bluuebunny/crossref_metadata_2025 huggingface dataset:
Catheter ablation versus antiarrhythmic drugs with risk factor modification for treatment of atrial fibrillation: a protocol of a randomised controlled trial (PRAGUE-25 trial)
Authors: Osmancik Pavel , Havránek Štěpán , Bulková Veronika , Chovančík Jan , Roubíček Tomáš , Heřman Dalibor , Čarná Zuzana , Tuka Vladimír , Matoulek Martin , Fiala Martin , Jiravský Otakar , Stregl-Hruskova Sylvie , Latiňák Adam , Kotryová Jiřina , Jarkovský Jiří
Published: June 2022

Introduction

Atrial fibrillation (AF), with a prevalence of 2%, is the most common cardiac arrhythmia. Catheter ablation (CA) has been documented to be superior to treatment by antiarrhythmic drugs (AADs) in terms of sinus rhythm maintenance. However, in obese patients, substantial weight loss was also associated with AF reduction. So far, no study has compared the modern non-invasive (AADs combined with risk factor modification (RFM)) approach with modern invasive (CA) treatment. The aim of the trial is to compare the efficacy of modern invasive (CA) and non-invasive (AADs with risk factor management) treatment of AF.

Methods and analysis

The trial will be a prospective, multicentre, randomised non-inferiority trial. Patients with symptomatic AF and a body mass index >30 will be enrolled and randomised to the CA or RFM arm (RFM+AAD) in a 1:1 ratio. In the CA arm, pulmonary vein isolation (in combination with additional lesion sets in non-paroxysmal patients) will be performed. For patients in the RFM+AAD arm, the aim will be a 10% weight loss over 6–12 months, increased physical fitness and a reduction in alcohol consumption. The primary endpoint will be an episode of AF or regular atrial tachycardia lasting >30 s. The secondary endpoints include AF burden, clinical endpoints associated with AF reoccurrence, changes in the quality of life assessed using dedicated questionnaires, changes in cardiorespiratory fitness and metabolic endpoints. An AF freedom of 65% in the RFM+AAD and of 60% in the CA is expected; therefore, 202 patients will be enrolled to achieve the non-inferiority with 80% power, 5% one-sided alpha and a non-inferiority margin of 12%.

Ethics and dissemination

The PRAGUE-25 trial will determine if modern non-invasive AF treatment strategies are non-inferior to CA. The study was approved by the Ethics Committee of the University Hospital Kralovske Vinohrady. Results of the study will be disseminated on scientific conferences and in peer-reviewed scientific journals. After the end of follow-up, data will be available upon request to principal investigator.

Trial registration number

ClinicalTrials.gov Registry (NCT04011800).
High-definition transcranial infraslow pink noise stimulation for chronic low back pain: protocol for a pilot, safety and feasibility randomised placebo-controlled trial
Authors: Adhia Divya Bharatkumar , Mani Ramakrishnan , Reynolds John N J , Vanneste Sven , De Ridder Dirk
Published: June 2022

Introduction

Chronic low back pain (CLBP) is a common disabling health condition. Current treatments demonstrate modest effects, warranting newer therapies. Brain imaging demonstrates altered electrical activities in cortical areas responsible for pain modulation, emotional and sensory components of pain experience. Treatments targeting to change electrical activities of these key brain regions may produce clinical benefits. This pilot study aims to (1) evaluate feasibility, safety and acceptability of a novel neuromodulation technique, high-definition transcranial infraslow pink noise stimulation (HD-tIPNS), in people with CLBP, (2) explore the trend of effect of HD-tIPNS on pain and function, and (3) derive treatment estimates to support sample size calculation for a fully powered trial should trends of effectiveness be present.

Methods and analysis

A pilot, triple-blinded randomised two-arm placebo-controlled parallel trial. Participants (n=40) with CLBP will be randomised to either sham stimulation or HD-tIPNS (targeting somatosensory cortex and dorsal and pregenual anterior cingulate cortex). Primary outcomes include feasibility and safety measures, and clinical outcomes of pain (Brief Pain Inventory) and disability (Roland-Morris disability questionnaire). Secondary measures include clinical, psychological, quantitative sensory testing and electroencephalography collected at baseline, immediately postintervention, and at 1-week, 1-month and 3 months postintervention. All data will be analysed descriptively. A nested qualitative study will assess participants perceptions about acceptability of intervention and analysed thematically.

Ethics and dissemination

Ethical approval has been obtained from Health and Disability Ethics Committee (Ref:20/NTB/67). Findings will be reported to regulatory and funding bodies, presented at conferences, and published in a scientific journal.

Trial registration number

ACTRN12620000505909p.
Anti-cancer potential of cannabis terpenes in a Taxol-resistant model of breast cancer
Authors: Tomko Andrea M. , Whynot Erin G. , O'Leary Lauren F. , Dupré Denis J.
Published: June 2022

Chemotherapeutic resistance can limit breast cancer outcomes; therefore, the exploration of novel therapeutic options is warranted. Isolated compounds found in cannabis have previously been shown to exhibit anti-cancer effects, but little is known about their effects in resistant breast cancer. Our study aimed to evaluate the effects of terpenes found in cannabis in in vitro chemotherapy-resistant model of breast cancer. We aimed to identify whether five terpenes found in cannabis produced anti-cancer effects, and whether their effects were improved upon co-treatment with cannabinoids and flavonoids also found in cannabis. Nerolidol and β-caryophyllene produced the greatest cytotoxic effects, activated the apoptotic cascade, and reduced cellular invasion. Combinations with the flavonoid kaempferol potentiated the cytotoxic effects of ocimene, terpinolene, and β-myrcene. Combinations of nerolidol and Δ9-tetrahydrocannabinol or cannabidiol produced variable responses ranging from antagonism and additivity to synergy, depending on concentrations used. Our results indicate that cannabis terpenes, alone or combined with cannabinoids and flavonoids, produced anti-cancer effects in chemotherapy-resistant breast cancer cell lines. This study is a first step in the identification of compounds that could have therapeutic potential in the treatment of resistant breast cancer.
Characteristics analysis of LNG fuel storage module according to low-temperature materials
Authors: Yoon Sung Won , Kim Tae Yeob
Published: June 2022

The purpose of this study is to correctly estimate the applicability of an LNG fuel storage module for cryogenic materials. To prevent pollution from ships, the demand for liquefied natural gas (LNG) fuel-powered ships, known as a form of clean energy, is increasing as a way to satisfy the strengthened emission standards required of ships. Applying LNG fuel engines to ships can solve SO[Formula: see text] reduction problems, reduce the CO2-related EEDI index by 20%, and reduce PMs, which are a target of discussion for future regulations. Therefore, in this study, welding conditions were derived and mechanical properties were tested for the manufacture of small and medium-sized vessel fuel storage modules to which cryogenic materials were applied. In addition, the results of the finite element analysis for the two shapes were compared to derive suitable design conditions by studying the characteristics according to the internal conditions of the fuel storage module.
Theoretical proposal for geometrical prevalences on a magnetic nanobulk
Authors: Aguirre C. A. , Barba-Ortega J.
Published: June 2022

In this work, we study a magnetic nanowire system composed of finite layers, forming a nanobulk. The interaction between the layers (inter-layers) is given by an exchange term [Formula: see text] and the interactions within each layer (intra-layer) are given by a magneto-static interaction energy between the nanowires. We propose to create a geometrical pattern inside of each nanobulk in order to decrease the magneto-static energy through three geometrical configurations of the nanobulk: (i) rectangular–rectangular, (ii) rectangular-cylindrical and (iii) cylindrical–cylindrical. In addition, we incorporate surface/interface effects (another material) to study energy variations inside the nanobulk. As a result, we show that there are certain geometries that minimize drastically the magneto-static energy, also that when the intensity of the [Formula: see text] coupling between the layers is too intense it implies that the energy tends to dissipate inside the nanobulk. In addition, a drop in the magneto-static energy is observed when the interfaces/surfaces of the finite-layer nanobulk are modified.
An Innovative Approach for Personnel Positioning
Authors: Pampouktsi Panagiota , Avdimiotis Spyridon , Kermanidis Katia-Lida , Avlonitis Markos
Published: June 2022

The contribution of the paper is the building of a model to predict the proper employees’ allocation in the Greek public sector. To acknowledge the set and weights of criteria upon which our model feeds data, a validated questionnaire was developed and used to conduct a primary quantitative survey amongst HR departments and employees of state organizations in Greece. On the acquired findings, several experiments were administered using linear and machine learning tools, aiming to replace time consuming and subjective procedures, followed by many organizations. Concluding, data classification algorithms are proposed to predict the best matching of employees, giving as inputs personnel qualifications as well as job specifications, leading to a model based on J48, a decision tree algorithm.
Enabling Practical Cloud Performance Debugging with Unsupervised Learning
Authors: Gan Yu , Liang Mingyu , Dev Sundar , Lo David , Delimitrou Christina
Published: June 2022

Abstract-Cloud applications are increasingly shifting from large monolithic services to complex graphs of loosely-coupled microservices. Despite their benefits, microservices are prone to cascading performance issues, and can lead to prolonged periods of degraded performance.

We present Sage, a machine learning-driven root cause analysis system for interactive cloud microservices that is both accurate and practical. We show that Sage correctly identifies the root causes of performance issues across a diverse set of microservices and takes action to address them, leading to more predictable, performant, and efficient cloud systems.
VAIF
Authors: Toslali Mert , Ates Emre , Huye Darby , Zhang Zhaoqi , Liu Lan , Puterman Samantha , Coskun Ayse K. , Sambasivan Raja R.
Published: June 2022

Developers use logs to diagnose performance problems in distributed applications. But, it is difficult to know a priori where logs are needed and what information in them is needed to help diagnose problems that may occur in the future. We summarize our work on the Variance-driven Automated Instrumentation Framework (VAIF), which runs alongside distributed applications. In response to newly-observed performance problems, VAIF automatically searches the space of possible instrumentation choices to enable the logs needed to help diagnose them. To work, VAIF combines distributed tracing (an enhanced form of logging) with insights about how response-time variance can be decomposed on the criticalpath portions of requests' traces.
Pharos
Authors: Vippagunta Srinivas , Finnigan Ken , Pusukuri Kishore
Published: June 2022

Observability is a necessary capability of modern distributed systems as it allows us to gain actionable insights about reliability, availability, performance, etc., of the system.
Data-Aware Compression for HPC using Machine Learning
Authors: Plehn Julius , Fuchs Anna , Kuhn Michael , Lüttgau Jakob , Ludwig Thomas
Published: June 2022

While compression can provide significant storage and cost savings, its use within HPC applications is often only of secondary concern. This is in part due to the inflexibility of existing approaches where a single compression algorithm has to be used throughout the whole application but also because insights into the behaviour of the algorithms within the context of individual applications are missing.
SLRL
Authors: Nicolas Louis-Marie , Thomas Luis , Hadjadj-Aoul Yassine , Boukhobza Jalil
Published: June 2022

HPC systems are composed of multiple tiers of storage, from the top high performance tier (high speed SSDs) to the bottom capacitive one (tapes). File placement in such architecture is managed through prefetchers (bottom-up) and eviction policies (top-down). Most state-of-the-art work focus on the former while using algorithm flavors of LRU, LFU and FIFO for the latter. LRU was for long considered the best choice. However, recent studies has shown that the simplicity of FIFO could make it more scalable than LRU because of metadata management, and thus more adequate in several cases. In this paper, we propose a new eviction policy based on predicted files lifetimes. It is comparable to FIFO in terms of metadata overhead and simplicity (thus scalability), while giving a hit ratio comparable to LRU (or even 10% better for some tested traces). We also propose a naive multi-tier heterogeneous storage simulator implementation to evaluate such policies.
When Left Is Right and Right Is Wrong: A Case Report of Two Near-Miss Wrong-Sided Peripheral Nerve Blocks
Authors: DeLeon Alexander M. , Samworth Alexander G. , Kazanji Bashar F.
Published: June 2022

Wrong-sided peripheral nerve blocks occur with a surprisingly high frequency despite being described as a “never event.” Timeout procedures are performed and documented, yet timeout omission is rarely cited as a contributing factor for wrong-sided blocks. We present two cases of near-miss wrong-sided peripheral nerve blocks and provide recommendations based on the current literature and the most common contributing factors.
The Flipped Classroom Model of Japanese Teaching Based on Intelligent Decision-Making System
Authors: Wang Xiaodong , Li Zhaohui , Dong Lin , Li Wanting
Published: June 2022

Invert the model of learning in the classroom as a new model in the field of education as modern Internet technologies develop and the concept of learning is updated. It is widely used and promoted in various disciplines. Scholars and front-line teachers have begun to try to introduce the flipped classroom teaching model into language classrooms. With this opportunity, practical studies on flipping classes in foreign languages have emerged. At the same time, the study of the learning process in the classroom has become a problem that needs to be urgently addressed. At present, the linguistic field generally regards the specific teacher-student discourse interaction and verbal communication patterns in the teaching process as a research trend. For the Japanese teaching field, the research on the specific characteristics and patterns of teacher-student verbal communication in classroom discourse is a top priority. Drawing on previous research theories and research methods, the two key research topics are combined. Taking the foreign language curriculum under two different classroom teaching modes as the empirical research object, this paper studies the specific classroom teaching process by using the interaction theory of sociology. At the same time, it uses the Flanders Interaction Analysis System (FIAS) to conduct detailed quantitative research on the interaction of teachers and students in classroom discourse, and analyze and discuss the statistical results. The relevant teaching suggestions for the application of the Japanese flipped classroom teaching mode are put forward, and the problems that must be paid attention to in the practical application are pointed out, in order to provide meaningful reference and reference for the construction of the Japanese teaching mode.
α
,
β

-Normal Operators in Several Variables
Authors: Ahmed Mahmoud Sid Ahmed Ould , Ahmed Ahmed Himadan , Sarosh Ahmad
Published: June 2022

We consider an extension of the concept of

α
,
β

-normal operators in single variable operator to tuples of operators, similar to those extensions of the concepts of normality to joint normality, hyponormality to joint hyponormality, and quasi-hyponormality to joint quasi-hyponormality.
Effect of Yisui Multipurpose Soup’s Amelioration on D-Galactose-Induced Neuronal Cells
Authors: Yan Junfeng , Zhang Xia , Xiao Caixian , Yi Junlu , Chen Qian , Gong Tingliang , Xie Xin , Tao Wenqiang
Published: June 2022

This study clarified the regulatory effect of Yisui multipurpose Soup towards D-galactose-induced cognitive impairment cell model on the molecular level. We first constructed and cultured the cell model of cognitive impairment induced by D-galactose in neurons in vitro and then cultured the cells in the medium supplemented with different doses of drug-containing serum of Yisui multipurpose soup. Expressions of inflammatory cytokine tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), nitric oxide (NO), and interleukin-1β (IL-1β) were assessed by the ELISA and western blot, and cell apoptosis was determined by flow cytometry and TUNEL. The expression changes of apoptosis-related proteins Bcl-2 and Bax were estimated by immunofluorescence, qPCR, and western blot. Finally, we analyzed and made the network interaction diagram of Yisui multipurpose soup-components-targets through the network pharmacology method, from which we could learn that there were 1104 gene targets related to vascular cognitive impairment (VCI) and 1071 component targets of Yisui multipurpose soup. And there were 251 overlapping genes, mainly gathering in protein binding, protein modification, MAPK signaling pathway, and calcium signaling pathway. The expressions of TNF-α, iNOS, NO, and IL-1β were significantly decreased after the culture medium was replaced by medium containing drug serum. We also found that the effect of high-dose drug-containing serum on the expression of inflammatory factors was better than that of low dose. The Yisui multipurpose soup drug serum in the medium not only significantly increased Bcl-2 expression and effectively reduced Bax expression, but also inhibited the apoptosis of neurons induced by D-galactose. In conclusion, Yisui multipurpose soup could effectively protect D-galactose-induced neuronal cell cognitive impairment by orchestrating expressions of the inflammatory factors TNF-α, iNOS, NO, and IL-1β and the apoptosis-related proteins Bcl-2 and Bax.
Stability and Bifurcation Analysis of a Fractional‐Order Food Chain Model with Two Time Delays
Authors: Qi Hao , Zhao Wencai
Published: June 2022

In this study, the stability and bifurcation problems of a fractional food chain system with two kinds of delays are studied. Firstly, the nonnegative, bounded, and unique properties of the solutions of the system are proved. The asymptotic stability of the equilibrium points of the system is discussed. Furthermore, the global asymptotic stability of the positive equilibrium point is deduced by using Lyapunov function method. Secondly, the system takes two kinds of time delays as bifurcation parameters and calculates the critical values of Hopf bifurcation accurately. The results show that Hopf bifurcation can advance with increasing fractional order and another delay. In conclusion, numerical simulation verifies and illustrates the theoretical results.
Efficacy of Endoscopic Intervention plus Growth Inhibitor and Patient Self-Management in the Treatment of Esophagogastric Variceal Bleeding in Cirrhosis
Authors: Yang Zhaoyun , Wang Yizhen , Yu Qin , Wang Shouli , Kong Derun
Published: June 2022

Objective. To assess the efficacy of endoscopic intervention plus growth inhibitor and patient self-management in the treatment of esophagogastric variceal bleeding. Methods. Between January 2019 and December 2021, 60 patients with esophagogastric variceal bleeding treated in our hospital were assessed for eligibility and randomly recruited. They were concurrently and randomly assigned at a ratio of 1 : 1 to receive either endoscopic intervention plus growth inhibitor (control group) or endoscopic intervention plus growth inhibitor and patient self-management (observation group). The endpoint is clinical efficacy. Results. All eligible patients showed a similar time of hemostasis, success rate of hemostasis, rebleeding rate, and disappearance rate of varicose veins (

P
>
0.05

). Endoscopic intervention plus growth inhibitor and patient self-management were associated with a lower incidence of complication (6.67%, including 1 (3.34%) case of ulcer and 1 (3.34%) case of fever) than endoscopic intervention plus growth inhibitor (26.67%, including 3 (10.00%) cases of ulcer, 2 (6.67%) cases of retrosternal pain, and 3 (10.00%) cases of fever) (

P
<
0.05

). Patients in the observation group had significantly higher life satisfaction scores (25.17 ± 4.28 and 23.68 ± 5.17) than those in the control group (22.13 ± 2.24 and 18.12 ± 3.28) (

P
<
0.05

). A decrease in life satisfaction scores was observed at 6 months after treatment, and the patients given patient self-management showed a higher satisfaction (

P
<
0.05

). Conclusion. Endoscopic intervention plus growth inhibitor and patient self-management yielded remarkable clinical efficacy in the treatment of esophagogastric variceal bleeding as it reduces the incidence of complication and enhances the life satisfaction of patients, and so it is worthy of clinical promotion.
Kakeya Inequalities by Maximal Functions in Hardy Spaces
Authors: Hu ZhuoRan
Published: June 2022

In this paper, we will introduce and study several types of Kakeya inequalities by the maximal functions in Hardy spaces in

ℝ

n

,

n
≥
2

, and we could obtain several inequalities associated with the Kakeya inequalities. We will show that

M

δ

S

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,
β

t

f

p

≲

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,
n
,
φ
,
ε

1
/
δ

5

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/
r

+
2

ε

f

p

, when

f

x

∈

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p

ℝ

n

and

supp

f
^

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⊆
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.
Abstract 1: Transcriptional profiling of prostatic Skp2 knock-in mouse model and development of the associated prostate organoids for testing Skp2 targeting agents
Authors: Song Liankun , Nguyen Vyvyan , Xu Shan , Yamak Jana , Arabzadehkaffash Kia , Fazelpour Ali , Mino Merci , Tippin Matthew , Meng Shuang , Zi Xiaolin
Published: June 2022

S-phase kinase associated protein 2 (Skp2) is a promising drug target as studies have demonstrated that Skp2 is required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb), Pten, or p53 deficient mice. We, therefore, aim to establish CRISPR human Skp2 (hSkp2) knock-in in the prostates of mice to study the molecular profiling features in prostate carcinogenesis. Prostate weights increased in transgenic mice and overexpression of hSkp2 induced prostatic lesions including hyperplasia, mouse prostate intraepithelial neoplasia (mPIN), and carcinoma, which suggested the initial role of hSkp2 in early prostate carcinogenesis. RNAseq results revealed Myl3 and Ctgf as the top down-expressed and up-expressed genes respectively in hSkp2 mice prostates. Gene set enrichment analysis (GSEA) demonstrated the significant upregulations of ribosome and proteasome pathways which had similar alterations in the human prostate cancer dataset with Skp2 overexpression, suggesting the potential role of ribosome biogenesis in prostate tumorigenesis and for drug development. In addition, Skp2 organoids derived from transgenic mice prostates were being developed for convenient and efficient screening of specific Skp2 inhibitors. Flavokawain A (FKA) and Skp2 inhibitor C1 both selectively decreased the viability and altered the morphologies of hSkp2 organoids, meanwhile FKA exhibited less toxicity on wild-type organoids.

Citation Format: Liankun Song, Vyvyan Nguyen, Shan Xu, Jana Yamak, Kia Arabzadehkaffash, Ali Fazelpour, Merci Mino, Matthew Tippin, Shuang Meng, Xiaolin Zi. Transcriptional profiling of prostatic Skp2 knock-in mouse model and development of the associated prostate organoids for testing Skp2 targeting agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1.
Abstract 1000: E-cadherin and EGFR interactions result in hyper-proliferation via ERK signaling in breast cancer
Authors: Russo Gabriella C. , Crawford Ashleigh , Clark David J. , Cui Julie , Carney Ryan , Karl Michelle N. , Su Boyang , Starich Batrholomew , Lee Tung-Shing , Zhang Qiming , Wu Pei-hsun , Lee Meng-Horng , Leong Hon S. , Rebecca Vito , Zhang Hui , Wirtz Denis
Published: June 2022

The loss of the intercellular adhesion molecule E-cadherin is a hallmark of the epithelial-mesenchymal transition (EMT), during which tumor cells transition into an invasive phenotype. Thus, E-cadherin has long been considered a tumor suppressor gene. However, recent studies have provided evidence that E-cadherin may promote metastasis rather than suppress it, suggesting oncogenic behavior. Here we provide data that E-cadherin plays an oncogenic role in breast cancer by promoting a hyper-proliferative phenotype in breast cancer cells via interaction with EGFR. This interaction results in the activation of the MEK/ERK signaling pathway, leading directly to changes in proliferation via transcription factors such as c-Fos. Pharmacological inhibition of MEK in E-cadherin positive breast cancer cells significantly decreases both tumor growth and macro-metastasis in vivo. This work provides evidence for a novel role of E-cadherin in breast tumor progression and identifies a potential new target to treat hyper-proliferative E-cadherin-positive breast tumors.

Citation Format: Gabriella C. Russo, Ashleigh Crawford, David J. Clark, Julie Cui, Ryan Carney, Michelle N. Karl, Boyang Su, Batrholomew Starich, Tung-Shing Lee, Qiming Zhang, Pei-hsun Wu, Meng-Horng Lee, Hon S. Leong, Vito Rebecca, Hui Zhang, Denis Wirtz. E-cadherin and EGFR interactions result in hyper-proliferation via ERK signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1000.
Abstract 1001: Investigates the role of vesicle trafficking in E-cadherin dynamics in collective migrated colon cancer cells
Authors: Koo Hui Min , Hou Xiang-Ling , Li Yu-Lin , Lu Yi-Wen , Winarso Viriya Adhiguna , Weng Yu-Cheng , Chao Wei-Ting
Published: June 2022

Cell adherens junction plays an important role in cell communication and regulation. E-cadherin is an important protein as adherens junctions. Loss of E-cadherin leads to epithelial cells transit to mesenchymal cells. Studies has demonstrated that E-cadherin dominates cell contact inhibition, which plays an important role in cell growth, however, recent studies demonstrated collective cell migration required E-cadherin expression escaping cell growth inhibition is important in metastasis. E-cadherin dynamics has been shown to be regulated by vesicle trafficking, however, the detail mechanism of vesicle trafficking in collective cell migration is not clear. This study is investigating the relationship between the endocytosis mechanism of E-cadherin and its dynamic expression resulting in collective cell migration. The expression of E-cadherin was controlled by regulating the concentration of calcium and EDTA to observe its effect on cell-cell contact. Through Transmission electron microscope, immunofluorescence staining and western blotting to observe the relationship between vesicle trafficking and E-cadherin. Collective cell migration is analyzed by transwell assay. When calcium concentration was increased, the E-cadherin in cell-cell contacts became stronger. Conversely, when EDTA concentration was increased, the E-cadherin in the cell-cell contacts became weaker. Meanwhile, we found colocalization occurs in Rab5 and Rab11 with E-cadherin. Besides, intracellular E-cadherin transported to the lysosome for degradation was also observed. We identified the role of E-cadherin is regulated in endocytosis mechanism and at cell-cell contacts through different regulatory, which provides a basis for the future use of drugs to affect E-cadherin expression to inhibit collective cell migration.

Citation Format: Hui Min Koo, Xiang-Ling Hou, Yu-Lin Li, Yi-Wen Lu, Viriya Adhiguna Winarso, Yu-Cheng Weng, Wei-Ting Chao. Investigates the role of vesicle trafficking in E-cadherin dynamics in collective migrated colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1001.
Abstract 1022: Disparities in accessibility to oncology care centers in France
Authors: Daoud Eric , Hamy Anne-Sophie , Dumas Elise , Delrieu Lidia , Grandal Beatriz , Le Bihan-Benjamin Christine , Houzard Sophie , Bousquet Philippe-Jean , Hotton Judicael , Savoye Aude-Marie , Jouannaud Christelle , Azencott Chloé-Agathe , Lelarge Marc , Fabien Reyal
Published: June 2022

Background: Cancer caused nearly 10 million deaths in 2020. While most of the ongoing research focuses on finding new treatments, accessibility to oncology care receives less attention. However, access to health services plays a key role in cancer survival. Spatial accessibility methods have been successfully applied to measure accessibility to primary care. Yet, little research to date focused on oncology care specifically.

Methods: We focused on all care centers with medicine, surgery, or obstetric activity in metropolitan France. We propose a clustering algorithm to automatically label the hospitals in terms of oncology specialization. Then, we computed an accessibility score to these hospitals for every municipality in metropolitan France. Finally, we proposed an optimization algorithm to increase the oncology accessibility by identifying centers which should increase their capacity.

Results: We labelled 1,662 care centers into 8 clusters. Half of them were eligible for oncology care and 118 centers were identified as experts. We computed the oncology accessibility score for 34,877 municipalities in metropolitan France. Half of the population lived in the top 20% accessibility areas, and 6.3% in the bottom 20% zones. Accessibility was higher near dense cities, where the experts care centers were located. By combining the care centers clusters and the accessibility distributions, our optimization algorithm could identify hospitals to grow, to reduce accessibility disparities.

Conclusion: Our method made it possible to quantify oncology care accessibility across all metropolitan France, as well as to make suggestions on where to increase hospital capacity to improve accessibility, especially in more populated suburban areas. Our approach was deliberately non-specific to cancer type nor to the kind of stays, but it could be adapted to more specific scenarios. We packaged our method into a web application allowing the users to run the algorithms with various parameters and visualize the results.

Citation Format: Eric Daoud, Anne-Sophie Hamy, Elise Dumas, Lidia Delrieu, Beatriz Grandal, Christine Le Bihan-Benjamin, Sophie Houzard, Philippe-Jean Bousquet, Judicael Hotton, Aude-Marie Savoye, Christelle Jouannaud, Chloé-Agathe Azencott, Marc Lelarge, Reyal Fabien. Disparities in accessibility to oncology care centers in France [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1022.
Abstract 1026: The costs of waiting to get treated for new AML patients: Medical expenditures, mortality rate, and length of hospital stay
Authors: Hsieh Kang Lin , Ko Bor-Sheng , Jiang Xiaoqian , Chang Teng-Jen , Wang Yu-Fen
Published: June 2022

Introduction: We studied the association of waiting time from diagnostic Acute Myeloid Leukemia (AML) tests to initial treatment and medical expenditures, length of hospitalization, and survival rates for new AML patients.

Method: We extracted 3,976 new AML patients from Optum’s de-identified Clinformatics࣪ Data Mart Database, a data warehouse of adjudicated commercial and medicare advantage claims. Their waiting days from standard diagnostic testings to the initial AML-specific treatment as the risk factor. Medical expenditures occurring within 6 months, 1 year, and 2 years after the index AML diagnosis was measured for the patients’ financial wellbeing, along with the survival rate and the length of hospital stay. We compared these outcomes for patients falling in each waiting time category. Different types of expenditures, including inpatient and outpatient costs for patients with different waiting lengths were compared.

Results: For patients with moderate lengths of waiting time, medical expenditure and mortality rate increases and length of hospital stay decreased with waiting time. Within 2 years after the index AML diagnosis, the average expenditures per day goes from $4,803 for patients waiting for 0-2 days to $7,489 for patients waiting for 1-2 weeks, while the survival rate goes from 42.8% to 28.1% and the average length of stay goes from 45.6 days to 35.0 days. The increment in medical expenditure is mostly accounted for by outpatient costs, but is off-set by inpatient costs. The patterns for medical expenditure and survival rate reverse as waiting time becomes severe (3-4 weeks). Similar reverse is not observed for length of stay.

Conclusion: The waiting time between AML diagnostic tests and initial treatments is associated with higher medical expenditure and higher mortality rate for moderate waiters. Our findings suggest that reducing waiting time has strong potential in improving AML patients’ survival and financial sustainability.

Medical expenditure, survival rate, and length of hospital stay within 2 years by waiting time Medical expenditure per day ($) 2-yr Survival rate (%) Length of hospital stay (days) <2d 4803 42.8 45.6 2-7d 5008 30.3 36.6 7-14d 7489 28.1 33.9 14-28d 4174 29.8 30.4 >28d 2224 51.0 35.0

Citation Format: Kang Lin Hsieh, Bor-Sheng Ko, Xiaoqian Jiang, Teng-Jen Chang, Yu-Fen Wang. The costs of waiting to get treated for new AML patients: Medical expenditures, mortality rate, and length of hospital stay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1026.
Abstract 1030: IX2X2
Authors: Ponnusamy Thamarai U. , Thiyagarajan Thirumagal T. , Narayanan Ramesh
Published: June 2022

Introduction: Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men. More than 85% of PCa and advanced aggressive castration-resistant prostate cancer (CRPC) depend on the androgen receptor (AR) for growth. AR-targeted therapeutics are the mainstay treatment option for PCa. Majority of PCa and CRPC respond to AR-LBD-binding antagonists such as enzalutamide and become refractory after a brief period of response. One of the main resistance mechanisms is the expression of AR splice variants (AR-SVs). AR-SVs lack LBD and are constitutively active, causing aggressive phenotype.

Description: Rationale-based drug design was employed to synthesize selective AR irreversible covalent antagonists (SARICA). SARICAs were evaluated in AR transactivation to determine the antagonistic activity. SARICAs were incubated with purified recombinant AR activation function-1 (AF-1) protein and mass spectrometry was performed to determine their covalent binding. SARICAs were evaluated in AR-SV transactivation assay and in a Schild’s plot to determine the nature of inhibition (reversible Vs irreversible). SARICAs were tested in PCa cell line gene expression and proliferation assays and in tumor xenograft experiments.

Summary: SARICAs inhibited AR transactivation in submicromolar range. Mass spectrometry with purified AF-1 protein demonstrated covalent binding of SARICAs and identified C406 and C327 as SARICA-interacting nucleophiles. Both amino acids are important for AR-V7 function and stability, making them appropriate drug targets. SARICAs inhibited the activity of AR-V7 and irreversibly inhibited AR transactivation, indicating that these covalent binders are irreversible antagonists. SARICAs selectively inhibit the proliferation and growth of AR-positive prostate cancer cells and tumors, but not AR-negative cells and tumors.

Conclusion: These first-in-class AR-selective covalent molecules thus serve as chemical probes to advance our understanding of the AR-AF-1 and they potentially offer an opportunity to treat refractory cancers.

Disclosure: This work was supported by an NCI grant (CA229164 and CA229164S1), a DOD grant (W81XWH2110055), and by Muirhead endowment. The SARICAs are licensed to Oncternal therapeutics, San Diego, CA. RN is a consultant to Oncternal therapeutics.

Citation Format: Thamarai U. Ponnusamy, Thirumagal T. Thiyagarajan, Ramesh Narayanan. IX2X2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1030.
Abstract 1034: Pharmacological GLUT3 salvage augments the efficacy of vitamin C induced TET2 restoration in AML cells
Authors: Liu Jun , Min Suji , Kim Seojeong , Gwak Daehyeon , Hong Junshik , Yoon Sungsoo
Published: June 2022

Background and purpose: Vitamin C has been demonstrated to regulate hematopoietic stem cells (HSC) frequencies and leukemogenesis by augmenting and restoring TET2 function, potentially acting as a novel treatment strategy for leukemia. In a previous study (Liu et al, 2020 Br J Cancer), we showed that GLUT3, a major vitamin C transporter in acute myeloid leukemia (AML) cells, was significantly decreased in AML blasts compared with normal hematopoietic cells, which impedes TET2 restoration and promotes leukemia progression. Although GLUT3 could be a potential biomarker to predict the vitamin C treatment efficiency, a remaining question was whether GLUT3 can be a druggable target in AML. In this study, we aim to investigate the therapeutic value of GLUT3 salvage in AML

Methods: GLUT3 salvage was conducted on GLUT3 deficient AML cell line OCI-AML3 using GLUT3 overexpression lentivirus transduction or AICAR (an AMPK activator, Phase 3) treatment. The 5hmC DNA dot blotting assay was carried out to explore the TET2 function. The leukemic phenotypes were evaluated using soft agar colony formation assay, migration assay, and invasion assay.

Results: To verify if turning on GLUT3 enhances the efficacy of vitamin C treatment, the GLUT3 overexpression lentivirus or empty vector lentivirus was transduced into the OCI-AML3 cell line. The transcription level of SLC2A3 (gene encoded GLUT3) was increased to 8 times in the GLUT3 overexpression cell line. Then, 5hmC DNA dot blotting results showed that GLUT3 overexpression further significantly raised the 5hmC level after 250 µM vitamin C treatment. Consistent with augmentation of TET2 function, turning on GLUT3 with vitamin C treatment alleviated leukemic phenotypes compared with empty vector group. Pharmacological GLUT3 salvage using AICAR 0.5 mM 48 hours could achieve the same effect as lentivirus transduction, in terms of GLUT3 expression level, augmentation of TET2 function, and enhancement of vitamin C anti-leukemic effect. Notably, AICAR treatment only induced GLUT3 expression while showed no effect on GLUT5.

Conclusion: GLUT3 salvage could augment the efficacy of vitamin C induced TET2 restoration in AML cells. Pharmacological GLUT3 salvage using AICAR sheds new light on overcoming GLUT3 deficiency in AML.

Citation Format: Jun Liu, Suji Min, Seojeong Kim, Daehyeon Gwak, Junshik Hong, Sungsoo Yoon. Pharmacological GLUT3 salvage augments the efficacy of vitamin C induced TET2 restoration in AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1034.
Abstract 1035: VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity
Authors: Wang Jieqiong
Published: June 2022

Pancreatic cancer is the most lethal malignant neoplasms across the world with the lowest overall five-year survival rate (9%). TP53 is mutated in ~70% of pancreatic ductal adenocarcinomas (PDACs). Hotspot p53 mutants promote cancer cell proliferation, metastasis and metabolism through their gain-of-function (GOF). Among the p53 “hotspot” mutations, R273 is the most frequent mutation position (~12%) with R273H as the most commonly mutated codon (~8%) in PDACs. However, the mechanisms underlying regulation of mutant p53s’ GOF in PDACs remain incompletely understood. In our attempt to address this question, we recently identified the ATPase valosin-containing protein (VCP)/p97 as a novel mutant p53-binding protein by performing immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) analysis. VCP bound to p53-R273H via the DNA-binding domain. VCP inhibition either by genetic depletion or pharmacological inhibition by CB-5083 resulted in the increase of MDM2-mediated ubiquitination and degradation of p53-R273H. VCP did so by binding to MDM2 and disturbing its interaction with mutant p53. As a result, VCP protected mutant p53 from degradation and enhanced its GOF in cancer development. Ablation of VCP retarded PDAC cell growth in vitro and in vivo. Our further studies also unveiled the negative regulation of wt p53 by VCP in cancer cells. Together, these results demonstrate that VCP can strengthen mutant p53’s oncogenic function by stabilizing it and negating wt p53 function, suggesting VCP as a resistant factor for chemotherapy against PDACs and thus a potential therapeutic target of the mutant p53-harboring pancreatic cancers as well as of the wt p53-containing cancer cells.

Citation Format: Jieqiong Wang. VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1035.
Abstract 1040: Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma
Authors: Sarnella Annachiara , Ferrara Ylenia , Auletta Luigi , Albanese Sandra , Alterio Vincenzo , Winum Jean-Yves , Supuran Claudiu T , Cerchia Laura , De Simone Giuseppina , Zannetti Antonella
Published: June 2022

The head and neck squamous carcinomas (HNSSCs) are the sixth most common cancer worldwide. Given the heterogeneous nature of HNSCC, this carcinoma results in higher resistance to chemoradiotherapy. Recent evidence highlight the importance of the hypoxic microenvironment in contributing to cisplatin resistance. Therefore, the aim of this study was to investigate the role played by hypoxia-induced protein carbonic anhydrase 9 (CA9) in supporting HNSCC cisplatin resistance. Furthermore, we purpose to investigate the ability of CA9 inhibitor, SLC-0111, a small molecule already used in Phase I clinical trial, to sensitize HNSSC cells to chemotherapy in vitro and in vivo. We analyzed the expression of CA9 in a public data set of 103 HNSCC samples and 22 oral cavity normal tissues and in two HNSSC cell lines (FaDu; SCC-011). HNSCC cells grown in 2D and 3D models under hypoxic conditions (1% O2) showed increased levels of CA9 and greater resistance to cisplatin than cells grown under normoxic conditions. The addition of CA9 inhibitor SLC-0111 to cisplatin sensitized cells to the chemotherapeutic agent and caused a reduction of colony number, spheroid formation, tumor cell, and spheroid migration and invasiveness. Furthermore, the combination therapy hampered activation of STAT3, AKT, ERK, and EMT program whereas it induced apoptosis. Notably, the combined treatment caused inhibition of tumor growth and induction of apoptosis in HNSCC subcutaneous xenografts, as assessed by high-frequency ultrasonography and fluorescent molecular tomography (FMT) with NIR-Annexin V, respectively, at a higher extent than single agents. In addition, FMT with NIR-Prosense revealed a stronger reduction of lymph nodes metastases when mice bearing orthotopic xenografts were treated with cisplatin plus SLC-0111 with respect to a single treatment. Our findings taken together demonstrate the crucial role played by CA9 in promoting cisplatin resistance in HNSCC and the efficacy of SLC-0111 to sensitize tumor cells and xenografts to chemotherapy.

Citation Format: Annachiara Sarnella, Ylenia Ferrara, Luigi Auletta, Sandra Albanese, Vincenzo Alterio, Jean-Yves Winum, Claudiu T Supuran, Laura Cerchia, Giuseppina De Simone, Antonella Zannetti. Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1040.
Abstract 1070: Dual inhibition of AR and β-catenin induces cell death in abiraterone-resistant prostate cancer
Authors: Atawia Ibrahim M. , Kushwaha Prem P. , Verma Shiv S. , Lin Spencer , Shankar Eswar , Abdel-Gawad Osama , Gupta Sanjay
Published: June 2022

Abiraterone acetate has been clinically approved for treatment of patients with advanced-stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha-hydroxylase. Despite exhibiting improved survival outcomes, almost all patients with advance-stage disease relapse, progressing to a more aggressive and lethal castration-resistant prostate cancer. Our pathway-related analysis and characterization of gene expression identified activation of the β-catenin pathway in abiraterone-resistant prostate cancer. Increased expression of androgen receptor (AR) and β-catenin and their crosstalk between distinct signaling pathways causes activation of AR target genes and regulatory networks for which overcoming innate or acquired resistance remains a major challenge. Here we show that co-targeting AR and β-catenin induces cell death in abiraterone-resistant prostate cancer. For these studies, we generated abiraterone-resistant C4-2B cells (C4-2B-Abi) by growing them in progressive concentration of abiraterone 5-20µM to develop resistance and maintained in 5µM abiraterone in the culture medium for >20 generations. Treatment of C4-2B-Abi cells individually with abiraterone (20µM) and ICG001 (2µM) for 72 h exhibited a partial suppressive effect in cell growth compared to C4-2B parental cell line. A combination of abiraterone and ICG001 (20µM + 2µM) exhibited marked cell growth inhibition with significant increase in G1-phase cell cycle arrest, inhibition of migration and invasion in C4-2B-Abi cells, compared to the parental counterpart. Furthermore, combination treatment led to significant reduction in cell proliferation as assessed by PCNA along with reduction in the protein expression of AR, AR-v7, CDC20, PSA, β-catenin and its downstream targets, cyclinD1 and c-Myc, which were more prominent in C4-2B-Abi cells, compared to parental C4-2B cells. Co-targeting AR and β-catenin potentiated cell death in C4-2B-Abi cells as evident by increased PARP cleavage. Together, our data identify activation of the β-catenin pathway as a major mechanism contributing to abiraterone resistance and demonstrate that combined treatment with abiraterone and ICG001 appears to be an effective regimen for treatment of abiraterone-resistant cancer cells. This opens new therapeutic modality for advance-stage castration-resistant prostate cancer patients.

Citation Format: Ibrahim M. Atawia, Prem P. Kushwaha, Shiv S. Verma, Spencer Lin, Eswar Shankar, Osama Abdel-Gawad, Sanjay Gupta. Dual inhibition of AR and β-catenin induces cell death in abiraterone-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1070.