bluuebunny/crossref_metadata_2025 huggingface dataset:
Review—Basic and Advanced Inertial Navigation Fluid-Based Technology
Authors: Elaswad R. , El-Sheimy N. , Mohamad A. A.
Published: April 2023

The article reviews most published inertial sensor technologies, including dynamically tuned, optical, MEMS vibratory, mechanical, solid-state, and fluid-based. The working principles of the technologies are elaborated. Also, the advantages and disadvantages of those sensors are laid out. Owing to its excellent overall performance, such as its simple structure, low cost, large measurement range, etc, the current review focuses on the state-of-the-art of fluid-based technology of accelerometers and gyroscopes. The sensing elements of the fluid-based technology that are used in the accelerometer and gyroscope are explained. Moreover, a comparison and analysis of those sensing elements are presented. The comparison shows that the thermal resistor has five orders of magnitude which is the highest dynamic range. However, the porous transducer is higher in bandwidth which is almost 120 Hz. Furthermore, the particle imaging velocimetry gyroscope (PIVG) is reviewed. The PIVG is an innovative technology that is used to measure the angular rate where fluid is used as proof of mass. The review shows that the PIVG is low-cost and almost drift-free. Additionally, compared to commercially available gyroscopes, PIVG provides a superior signal-to-noise ratio (SNR).
Modulation of cytoskeleton in cardiomyopathy caused by mutations in LMNA gene
Authors: Chatzifrangkeskou Maria , Le Dour Caroline , Muchir Antoine
Published: May 2023

Dilated cardiomyopathy caused by mutations in LMNA, encoding A-type lamins (i.e., LMNA cardiomyopathy), is characterized by a left ventricle enlargement and ultimately results in poor cardiac contractility associated with conduction defects. Despite current strategies to aggressively manage the symptoms, the disorder remains a common cause of sudden death and heart failure with decreased ejection fraction. Patient care includes cardioverter defibrillator implantation but the last therapeutic option remains cardiac transplantation. A-type lamins are intermediate filaments and are the main components of the nuclear lamina, a meshwork underlying the inner nuclear membrane, which plays an essential role in both maintaining the nuclear structure and organizing the cytoskeletal structures within the cell. Cytoskeletal proteins function as scaffold to resist external mechanical stress. An increasing amount of evidence demonstrates that LMNA mutations can lead to disturbances in several structural and cytoskeletal components of the cell such as microtubules, actin cytoskeleton, and intermediate filaments. Collectively, this review focuses on the significance of these cytoskeletal modulators and emphasizes their potential therapeutic role in LMNA cardiomyopathy. Indeed, molecular tuning of cytoskeletal dynamics has been successfully used in preclinical models and provides adequate grounds for a therapeutic approach for patients with LMNA cardiomyopathy.
Two weeks of arm cycling sprint interval training enhances spinal excitability to the biceps brachii
Authors: Lockyer Evan J. , Alizadeh Shahab , Compton Chris T. , Button Duane C. , Power Kevin E.
Published: April 2023

Two weeks of arm cycling sprint interval training (SIT) improves subsequent aerobic exercise performance and induces changes within the descending corticospinal pathway. Specifically, spinal excitability is enhanced following training, whereas overall corticospinal excitability does not change. These results suggest that the enhanced spinal excitability may represent a neural adaptation to training. Future work is required to discern the precise neurophysiological mechanisms underlying these observations.
Impact of sex on the cerebrovascular response to incremental aerobic exercise in moderately trained endurance athletes
Authors: Chamoun Nassif , Drapeau Audrey , Labrecque Lawrence , Imhoff Sarah , Roy Marc-Antoine , Billaut François , Rahimaly Kevan , Brassard Patrice
Published: April 2023

The results of this study suggest the cerebrovascular response between moderately endurance-trained males and females is comparable in spite of a higher arterial carbon dioxide and cardiac output in males compared with females during incremental aerobic exercise until volitional exhaustion. This could help in providing a better understanding of the key differences in cerebral blood flow regulation between males and females during aerobic exercise.
A Predictive Disease Risk Model for Ankylosing Spondylitis: Based on Integrated Bioinformatic Analysis and Identification of Potential Biomarkers Most Related to Immunity
Authors: Gao Wenxin , Hou Ruirui , Chen Yungang , Wang Xiaoying , Liu Guoyan , Hu Wanli , Yao Kang , Hao Yanke
Published: April 2023

Background. The pathogenesis of ankylosing spondylitis (AS) is still not clear, and immune-related genes have not been systematically explored in AS. The purpose of this paper was to identify the potential early biomarkers most related to immunity in AS and develop a predictive disease risk model with bioinformatic methods and the Gene Expression Omnibus database (GEO) to improve diagnostic and therapeutic efficiency. Methods. To identify differentially expressed genes and create a gene coexpression network between AS and healthy samples, we downloaded the AS-related datasets GSE25101 and GSE73754 from the GEO database and employed weighted gene coexpression network analysis (WGCNA). We used the GSVA, GSEABase, limma, ggpubr, and reshape2 packages to score immune data and investigated the links between immune cells and immunological functions by using single-sample gene set enrichment analysis (ssGSEA). The value of the core gene set and constructed model for early AS diagnosis was investigated by using receiver operating characteristic (ROC) curve analysis. Results. Biological function and immune score analyses identified central genes related to immunity, key immune cells, key related pathways, gene modules, and the coexpression network in AS. Granulysin (GNLY), Granulysin (GZMK), CX3CR1, IL2RB, dysferlin (DYSF), and S100A12 may participate in AS development through NK cells, CD8+ T cells, Th1 cells, and other immune cells and represent potential biomarkers for the early diagnosis of AS occurrence and progression. Furthermore, the T cell coinhibitory pathway may be involved in AS pathogenesis. Conclusion. The AS disease risk model constructed based on immune-related genes can guide clinical diagnosis and treatment and may help in the development of personalized immunotherapy.
Cluster Synchronization in Networked Phase Oscillators under Periodic Coupling
Authors: Li S. S.
Published: May 2023

The synchronization behaviors of coupled oscillators under time-varying couplings are of both theoretical and practical significance. While recent studies show that synchronization is suppressed by time-varying coupling in general, the underlying mechanism is still not very clear. Here, by the kernel of sinusoidal coupling function, we revisit the effects of periodic coupling on the synchronization of networked phase oscillators. It is found that the suppressed synchronization by periodic coupling is attributed to the formation of synchronization clusters in the transition from desynchronization to global synchronization. The clusters are different in size and frequency but are all locked to the frequency of the periodic coupling. We demonstrate this phenomenon numerically in different network models and conduct a theoretical analysis on the numerical results based on the method of dimension reduction. The findings extend our knowledge on the dynamical responses of a complex network to external drivings, and shed lights on the mechanism of suppressed synchronization in periodically coupled oscillators.
Stability and Finite-Time Synchronization Analysis for Recurrent Neural Networks with Improved Integral-Type Time-Varying Delays
Authors: Li Meng , Maimaitiaili Gulijiamali
Published: April 2023

This paper studies the stability criterion of integral time-varying recurrent neural networks (RNNs) with zero lower bound and finite-time synchronization based on improved sliding mode control (SMC). Firstly, a sufficient criterion for universal asymptotic stability of RNNs with integral time-varying delays is obtained by estimating a tight upper bound of augmented Lyapunov-Krasovskii functional (LKF) derivative with inequality scaling technique and mutually convex combined inequality. Secondly, in order to eliminate the time that error system state trajectory slides along sliding mode flow pattern until convergence at the origin, based on drive response and SMC theory, a suitable sliding mode controller is designed by considering that sliding mode flow pattern is equal to synchronization error. Finally, maximum allowable upper bound of delay under different delay derivatives are obtained by considering trajectory change of input function under different initial value. Synchronization trajectory of drive and response systems with mismatched parameters and activation functions under the influence of controller are studied, and synchronization time which is required for error system to reach stability is obtained. Simulation results show that the introduction of integral delay can be more comprehensive from both difference and area, so that drive system state is eventually steady at equilibrium point and synchronized with response system. Stability criterion of this paper not only has less conservative and computation complexity but also has shorter synchronization control time.
Study on Anisotropic Petrophysical Modeling of Shale: A Case Study of Shale Oil in Qingshankou Formation in Sanzhao Sag, Songliao Basin, China
Authors: Li Ang , Zhang Liyan , Yang Jianguo , Li Shichao , Xiao Fei , Yao Yulai , Huang Yiming , Liu Bo , Li Longsheng
Published: April 2023

Seismic petrophysics is an important link between seismic elastic properties and reservoir physical properties. Based on the petrological and microstructure characteristics of shale in the Qingshankou formation of Sanzhao sag in the north of Songliao Basin, this paper presents an anisotropy petrophysical model with complex pore structure suitable for organic shale constructed with the use of the Voigt-Reuss-Hill average model, an anisotropy self-consistent approximation+differential effective medium model, and the layering of clay and kerogen is simulated by using the Voigt-Reuss-Hill average and bond transform to achieve the simulation of shale anisotropy. Based on the proposed model, the effects of the organic volume fraction, porosity, and pore aspect ratio on rock elastic properties are discussed. The result shows that with the increase of matrix porosity, all elastic parameters show a decreasing trend; with the increase of the organic volume fraction, except shear modulus, other elastic parameters show an increasing trend. Through comparative analysis, the elastic parameters (Lamé impedance and Shear impedance) sensitive to the organic volume fraction and porosity are optimized; the seismic petrophysical cross-plot template with core calibration is constructed. The application shows that the predicted S-wave velocity based on the proposed model is in good agreement with the S-wave velocity derived from dipole source logging. Combined with the high-precision prestack elastic parameter inversion, the “sweet spot” characteristics can be well described, and the research could contribute to a better “sweet spot” description and provide a better support for shale exploration in Sanzhao sag.
Phytosterols Alleviate Hyperlipidemia by Regulating Gut Microbiota and Cholesterol Metabolism in Mice
Authors: Lv Wei-Jie , Huang Jie-Yi , Lin Jin , Ma Yi-Mu , He Shi-Qi , Zhang Ying-Wen , Wang Tian-Ze , Cheng Ke , Xiong Ying , Sun Feng-Gang , Pan Zhong-Chao , Sun Jing-Bo , Mao Wei , Guo Shi-Ning
Published: April 2023

Phytosterols (PS) have been shown to regulate cholesterol metabolism and alleviate hyperlipidemia (HLP), but the mechanism is still unclear. In this study, we investigated the mechanism by which PS regulates cholesterol metabolism in high-fat diet (HFD) mice. The results showed that PS treatment reduced the accumulation of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in the serum of HFD mice, while increasing the serum levels of high-density lipoprotein cholesterol (HDL-C). Compared with HFD mice, PS not only increased the antioxidant activity of the liver but also regulated the mRNA expression levels of enzymes and receptors related to cholesterol metabolism. The hypolipidemic effect of PS was abolished by antibiotic (Abx) intervention and reproduced by fecal transplantation (FMT) intervention. The results of 16S rRNA sequencing analysis showed that PS modulated the gut microbiota of mice. PS reduced the relative abundance of Lactobacillus and other bile salt hydrolase- (BSH-) producing gut microbiota in HFD mice, which are potentially related to cholesterol metabolism. These findings partially explain the mechanisms by which PS regulates cholesterol metabolism. This implies that regulation of the gut microbiota would be a potential target for the treatment of HLP.
Fabrication of UV Photodetectors Based on Photoelectrochemically Etched Nanoporous Silicon: Effect of Etchants Ratio
Authors: Thahe Asad A. , Qaeed Motahher A. , Abdullah Suhail Najm , Badawy Ibrahim M. , Alqaraghuli Hasan , Alajerami Yasser Saleh Mustafa , Mindil A. , AL-Farga Ammar
Published: April 2023

Despite several attempts to enhance the electrical and charge carrier transport characteristics of porous silicon (PSi), the requisite conditions for optimally synthesizing n-PSi with appealing optoelectronic properties are yet to be achieved. Therefore, this research explores the effect of the chemical ratio of precursor materials (HF:C2H6O:H2O2) on the surface morphology, crystalline structure, and optical and electric properties of PSi. The PSi was produced by photoelectrochemical etching followed by anodization of the n-type Si under light illumination. The properties of the as-prepared PSi were studied by means of microscopic and spectroscopic techniques. The HF:C2H6O:H2O2 chemical ratio was optimized at 2 : 1 : 1. A metal–semiconductor–metal (MSM) ultraviolet photodetector (Pt/n-PSi/Pt) was fabricated, which exhibited high performances under UV light (365 nm) illumination. The photodetector was shown to be highly stable and reliable with a rapid rise time of 0.56 s at a bias voltage of +5 V. The MSM photodetector displayed responsivity (Rp) of 9.17 A/m at 365 nm, which significantly exceeds the values reported for TiC/porous Si/Si in some contemporary research. The photodetector fabricated from n-PSi, synthesized at an optimum chemical ratio (2 : 1 : 1) exhibited the best photodetection performance, possibly due to the high porosity and defect-free state of the n-PSi thin films.
The Effect of Superabsorbent Polymer on Fair-Faced Concrete Performance Based on White Cement
Authors: Shi Jun , Wu Zhangbao , Zhuang Jinping , Chen Rong , Zhu Tongran , Yuan Chenzheng , Li Huixia
Published: April 2023

Introducing superabsorbent polymer (SAP) into white fair-faced concrete can achieve the purpose of internal curing, which is beneficial to the popularization and application of white fair-faced concrete. The effects of the SAP mixture and internal curing water content on the properties of white fair-faced concrete were investigated macroscopically through the indexes, including slump, electric flux, standard cube compressive strength, and tensile splitting strength. The mechanism of these influence laws was further analyzed by scanning electron microscope (SEM). The results show that the slump increases with the increase of SAP content and internal curing water; the incorporation of SAP can significantly reduce the electric flux of white fair-faced concrete and improve its durability; with the increase of SAP admixture and internal curing water content, the compressive strength of white fair-faced concrete decreases, which has a significant impact on the early compressive strength; the addition of SAP is beneficial to the improvement of the tensile properties and tensile-compression ratio of white fair-faced concrete. When the SAP content is 0.2%, and the internal curing water is ten times the mass of SAP, the optimal performance of white fair-faced concrete can be achieved; the water released by the SAP promotes the secondary hydration reaction, which can refine the internal structure of white fair-faced concrete.
Study on the Cotton Fabrics with Photoinduced Reversibly Switchable Wettability
Authors: Zhang Caining , Wang Xuman
Published: April 2023

Superhydrophobic cotton fabric with photoinduced reversibly switchable wettability was prepared by a coating of the hydrophobic copolymer and α-Fe2O3 nanoparticles. The surface morphology of the fabric was observed by scanning electron microscope (SEM). The wettability of the surface was tested under UV illumination and after storage in the dark. The chemical composition of the cotton fabric surfaces before and after UV illumination was analyzed using an X-ray photoelectron spectroscope (XPS) and FTIR. The experimental results showed that the prepared cotton fabric exhibited the excellent superhydrophobic property with a contact angle (CA) of 157.3 ± 2.9°, and became superhydrophilic after UV illumination for 64 h. The surface wettability reverted back to its initial superhydrophobic state after being stored in the dark for 30 d. Based on the XPS and FTIR analyses, the possible mechanism was discussed, and the switchable wettability was caused by the content change of the hydroxyl groups on the α-Fe2O3 surface. Moreover, the superhydrophobic cotton fabric also became superhydrophilic after sunlight illumination for 120 h.
Research on Social Governance of Network Public Opinion: An Evolutionary Game Model
Authors: Qiu Zeguo , Yuan Xiuang , Yin Yuchen
Published: April 2023

Compared with the past, public opinion in the we-media era has become more difficult. How to incentivize social networking providers (SNPs) to participate in network public opinion governance and guide we-media practitioners (WPs) to standardize their dissemination are prominent problems that urgently need to be solved in response to network public opinion. This article supplements the perspective of network public opinion governance research and constructs a tripartite evolutionary game model including government, SNPs, and WPs. Then, after analyzing the influencing factors of the evolution of different agents’ strategies through model solving and numerical simulation, this article finds that reasonable rewards and punishments can promote SNPs to participate in network public opinion governance. Finally, this article proposes that the government should build a social governance system for network public opinion, which will effectively reduce governance costs and improve governance efficiency.
[Retracted] A Multicentre Randomized Controlled Clinical Study of Cross Electro‐Nape‐Acupuncture (CENA) for the Treatment of Pseudobulbar Palsy in Patients with Tracheotomy Intubation for Severe Cerebral Haemorrhage
Authors: Xu Shengnan , Guo Sihui , Sun Manchao , Cui Cheng , Xu Ke , He Xue , Cui Yanan , Gao Ziyin , Wu Zhenqi , Xue Jiaxin , Ma Yucai , Sun Jiahong , Zhang Rui , Cai Guoliang , Cai Guofeng
Published: April 2023

Objective. The objective is to evaluate the clinical efficacy of cross electro‐nape‐acupuncture (CENA) in the treatment of pseudobulbar palsy in patients with tracheotomy intubation for severe cerebral haemorrhage and to provide an innovative acupuncture method for the treatment of such patients. Methods. A total of 126 patients from six trial centres who met the inclusion criteria were randomly divided into three groups according to the random number table method in the ratio of 1 : 1 : 1, with 42 patients in each group, and the three groups were divided into CENA group, electro‐acupuncture group, and acupuncture group. Each group’s acupuncture treatment lasted for 30 minutes, and the needles were removed at the end of the treatment. Acupuncture was performed once a week on Sunday only and twice a day from Monday to Saturday, a total of 4 weeks of treatment. The SWT, FDA, ChSWAL‐QOL, and TCRGS scores of the three groups of patients before and after treatment were compared to evaluate the effect of CENA on remodelling the function of swallowing reflex and cough reflex and promoting the recovery of dysarthria and swallowing quality of life in pseudobulbar palsy in patients with tracheotomy intubation for severe cerebral haemorrhage. Results. After treatment, the WST and TCRGS grade scores decreased and the FDA and ChSWAL‐QOL scores increased significantly in all three groups compared with the pretreatment scores and were statistically significant. There was a significant difference between the three groups for these four indicators after treatment; the comparison between groups showed significant differences in the CENA group compared to the electro‐acupuncture and acupuncture groups. The efficiency of the CENA group was significantly better than that of the electro‐acupuncture and acupuncture groups. Conclusion. Compared with the acupuncture and electro‐acupuncture groups, the CENA could better promote the remodelling of swallowing function and cough reflex function, promote the recovery of dysarthria, and better improve the quality of life of patients with pseudobulbar palsy from tracheotomy intubation in severe cerebral haemorrhage.
N6-Methyladenosine Promotes Translation of VEGFA to Accelerate Angiogenesis in Lung Cancer
Authors: Zhang Haisheng , Zhou Jiawang , Li Jiexin , Wang Zhaotong , Chen Zhuojia , Lv Ziyan , Ge Lichen , Xie Guoyou , Deng Guoming , Rui Yalan , Huang Hongbing , Chen Likun , Wang Hongsheng
Published: April 2023

Angiogenesis is hijacked by cancer to support tumor growth. RNA modifications such as N6-methyladenosine (m6A) can regulate several aspects of cancer, including angiogenesis. Here, we find that m6A triggers angiogenesis in lung cancer by upregulating VEGFA, a central regulator of neovasculature and blood vessel growth. m6A-sequencing and functional studies confirmed that m6A modification of the 5′UTR (untranslated region) of VEGFA positively regulates its translation. Specifically, methylation of a 5′UTR internal ribosome entry site (IRES) recruited the YTHDC2/eIF4GI complex to trigger cap-independent translation initiation. Intriguingly, the m6A methylation site A856 of the 5′UTR was located within the conserved upstream open reading frame (uORF) of VEGFA IRES-A, which overcomes uORF-mediated translation suppression while facilitating G-quadruplex–induced translation of VEGFA. Targeted specific demethylation of VEGFA m6A significantly decreased expression of VEGFA and reduced lung cancer cell–driven angiogenesis. In vivo and clinical data confirmed the positive effects of m6A modification of VEGFA on angiogenesis and tumor growth of lung cancer. This study not only reveals that the m6A/VEGFA axis is a potential target for lung cancer therapy but also expands our understanding of the impact of m6A modification of IRES in the 5′UTR of mRNA on translation regulation.

Significance:

Methylation of the 5′UTR IRES of VEGFA mRNA increases cap-independent translation via recruitment of the YTHDC2/eIF4GI complex, which stimulates angiogenesis to promote lung tumor growth.
Data from NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer
Authors: Janssens Katleen , Vanhoutte Greetje , Lybaert Willem , Demey Wim , Decaestecker Jochen , Hendrickx Koen , Rezaei Kalantari Hassan , Zwaenepoel Karen , Pauwels Patrick , Fransen Erik , Op de Beeck Ken , Van Camp Guy , Rolfo Christian , Peeters Marc
Published: May 2023

AbstractPurpose:
Analysis of methylation markers in liquid biopsies is a promising technique for the follow-up of patients with metastatic colorectal cancer (mCRC), because they can be used in all patients, regardless of their mutational status. Therefore, we studied the value of NPY methylation analysis in circulating tumor DNA (ctDNA) for accurate response monitoring in patients with mCRC in the PANIB trial.
Experimental Design:
The PANIB trial was a randomized phase II trial designed to compare FOLFOX plus panitumumab and FOLFOX plus bevacizumab in patients with RAS wild-type unresectable mCRC. The results of sequential liquid biopsies were correlated with results of imaging.
Results:
Forty patients were included from six Belgian hospitals. Analysis of the liquid biopsies revealed that higher baseline levels of methylated ctDNA was associated with a significantly shorter overall survival [HR, 1.015; 95% confidence interval (CI), 1.005–1.025; P = 0.002]. Furthermore, 37 patients provided at least two liquid biopsies. Thirty-one of them showed a decrease in the methylation ratio after the start of therapy, which corresponded with stable disease or response on imaging at the first evaluation. When comparing the panitumumab and bevacizumab arm, significantly higher objective response and early tumor shrinkage rates were observed in the panitumumab arm (P = 0.048 and 0.015, respectively). However, due to a small study population, the trial was underpowered to detect a significant difference in survival.
Conclusions:
The results of this study confirm that baseline methylated ctDNA is a prognostic marker and indicate that NPY methylation is a promising marker for response monitoring in patients with mCRC.
Cytochrome P450 Oxidoreductase (POR) Associated with Severe Paclitaxel-Induced Peripheral Neuropathy in Patients of European Ancestry from ECOG-ACRIN E5103
Authors: Shen Fei , Jiang Guanglong , Philips Santosh , Gardner Laura , Xue Gloria , Cantor Erica , Ly Reynold C. , Osei Wilberforce , Wu Xi , Dang Chau , Northfelt Donald , Skaar Todd , Miller Kathy D. , Sledge George W. , Schneider Bryan P.
Published: May 2023

Purpose:

Paclitaxel is a widely used anticancer therapeutic. Peripheral neuropathy is the dose-limiting toxicity and negatively impacts quality of life. Rare germline gene markers were evaluated for predicting severe taxane-induced peripheral neuropathy (TIPN) in the patients of European ancestry. In addition, the impact of Cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5 metabolizer status on likelihood of severe TIPN was also assessed.

Experimental Design:

Whole-exome sequencing analyses were performed in 340 patients of European ancestry who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Patients who experienced grade 3–4 (n = 168) TIPN were compared to controls (n = 172) who did not experience TIPN. For the analyses, rare variants with a minor allele frequency ≤ 3% and predicted to be deleterious by protein prediction programs were retained. A gene-based, case–control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of severe TIPN. CYP star alleles for CYP2C8, CYP3A4, and CYP3A5 were called. An additive logistic regression model was performed to test the association of CYP2C8, CYP3A4, and CYP3A5 metabolizer status with severe TIPN.

Results:

Cytochrome P450 oxidoreductase (POR) was significantly associated with severe TIPN (P value = 1.8 ×10−6). Six variants were predicted to be deleterious in POR. There were no associations between CYP2C8, CYP3A4, or CYP3A5 metabolizer status with severe TIPN.

Conclusions:

Rare variants in POR predict an increased risk of severe TIPN in patients of European ancestry who receive paclitaxel.
Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial
Authors: Dorigo Oliver , Oza Amit M. , Pejovic Tanja , Ghatage Prafull , Ghamande Sharad , Provencher Diane , MacDonald Lisa D. , Torrey Heather , Kaliaperumal Valarmathy , Ebrahimizadeh Walead , Hirsch Heather A. , Bramhecha Yogesh , Villella Jeannine , Fiset Stephan
Published: May 2023

Purpose:

Patients with platinum-resistant ovarian cancer respond poorly to existing therapies. Hence there is a need for more effective treatments.

Patients and Methods:

The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase II study to evaluate the safety and effectiveness of maveropepimut-S with cyclophosphamide in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL maveropepimut-S 3 weeks apart, followed by one 0.1-mL doses, every 8 weeks up to progression. Oral cyclophosphamide, 50 mg twice daily, was administered in repeating weekly on and off cycles.

Results:

Twenty-two patients were enrolled. Median age was 58 years (38–78 years). Among the evaluable population, the objective response rate (ORR) was 21% [90% confidence interval (CI), 7.5%–41.9%], with a disease control rate (DCR) of 63% (90% CI, 41.8%–81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four SD patients maintained clinical benefit up to 25 months. Most treatment-related adverse events (TRAE) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T-cell responses were observed in treated patients with clinical benefit.

Conclusions:

Maveropepimut-S with intermittent low-dose cyclophosphamide is well-tolerated, with clinical benefit for patients with recurrent ovarian cancer. Observed responses are irrespective of the platinum status.
Abstract A022: Translation initiation factor 2B (eIF2B) stimulates mutant KRAS function in cancer
Authors: Kim Hyungdong , Ghaddar Nour , Ghahnavieh Laleh Ebrahimi , Wang Shuo , Cho Kwang-Jin , Sasaki Atsuo , Koromilas Antonis E.
Published: May 2023

KRAS mutations appear with high frequency in colorectal, lung and pancreatic cancers, which are the three leading causes of new cancer deaths worldwide. Mutant KRAS is preferentially bound to GTP resulting in continuous cell proliferation. Mutant KRAS exposes cells to oncogenic forms of stress (i.e. genotoxic, metabolic, proteostatic stress), which disrupt proliferation and tissue homeostasis. To cope with stress, cells engage pro-adaptive mechanisms, which act in favor of mutant KRAS to transform cells. An important adaptation mechanism to stress acts at the level of mRNA translation and involves the functional interplay between the translation initiator factors eIF2 and eIF2B. Phosphorylated eIF2 mediates a translational and transcriptional reprogramming to promote adaptation under stress, a process that is antagonized by the guanine exchange function (GEF) of eIF2B. We demonstrate the physical interaction between mutant KRAS and eIF2B by mass spectrometry. Using genetic approaches, we show that eIF2B is required for the survival and proliferation of tumor cells with KRAS mutations via the stimulation of MAPK signaling. We also show that eIF2B contributes to increased resistance of tumor cells to pharmacological inhibition of mutant KRAS forms. Genetic inactivation of eIF2B promotes the formation of mutant KRAS-GDP complexes whereas its pharmacological stimulation facilitates mutant KRAS-GTP complex formation in tumor cells; this data supports a potential GEF function for eIF2B towards mutant KRAS. Cell imaging experiments provide strong evidence for the implication of eIF2B in the association of mutant KRAS with the plasma membrane of tumor cells. Our findings reveal a stimulatory role of eIF2B in mutant KRAS signaling and provide a previously unidentified link between mutant KRAS and mRNA translation with implications in the growth and treatment of cancers with KRAS mutations.

Citation Format: Hyungdong Kim, Nour Ghaddar, Laleh Ebrahimi Ghahnavieh, Shuo Wang, Kwang-Jin Cho, Atsuo Sasaki, Antonis E. Koromilas. Translation initiation factor 2B (eIF2B) stimulates mutant KRAS function in cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A022.
Abstract A023: Structural basis for regulation of MAPK signaling by DUSP5 and DUSP6
Authors: Kung Jennifer E. , Sudhamsu Jawahar
Published: May 2023

The Ras/mitogen-activated protein kinase (MAPK) cascade plays an essential role in several critical cellular processes, such as cell growth and proliferation, and hyperactivation of this pathway is frequently observed in cancer. DUSP5 and DUSP6 are dual specificity phosphatases (capable of dephosphorylating phospho-tyrosines as well as phospho-serines/threonines) that act as key regulators of MAPK signaling that inactivate ERK by dephosphorylating its activation loop and sequestering ERK in an inactive state. DUSP5 and DUSP6 have been reported to function as tumor suppressors in some Ras-driven cancers, including skin cancer and pancreatic cancer, while promoting tumorigenesis in other contexts, such as thyroid cancer or glioblastoma. Despite the importance of these phosphatases in modulating ERK signaling, the structural basis for their interaction with ERK and their dual specificity remain poorly understood. It has also been reported that ERK binding allosterically activates DUSP6, but not DUSP5, and the mechanism underlying this is unclear. While structures of individual domains of these proteins have been solved, there are no structures of full-length DUSP5 or DUSP6, or of an ERK/DUSP complex. To gain insight into the molecular determinants of ERK dephosphorylation by these phosphatases, we have purified full-length DUSP5 and DUSP6, as well as the phosphatase domains of both proteins. We have also generated full-length phosphorylated ERK2 (pERK2). Through in vitro dephosphorylation assays, we have observed that full-length DUSP5 and DUSP6 dephosphorylate ERK2 much more rapidly than the isolated phosphatase domains, indicating an essential role for their N-terminal regulatory domains in this process. Using biolayer interferometry, we show that catalytically inactive mutants of full-length DUSP5 and DUSP6 bind very tightly to pERK2 with low nanomolar affinity. We have reconstituted complexes of pERK2 bound to catalytically inactive full-length DUSP5 or DUSP6, and we are pursuing structures of these complexes using x-ray crystallography and cryo-electron microscopy. These studies will improve our understanding of the regulation of ERK and its phosphatases DUSP5 and DUSP6 and shed light on the similarities and differences between these complexes. These structures could also potentially reveal the structural features underlying the dual specificity of DUSP5 and DUSP6.

Citation Format: Jennifer E. Kung, Jawahar Sudhamsu. Structural basis for regulation of MAPK signaling by DUSP5 and DUSP6 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A023.
Abstract A025: Investigating the molecular mechanisms of regulation of the RAS guanine nucleotide exchange factor, SOS1 by Grb2 and 14-3-3
Authors: Martinez Orlando E. , Sudhamsu Jawahar
Published: May 2023

The MAPK/ERK signaling pathway is one of the most heavily mutated in human cancers. In normal cells, the stimulation of receptor tyrosine kinases (e.g. EGFR) on the plasma membrane signals the GTP-loading and activation of RAS through a mechanism catalyzed by the guanine nucleotide exchange factor (GEF) Son of Sevenless 1 (SOS1). RAS activation, in turn, initiates the RAF-MEK-ERK kinase cascade which triggers many downstream signals that can affect gene transcription, protein translation, cell proliferation, and feedback regulation. Several factors regulate SOS1 GEF activity, including two autoinhibitory domains within its own multi-domain architecture. First, the N-terminal domains of SOS1 occlude the allosteric RAS-GTP binding site in the RAS exchanger motif—thereby precluding SOS1 GEF activity—and this inhibition is relieved upon membrane recruitment and PIP2 phospholipid binding. Second, the C-terminal Proline-Rich Region (PRR) of SOS1 also occludes allosteric RAS-GTP binding by an unknown mechanism and is relieved when the growth factor receptor-bound protein 2 (Grb2) binds to motifs in the PRR. While the independent functions of these domains and interactions to inhibition and activation of GEF activity of SOS1 are known, the molecular mechanisms are poorly understood. An additional negative feedback loop involves the phosphorylation of the SOS1 PRR at two sites by the ribosomal protein S6 kinase 1 (RSK1), a substrate of downstream ERK. These modifications create 14-3-3 binding sites on SOS1, where 14-3-3 binding downregulates GEF activity, possibly by obstructing Grb2 association with the SOS1 PRR and membrane localization of SOS1. This work reconstitutes the SOS1:Grb2 and the SOS1:14-3-3 protein complexes in vitro to study the molecular mechanisms underlying SOS1 activity regulation.

Citation Format: Orlando E. Martinez, Jawahar Sudhamsu. Investigating the molecular mechanisms of regulation of the RAS guanine nucleotide exchange factor, SOS1 by Grb2 and 14-3-3 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A025.
Abstract A037: Oncogenic RAS signals from lysosomes to activate mTORC1 in multiple myeloma
Authors: Bolomsky Arnold , Young Ryan M.
Published: May 2023

Oncogenic mutations of both NRAS and KRAS are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in MM have remained enigmatic, and there is little evidence to support a dominant role for classical MAPK signaling downstream of RAS in this disease. We recently used an unbiased proteogenomic approach to dissect RAS signaling in MM and discover that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on lysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways (PMID: 36115844). To gain further insights into this novel mode of RAS signaling located away from the plasma membrane, we have employed mass spectrometry to characterize proteins associated with lysosomes isolated from MM cell lines. We observed that RAS isoforms, SLC3A2 and several components of the mTORC1 signalosome were purified with lysosomes, consistent with RAS activation of mTORC1 on lysosomes. To identify novel regulators of oncogenic RAS signaling at the lysosome, we used phospho-proteomics to identify proteins with significantly reduced levels of phosphorylation following acute inhibition of KRAS activity with the KRAS G12D inhibitor, MRTX1133, in a MM cell line bearing a KRAS G12D mutation. Many of these phospho-proteins were also associated with lysosomes, including MTOR, which had substantially reduced phosphorylation at the amino-acid dependent phosphorylation site S1261 following KRAS inhibition. Pathway analysis of proteins present in lysosomes and phosphorylated downstream of oncogenic KRAS showed enrichment for proteins that regulate intracellular trafficking. Among these proteins, we found that disruption of a RAB GAP essential for survival in RAS-dependent MM cells substantially reduced associations between RAS and MTOR and nearly abolished RAS-dependent mTORC1 activity. These data suggest that mutant RAS utilizes lysosomal resident proteins to coordinate the colocalization of itself with mTORC1 on lysosomes to drive pathogenic signaling in MM. More generally, these studies suggest that targeting the intracellular localization of RAS may be an alternative route to inhibit oncogenic RAS signaling in MM.

Citation Format: Arnold Bolomsky, Ryan M. Young. Oncogenic RAS signals from lysosomes to activate mTORC1 in multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A037.
Abstract B022: A non-conserved histidine residue on KRAS drives paralog selectivity of the KRAS G12D inhibitor MRTX1133
Authors: Keats Miles , Han John , Lee Yeon-Hwa , Lee Chih-Shia , Luo Ji
Published: May 2023

The discovery of small molecule inhibitors against mutant KRAS protein has been a breakthrough in targeted therapy. MRTX1133 is the first non-covalent inhibitor with selectivity for the mutant KRAS G12D protein. Using isogenic cell lines expressing single Ras allele to test the selectivity of this compound, we found that in addition to KRAS G12D, MRTX1133 shows significant activity against several other KRAS mutants as well as wildtype KRAS protein. In contrast, MRTX1133 exhibits no activity against both G12D and wildtype forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 towards KRAS is associated with its binding to histidine 95 on KRAS, a residue that is not conserved in HRAS and NRAS. Reciprocal mutation of amino acid 95 among the three Ras paralogs resulted in reciprocal change in their sensitivity towards MRTX1133. Thus, histidine 95 is an essential selectivity handle for MRTX1133 towards KRAS. This knowledge could aid the development of other KRAS-selective inhibitors. (Funding: this research was supported by the Intramural Research Program of the National Cancer Institute, NIH)

Citation Format: Miles Keats, John Han, Yeon-Hwa Lee, Chih-Shia Lee, Ji Luo. A non-conserved histidine residue on KRAS drives paralog selectivity of the KRAS G12D inhibitor MRTX1133 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B022.
Abstract IA05: Uncovering new structural insights into RAS interactions with effectors and regulators
Authors: Simanshu Dhirendra K.
Published: May 2023

RAS proteins, which act as binary molecular switches, are implicated in approximately 20% of all cancer cases and are known to play a critical role in the initiation and progression of some of the deadliest cancers, such as lung, colon, and pancreatic cancers. When RAS proteins are in the GTP-bound state, they interact with various effector proteins, such as RAF Kinase, PI 3-Kinase, and RalGDS, leading to the activation of multiple signaling pathways in the cell. Our recent structural studies, including investigations into the KRAS-SIN1 (RBD-PH domain), KRAS-RAF1 (RBD-CRD), and SHOC2-MRAS-PP1C complex, have provided new insights into the vital role played by the switch-II and interswitch regions in the interaction between RAS and downstream effectors and regulators. These findings extend beyond the earlier observations that the switch-I region of RAS proteins alone plays a more significant role in RAS-effector interactions. Furthermore, research into the KRAS4a-SIN1 complex and the reported interaction between KRAS4a and hexokinase have given us a glimpse into the isoform-specific RAS-effector interaction. Finally, the investigation of the SHOC2-MRAS-PP1C complex has also revealed the crucial role played by other members of the RAS subfamily, such as MRAS, in RAF activation by canonical RAS isoforms. Collectively, these studies have shed new light on the mechanisms by which RAS interacts with downstream effectors and regulators.

Citation Format: Dhirendra K. Simanshu. Uncovering new structural insights into RAS interactions with effectors and regulators [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA05.
Abstract IA13: Identifying metabolic dependencies in pancreatic cancer
Authors: Kimmelman Alec
Published: May 2023

Pancreatic cancers are highly resistant to currently available therapeutics which results in a 5-year survival rate of approximately 11%. We believe that this resistance points toward altered cell metabolic pathways. In this regard we have previously shown that that oncogenic Kras promotes a rewiring of pancreatic cancer metabolism allowing carbon sources to be utilized in a variety of biosynthetic pathways. Importantly, several of these metabolic pathways are critical for tumor growth and therefore represent potential therapeutic targets. Ongoing studies from our group are exploring targeting various aspects of metabolism as therapeutic approaches. Additional studies from our group have demonstrated pancreatic cancers have elevated basal autophagy which is required for their continued growth. Importantly, inhibition of autophagy pharmacologically or genetically leads to decreased oxidative phosphorylation, a drop in ATP production, and ultimately growth inhibition. These findings have implicated autophagy as a key component of pancreatic cancer metabolism and have motivated the opening of multiple clinical trials assessing the efficacy of hydroxychloroquine as an autophagy inhibitor in pancreatic cancer, which have now shown clinical activity in pancreatic cancer patients. Recently, we have identified a novel selective autophagy pathway that degrades MHC-I and promotes immune evasion in pancreatic tumors. Ongoing work from our group seeks to understand the metabolic contributions that autophagy makes in pancreatic tumors. These and other aspects of pancreatic cancer metabolism will be discussed.

Citation Format: Alec Kimmelman. Identifying metabolic dependencies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA13.
Supplementary Figure S9: from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Genomic regions marked by increased trimethyl-H3K4 are enriched in IDH1-mutant glioma MCTS lines when compared to IDH1-wild-type MCTS lines.
Data from (R)-2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in IDH-Mutant Cancers
Authors: Gunn Kathryn , Myllykoski Matti , Cao John Z. , Ahmed Manna , Huang Bofu , Rouaisnel Betty , Diplas Bill H. , Levitt Michael M. , Looper Ryan , Doench John G. , Ligon Keith L. , Kornblum Harley I. , McBrayer Samuel K. , Yan Hai , Duy Cihangir , Godley Lucy A. , Koivunen Peppi , Losman Julie-Aurore
Published: May 2023

Abstract
Oncogenic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG], an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only (R)-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2. However, there is ample evidence to suggest that (R)-2HG has other functionally relevant targets in IDH-mutant cancers. Here, we show that (R)-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in IDH-mutant AML and IDH-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in IDH-mutant cancers.
Significance:
Mutant IDH is known to induce histone hypermethylation. However, it is not known if this hypermethylation is functionally significant or is a bystander effect of (R)-2HG accumulation in IDH-mutant cells. Here, we provide evidence that KDM5 inhibition by (R)-2HG contributes to mutant IDH–mediated transformation in AML and glioma.