bluuebunny/crossref_metadata_2025 huggingface dataset:
A two-weight boundedness criterion and its applications
Authors: Yang Sibei , Yang Zhenyu
Published: April 2024

In this paper, the authors establish a general (two-weight) boundedness criterion for a pair of functions, [Formula: see text], on [Formula: see text] in the scale of weighted Lebesgue spaces, weighted Lorentz spaces, (Lorentz–)Morrey spaces, and variable Lebesgue spaces. As applications, the authors give a unified approach to prove the (two-weight) boundedness of Calderón–Zygmund operators, Littlewood–Paley [Formula: see text]-functions, Lusin area functions, Littlewood–Paley [Formula: see text]-functions, and fractional integral operators, in the aforementioned function spaces. Moreover, via applying the above (two-weight) boundedness criterion, the authors further obtain the (two-weight) boundedness of Riesz transforms, Littlewood–Paley [Formula: see text]-functions, and fractional integral operators associated with second-order divergence elliptic operators with complex bounded measurable coefficients on [Formula: see text] in the aforementioned function spaces.
Controllable Preparation and Sodium Storage Properties of Sb2Te3–Te Heterojunction
Authors: Jia Shupei , Jiang Sheng , Li Saisai , Liu Peng , Wang Feng , Wang Dianhui , Liu Wenping , Qin Haiqing , Deng Jianqiu
Published: April 2024

Antimony-based materials possess high theoretical capacities and suitable potential, which could be promising anode materials for sodium-ion batteries (SIB). However, poor stabilities and sluggish kinetics are drawbacks. Building heterojunction is an ideal method to solve these issues. Its unique structure develops internal electric fields spontaneously to boost the charge transport and relieve stress. Nevertheless, the controllable preparation of face-to-face (2D) heterojunctions is still hard-pressed. Herein, [Formula: see text]–[Formula: see text] nanoheterojunctions, which consist of two-dimensional [Formula: see text]–[Formula: see text] nanoblades attached to a one-dimensional Te nanorod, are fabricated through a two-step solvothermal method. Among that, the density of nanoblades is adjustable through the engineering feed ratio. When employed as anodes for SIBs, [Formula: see text]–[Formula: see text] nanoheterojunctions display a reversible capacity of 463.2[Formula: see text]mAh[Formula: see text]g[Formula: see text] at 100[Formula: see text]mA[Formula: see text]g[Formula: see text]. Even a capacity of 305.5[Formula: see text]mAh[Formula: see text]g[Formula: see text] remains after 1000 cycles under a high current of 1.5[Formula: see text]A[Formula: see text]g[Formula: see text]. Moreover, the density functional theory (DFT) calculations also identify the high conductivity of heterojunction. This work offers an effective way to design the structures and properties of heterojunctions, further expanding their application range.
Evolution of Elastic Shear Modulus During Shearing Under Different Stress Paths Considering Anisotropic Stress History
Authors: Fani Kamran , Akhtarpour Ali , Bazaz Jafar Bolouri
Published: April 2024

Continuous shear wave velocity measurements are conducted on cylindrical triaxial sandy specimens consolidated with isotropic and anisotropic stress histories to characterize the evolution of the elastic shear modulus under different stress paths. The shear wave velocity is measured using an automatic device capable of consecutive measurements of travel time. All specimens were prepared using the Water Sedimentation (WS) method, and after undergoing a stress-controlled path representing the stress history of the specimens, they were subjected to stress-controlled drained shearing along eight different paths. The stress components used in the existing correlations estimating the shear moduli are specified under different stress paths. The results demonstrate that the existing empirical correlations can appropriately be used within the elastic region or the loading surface. However, the accuracy of such models estimating shear moduli might be depreciated as shearing commences, particularly if the stress path involves deviatoric stress, diverging from the expected trends at a specific stress ratio, which is strongly linked to the consolidation stress state. A criterion at which the shear modulus is diverted is also suggested, found to be directly related to the initial stress anisotropy.
On the topological pressure spectrum of rates of shadowing time
Authors: Liang Yali , Zhang Junjie , Wang Wei
Published: April 2024

In this paper, we introduce multifractal spectra associated with rates of recurrence time. By using characteristics of a dynamical system, we establish an exact formula on multifractal spectrum of rates of shadowing time.
Fabricating waxberry-shaped N–C–TiO2 composite with excellent visible light catalytic activity
Authors: Zhao Fengyang , Yu Runmeng , Jiang Yongjian
Published: April 2024

Herein, a nitrogen, carbon co-doped anatase and rutile double-phase waxberry-shaped [Formula: see text] composite photocatalyst is prepared with the one-step simple hydrothermal synthesis process, in which P25 was used as the precursor, and urea as the source of nitrogen and carbon. A suitable valence band position (2.52 eV) is provided by [Formula: see text], with more active species (e.g. [Formula: see text], [Formula: see text], •[Formula: see text] and •[Formula: see text]) being formed on the active catalysis surface, which is helpful to the redox reaction. Further comparison of experimental results ([Formula: see text] = 3.01 eV) proved that the novel [Formula: see text] has preferable photocatalytic activity. In this study, an ingenious nitrogen- carbon co-doping structure was designed for the improvement of [Formula: see text] photocatalytic performance, which is much for reference of this method to other photocatalyst designs.
In situ preparation of two-dimensional mortise and tenon structure g-C3N4/MoO3 photocatalyst for the reduction of aqueous Cr(VI)
Authors: Wu Xinzhuo , Chen Shaojie , Li Zhao , Tian Lin , Yang Zongfei , Li Jing
Published: April 2024

In situ solid-state synthesis was employed to prepare the [Formula: see text] (CM) heterojunctions with a two-dimensional mortise and tenon structure. The prepared products were characterized using X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy, suggesting that amorphous graphitic carbon was obtained. The photocatalytic performance of the prepared photocatalysts was evaluated in aqueous Cr(VI) reduction reactions under visible-light ([Formula: see text] > 420 nm) irradiation. The results of the experiments showed that the photocatalytic activity of CM is influenced by the composition of heterojunctions. The optimum photocatalytic activity for the photocatalytic reduction of Cr(VI) was found in the compound CM-25, which contains a 25% [Formula: see text] concentration. The Cr(VI) reduction rate on CM-25 was four times that of [Formula: see text] and 14.5 times that of [Formula: see text], the photocatalytic activity of CM-25 only dropped by 7.7% in four cycles. Scavenger investigations and EPR tests indicated that the major photogenerated radicals in the reduction of Cr(VI) were superoxide negative radicals (•[Formula: see text]) and hydroxyl radicals (•[Formula: see text]OH). CM-25 was discovered to be an S-scheme heterojunction that effectively suppressed photogenerated charge carrier recombination and retained photogenerated holes (in the valence band of [Formula: see text]) and electrons (in the conduction band of [Formula: see text]) with higher redox capabilities. CM-25 has potential applications in the photocatalytic reduction of Cr(VI) in wastewater.
Thermal wave reflection and propagation in temperature rate-dependent non-local diffusive solids
Authors: Nadeem Muhammad , Ali Hashmat , Azhar Ehtsham , Jamal Muhammad
Published: April 2024

The propagation and reflection of thermo-elastic waves through diffusive nonlocal isotropic medium had been studied in this paper. The Green–Lindsay model of thermo-elasticity is incorporated in the context of Temperature Rate Dependent Theory. Using Helmholtz vector decomposition rule, the system of governing equations has been transformed to their respective components. The dispersion relation in frequency indicates the existence of three coupled waves and one independent wave propagating through the medium. The coupled waves are affected by non-locality, temperature field and diffusivity in the medium; anyhow, un-coupled shear vertical wave is only affected by the non-local parameter. The reflection of [Formula: see text]-wave is also studied at the free boundary of the solid and their corresponding amplitude ratios are computed using set of suitable boundary conditions. The obtained results are further discussed graphically for significant physical parameters of interest. The results in the literature are obtained as a special case after ignoring the diffusivity in the solid.
Investigating Enzyme Biochemistry by Deep Learning: A Computational Tool for a New Era
Authors: Rayka Milad , Mirzaei Morteza , Farnoosh Gholamreza , Latifi Ali Mohammad
Published: April 2024

Enzymes are protein molecules that play a crucial role in various biological processes in living organisms. They function as catalysts in biological reactions such as digestion, metabolism, DNA replication and other physiological processes. Furthermore, enzymes are widely used in food production, pharmaceuticals and biofuel production. In these industries, they accelerate desired chemical reactions as biocatalysts. Therefore, applying computational methods and data-driven algorithms to predict enzyme properties is essential. Over the past decade, deep learning has made remarkable advancements in science and technology. Deep learning is a subset of machine learning algorithms that rely on artificial neural networks. These algorithms can be employed for supervised, semi-supervised and unsupervised learning. Here, to provide an update on the current literature, we provide an overview of various deep learning algorithms and recent advancements in their application to enzyme science. These applications can generally be categorized into diverse subjects: function prediction, enzyme kinetic parameters prediction, enzyme-substrate identification, condition optimization, thermophilic property prediction, enzyme catalytic site prediction and enzyme design. In conclusion, we discuss the convergence of enzyme science and deep learning, highlighting the potential opportunities and challenges.
Cenozoic structure of the Zhu 3 Depression in the Pearl River Mouth Basin and its response to the dynamic background of the South China Sea
Authors: Li Wei , Cao Mingyue , Wang Di , Li Hui , Fu Dawei , Chen Xingpeng , Meng Meifang , Wu Wanqiu , Li Jia , Chen Yong
Published: April 2024

The Zhu 3 Depression is located at the transition between the South China Sea and the South China Block. The Cenozoic structure reflects the dynamic background of the South China Sea. We used 3D seismic and log data to study the structural evolution of the Zhu 3 Depression. We defined the characteristics of Cenozoic rift deformation and the migration of the depocentre based on fault activity and the distribution of sediment thickness. The spatial and temporal differences in the Cenozoic structure of the Zhu 3 Depression are due to the influence of pre-existing faults and regional stresses. Our results show that there are three populations of faults in the Zhu 3 Depression, striking NE, east–west and NW. The NE-striking faults are mainly large-scale boundary faults. The east–west-striking faults are small and were activated in the later stages of deformation. The NW-striking faults are continuous at depth, but are en echelon and parallel to each other at shallow depths. Based on these results, we suggest that the NE- and NW-striking pre-existing faults divide the Zhu 3 Depression into different structural zones and controlled the differences in deformation in the basin. The regional stress direction, which is controlled by regional plate interactions and the Red River Fault Zone, changed clockwise from NW-trending during the Paleocene to NE-trending during the Mid-Miocene. These findings will contribute to a better understanding of the evolution of the entire South China Sea.

Thematic collection:
This article is part of the Emerging knowledge on the tectonics of the South China Sea collection available at:
https://www.lyellcollection.org/topic/collections/south-china-sea
Application of Antithrombotic Drugs in Different Age‐Group Patients with Upper Gastrointestinal Bleeding
Authors: Peng Ding , Zhai Huihong
Published: April 2024

Objective. This study aimed at exploring the safety and timing of antithrombotic drugs in different age‐group patients with UGIB. Methods. An observational study retrospectively based on the single‐center database with 713 patients with UGIB. Result. Among the 713 patients, 62.13% were elderly patients (aged > 60 years) and the mortality was 2.9%. In elderly patients with UGIB, we found that previous medication history, resumption of medication, and time of resumption did not affect the in‐hospital mortality. The resumption of anticoagulants increased the risk of rebleeding. The independent risk factors of mortality were CHF, cirrhosis, creatine kinase, and albumin. The independent risk factors of rebleeding were the application of anticoagulants during hospitalization, variceal bleeding, black stool, red blood cells (lab), platelets (lab), and heart rate. Conclusions. In UGIB patients, a history of antiplatelet or antithrombotic drugs and the use of antiplatelet drugs after UGIB did not affect the patient’s prognosis. In elderly UGIB patients, although antithrombotic drugs did not increase the risk of death, the increased risk of rebleeding after resumption of use deserved careful treatment. It was safe to recover anticoagulant drugs as soon as possible in young UGIB patients.
Effect of Addition of Cetylpyridinium Chloride Cationic Surfactant on the Antimicrobial Activity of Chlorhexidine Endodontic Irrigant
Authors: Al-Sada Hiba A. , Al-Gharrawi Hikmet A.
Published: April 2024

Background. Endodontic irrigants are essential for disinfecting the root canal system. None of the currently available irrigants perfume sufficiently. However, most products contain surfactants, which enhance the antimicrobial properties of the irrigants. Objectives. To evaluate the effect of cetylpyridinium chloride (CPC) surfactant on the antimicrobial activity of chlorhexidine and compare it with that of chlorhexidine (CHX) and Biopure MTAD against Enterococcus faecalis, Staphylococcus aureus, and Candida albicans. Materials and Methods. In this in vitro study, three microorganisms were used (E. faecalis, S. aureus, and C. albicans), and each organism was treated with three different irrigants: 2% CHX, 2% CHX + 0.2% CPC, and 100% Biopure MTAD. The antimicrobial activity was evaluated by direct contact assay for 5 min of contact time. The colony‐forming unit per mL was calculated after antimicrobial treatment and 24 hr of incubation at 37°C. The data were statistically analyzed using Statistical Package for Social Science (SPSS) version 22. The Kruskal–Wallis and the multiple Wilcoxon sum rank tests were used. The level of significance was set at 0.05. Results. The result showed a nonsignificant difference between the different irrigants against E. faecalis. Among S. aureus subgroups, 2% CHX was statistically significant and more efficient than MTAD. Among C. albicans subgroups, 2% CHX and combined irrigant (2% CHX + 0.2% CPC) were statistically more efficient than MTAD. The 2% CHX and combined irrigants were equally effective against all the tested microorganisms. Conclusions. All the used irrigants have comparable effects against E. faecalis after 5 min. CHX have a comparable effects to that of the combined irrigant and more efficient against S. aureus than MTAD. CHX and the combined irrigant have potent antimicrobial activity against C. albicans superior to MTAD. CPC surfactant can be used with CHX to overcome its clinical drawbacks or limitations without altering or reducing its antimicrobial activity.
VCH: A Velocity Measurement Method Combining HFM Signals
Authors: Yan Wei , Song Caixia , Peng Yuankun , Liang Zeng
Published: April 2024

During sonar detection, the fuzzy function of hyperbolic frequency modulation (HFM) in the waveform of active signal is in the shape of a “oblique blade,” which leads to the coupling characteristics of its fuzzy function in the time dimension and frequency dimension. Doppler causes a frequency shift in the frequency dimension and a time delay in the time dimension, which makes it impossible for a single HFM signal to measure speed accurately. However, the time delay caused by the same moving target to HFM signals with different frequency bands and different pulse widths is also different. A velocity measurement method combining HFM signals (VCH) is proposed, which employs the time delay correlation between the combined HFM signals to achieve the target distance and speed. In the VCH method, the echo signal is no longer matched and filtered as a whole but is divided into two channels and matched and filtered separately. And then, the combined HFM signals are used to obtain the distance and speed of the target. Extensive simulation results show that the proposed method can estimate the distance and speed of moving targets accurately, and it has reference value for engineering application.
Postharvest Practices, Perceptions, and Knowledge of Mycotoxins among Groundnut Farmers in the Adamawa, Centre, and North Regions of Cameroon
Authors: Ntsoli Pierre Germain , Boat Bedine Marie Ampères , Baleba Cynthia Claire , Tchatcho Ngalle Steve Freddy , Djoko Kouam Idriss , Titti Roland Wilfried , Etame Kossi Georges Marius , Yaouba Aoudou
Published: April 2024

In many parts of the world, including Cameroon, mycotoxin contamination of groundnuts remains a major constraint affecting their use as food. Understanding the contributing factors is an essential intervention to reduce contamination and people’s exposure to these harmful toxins. The aim of this research was to identify the factors associated with the knowledge, perceptions, and postharvest practices of groundnut farmers in three production basins in Cameroon. Data were collected through surveys and analyzed using descriptive methods and logistic regression models. The results show that groundnut farmers are little aware of the existence of mycotoxins (12%) and totally unaware of the existence of aflatoxins (100%). Only 7.1% of these farmers are aware of the effects of mycotoxins on consumer health. After evaluation, the large majority of farmers scored poor marks for knowledge (86%) and practice (98.7%) in the management of mould and mycotoxins in groundnuts. Knowledge of mycotoxins was positively associated with the level of education [OR = 3.42; (95%-IC: 1.00–16.00); p<0.05] and region [OR = 4.49; (95%-IC: 1.09–20.3); p<0.05]. Farmers’ good practices were linked to their production experience [OR = 6.06, (95% CI: 0.91-18.4), p=0.035]. The use of mouldy groundnut for feed was associated with age [OR = 3.34, (95% CI: 1.14–10.2), p=0.03], sex [OR = 0. 43, (IC-95%: 1.14–1.05), p=0.026], marital status [OR = 0.35, (IC-95%: 0.14–0.79), p=0.015], and production region [OR = 0.27, (IC-95%: 0.13–0.56)]. In conclusion, groundnut farmers had insufficient knowledge of mycotoxins, no knowledge of aflatoxins, and suboptimal handling and storage practices for this commodity. This contributes to increasing the risk of exposure for the population and requires mitigation measures, including awareness campaigns on mycotoxins, specifically aflatoxins, and capacity building for farmers in terms of storage and postharvest management of foodstuffs.
Plasmodium Parasitaemia and Urine Alterations among Pregnant Women Attending Antenatal Care in Aba Metropolis, Abia State, Nigeria
Authors: Melariri Paula , Ihemanma Chioma , Chigbo Udoka , Eastwood Kirstie , Uche Chika , Etusim Paschal
Published: April 2024

Malaria presents a huge threat to pregnant women, their foetus, and children below five years. This study is aimed at assessing malaria prevalence, associated clinical symptoms, and urine abnormalities among pregnant women in Aba metropolis, Abia State, Nigeria. A cross-sectional study involving 450 pregnant women purposively selected from nine health care centres was conducted. Data were analysed using SPSS version 26. The overall malaria prevalence rate was 68.4% (n=308). Age group of 21-25 years had the highest prevalence rate of 20.4% (n=92) while the least was recorded among the age group of 41-45 years (17 (3.8%)). Pregnant women in their first trimester had the greatest prevalence rate of 28.6% (n=129), and the least prevalence was recorded among those in their third trimester (7 (15.6%)). The primigravidae were mostly infected at the rate of 27.7% (n=125) whereas the multigravidae recorded the least prevalence of 85 (18.9%). Participants with secondary education were the most susceptible at the rate of 38.6% (n=174). The infected participants exhibited significantly higher frequencies of reported fever (p>0.001, OR 12.881, 95% CI 3.977-41.725) and headaches (p<0.001, OR 4.688, 95% CI 1.819-12.083). However, cold, cough, body pains, poor appetite, and catarrh showed no significant association with malaria infection at p>0.05. Participants using long-lasting insecticidal nets (LLINs) showed significantly lower prevalence rate of malaria infection (p<0.001, OR 2.485, 95% CI 1.619-3.814). Malaria-infected participants showed statistically significant frequencies of proteinuria (p<0.001, OR 274.14, 95% CI 16.91-4444.0), bilirubinuria (p<0.001, OR 49.29, 95% CI 11.01-186.34), and urobilinogenuria (p<0.001, OR 65.16, 95% CI 4.00-1062.40) than those not infected. Ascorbic acid, nitrate, and ketone showed no significant associations with malaria infection at p>0.005. Infected participants had statistically significant amber and clear urine colour whereas there was no statistically significant difference between the pH levels of urine of the malaria-infected and malaria-noninfected pregnant women.
Application of the Effect of Nonthermal Technologies on the Oxidation of Proteins and Lipids in Pigeon Meat during Chilled Storage
Authors: Tong Xiao-Yang , Zhang Yi , Pang Jin-Xin , Liu Bao-Lin , Biron Eric , Rahman Md R. T. , Qiao Yong-Jin , Bing Qi-Jie , Gao Xu-Ying
Published: April 2024

This study investigated the effects of low-voltage electrostatic field (LVEF), electron beam irradiation (EBI), and modified atmosphere packaging (MAP) on protein and lipid oxidation of pigeon meat (PM) during chilled storage. The water-holding capacity (WHC) and color reflected that the difference between the LVEF-treated (1.20 kV/m) group and the fresh groups was the smallest. The oxidation analysis of protein showed that the LVEF-treated group had smaller values of carbonyl concentration (0.0551 ± 0.0048 μmol/g), larger values of sulfhydryl concentration (0.737 ± 0.0364 μmol/g), and higher Ca2+-ATPase activity (30.10 ± 1.52 U/g) than the C4 group (0.0649 ± 0.0013 μmol/g, 0.510 ± 0.0225 μmol/g, and 25.18 ± 1.42 U/g, respectively). SDS-PAGE demonstrated the ability of LVEF to inhibit the hydrolysis and cross-linking of proteins. Meanwhile, the LVEF-treated group had lower values of TBARs (2.26 ± 0.0371 μg/kg) than the other groups and had a lower lipid oxidation level. In addition, the fatty acids in the LVEF-treated group were similar to those in the fresh group and were beneficial to human health. In conclusion, LVEF (1.20 kV/m) could inhibit protein and lipid oxidation of PM during chilled storage.
Mechanical Performance of Tube‐Gusset X‐Joints Enhanced by Ring Plates
Authors: Li Xiaolu , Yang Zhe , Zhao Yan , Wang Xinwu , Xue Xiaomin , Wang Xueming
Published: April 2024

This study aims to investigate the effect of the ring plate on the mechanical performance of X‐type tube‐gusset joints. The failure modes, ultimate strengths, and failure mechanisms of X‐joints with ring plates were investigated through experiments and finite element analyses. The results indicated that the ring plate and the chord within the effective range of the ring plate constituted the primary bearing structure of the X‐joint. Increases in the ring plate thickness and width increased the ultimate strength of the X‐joint. By considering the forces of the braces as a superposition of the bending moment and the force acting on the gusset of the X‐joint, a simplified calculation method for the ultimate strength of X‐joints was established. The derivation process was validated and refined through experiments and finite element analyses. Finally, a safe and reliable formula was derived for evaluating the ultimate strength of X‐joints.
Characterizing Cancer Burden in the American Indian Population in North Carolina
Authors: Spees Lisa P. , Jackson Bradford E. , Raveendran Yadurshini , Morris Hayley N. , Emerson Marc A. , Baggett Christopher D. , Bell Ronny A. , Salas Ana I. , Meernik Clare , Akinyemiju Tomi F. , Wheeler Stephanie B.
Published: April 2024

Background:

The American Indian (AI) population in North Carolina has limited access to the Indian Health Service. Consequently, cancer burden and disparities may differ from national estimates. We describe the AI cancer population and examine AI–White disparities in cancer incidence and mortality.

Methods:

We identified cancer cases diagnosed among adult AI and White populations between 2014 and 2018 from the North Carolina Central Cancer Registry. We estimated incidence and mortality rate ratios (IRR and MRR) by race. In addition, between the AI and White populations, we estimated the ratio of relative frequency differences [RRF, with 95% confidence limits (CL)] of clinical and sociodemographic characteristics. Finally, we evaluated the geographic distribution of incident diagnoses among AI populations.

Results:

Our analytic sample included 2,161 AI and 204,613 White individuals with cancer. Compared with the White population, the AI population was more likely to live in rural areas (48% vs. 25%; RRF, 1.89; 95% CL, 1.81–1.97) and to have Medicaid (18% vs. 7%; RRF, 2.49; 95% CL, 2.27–2.71). Among the AI population, the highest age-standardized incidence rates were female breast, followed by prostate and lung and bronchus. Liver cancer incidence was significantly higher among the AI population than White population (IRR, 1.27; 95% CL, 1.01–1.59). AI patients had higher mortality rates for prostate (MRR, 1.72; CL, 1.09–2.70), stomach (MRR, 1.82; 95% CL, 1.15–2.86), and liver (MRR, 1.70; 95% CL, 1.25–2.33) cancers compared with White patients.

Conclusions:

To reduce prostate, stomach, and liver cancer disparities among AI populations in North Carolina, multi-modal interventions targeting risk factors and increasing screening and treatment are needed.

Impact:

This study identifies cancer disparities that can inform targeted interventions to improve outcomes among AI populations in North Carolina.
Co-occurring EGFR p.E709X Mutation Mediates Primary Resistance to the Third-Generation EGFR-TKIs in EGFR p.G719X-Mutant Patients with Advanced NSCLC
Authors: Pang Lanlan , Huang Yihua , Zhuang Weitao , Zhang Yaxiong , Liao Jun , Hao Yue , Hao Feng , Wang Guoqian , Chen Ze-xin Chase , Zhu Yu , Li Mengzhen , Song Zhengbo , Deng Bo Peng , Li Jing , Zhang Li , Fang Wenfeng
Published: April 2024

Purpose:

The current National Comprehensive Cancer Network (NCCN) guidelines recommend afatinib or osimertinib as the preferred first-line treatment strategy for patients with advanced NSCLC harboring EGFR p.G719X mutation. However, in the absence of head-to-head trials comparing afatinib with osimertinib in EGFR p.G719X-mutant patients, it is unclear which regimen is the preferred treatment option.

Experimental Design:

A large cohort of 4,228 treatment-naïve patients with lung cancer who underwent targeted next-generation sequencing (NGS) testing was screened for EGFR p.G719X mutation. A multicenter cohort involving 68 EGFR p.G719X-mutant patients with advanced NSCLC and NGS profiling was retrospectively enrolled to evaluate clinical responses to afatinib (n = 37) and the third-generation EGFR-TKIs (n = 31). Ba/F3 cells stably expressing the EGFR p.G719A mutation were created to investigate the response to EGFR-TKIs in vitro.

Results:

Concurrent EGFR p.E709X mutations, being the most frequent co-occurring EGFR mutation in EGFR p.G719X-mutant NSCLC (∼30%), exerted a detrimental effect on outcomes in patients treated with third-generation EGFR-TKI [G719X/E709X vs. G719X; objective response rate (ORR): 0.00% vs. 47.62%, P < 0.001; mPFS: 7.18 vs. 14.2 months, P = 0.04, respectively]. Conversely, no significant difference was found in the treatment efficacy of afatinib between EGFR p.G719X/E709X and EGFR p.G719X patients (G719X/E709X vs. G719X; ORR: 71.43% vs. 56.67%, P = 0.99; mPFS: 14.7 vs. 15.8 months, P = 0.69, respectively). In vitro experiments elucidated a resistant drug sensitivity and poor inhibition of EGFR phosphorylation in Ba/F3 cells expressing EGFR p.G719A/E709K mutation upon the third-generation EGFR-TKI treatment.

Conclusions:

Co-occurring EGFR p.E709X mutation mediated primary resistance to the third-generation EGFR-TKIs in EGFR p.G719X-mutant patients but remained sensitive to afatinib. A personalized treatment strategy should be undertaken based on the coexisting EGFR p.E709X mutation status.
Abstract CT116: Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors
Authors: Fu Siqing , Sanborn Rachel E. , Cai Minxia , Zhang Lijia , Xu Yanhua , Lin Kui
Published: April 2024

PIM proto-oncogenes encode a family of three serine/threonine kinases (PIM1, PIM2, PIM3), which are frequently overexpressed in human hematological malignancies and solid cancers. PIM kinases are promising cancer therapeutic targets for pharmacological inhibition. NB004 (aka GDC-0570) is a novel, potent, selective, orally available small molecule pan-PIM inhibitor, which exhibits antiproliferative activity as a single agent in a variety of preclinical models and can augment the activity of standard of care or targeted therapies, both in vitro and in vivo. In multiple patient-derived xenograft (PDX) models of human solid tumors, NB004 demonstrates both single agent and combination activity with agents targeting the RTK/RAS/MAPK pathways, including synergistic effects with KRAS inhibitors (KRASis). Remarkably, in NSCLC PDX models with acquired resistance to KRASis, strong combination efficacy was observed between NB004 and sotorasib, resulting in complete tumor regression. Based on the promising preclinical data, NB004 is currently being assessed in an open-label, first-in-human phase I clinical trial as monotherapy or combination therapy in patients with advanced solid tumors. The primary objective is to characterize the safety and tolerability and to recommend the phase 2 dose (RP2D). Secondary objectives include PK characterization and preliminary antitumor activity evaluation. In the phase I monotherapy dose escalation part, NB004 was administered daily in 5 dose levels, ranging from 75mg to 600mg, following a standard 3+3 design. As of December 22, 2023, a total of 18 patients were treated. Of the 13 patients (72.2%) who reported any treatment-related adverse events (TRAEs), 12 (66.7%) had Grade 1 or 2 TRAEs, 1 patient (5.6%) experienced Grade 3 neutrophil count decrease and white blood cell count decrease. No dose-limiting toxicity (DLT) or treatment-related serious adverse event (SAE) was reported, and PK exposure is in general dose proportional. These results warrant further evaluation of this drug in combination with other therapeutic agents. The combination part of the trial is currently open for enrollment (NCT05036291).

Citation Format: Siqing Fu, Rachel E. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin. Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT116.
Abstract CT291: A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1
Authors: Yamamoto Noboru , Doi Toshihiko , Patel Manish R. , Garrido-Laguna Ignacio , Wu Sutun , Nishioka Satoshi , Nakajima Keiko , Carneiro Benedito A.
Published: April 2024

Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (deruxtecan [DXd]). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors.

Trial design: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll a maximum of 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a.

Citation Format: Noboru Yamamoto, Toshihiko Doi, Manish R. Patel, Ignacio Garrido-Laguna, Sutun Wu, Satoshi Nishioka, Keiko Nakajima, Benedito A. Carneiro. A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT291.
Abstract LB027: Identifying natural inhibitors of androgen receptor (AR) and its variants from NCI Natural Product Repository
Authors: Tyagi Neha , Hosseiniporgham Sepideh , Tyagi Ashish , Chandrasekaran Balaji , Bonilla Katherine , Kriger Inna , Saccchettini James , Damodaran Chendil
Published: April 2024

Second-generation androgen ablation therapies (ADT), enzalutamide, and abiraterone are initially effective on metastatic castration-resistant prostate cancer (mCRPC). However, nearly 30-40% of patients eventually become resistant to these treatments due to the presence of androgen-receptor variants (AR-V), which lack a ligand-binding domain. The grim reality that metastatic CRPC is virtually incurable for most patients poses a significant challenge for clinicians striving to enhance these individuals' quality of life and lifespan. Considering drug discovery efforts, we partnered with the National Cancer Institute's (NCI) Natural Product Repository, which possesses a diverse collection of natural product extracts derived from plant, marine, and microbial organisms. We developed high-throughput phenotypic screening assays to screen the crude natural product extract libraries on AR and AR-variants CRPC cell lines (C4-2B and 22Rv1). Several extracts inhibited the growth of both CRPC cell lines and were further confirmed for dose-dependent cell viability inhibition assays. Once we determined the IC50 dose, we performed a Western blot analysis that confirmed the inhibition of AR and AR-V7 expression in CRPC cells.In subsequent studies, we narrowed down by fractionating the most potent extracts and confirmed their ability to inhibit AR expression and signaling on CRPC cell lines. Currently, we are characterizing the potent compounds and their inhibitory activity on AR and AR-variants, in vitro and in vivo CRPC models. Many nutraceuticals have been shown to target AR signaling, synthesis, or degradation which effectively inhibited the growth of CRPC. Our collaborative efforts with NCI will permit us find N-terminal AR degrading molecules (AF-1), which are essential for the AR transcriptional activities of CRPC. In sum, discovery of ovel small molecules from our drug development program have the potential to translate these effective natural products into drugs with clinical benefits to treat CRPC.

Citation Format: Neha Tyagi, Sepideh Hosseiniporgham, Ashish Tyagi, Balaji Chandrasekaran, Katherine Bonilla, Inna Kriger, James Saccchettini, Chendil Damodaran. Identifying natural inhibitors of androgen receptor (AR) and its variants from NCI Natural Product Repository [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB027.
Abstract LB031: Discovery and Characterization of HH100937, a potent and selective SOS1 inhibitor demonstrates synergistic efficacy in combination with KRAS/MAPK therapies
Authors: Xie Qing , Li Dongsheng , Jiang Shujuan , Zhu Jie , Yu Songda , Yang Maozhi , Cai Yalei , Liu Lei , Yu Bing , Tu Wangyang , Zhang Yixiang , Li Leping
Published: April 2024

Besides marketed inhibitors targeting KRAS G12C, novel therapies are needed to effectively treat cancer patients harboring other KRAS mutations. SOS1, a guanine nucleotide-exchange factors (GEFs), plays a critical role in catalyzing the conversion of KRAS from its GDP- to GTP-bound form, regardless of KRAS mutation status and represents a promising therapeutic target for all KRAS-driven tumors. Up to date, several SOS1 inhibitors have entered early phase clinical trials. But a more potent SOS1 inhibitor with improved drug-like properties is still needed to prove efficacy as monotherapy or in combination with other drugs targeting the KRAS/MAPK pathway.We discovered a potent SOS1 inhibitor, HH100937 that effectively disrupted the interaction between SOS1 and wild-type KRAS or with G12C, G12D or G12V mutations. HH100937 exhibited lower IC50s than BI-3406 and MTRX0902 in blocking ERK phosphorylation and cancer cell proliferation, leading to better anti-tumor efficacies in xenografts than reference compounds at same doses. HH100937 also showed synergistic effect with AMG510 in cancer cells with KRAS G12C mutation but refractory to AMG510. The combination of HH100937 and AMG510 in xenografts led to tumor regression in all mice, while some tumors did not response well to AMG510 monotherapy. Our SOS1 inhibitor also exhibited synergistic effect with HH2710, a clinical-stage ERK inhibitor, in a broad panel of cancer cells with KRAS mutations.The pharmacological potency of HH100937 was highly selective over SOS2, other kinases tested or other targets in a safety panel of 47 targets. HH100937 was well tolerated in 28-day DRF study in rats and dogs up to 250 mg/kg QD and 30 mg/kg QD, respectively. The AUC of drug exposure in DRF studies was approximately three to six times higher than that at the efficacious dose. HH100937 also showed favorable DMPK properties in mice, rats and dogs, and acceptable safety profiles in vitro.Taken together, HH100937 is a highly potent and selective SOS1 inhibitor with better anti-tumor activities than some SOS1 inhibitors at clinical stage. It can be developed as mono therapy or in combination with other KRAS/MAPK targeting therapies.

Citation Format: Qing Xie, Dongsheng Li, Shujuan Jiang, Jie Zhu, Songda Yu, Maozhi Yang, Yalei Cai, Lei Liu, Bing Yu, Wangyang Tu, Yixiang Zhang, Leping Li. Discovery and Characterization of HH100937, a potent and selective SOS1 inhibitor demonstrates synergistic efficacy in combination with KRAS/MAPK therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB031.
Abstract LB033: Identification of small molecule Pan-TEAD inhibitors disrupting YAP-TEAD protein-protein interaction and targeting gastric cancer cells
Authors: Kumar Ramesh , Toh Joel , Thian Joanne , Mohideen Noorul Farzana , Sun Jialin , Chakraborty Sayan , Gunaratne Jayantha , Hong Wanjin
Published: April 2024

Because of the Hippo pathway’s unique ability to restrict TAZ/YAP-TEAD in promoting regeneration, any abnormality of its core components, may promote the migration, invasion, and malignancy of cancer cells. Aberrant overexpression of YAP/TAZ-TEAD promotes tumorigenesis and is therefore considered oncogenes in many solid tumors. Drug resistance is a major factor undermining the efficacy of cancer drugs. As YAP/TAZ-TEAD complex plays a role in intrinsic and acquired resistance to various chemotherapeutic and targeted therapy drugs, there is increasing interest in combining a TEAD inhibitor with various cancer therapies. Since elevated YAP/TAZ-TEAD activity has been implicated in multiple cancer types at various stages of cancer progression and cancer types, Drugging the TEAD hydrophobic pocket, which was discovered in 2015, remains as an attractive and proven strategy to modulate the activity. Despite the progresses, only 3 small molecule TEAD inhibitors are currently being tested in Phase I clinical trials which includes: VT3989b NCT04665206 from Vivacare, IK-930b NCT05228015 from Ikena Oncology and IAG-933, NCT0485737 from the Novartis Oncology. As such, there is a need to uncover alternative TEAD inhibitors for cancer therapeutics. We report novel small molecule inhibitors that form a covalent complex with the conserved cysteine of the TEAD palmitoylation site. Compounds inhibited TEAD transcriptional target genes in cancer cells. Cellular proliferation and colony forming assay data strongly displayed cellular sensitivity in Hippo signaling altered cancer cell lines. TEAD1 dependency of gastric cancer cell lines enhance cellular sensitivity in response to small molecule inhibitors. Transcriptional profiling and RNA seq data indicate that the covalent inhibitors specifically downregulate down-stream transcriptional target genes. With our exciting key data, we are exploring multiple other oncology targets to use our Pan-TEAD inhibitors either as a monotherapy or combination therapy. We expect to complete our Technology Disclosure on additional targets before the meeting and to add exciting data for the Cancer drug development community.

Citation Format: Ramesh Kumar, Joel Toh, Joanne Thian, Noorul Farzana Mohideen, Jialin Sun, Sayan Chakraborty, Jayantha Gunaratne, Wanjin Hong. Identification of small molecule Pan-TEAD inhibitors disrupting YAP-TEAD protein-protein interaction and targeting gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB033.
Abstract LB048: Unleashing the power of p53 mRNA therapeutics to suppress proliferation of p53 mutant tumors
Authors: Heo Yong Ho , Shin Seung-Hyun , Han Youngjin , Lim Chang Gyu , Kim Innah , Lee Ji Hee , Lee Gunwoo , Jeong Seongju , Kim Yunjae , Byun Jooyun , Kim Daejin , Choi In Young
Published: April 2024

The p53 protein, recognized as the guardian of the genome, plays a pivotal role in suppressing tumor formation. The TP53 gene, which encodes the p53 protein, is commonly subject to mutations and deletions in many cancer types resulting in loss of tumor suppressor activity. A significant proportion of patients diagnosed with lung, pancreatic, ovarian, and head and neck cancers exhibit the expression of mutant p53 in their tumors, correlating with unfavorable prognosis and survival outcomes.This study endeavors to assess the efficacy of therapeutic tumor suppressive mRNA which induces expression of wild-type p53 protein across diverse cancer types. Optimization of the 5’ and 3’ untranslated regions (UTRs) and the 5’ cap has been undertaken to enhance the efficient expression of p53 mRNA. The growth inhibitory potential of p53 mRNA therapy has been evaluated across p53 mutant cancer cell lines representing various cancer origins, along with normal or p53 wild-type cancer cell lines. We have substantiated that the p53 mRNA therapeutics can selectively inhibit the proliferation of p53 mutant cancer cells. Furthermore, we have confirmed that p53 mRNA treatment upregulated modulator of apoptosis (PUMA) and B-cell translocation gene 2 (BTG2) and cell cycle arrest via p21 upregulation. In vivo efficacy assessments of the lipid nanoparticle (LNP)-encapsulated p53 mRNA have been conducted in lung, pancreatic, and ovarian cancer xenograft models. Both regional intratumoral (i.t) and systemic intravenous (i.v) administrations of the p53 mRNA therapeutics have shown substantial suppression of tumor growth, leading to prolonged mouse survival. These results underscore the potential of the p53 mRNA therapeutics as a promising avenue for targeted cancer treatment, offering insights into the selective inhibition of p53 mutant cancer cells.

Citation Format: Yong Ho Heo, Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Innah Kim, Ji Hee Lee, Gunwoo Lee, Seongju Jeong, Yunjae Kim, Jooyun Byun, Daejin Kim, In Young Choi. Unleashing the power of p53 mRNA therapeutics to suppress proliferation of p53 mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB048.