bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of the Dynamic Mechanical Properties of Recycled Concrete Containing Ferronickel Slag Subjected to Impact
Authors: Luo Caisong , Qi Ai , Zhou Changlin , Liu Ruifeng , Qiu Hao , Lang Lin , Zhu Zheming
Published: July 2021

In order to study the dynamic mechanical properties of recycled concrete with ferronickel slag, dynamic experiments on cylindrical specimens (φ 73 mm × 36.5 mm) were performed using a split Hopkinson pressure bar (SHPB) system. The effects of loading rate and recycled aggregate replacement rate on the compressive strength, toughness index, peak strain, and failure pattern of the concrete were investigated, and four different loading rates and aggregate replacement rates were selected. In addition, cohesive elements were embedded between C3D8R elements in the numerical model using Python language to simulate the failure process of the recycled concrete, and the reliability of the simulation was validated by the obtained experimental results. It was found that the peak strain of the recycled concrete was significantly higher than that of the ordinary concrete; however, its peak stress was lower than that of the ordinary concrete. In comparison to the recycled concretes containing 70% and 100% recycled coarse aggregates (RCAs), the toughness index amplification of the recycled concrete containing 30% RCAs was the most obvious. The failure pattern and mechanical properties of the numerical model were consistent with those of the test specimens, thus validating the reliability of the numerical simulation.
Data Authentication for Wireless Sensor Networks with High Detection Efficiency Based on Reversible Watermarking
Authors: Gao Guangyong , Feng Zhao , Han Tingting
Published: July 2021

Data authentication is an important part of wireless sensor networks (WSNs). Aiming at the problems of high false positive rate and poor robustness in group verification of existing reversible watermarking schemes in WSNs, this paper proposes a scheme using reversible watermarking technology to achieve data integrity authentication with high detection efficiency (DAHDE). The core of DAHDE is dynamic grouping and double verification algorithm. Under the condition of satisfying the requirement of the group length, the synchronization point is used for dynamic grouping, and the double verification ensures that the grouping will not be confused. According to the closely related characteristics of adjacent data in WSNs, a new data item prediction method is designed based on the prediction‐error expansion formula, and a flag check bit is added to the data with embedded watermarking during data transmission to ensure the stability of grouping, by which the fake synchronization point can be accurately identified. Moreover, the embedded data can be recovered accurately through the reversible algorithm of digital watermarking. Analysis and experimental results show that compared with the previously known schemes, the proposed scheme can avoid false positive rate, reduce computation cost, and own stronger grouping robustness.
Effects of Landslides on the Displacement of a Bridge Pile Group Located on a High and Steep Slope
Authors: Zhang Y. F. , Li J. , Li W. , Li J. M. , Liu H. Y.
Published: July 2021

Engineering practice shows that the deformation of the slide‐resistant pile may be transferred to the adjacent bridge foundation on an inclined slope, which can compromise the safety of the entire bridge. However, this phenomenon has rarely been considered in the past. To reveal the deformation transfer mechanism between the slide‐resistant pile and the adjacent structures, a full‐scale field test was performed on a high and steep slope located in a section of a certain railway. A numerical analysis model was constructed to simulate the field test and validate its parameters. Moreover, parametric analysis was also conducted to examine the influence of the pile length, pile diameter, and arrangement of the pile foundation. The results show that the bridge pile foundation is simultaneously affected by the “load transfer effect” caused by the slide‐resistant pile and “traction effect” of the sliding slope. With the distance between the pile foundation and the slide‐resistant pile increasing, the dominant factor affecting the deformation mode of the pile body is switched from the “load transfer effect” to the “traction effect.” Furthermore, a critical embedment depth exists for the bridge pile foundation built on a high and steep slope, which varies at different locations along the inclined stratum. In addition, using a pile arrangement with a larger pile diameter and lower number of piles is more beneficial for controlling the horizontal displacement of the bridge foundation. The results of the research provide a reference for the safety control of the engineering on the high and steep slope.
Inhibitory Control Deficits in Children with Tic Disorders Revealed by Object-Hit-and-Avoid Task
Authors: Cothros Nicholas , Medina Alex , Martino Davide , Dukelow Sean P. , Hawe Rachel L. , Kirton Adam , Ganos Christos , Nosratmirshekarlou Elaheh , Pringsheim Tamara
Published: July 2021

Background. Tic disorders may reflect impaired inhibitory control. This has been evaluated using different behavioural tasks, yielding mixed results. Our objective was to test inhibitory control in children with tics through simultaneous presentation of multiple, mobile stimuli. Methods. Sixty-four children with tics (mean age 12.4 years; 7.5-18.5) were evaluated using a validated robotic bimanual exoskeleton protocol (Kinarm) in an object-hit-and-avoid task, in which target and distractor objects moved across a screen and participants aimed to hit only the targets while avoiding distractors. Performance was compared to 146 typically developing controls (mean age 13 years; 6.1-19.9). The primary outcome was the percentage of distractors struck. Results. ANCOVA (age as covariate) showed participants struck significantly more distractors (participants without comorbid ADHD, 22.71% [SE 1.47]; participants with comorbid ADHD, 23.56% [1.47]; and controls, 15.59% [0.68]). Participants with comorbid ADHD struck significantly fewer targets (119.74 [2.77]) than controls, but no difference was found between participants without comorbid ADHD (122.66 [2.77]) and controls (127.00 [1.28]). Participants and controls did not differ significantly in movement speed and movement area. Just over 20% of participants with tics fell below the age-predicted norm in striking distractors, whereas fewer than 10% fell outside age-predicted norms in other task parameters. Conclusions. In children with tics (without comorbid ADHD), acting upon both targets and distractors suggests reduced ability to suppress responses to potential triggers for action. This may be related to increased sensorimotor noise or abnormal sensory gating.
Innovative Landslide Susceptibility Mapping Portrayed by CA‐AQD and K‐Means Clustering Algorithms
Authors: Yimin Mao , Yican Li , Simon Mwakapesa Deborah , Genglong Wang , Ahangari Nanehkaran Yaser , Asim Khan Muhammad , Maosheng Zhang
Published: July 2021

This study aims at proposing and designing an improved clustering algorithm for assessing landslide susceptibility using an integration of a Chameleon algorithm and an adaptive quadratic distance (CA‐AQD algorithm). It targets improving the prediction capacity of clustering algorithms in landslide susceptibility modelling by overcoming the limitations found in present clustering models, including strong dependence on the initial partition, noise, and outliers as well as difficulties in quantifying the triggering factors (such as rainfall/precipitation). The model was implemented in Baota District, Shaanxi province, China. The CA‐AQD algorithm was adopted to split all grids in the study area into many groups with more similar characteristic values, which also owed to efficiently quantifying the uncertain (rainfall) value by using AQD. The K‐means algorithm divides these groups into five susceptibility classes according to the values of landslide density in each group. The model was then evaluated using statistical metrics and the performance was validated and compared to that of the traditional Chameleon algorithm and KPSO algorithm. The results show that the CA‐AQD algorithm attained the best performance in assessing landslide susceptibility in the study area. Thus, this work adds to the literature by introducing the first empirical integration and application of the CA‐AQD algorithm to the assessment of landslides in the study area, which then is a new insight to the field. Also, the method can be helpful for dealing with landslides for better social and economic development.
Blockchain-Enabled Privacy-Preserving Location Sharing Scheme for LBSNs
Authors: Zhu Liang , Liu Xiaowei , Yu Liping , Cai Zengyu , Zhang Jianwei
Published: July 2021

The rise of Internet of Things (IoT) technology promotes the rapid development of location services industry. The idea of smart connectivity also provides a new direction for Location-Based Social Networks (LBSNs). However, due to limited calculate ability and internal storage space of IoT devices, historical location data of users is generally stored in the central server, which is likely to cause the disclosure of users’ private data. In this paper, we propose a Blockchain-enabled Privacy-Preserving Location Sharing (B-PPLS) scheme, which is a new framework that not only protects user location privacy but also provides effective location sharing services for users. For B-PPLS, location data owners can share the location area instead of location coordinates to Requesters, in order to realize the location privacy preserving. Also, the Merkle hash tree is utilized to divide the location area, so as to realize the multilevel privacy preserving. Furthermore, four algorithms are proposed to achieve the four stages of initialization, location record, location sharing, and location verification, respectively. Finally, we analyze the security of the proposed B-PPLS scheme and compare the performance with other related location privacy-preserving schemes by experimental evaluation.
unfolding consequences of postponing routine dental care
Authors: Ortuño Borroto Duniel Ricardo , Vargas Buratovic Juan Pablo , Carrasco-Labra Alonso
Published: July 2021

The COVID-19 pandemic represents some of the most distressing challenges for health systems all over the world in the past decades, forcing clinicians to modify standards, prioritise treating conditions that require immediate care, and implement elements of remote attention in record time (Douglas et al., 2020). These challenges have also had an impact in the population’s oral health.
Abstract 1011: Disulfiram superior to ALDH1A1 inhibitor analogs in targeting ovarian cancer stem cells
Authors: Caminear Michael , Harrington Brittney , Annunziata Christina
Published: July 2021

Epithelial ovarian cancer (EOC) is a global health burden and remains the fifth leading cause of cancer related death in women worldwide with the poorest five-year survival rate of the gynecological malignancies. Disease recurrence is the major cause of morbidity and mortality of EOC, considered to be driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs). TIC populations in EOC can be identified by the expression of molecular markers such as aldehyde dehydrogenase (ALDH), CD133, Nanog and Sox2. Although the TICs have been characterized, little progress has been made in finding drugs to specifically target this population, which has driven the research and development of novel therapies to prevent relapse. We previously showed that disulfiram, an ALDH inhibitor, effectively targeted TICs in terms of viability, spheroid formation, oxidative stress and also prevented relapse in an in vivo model of EOC. In this study we sought to determine whether specific targeting of ALDH isoenzyme ALDH1A1 would provide similar benefit as the broader pathway inhibition by disulfiram. NCTs 505 and 506 are isoenzyme specific ALDH1A1 inhibitors whose activity was compared to the effects of disulfiram. Following treatment with either the NCTs or disulfiram, the viability of TICs versus adherent cells, sphere formation, oxidative stress and cell death in our in vitro relapse model were measured and compared in OC cell lines. We found that disulfiram decreased the viability of TICs significantly more effectively versus non-TIC cells, while no trend was observed when the cells were treated with the NCTs. Disulfiram also induced greater amounts of ROS than the NCTs and affected the expression of proteins associated with the NFkB and JNK signaling pathways. Comparison of disulfiram to the direct targeting of ALDH1A1 with the NCTs suggests that disulfiram's broader cellular effects are more suitable as a therapeutic to eradicate TICs from tumors and prevent OC relapse. In addition to providing insight into a fitting treatment for TICs, the comparison of disulfiram to NCTs 505 and 506 has increased our understanding of disulfiram's mechanism of action. Further elucidation of disulfiram's mechanism has the potential to reveal additional targets to treat OC TICs and prevent disease recurrence.

Citation Format: Michael Caminear, Brittney Harrington, Christina Annunziata. Disulfiram superior to ALDH1A1 inhibitor analogs in targeting ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1011.
Abstract 1021: Investigating the mechanism of PARP7 inhibition in type I interferon signaling by arrayed CRISPR screening
Authors: Gui Bin , Abo Ryan , Flynn Patrick , Lu Alvin Z. , Mo Jan-Rung , Gozgit Joseph M. , Vasbinder Melissa M. , Varsamis Zacharenia A. , Santospago Andrew , Richon Victoria M. , Kuntz Kevin W. , Keilhack Heike , Mitchison Timothy J. , Niepel Mario
Published: July 2021

Genomic instability in cancer cells leads to cellular stress through the accumulation of aberrant nucleic acid species in the cytosol. We have shown that PARP7, a monoPARP, is a negative regulator of cytosolic nucleic acid sensing in cancer cells. RBN-2397 is a potent and selective PARP7 inhibitor that induces antitumor immunity in preclinical models and is currently being evaluated in a Phase I clinical trial. In our preclinical investigations, we found that in a subset of cancer cell lines, such as NCI-H1373, inhibition of PARP7 triggers Type I IFN release, STAT1 phosphorylation, and growth arrest. In contrast, other cell lines, for example, HARA, do not mount an IFN-response upon PARP7 inhibition, even though they are responsive to transfection of exogenous nucleic acids and PARP7 is expressed and enzymatically active. To investigate the underlying mechanism of PARP7 inhibition and to determine the drivers of the differential sensitivity across cell lines we performed arrayed CRISPR knockout screens, targeting approximately 240 genes in the nucleic acid sensing and IFN signaling pathways, in the presence and absence of PARP7 inhibition. Our arrayed screens confirmed multiple hits from a previous genome-wide pooled synthetic/lethal CRISPR dropout screen. For example, targeting genes in the cGAS/STING pathway conferred resistance to PARP7 inhibition in the NCI-H1373 responder cells, suggesting a critical dependence on this sensing pathway. In the PARP7 inhibitor-resistant HARA cells, deletion of components of innate immune-signaling (such as AIM2 and ADAR1), the NF-κB pathway, and genes involved in autophagy sensitized the cells to PARP7 inhibition. We further delineated the function of PARP7 by comparing the effects of the CRISPR perturbation across different cellular readouts such as STAT1 phosphorylation, IFN release, and proliferation. With our work, we shed light on the mechanism by which PARP7 acts as a critical suppressor of the innate immune response. Our findings demonstrate both redundancy and crosstalk between different nucleic acid-sensing pathways and may explain why some cell lines are resistant to PARP7 inhibition.

Citation Format: Bin Gui, Ryan Abo, Patrick Flynn, Alvin Z. Lu, Jan-Rung Mo, Joseph M. Gozgit, Melissa M. Vasbinder, Zacharenia A. Varsamis, Andrew Santospago, Victoria M. Richon, Kevin W. Kuntz, Heike Keilhack, Timothy J. Mitchison, Mario Niepel. Investigating the mechanism of PARP7 inhibition in type I interferon signaling by arrayed CRISPR screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1021.
Abstract 1101: Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer
Authors: Wu Shaocong , Luo Min , To Kenneth K. , Zhang Jianye , Su Chaoyue , Zhang Hong , An Sainan , Wang Fang , Chen Da , Fu Li-Wu
Published: July 2021

Epidermal growth factor receptor (EGFR)-mutated lung cancer constitutes a major subgroup of non-small cell lung cancer (NSCLC) and osimertinib is administrated as first-line treatment. However, most patients with osimertinib treatment eventually relapse within one year. The underlying mechanisms of osimertinib resistance remain largely unexplored. In this study, we found that osimertinib resistance could be triggered by the intercellular transfer of wild type EGFR protein encapsulated in exosomes from osimertinib-insensitive NSCLC cells to EGFR-mutated osimertinib-sensitive cells and then the activation of PI3K/AKT and MAPK signaling pathways both in vitro and in vivo. Importantly, osimertinib significantly increased the formation and secretion of exosomes linked to the upregulation of a Rab GTPase (RAB17). These results demonstrate the intercellular transfer of exosomal wild type EGFR maybe a novel resistant mechanism of osimertinib. These findings provide a proof of concept for targeting exosomes to prevent and reverse the osimertinib resistance.

Citation Format: Shaocong Wu, Min Luo, Kenneth K. To, Jianye Zhang, Chaoyue Su, Hong Zhang, Sainan An, Fang Wang, Da Chen, Li-Wu Fu. Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1101.
Abstract 1108: A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters
Authors: Zhang Haiyun , Wang Xuan , Chen Xiaozhuo
Published: July 2021

Cancer is the second leading cause of death in the US. Multidrug resistance (MDR) and the resulting ineffectiveness of the drug treatment are responsible for most relapses of cancer and cancer-related death. One major mechanism of MDR is the efflux of multiple drugs mediated by ATP-binding Cassette (ABC) multidrug transporters. ABC transporters pump drugs with different structures and mechanisms of action out of cancer cells using ATP-provided energy. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism1. Intratumoral extracellular ATP levels of various cancer types are 103 to 104 times higher than those in their corresponding normal tissues2. Our previous studies have shown that extracellular ATP is internalized by cancer cell via macropinocytosis, and promotes cancer drug resistance by fueling ABC transporters and increase its efflux activities3. However, whether extracellular ATP can indeed enhance efflux of drugs, and the underlying mechanism besides providing energy remain unclear. Our current study results showed extracellular ATP decreased intracellular accumulation and thereby enhanced efflux of 3H-labeled chemotherapeutic drug and targeted drug in human cancer cells. The results of quantitative reverse transcription PCR, western blot and immunofluorescence microscopy demonstrated that extracellular ATP can also significantly upregulate ABC transporters at mRNA and protein levels, and change the intracellular localization of the latter. These results suggest that extracellular ATP has profound regulatory effects on ABC transporters and thus promotes drug resistance, linking the ATP-rich tumor microenvironment with cancer drug resistance. The completion of the study will expand our understanding of the roles of extracellular ATP in cancer, and reveal new therapeutic targets for reducing drug resistance and enhance anticancer efficacy of chemotherapeutics and targeted drugs. 1. Pavlova N, Thompson C. Cell Metab. (2016) 23:27-47 2. Falzoni S, et al., Interface Focus. (2013) 3: 20120101 3. Wang X, et al., Oncotarget. (2017) 8(50):87860-87877

Citation Format: Haiyun Zhang, Xuan Wang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1108.
Abstract 1126: Solute carrier (SLC) transporter-mediated metabolic reprogramming during enzalutamide resistance in prostate cancer
Authors: Verma Shiv Shankar , Shankar Eswar , Chan Ricky , Gupta Sanjay
Published: July 2021

Prostate cancer is the second-leading cause of cancer-related mortality among men in the United States. Androgen receptor (AR) signaling is dominant survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) through medical or surgical castration is the mainstay treatment for prostate cancer patients. Enzalutamide (Xtandi®), a second generation antiandrogen, is frequently prescribed for use in this clinical setting. Patient's response to this medication is usually temporary, and prolong treatment results in the emergence of drug resistance. A better understanding of molecular mechanism and its association with enzalutamide resistance will facilitate circumventing this problem. We employed next generation sequencing (NGS) and compared the transcriptomic profile of paired enzalutamide-sensitive and resistant human prostate cancer LNCaP and C4-2B cells for identification of genes involved in drug resistance along with in silico analysis. NGS data identified 9409 and 7757 genes differentially expressed in LNCaP and C4-2B cells compared to their parental counterparts. A subset of differentially expressed genes in both cell lines were validated at transcript level by qRT-PCR. Data analysis performed by IPA/i-pathway revealed metabolic signaling as predominantly overrepresented pathway and membrane transporters including solute carrier proteins, ATP-binding cassette transporters and other metabolizing enzymes as the most prominent genes dysregulated during metabolic reprogramming in both resistant cell lines. RNA-Seq data of resistant LNCaP cells demonstrate predominance of solute carrier genes, in particular, SLC12A5, SLC25A17 and SLC27A6, during metabolic reprogramming and in the development of drug resistance. Upregulation of these genes were associated with an increase in stemness; higher uptake of lactic/citric acid and lower glucose intake by the resistant cells. Our data suggest predominance of solute carrier genes (SLCs) during metabolic reprogramming of prostate cancer cells in an androgen-deprived environment. SLCs are important in cellular uptake of nutrients and drug absorption, thus could play a significant role in the emergence of drug-resistant phenotype, designating SLC genes as potentially attractive therapeutic targets.

Citation Format: Shiv Shankar Verma, Eswar Shankar, Ricky Chan, Sanjay Gupta. Solute carrier (SLC) transporter-mediated metabolic reprogramming during enzalutamide resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1126.
Abstract 1140: A novel MTA non-competitive PRMT5 inhibitor
Authors: Malik Rohit , Park Peter K. , Barbieri Christopher M. , Blat Yuval , Sheriff Steven , Weigelt Carolyn A. , Kopcho Lisa M. , Celiktas Muge , Ruzanov Max , Naglich Joseph G. , Price Jennifer L. , Harner Mary , Omalley Kevin M. , Deng JIngjing , Schmitz William , Li Guo , Ruan Zheming , Qin Lan-ying , Duke Gerald J. , Rodrigo Iyoncy , Witmer Mark R. , Harden David G. , Demes Shilpa , Arey Brian J. , Soars Matt , Fink Brian E. , Gavai Ashvinikumar V. , Vite Gregory D. , Voliva Charles F.
Published: July 2021

The chromosome 9p21 (chr9p21) locus is deleted in almost 10% of all cancer types. This locus includes the CDKN2A gene that encodes the critical tumor suppressors p19-ARF and p16-INK4a. Methylthioadenosine phosphorylase (MTAP), a gene proximal to CDKN2A, is co-deleted in 80%-90% of tumors with CDKN2A deletion. MTAP plays a critical role in the methionine salvage pathway, and the deletion of MTAP results in the accumulation of its substrate methythioadenosine (MTA). Accumulation of MTA partially inhibits the activity of the arginine methyltransferase PRMT5, causing MTAP deficient cancer cells to be more sensitive to the genetic knockdown of PRMT5. In contrast to genetic knockdown, sensitivity to pharmacological inhibition of PRMT5 does not appear to stratify with MTAP status. However, currently known PRMT5 inhibitors all possess SAM competitive or uncompetitive MOIs, which generally require displacement of MTA from the active site for binding. We hypothesize that leveraging the high MTA state induced by MTAP deficiency will require an inhibitor that can bind PRMT5 without disrupting bound MTA. Here we report the discovery of a PRMT5 inhibitor with a novel binding mode that is compatible with MTA binding. While this compound possesses the desired MOI, it shows only modestly increased potency toward MTAP-null cells. Mathematical simulations of different inhibitor mechanisms indicate that the degree of selectivity that can be achieved depends on the difference in MTA levels between MTAP-null and WT cells. Our in vitro data suggest that the elevation in intracellular MTA concentrations that occurs with MTAP deletion is not sufficient to confer significantly increased sensitivity to PRMT5 inhibition. We anticipate that the therapeutic index that can be achieved between MTAP-null tumor cells and PRMT5-sensitive normal tissues will be similarly limited in vivo.

Citation Format: Rohit Malik, Peter K. Park, Christopher M. Barbieri, Yuval Blat, Steven Sheriff, Carolyn A. Weigelt, Lisa M. Kopcho, Muge Celiktas, Max Ruzanov, Joseph G. Naglich, Jennifer L. Price, Mary Harner, Kevin M. Omalley, JIngjing Deng, William Schmitz, Guo Li, Zheming Ruan, Lan-ying Qin, Gerald J. Duke, Iyoncy Rodrigo, Mark R. Witmer, David G. Harden, Shilpa Demes, Brian J. Arey, Matt Soars, Brian E. Fink, Ashvinikumar V. Gavai, Gregory D. Vite, Charles F. Voliva. A novel MTA non-competitive PRMT5 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1140.
Abstract 1159: Hexamethylene bisacetamide (HMBA) inhibits the induction of alkaline phosphatase by butyrate in some bladder and colon cancer cell lines
Authors: Lea Michael A.
Published: July 2021

Induction of alkaline phosphatase in colon cancer cells by inhibitors of histone deacetylase activity has been widely used to monitor the induction of differentiation. We have previously identified three human bladder cancer cell lines in which alkaline phosphatase activity can be induced by inhibitors of histone deacetylase (5637, HT1197 and HT1376 cells). In earlier work it was observed that some bromodomain inhibitors inhibit growth and induction of alkaline phosphatase in these cells. After a recent report that HMBA acts as a bromodomain inhibitor, the effects of HMBA on growth and induction of alkaline phosphatase were investigated in two colon cancer cell lines (Caco-2 and HT29) and in 5637, HT1197 and HT1376 bladder cancer cells. Growth was monitored by staining with sulforhodamine B. Incubation with 2 mM butyrate for 72 hours caused induction of alkaline phosphatase in the five cell lines. In some cell lines there was inhibition of growth and of the induction of alkaline phosphatase activity by 2 mM HMBA. Increasing the HMBA concentration to 5 mM caused significant growth inhibition in all five cell lines and significant inhibition of induction of alkaline phosphatase activity by 2 mM butyrate in the 5637, Caco-2 and HT1376 cells, whether expressed as total activity or activity per unit protein. Although the effect of HMBA on induction of alkaline phosphatase in HT29 cells was not statistically significant there is evidence in the literature for inhibition with longer incubation times. The most marked effects on enzyme induction were seen with the HT1376 bladder cancer cells and this distinction was in line with previous studies on the combined effects of butyrate and the well-established bromodomain inhibitor, JQ1. HMBA has been found by several investigators to be an effective inducer of differentiation in erythroleukemia cells as judged by hemoglobin production. The lack of induction of alkaline phosphatase by HMBA as a single agent in any of the cell lines investigated in the present work suggests that different mechanisms of induction of differentiation operate in erythroleukemia cells than in bladder and colon cancer cells.

Citation Format: Michael A. Lea. Hexamethylene bisacetamide (HMBA) inhibits the induction of alkaline phosphatase by butyrate in some bladder and colon cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1159.
Abstract 1164: Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs
Authors: Ammoun Sylwia , Maze Emmanuel A. , Agit Bora , Belshaw Robert , Hanemann C Oliver
Published: July 2021

Deficiency of the tumor suppressor Merlin causes the development of schwannoma, meningioma and ependymoma tumors. These can occur spontaneously or in the hereditary disease Neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Currently available treatments are surgery or radiosurgery which are only partially effective, with tumors frequently reoccurring and in case of meningioma often as a higher grade. There is an urgent need for effective drug treatments.In this study, we investigated the role of Human Endogenous Retrovirus Type K (HERV-K) and its targetability in Merlin negative schwannoma and meningioma tumors by using tissues and primary cells isolated form patients employing immunohistochemistry, immunocytochemistry, western blotting and proliferation assays.

We demonstrate that HERV-K proteins are overexpressed in Merlin negative schwannoma and all meningioma grades. Furthermore, we implicate CRL4DCAF1 and YAPT/EAD Hippo pathway in this overexpression and suggest that exosome transport of the HERV-K Envelope (Env) protein might contribute to schwannoma development.

We also show that: (i) Ectopic overexpression of HERV-K Env in normal Schwann cells increased proliferation and upregulated the transcription factor c-Jun. Env overexpression also increased activity of the extracellular signal-regulated kinase 1/2 (pERK1/2), a known mitogenic pathway in schwannoma. (ii) An anti-Env monoclonal antibody decreased pERK1/2 and reduced proliferation of schwannoma cells. iii) FDA-approved retroviral protease inhibitors Ritonavir, Atazanavir and Lopinavir decreased pERK1/2 and cyclin D1 and reduced proliferation of schwannoma and grade I meningioma cells.

We provide evidence for HERV-K Env contributing to the development of NF2-associated schwannomas and meningiomas. Considering the urgent need of drugs to treat NF2, we suggest the trialling of antiretroviral protease inhibitors, and consideration of anti-HERV-K Env immunotherapy, as well as TEAD-specific inhibitors in these patients. The above treatments would also be potentially beneficial for patients with other tumors caused by Merlin deficiency. 

Citation Format: Sylwia Ammoun, Emmanuel A. Maze, Bora Agit, Robert Belshaw, C Oliver Hanemann. Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1164.
Abstract 1180: A novel synthetic lethality treatment strategy for metastatic breast cancer
Authors: Zonneville Justin , Wang Moyi , Alruwaili Mohammed , Eng Kevin , Melendy Thomas , Park Ben Ho , Iyer Renuka , Fountzilas Christos , Bakin Andrei V.
Published: July 2021

Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we present preclinical data supporting a novel combination therapy strategy for treatment of p53-deficient cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-deficient breast cancers. However, we found that BER-mediated repair was significantly dysregulated in p53-mutant cancer cells. Treatment with deoxyuridine analogues induced accumulation of DNA damage in p53-mutant cells and inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A in p53 wild-type cells conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients.

Citation Format: Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Thomas Melendy, Ben Ho Park, Renuka Iyer, Christos Fountzilas, Andrei V. Bakin. A novel synthetic lethality treatment strategy for metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1180.
Abstract 1191: Differences in gene mutation characteristics of gastric, intestinal and colorectal stromal tumors
Authors: Wang Qian , Zhang Hushan , Zhao Sihui , Wang Jianxun , Ma Ning , Zhu Jun
Published: July 2021

Background: Gastrointestinal stromal tumors (GIST), which were thought to originate from interstitial cells of Cajal,is the most common malignant mesenchymal neoplasm, and account for 1%-3% of digestive tract tumors. Drug development in GIST has successfully utilized the KIT/PDGFRA oncogenic mutation. At the same time, drug sensitivity and resistance, such as imatinib resistance, is a problem should be paid more attention. We analyzed features of kit/pdgfra mutation in different region GIST of Chinese patients, which will provide reference information for the use of targeted drugs among patients with gastric, intestinal or colorectal stromal tumors.

Methods: Tumor samples of 201 HCC patients were consecutively collected in China from January 2018 to June 2020, next generation sequencing (NGS) was performed to detect gene mutation by 3D Medicines, a laboratory accredited by College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA.

Results: All these tissue samples were divided as stomach (n=109), small intestine (n=79), colon and the rectum (n=13). The average age of three group were 57, 55 and 50, the proportion of males in gastric, intestinal and colorectal stromal tumor were 64.2% (79/109), 60.8% (48/79) and 61.5%(8/13), respectively. NGS analysis showed that, frequency of kit were 71.5% (78/109), 83.5% (66/79) and 61.5% (8/13), among witch, mutation of exon 9 were 1.8%(2/109), 27.8% (22/79), 30.7% (4/13), and exon 11 were 66.1%(72/109), 53.2%(42/79), 30.8%(4/13); frequency of pdgfra were 14.7%(16/109), 3.8%(3/79) and 7.7%(1/13), and mutation frequency of pdgfra exon 18 were 11.9% (13/109), 1.3%(1/79), 7.7%(1/13).

Conclusions: GIST is more inclined to occur in male. kit was the main mutation in GIST, however, only 1.8% of gastric GIST carry exon 9 mutations, a large proportion (66.1% and 53.2%) of gastric and intestinal GISTs carry exon 11 mutations. Besides, more mutation of pdgfra happened in gastric GIST than intestinal and colorectal GISTs. These results demonstrate that GIST occurred in different location may show different sensitivity or resistance to drugs targeting KIT/PDGFRA signals.

Citation Format: Qian Wang, Hushan Zhang, Sihui Zhao, Jianxun Wang, Ning Ma, Jun Zhu. Differences in gene mutation characteristics of gastric, intestinal and colorectal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1191.
Abstract 1197: A multi tumor survey of Nectin-4 expression to guide BT8009 indication selection
Authors: Campbell Carly T. , Smale Robert , Rigby Michael , Watson Shawn , Dickson Amy , Gelb Tara , Cohen Heather , Lee Pierre , Ragheb Josette William , Blakemore Stephen J.
Published: July 2021

Introduction: Bicycles® are a novel class of fully synthetic, short, constrained peptides. BT8009 consists of a bicyclic peptide targeting the tumor antigen Nectin-4, linked to the cytotoxin monomethyl auristatin E (MMAE) via a molecular spacer and cleavable linker. Nectin-4 is a validated tumor target and is highly expressed in a wide range of tumors. A Phase I/II dose escalation/expansion study, BT8009-100 (NCT04561362), enrolling patients with advanced solid tumors associated with Nectin-4 expression is ongoing in the US. Here we report the analysis of tumor tissue microarrays (TMAs) stained with a Nectin-4 immunohistochemistry (IHC) assay to support patient selection for the BT8009-100 study. Methods: We developed a clinical grade Nectin-4 IHC assay on the Leica platform using a proprietary rabbit monoclonal α-Nectin-4 primary antibody (Abcam, Burlingame, CA) and the BOND Polymer Refine detection kit. TMAs of cancer types reported to have high Nectin-4 expression, including esophageal, pancreatic, bladder, head & neck, stomach, non-small cell lung, breast, and ovarian cancer, were stained and manually scored for Nectin-4 levels, with the tumor microenvironment evaluated in a subset of samples. Nectin-4 H-scores (stain intensity on a scale of 0-3 x percent positive tumor cells) were generated by a pathologist independently for tumor cell membrane and tumor cytoplasm. H-scores ≥ 100 in the tumor membrane or cytoplasm were considered positive. Results: In all indications tested, a greater degree of Nectin-4 positivity was observed in the tumor cytoplasm as compared to tumor membrane. Breast and bladder cancer had the greatest frequency of Nectin-4 positivity. Subtype analysis in breast cancer identified enrichment of Nectin-4 expression in hormone receptor negative and human epidermal growth factor receptor 2 positive tumors.

Conclusion: The frequency of Nectin-4 expression as measured by IHC across multiple tumor types may guide clinical strategy for the BT8009 program.

TableIndicationTotal cores (n)Percent Tumor Membrane PositivePercent Tumor Cytoplasm PositivePercent Tumor Membrane or Cytoplasm PositiveBreast225164957Bladder142274256Esophagus14073032Head & Neck69102532Lung15731717Ovarian8921315Pancreas96123Stomach131022

Citation Format: Carly T. Campbell, Robert Smale, Michael Rigby, Shawn Watson, Amy Dickson, Tara Gelb, Heather Cohen, Pierre Lee, Josette William Ragheb, Stephen J. Blakemore. A multi tumor survey of Nectin-4 expression to guide BT8009 indication selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1197.
Abstract 1203: ZL-1211 exhibits broad anti-tumor activity in CLDN18.2 high- and low-expressing models
Authors: Konno Hiroyasu , Li Yong , Dai Xinchuan , Sun Bee , Shi Wenhua , Chen Min , Li Wenying , Li Shou , Kang Lishan , Li Holly , Tao Frank , Yin Sophia , Wang Bingbing , Shan Lishen , Wan Bing , Veiby Petter , Yan James , Hsu Karl , Bellovin David , Kabbarah Omar
Published: July 2021

Targeting the lineage marker CLDN18.2 with ADCC-eliciting monoclonal antibody therapeutics has shown promising clinical activity in the gastric, esophageal, and pancreatic cancer indications. However, clinical efficacy was mainly observed in tumors that expressed very high levels of CLDN18.2, which represented only ~30% of cases, and was much less pronounced in tumors with low levels of CLDN18.2. Here we present ZL-1211, a novel CLDN18.2-targeting monoclonal antibody that was engineered to promote enhanced ADCC and to drive efficacy in tumors that exhibit a broad range of CLDN18.2 expression levels. We demonstrate that ZL-1211 can robustly inhibit the growth of tumor cells that express not only high but also low levels of CLDN18.2 in vitro as well as a variety of in vivo models. ZL-1211 strongly induced ADCC, ADCP, and CDC and inhibited the growth of a series of in vitro models more potently than the leading clinical benchmark, including cell lines engineered to exogenously express varying levels of CLDN18.2 as well as gastric and pancreatic cancer cell lines that endogenously express low, medium, and high target levels. Consistent with our in vitro findings, ZL-1211 also exhibited greater anti-tumor efficacy than the leading clinical benchmark in CLDN18.2-positive patient-derived xenograft and syngeneic models in vivo. Together, our data suggest that ZL-1211 might provide therapeutic benefit for a wider spectrum of low- and high-CLDN18.2 expressing tumors than the leading clinical benchmark. A Ph1 dose escalation study to assess the safety and preliminary efficacy of ZL-1211 is planned.

Citation Format: Hiroyasu Konno, Yong Li, Xinchuan Dai, Bee Sun, Wenhua Shi, Min Chen, Wenying Li, Shou Li, Lishan Kang, Holly Li, Frank Tao, Sophia Yin, Bingbing Wang, Lishen Shan, Bing Wan, Petter Veiby, James Yan, Karl Hsu, David Bellovin, Omar Kabbarah. ZL-1211 exhibits broad anti-tumor activity in CLDN18.2 high- and low-expressing models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1203.
Abstract 1207: Thymoquinone-based drug development targeting SUCLA2 loss in advanced prostate cancer
Authors: Takahashi Chiaki
Published: July 2021

RB1 gene is often homozygously deleted or mutated in prostate adenocarcinomas following acquirement of castration resistance and/or metastatic ability. We found that SUCLA2 gene is frequently involved in the deletion of the RB1 gene region in advanced prostate cancer. SUCLA2 constitutes the β-subunit of succinate CoA ligase heterodimer that reversibly converts succinyl CoA into succinate. We sought the possibility that deletion of SUCLA2 gives rise to a metabolic vulnerability that could be targeted therapeutically. Indeed, we found a significant metabolic shift in SUCLA2-deleted prostate cancer cells, including lower mitochondrialrespiratory activity. By screening a number of libraries for compounds that induce cell death selectively in SUCLA2-deficient prostate cancer cells, we identified thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) and PMA (phorbol-12-myristate-13-acetate) from a natural compound library. Thymoquinone has been known for its anti-tumor efficacy. We examined the biological activity of a number of thymoquinone derivatives and synthesized chemical probes to identify molecular target of this agent. In this presentation, we will propose a new therapeutic approach to advanced prostate cancers.

Citation Format: Chiaki Takahashi. Thymoquinone-based drug development targeting SUCLA2 loss in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1207.
Abstract 1210: NFX1-123: A potential therapeutic target in cancer
Authors: Chintala Sreenivasulu , Anbarasu Anand , Katzenellenbogen Rachel A.
Published: July 2021

Background: NFX1-123 is the longer splice variant isoform of the NFX1 gene and is highly expressed in cervical cancer. Cervical cancer is caused by high-risk HPV infections, and NFX1-123 is a protein partner with the HPV oncoprotein E6. Together, NFX1-123 and E6 affect cellular growth, longevity, differentiation, and the immune response. The expression status of NFX1-123 in cancers beyond cervical cancer, and its potential as therapeutic target, has not been investigated.

Methods: TSVdb of TCGA was used to quantify NFX1-123 expression in 25 primary cancers tissues compared to adjacent normal tissues. The NFX1-123 protein structure was predicted using I-TASSER: Interactive Threading ASSEmbly Refinement tool. The modeled structure was submitted to the MTi-Openscreen Virtual screening web-server using ZINC-Database to retrieve suitable drug molecules, and further screening was evaluated by PyRx interphase and AutoDock Vina. The top four compounds, found to bind in silico to NFX1-123, were tested experimentally to determine their inhibitory effects on NFX1-123-related cellular growth and survival by MTT assay.

Results: 44% of cancers (11 of 25) had significant differences in NFX1-123 expression when compared to adjacent normal solid tissues. Nine of 11 cancers (88%) had greater NFX1-123 expression: breast invasive carcinoma, cholangiocarcinoma, colon adenocarcinoma, renal cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, sarcoma, and stomach adenocarcinoma. Two of 11 cancers (18%) had reduced NFX1-123 expression: lung squamous cell carcinoma, and pheochromocytoma and paraganglioma. Additionally, HPV+ head and neck cancers had greater expression of NFX1-123 compared to HPV- head and neck cancers. Bioinformatics and proteomic predictive analysis revealed the 3-D structure of the NFX1-123; with this structure, drug libraries were screened for high binding affinity compounds. 17 drugs with binding energies range from -11.3 to -10 Kcal/mol. were found. The top four compounds were used to treat HPV- and HPV+ cervical and head and neck cancer cell lines in culture, and two (R428 and Ketoconazole) were found to reduce NFX1-123 protein levels and inhibit cell growth and survival. R428 was also found to inhibit NFX1-123 and regulate autophagy and autophagy-mediated cell death.

Conclusion: Nine out of 25 (36%) cancers expressed high levels of NFX1-123, and drug targeting of NFX1-123 can lead to cell growth inhibition. NFX1-123 may be a potential novel therapeutic target in cancers that highly express NFX1-123.

Citation Format: Sreenivasulu Chintala, Anand Anbarasu, Rachel A. Katzenellenbogen. NFX1-123: A potential therapeutic target in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1210.