CDNs with IL-2 superkine (“super2”, in collaboration with C. Garcia), resulting in long-term tumor free survival in nearly all of the mice in the MHC I-deficient B16 and MC-38 models, indicating striking synergy between CDNs and super2. Our results suggest great potential for combining agonists of innate immune responses with superkines for treating cancers that are invisible to CD8 T cells, including MHC I-deficient cancers and potentially cancers with low neoantigen expression.

Citation Format: David H. Raulet. Innate immune defenses against cancer: Potential for mobilizing NK cells for cancer immunotherapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA05.
Abstract IA07: The QuEST for an effective immunotherapy for prostate cancer
Authors: Gulley James L.
Published: February 2021

Background: Immune checkpoint inhibitors have minimal activity in unselected CRPC patients (pts). Combination regimens that generate a tumor-directed immune response (vaccine) and facilitate the resulting anti-tumor immune activity (checkpoint blockade, cytokines) have shown synergy in preclinical models. BNVax is a therapeutic poxviral vaccine targeting brachyury, a transcription factor involved in invasion and metastasis. BA is a bifunctional fusion protein: anti-PD-L1 monoclonal antibody fused to the TGFb-β-RII receptor extracellular domain (a TGF-β trap). N-803 is an IL-15 superagonist complex. Here we report an interim efficacy analysis of the QuEST1 study, aimed to rapidly interrogate safety and efficacy of immunotherapy combinations in CRPC. Methods: Asymptomatic/minimally symptomatic CRPC pts received BNVax + BA (Arm 2.1) or BNVax + BA + N-803 (Arm 2.2). BNVax is given as 2 prime doses followed by boosts. BA 1,200 mg intravenously and N-803 15 µg/kg subcutaneously are given every 2 weeks. Efficacy is defined as objective response by RECIST v1.1 or PSA decrease ≥ 30% sustained for ≥ 21 days. Safety was a secondary endpoint. Results: As of 10/11/20, 26 CRPC pts enrolled and had 1 to 23 months follow up. 1/13 pts (Arm 2.1) had a PSA response sustained for 13 months. 5/12 (41.6%) pts on treatment for at least 12 weeks (Arm 2.2) had sustained PSA responses, including 2 pts who progressed on enzalutamide. Of 3 patients with measurable disease, 2 had confirmed PR by RECIST. Grade 3 TRAEs: 1 pancreatitis (Arm 2.1), 1 secondary adrenal insufficiency (Arm 2.1), 1 tumor hemorrhage (Arm 2.1), 1 hyperglycemia due to new onset diabetes mellitus (Arm 2.2), 1 cystitis (Arm 2.2), 1 Rash with eosinophilia (Arm 2.2). One patient had grade 4 neutropenia that resolved with growth factor support and oral corticosteroids. Conclusions: BVax + BA + N-803 demonstrated a manageable safety profile and preliminary evidence of efficacy in CRPC. Addition of N-803 in Arm 2.2 was associated with more activity in this small sample. Arm 2.2 met the predetermined threshold for efficacy and will expand (n=25).

Citation Format: James L. Gulley. The QuEST for an effective immunotherapy for prostate cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA07.
Abstract IA11: Viral vectored vaccines for prostate cancer
Authors: Hill Adrian V. S. , Tuthill M. , Cappuccini F. , Carter L. , Pollock E. , Poulton I. , Verrill C. , Evans T. , Marshall M. , Gillessen S. , Attard G. , Protheroe A. , Hamdy F. , Redchenko I.
Published: February 2021

New therapeutic antigen-specific approaches are required to generate and sustain therapeutic immune responses against tumour specific antigens in cancer. Based on twenty years of experience with attempt to maximise the induction of potent T cell responses against infectious pathogens in humans we have begun to assess the utility of non-replicating viral vectors in cancer. Two trials in prostate cancer patients have completed enrolment and another in lung cancer is planned. We have reported efficacy data for a novel vaccine based on two replication-deficient viruses, chimpanzee adenovirus (ChAdOx1) and MVA, targeting an oncofetal self-antigen 5T4, administered as a single agent and in combination with anti-PD-1 in mouse tumour models. Based on recently reported encouraging safety and exceptional T cell immunogenicity in a phase I “VANCE” study (NCT02390063) of me with localised prostate cancer, the phase I/II trial, ADVANCE (NCT03815942) was undertaken to test vaccine safety and efficacy in combination with PD-1 blockade in metastatic prostate castrate-resistant cancer (mCPRC). We find a satisfactory safety profile for the use of these viral vectored vaccines with anti-PD1 in mCRPC patients but with lower immunogenicity than in localised prostate cancer patients. However, an encouraging response rate, as measured the reduction in PSA levels by 50%, was observed in this trial and options for enhancing immunogenicity and efficacy further will be discussed.

Citation Format: Adrian V. S. Hill, M. Tuthill, F. Cappuccini, L. Carter, E. Pollock, I. Poulton, C. Verrill, T. Evans, M. Marshall, S. Gillessen, G. Attard, A. Protheroe, F. Hamdy, I. Redchenko. Viral vectored vaccines for prostate cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA11.
Abstract IA16: Discovery of new immunotherapy targets and mechanisms leveraging CRISPR
Authors: Sharpe Arlene H.
Published: February 2021

This talk discusses a CRISPR-Cas9 based platform for in vivo screening of immune genes. This platform facilitates discovery of regulators of tumor immunity and targets for combination therapy. We will discuss the use of this platform to perform in vivo CRISPR-based screens to enable rapid discovery of therapeutic targets in immune cells, and our identification of Ptpn2 as a negative regulator of exhausted CD8+ T cell responses using this CRISPR platform.

Citation Format: Arlene H. Sharpe. Discovery of new immunotherapy targets and mechanisms leveraging CRISPR [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA16.