bluuebunny/crossref_metadata_2025_split 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

IntroductionAtrial 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 analysisThe 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 disseminationThe 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 numberClinicalTrials.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

IntroductionChronic 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 analysisA 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 disseminationEthical 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 numberACTRN12620000505909p.
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.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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) &lt;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 &gt;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

Abstract
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

Abstract
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.