tbuckley/cabot-search huggingface dataset:
Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage pathway, to target glioma heterogeneity through mitochondrial oxidative stress
Authors: Pratibha Sharma, Jihong Xu, Katie Williams, Michelle Easley, J Brad Elder, Russell Lonser, Frederick F Lang, Rosa Lapalombella, Deepa Sampath, Vinay K Puduvalli
Journal: Neuro-Oncology (2021)

Abstract Background Tumor-specific metabolic processes essential for cell survival are promising targets to potentially circumvent intratumoral heterogeneity, a major resistance factor in gliomas. Tumor cells preferentially using nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway for synthesis of NAD, a critical cofactor for diverse biological processes including cellular redox reactions, energy metabolism, and biosynthesis. NAMPT is overexpressed in most malignancies, including gliomas, and can serve as a tumor-specific target. Methods Effects of pharmacological inhibition of NAMPT on cellular oxygen consumption rate, extracellular acidification, mitochondrial respiration, cell proliferation, invasion, and survival were assessed through in vitro and ex vivo studies on genetically heterogeneous glioma cell lines, glioma stem-like cells (GSCs), and mouse and human ex vivo organotypic glioma slice culture models. Results Pharmacological inhibition of the NAD salvage biosynthesis pathway using a highly specific inhibitor, KPT-9274, resulted in the reduction of NAD levels and related downstream metabolites, inhibited proliferation, and induced apoptosis in vitro in cell lines and ex vivo in human glioma tissue. These effects were mediated by mitochondrial dysfunction, DNA damage, and increased oxidative stress leading to apoptosis in GSCs independent of genotype, IDH status, or MGMT promoter methylation status. Conversely, NAMPT inhibition had minimal in vitro effects on normal human astrocytes (NHA) and no apparent in vivo toxicity in non-tumor-bearing mice. Conclusions Pharmacological NAMPT inhibition by KPT9274 potently targeted genetically heterogeneous gliomas by activating mitochondrial dysfunction. Our preclinical results provide a rationale for targeting the NAMPT-dependent alternative NAD biosynthesis pathway as a novel clinical strategy against gliomas.
Mirabegron for treatment of Erectile Dysfunction (ED) concomitant with Lower Urinary Tract Symptoms (LUTS) in patients with Benign Prostatic Hyperplasia (BPH): A randomized controlled trial
Authors: R.F. El-Baz, A. El-Assmy, M. H Zahran, A. Hashem, A. A.shokeir
Journal: European Urology (2021)
Abstract 1870: Novel conditionally active bispecific T cell engagers targeting solid tumors
Authors: Haizhen Liu, Jing Wang, Ana Paula G. Cugnetti, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William Boyle, Jay Short
Journal: Cancer Research (2021)

Abstract The use of CD3/target bispecific molecules has great therapeutic potential in oncology. This potential, however, is diminished due to severe cytokine release effects as well as serious on-target off-tumor toxicities. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates bispecific antibodies which have no or very little binding to CD3 and to the tumor target antigen (TAA) in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). Using our CAB technology, we have developed dual-CAB (CAB TAA x CAB CD3) bispecific antibodies targeting two well-established tumor associated antigens, B7H3 and Nectin4. These dual-CAB bispecific antibodies were developed so that they bind to recombinant CD3 and TAA as well as to CD3 and TAA expressing cells under in vitro tumor microenvironment conditions, but not in physiologic conditions. In vitro characterization and in vivo efficacy data of the dual-CAB TAA x CD3 bispecific antibodies targeting B7H3 and Nectin4 will be presented. The CAB technology allows the generation of a new class of potent T-cell engagers with increased safety margin and therapeutic index in the clinic. Citation Format: Haizhen Liu, Jing Wang, Ana Paula G. Cugnetti, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William Boyle, Jay Short. Novel conditionally active bispecific T cell engagers targeting solid 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 1870.
Multifunctional GelMA platforms with nanomaterials for advanced tissue therapeutics
Authors: Amal George Kurian, Rajendra K. Singh, Kapil D. Patel, Jung-Hwan Lee, Hae-Won Kim
Journal: Bioactive Materials (2021)

Polymeric hydrogels are fascinating platforms as 3D scaffolds for tissue repair and delivery systems of therapeutic molecules and cells. Among others, methacrylated gelatin (GelMA) has become a representative hydrogel formulation, finding various biomedical applications. Recent efforts on GelMA-based hydrogels have been devoted to combining them with bioactive and functional nanomaterials, aiming to provide enhanced physicochemical and biological properties to GelMA. The benefits of this approach are multiple: i) reinforcing mechanical properties, ii) modulating viscoelastic property to allow 3D printability of bio-inks, iii) rendering electrical/magnetic property to produce electro-/magneto-active hydrogels for the repair of specific tissues (e.g., muscle, nerve), iv) providing stimuli-responsiveness to actively deliver therapeutic molecules, and v) endowing therapeutic capacity in tissue repair process (e.g., antioxidant effects). The nanomaterial-combined GelMA systems have shown significantly enhanced and extraordinary behaviors in various tissues (bone, skin, cardiac, and nerve) that are rarely observable with GelMA. Here we systematically review these recent efforts in nanomaterials-combined GelMA hydrogels that are considered as next-generation multifunctional platforms for tissue therapeutics. The approaches used in GelMA can also apply to other existing polymeric hydrogel systems.
Survival after neoadjuvant/induction combination immunotherapy versus combination platinum-based chemotherapy for stage III urothelial cancer
Authors: S. Einerhand, N. Van Dijk, J. Van Dorp, J.M. De Feijter, M.L. Van Montfoort, M.W. Van De Kamp, T.N. Boellaard, K. Hendricksen, M.S. Van Der Heijden, B.W.G. Van Rhijn
Journal: European Urology (2021)
Abstract 1475: Discovery of ETS-001, a highly potent allosteric SHP2 inhibitor to treat RTK/RAS-driven cancers
Authors: Xi Xia, Lin Du, Hao Zhuge, Qiangang Zheng, Wenqi Cui, Jidong Zhu, Guo Li
Journal: Cancer Research (2021)

Abstract The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, functions as a convergent node downstream of multiple receptor tyrosine kinases (RTKs) and is required for full activation of the MAPK pathway. Suppression of SHP2 activity via either genetic silencing or pharmacological inhibition has been shown to inhibit RAS/MAPK signaling and cell growth in a wide spectrum of cancers, pointing to a therapeutic opportunity for targeting SHP2 in cancer therapy. Here we report the discovery of a highly potent, selective and orally bioavailable small-molecule allosteric inhibitor of SHP2, ETS-001, that is effective in various human cancer models bearing oncogenic alterations in the RTK/RAS/MAPK pathway. Treatment with ETS-001 as a single agent resulted in dramatic growth inhibition of cancer cells as well as in vivo tumor models bearing genetic alterations of EGFR, or components in the nucleotide cycling-dependent KRAS pathway. Besides, as the effectiveness of RAS pathway inhibitors are ultimately limited by rapid emergence of drug resistance via multiple mechanisms including bypass activation of alternative RTKs, SHP2 inhibition has the potential to overcome the resistance as combinational strategies associated with various RAS pathway-targeted therapies. Here we show that ETS-001 exhibited strong synergistic effect with EGFR-TKI (osimertinib), KRASG12Ci (AMG510) or CDK4/6i (ribociclib) in appropriate cancer models in vitro and in vivo. In EGFR mutant NSCLC cells, treatment with both ETS-001 and osimertinib showed combinational benefit that was coincident with sustained ERK inhibition. In a KRASG12C mutant pancreatic cancer cell xenograft model, ETS-001 greatly enhanced the efficacy of AMG510 to suppress in vivo tumor growth. In addition, combinational benefit of ETS-001 and ribociclib was observed in esophageal cancer models, which exhibited high frequency of concurrent oncogenic alterations in RTKs and cell cycle pathway. Taken together, our findings provide preclinical evidence that ETS-001 as a potent SHP2 inhibitor, alone or in combination with other targeted-therapy agents, can effectively inhibit MAPK activation and treat cancers with diverse oncogenic mutations in the RAS/MAPK pathway. Citation Format: Xi Xia, Lin Du, Hao Zhuge, Qiangang Zheng, Wenqi Cui, Jidong Zhu, Guo Li. Discovery of ETS-001, a highly potent allosteric SHP2 inhibitor to treat RTK/RAS-driven cancers [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 1475.
The Clinician and Dataset Shift in Artificial Intelligence
Authors: Samuel G. Finlayson, Adarsh Subbaswamy, Karandeep Singh, John Bowers, Annabel Kupke, Jonathan Zittrain, Isaac S. Kohane, Suchi Saria
Journal: New England Journal of Medicine (2021)

Dataset Shift in Clinical Trials This letter outlines how to identify, and potentially mitigate, common sources of “dataset shift” in machine-learning systems. This occurs when the model “training ...
Abstract 1200: Long-duration term TTFields treatment of glioblastoma cells induces cell death
Authors: Stefania Castiglione, Matteo Ranucci, Gaetano Cannavale, Francesca Cianci, Ivan Verduci, Michele Mazzanti
Journal: Cancer Research (2021)

Abstract Glioblastoma is the most aggressive among brain tumors. Radiotherapy and chemotherapy, as adjuvanttreatments after surgical removal of the tumor mass, are often accompanied by undesirable symptoms. Evenwith these available treatment options, patient prognosis is extremely poor. The only approved treatmentoption demonstrating improved life expectancy in the last twenty years has been the application of TumorTreating Fields (TTFields). However, despite different therapeutic actions, tumor relapse occurs inexorably inmost patients. It is essentially unanimously agreed upon that tumor recurrence is due to a small populationof cells named glioblastoma stem cells (GSCs). GSCs represent a restricted cellular subpopulation in the tumormass composed mainly of bulk cells. The main characteristic of GSCs is their tumorigenic capacity even if asmall number of cells are left after surgery. Our working hypothesis is based on evidence that TTFieldsexposure destabilizes the mitotic spindle of rapidly dividing cells to elicit cell death. Thus, TTFields stimulationshould preferentially target bulk cells due to their higher proliferation rates compared to GSCs. Preliminaryexperiments performed using glioblastoma primary cultures obtained from patients' biopsies demonstratedthe presence of two different cell populations. In glioblastoma primary cultures maintained in stem-cellselective medium, more than 90% of glioblastoma cells did not exhibit stemness characteristics. After 72hours of TTFields stimulation, cell death was ascertained in approximately 50% of cells. The remaining viablecells were more than 20% positive for three different stemness markers. Long duration TTFields treatmentexperiments (144 and 288 hours) showed that TTFields at 200 kHz is able to increase the percentage of GSCin glioblastoma cells, yet did exhibit a propensity to reestablish cellular proliferation.In conclusion, long duration TTFields (200 kHz) treatment demonstrated efficacy by inducing cell death anddelaying glioblastoma cell expansion. However, to prevent glioblastoma relapse it is important to combineTTFields with different combination partners that specifically target glioblastoma stem cells. Citation Format: Stefania Castiglione, Matteo Ranucci, Gaetano Cannavale, Francesca Cianci, Ivan Verduci, Michele Mazzanti. Long-duration term TTFields treatment of glioblastoma cells induces cell death [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 1200.
Abstract 2308: The protein interaction landscape of breast cancer
Authors: Minkyu Kim, Jisoo Park, Mehdi Bouhaddou, Kyumin Kim, Ajda Rojc, Maya Modak, Margaret Soucheray, Patrick O'Leary, Denise Wolf, Dominique C. Mitchell, Fan Zheng, John D. Gordan, Jean-Philippe Coppé, Danielle L. Swaney, Laura van' t Veer, Alan Ashworth, Trey Ideker, Nevan J. Krogan
Journal: Cancer Research (2021)

Abstract Cancers have been associated with a diverse array of genomic alterations, many of which are rare with unknown significance. To understand the cellular mechanisms impacted by such alterations in breast invasive carcinoma, we have applied affinity-purification mass spectrometry to delineate comprehensive biophysical interaction networks for 40 frequently altered breast cancer proteins across three human breast cell lines, providing a novel resource of context-specific and shared protein-protein interaction networks in breast cancer cells. These networks interconnect and enrich for common and rare cancer mutations, and are substantially rewired by mutations. Our analysis identifies novel PIK3CA-interacting proteins which repress AKT signaling, and UBE2N emerges as a BRCA1 interactor predictive of clinical response to PARP inhibition. We also show that Spinophilin interacts with and dephosphorylates BRCA1 to promote DNA double-strand break repair. Thus, cancer protein interaction landscapes provide a framework for recognizing oncogenic drivers and drug vulnerabilities. Citation Format: Minkyu Kim, Jisoo Park, Mehdi Bouhaddou, Kyumin Kim, Ajda Rojc, Maya Modak, Margaret Soucheray, Patrick O'Leary, Denise Wolf, Dominique C. Mitchell, Fan Zheng, John D. Gordan, Jean-Philippe Coppé, Danielle L. Swaney, Laura van' t Veer, Alan Ashworth, Trey Ideker, Nevan J. Krogan. The protein interaction landscape of 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 2308.
Abstract LB119: VRN08, a Selective Mps1 Kinase Inhibitor Induces Mitotic Catastrophe and Apoptosis Efficiently in Advanced Cancers Including Rb1-Deficient
Authors: Hong Ryul Jung, Yeonsil Kim, Haelee Kim, Ji-Hye Kwon, Dong-hyuk Seo, Jung Beom Son, Nam Doo Kim, Daekwon Kim, Sunghwan Kim
Journal: Cancer Research (2021)

Abstract Spindle assembly checkpoint (SAC) prevents mis-segregation of chromosome and allows accurate division in mitosis. Mps1 (also known as TTK) is one of the essential kinases for recruitment of SAC proteins after chromosome segregation. Failure of SAC induces chromosome instability, mitotic catastrophe, and ultimately apoptotic cell death and Mps1 is induced or activated in rapidly dividing tumor cells. Therefore, Mps1 has been considered an attractive anti-cancer drug target. VRN081569 is a potent type I kinase inhibitor of Mps1, which stabilizes Mps1 kinase domain in a closed conformation by forming a tight interface with its kinase domain. This structural stabilization appears to increase cellular potency for the induction of aneuploidy and apoptosis (~ 10 nM or less GI50 value). The loss of retinoblastoma tumor suppressor gene (Rb1), which is prevalent in advanced cancers, dysregulates cell cycle and promotes cell division. In particular, the resistance to CDK4/6 inhibitors has been reportedly mediated by loss of the Rb1 gene. We found that Rb1-negative cells express higher level of Mps1 than Rb1-positive cells and VRN081569 efficiently induce apoptosis of Rb1-negative Triple Negative Breast Cancer (TNBC) cell line MDA-MB-468 than Rb1-positive TNBC MDA-MB-231. Especially we confirmed that VRN081569 induces caspase 3/7 activity faster in Rb1-negative cells (~50-fold EC50 of caspase 3/7 activity compared to Rb1-positive cells), and cell cycle analysis has shown that our compound induces a dose-dependent dysregulation of mitosis, resulting in a decrease in the frequency of the G0/G1 phase, and also induces aneuploidy and apoptosis. Finally, we confirmed a combination effects with anti-microtubule agents BCL-2 inhibitor and PARP-1 inhibitor, suggesting that modulation of two different cellular processes may overcome the lack of single agent activity for TNBC. Citation Format: Hong Ryul Jung, Yeonsil Kim, Haelee Kim, Ji-Hye Kwon, Dong-hyuk Seo, Jung Beom Son, Nam Doo Kim, Daekwon Kim, Sunghwan Kim. VRN08, a Selective Mps1 Kinase Inhibitor Induces Mitotic Catastrophe and Apoptosis Efficiently in Advanced Cancers Including Rb1-Deficient [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 LB119.
Quantitative and Functional Alterations of 6-Sulfo Lacnac Dendritic Cells in Multiple Myeloma
Authors: Baptiste Lamarthée, Frédéric De Vassoigne, Nicolas Stocker, Ruoping Tang, Laurent Garderet, Zora Marjanovic, Eolia Brissot, Florent Malard, Mohamad Mohty, Béatrice Gaugler
Journal: Blood (2017)
Discordant histology of abdominal and thoracic post chemotherapy residual tumor resection in patients with metastatic germ cell tumor
Authors: C. Buddensieck, V. Besser, Y. Che, P. Albers, J. Schirren, S. Sponholz, M. Schirren, A.M. Schauer, W.T. Knoefel, A. Hiester
Journal: European Urology (2021)
Site-specific concordance of targeted and systematic biopsy cores at the index lesion on mpMRI: Can we spare the double-tap?
Authors: M. Droghetti, L. Bianchi, C. Beretta, A. Ercolino, M. Salvador, F. Chessa, C. Casablanca, S. Di Fresco, C. Roveroni, E. Balestrazzi, F. Costa, A. Feruzzi, C. Cacciapuoti, A. Rustici, A. Rustici, A. De Cinque, C. Gaudiano, B. Corcioni, R. Golfieri, R. Schiavina, E. Brunocilla
Journal: European Urology (2021)
Abstract 15068: Food Restriction Augmented Alpha1-Adrenergic Mediated Contraction in Rats Mesenteric Arteries
Authors: Rany Vorn, Hae Young Yoo
Journal: Circulation (2019)

Introduction: Food restriction (FR) enhances the sensitivity to cardiopulmonary reflexes and α1-adrenoreceptors in the female despite hypotension. However, the effect of male FR on cardiopulmonary ...
Abstract 14863: Athletes Performing Extraordinary Physical Activity (>10,000 MET·Min/Week) at No Greater Risk of All-Cause or Cardiovascular Disease Mortality
Authors: Laura F DeFina, Beth B Wright, Benjamin L Willis, David Leonard, Stephen W Farrell, Andjelka Pavlovic, Ambrose J Burfoot, William L Haskell, Nina B Radford, Benjamin D Levine
Journal: Circulation (2019)

Introduction: The relationship between very high volumes of long-term physical activity (PA) and mortality is uncertain. Small studies suggest that extreme joggers have higher mortality while a met...
Apalutamide (apa) for metastatic castration-sensitive prostate cancer (mcspc): Outcomes in high-volume (hv) and low-volume (lv) disease from the titan final analysis (fa)
Authors: S. Chowdhury, A. Bjartell, A.S. Merseburger, B.H. Chung, H. Uemura, D. Ye, M. Özgüroğlu, A.J.P. De Santana Gomes, Á. Juárez Soto, R. Given, S. Mundle, A. Bhaumik, S. Brookman-May, F. Lefresne, S.A. McCarthy, K.N. Chi, N. Agarwal
Journal: European Urology (2021)
Principal Morphomic and Functional Components of Secondary Mitral Regurgitation
Authors: Philipp E. Bartko, Gregor Heitzinger, Georg Spinka, Noemi Pavo, Suriya Prausmüller, Stefan Kastl, Max-Paul Winter, Henrike Arfsten, Timothy C. Tan, Catherine Gebhard, Julia Mascherbauer, Christian Hengstenberg, Guido Strunk, Martin Hülsmann, Georg Goliasch
Journal: JACC. Cardiovascular imaging (2021)
Abstract 14932: Detection of Adrenal Vein on Selective Retrograde CT Adrenal Venography in Comparison with Digital Subtraction Angiography in Subjects with Established Diagnosis of Either Right or Left Adrenal Aldosterone Producing Tumor Confirmed by Adrenal Vein Sampling, Histopathology and Clinical Course
Authors: Masae Uehara, Nobusada Funabashi, Takashi Higashide, Tomoaki Tanaka, Hidekazu Nagano, Hiroyuki Takaoka, Toshiki Kazama, Ken Motoori, Yoshio Kobayashi
Journal: Circulation (2011)

Purpose: Adrenal vein (AV) sampling (AVS) is considered the diagnostic gold standard for primary aldosteronism (PA), but right-sided AVS is especially difficult. We compared detection of the AV on ...
Abstract 347: TET1 mutation as potential biomarker for immune checkpoint blockade in colorectal cancer
Authors: Shaojun Yu, Ding Zhang, Shiqing Chen
Journal: Cancer Research (2021)

Abstract Background: TET1, a DNA demethylase, is encoded by TET1 gene. At present, TET1 mutation has been reported to be associated with enhanced tumor immunogenicity and activated anti-tumor immunity across multiple cancers. However, the clinical effect of TET1 mutation on immunotherapy in colorectal cancer is little known. Methods: 876 patients with colorectal cancer were enrolled in this study. Genomic profiling of DNA was performed on formalin-fixed paraffin-embedded tumor samples by NGS with 733 cancer-related genes panel. The somatic and germline mutation data were both obtained. Benign and likely benign mutations were excluded from our analysis. Programmed death ligand-1(PD-L1) expression status was determined by immunohistochemistry, evaluated with the combined positive score (CPS) and tumor proportion score (TPS). The efficiency of immunotherapy was analyzed in a cohort of 85 patients with colorectal cancer from Morris et al. Results: 40 of 876 patients (4.75%) harbored TET1 mutations, including nonsynonymous, frameshift and stopgain mutations. Totally, 66 TET1 single nucleotide mutation were identified. Median tumor mutation burden (TMB) value with TET1 mutations was 109.2 mutations/MB, significantly higher than 6.1 mutations/MB in TET1 wild-type group (p&amp;lt;0.001). Microsatellite instability-high (MSI-H) appeared more frequently in TET1 mutations group than TET1 wild-type group (50.0% vs 5.0%, p&amp;lt;0.001). For PD-L1 TPS, compare to TET1 wild type groups, the positive rate of PD-L1 expression in TET1 mutations was higher significantly (6.7% vs 2.7%, p&amp;lt;0.001). The same thing happened with PD-L1 CPS (50.0% vs 23.3%, p&amp;lt;0.001). Possibly, TET1 mutation was a potential marker for immunotherapy. The results were validated in a clinical cohort of immunotherapy, including 85 patients with colorectal cancer. The median overall survival was non-reached in 7 patients with TET1 mutations compare to 13 months in TET1 wild-type group (HR: 0.28, 95% CI 0.11-0.69, P=0.006). Conclusions: TET1 mutation was strongly associated with higher TMB, MSI-H and PD-L1 expression and improved OS in patients receiving immune checkpoint blockade treatment, suggesting that TET1 mutation is a novel predictive biomarker for immunotherapy in colorectal cancer. Citation Format: Shaojun Yu, Ding Zhang, Shiqing Chen. TET1 mutation as potential biomarker for immune checkpoint blockade in colorectal 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 347.
P-144 A comparative analysis of secondary data from the ToGA and EVIDENCE studies on the effectiveness of trastuzumab plus chemotherapy in Asian patients with HER2+ metastatic gastric cancer
Authors: L. Shen, T. Wu, P. Chen, S. Qin, J. Ji, Y. Wu, Y. Chen, Y. Chen, J. Wang, Y. Wu
Journal: Annals of Oncology (2021)