tbuckley/cabot-search huggingface dataset:
Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 in patients with metastatic breast cancer: phase II randomized, placebo-controlled study
Authors: Chiun-Sheng Huang, Alice L Yu, Ling-Ming Tseng, Louis W C Chow, Ming-Feng Hou, Sara A Hurvitz, Richard B Schwab, James L Murray, Hsien-Kun Chang, Hong-Tai Chang, Shin-Cheh Chen, Sung-Bae Kim, Jung-Tung Hung, Shir-Hwa Ueng, Su-Hua Lee, Chwen-Cheng Chen, Hope S Rugo
Journal: Journal for ImmunoTherapy of Cancer (2020)

Purpose This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC). Methods At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety. Results Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5–10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3–11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74–1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3–17.6)) versus those with titers &lt;1:160 (5.5 months (95% CI: 3.7–5.6); HR=0.52; p&lt;0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer &lt;1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%). Conclusion AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated. NCT01516307.
Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging
Authors: Christian Schmidkonz, Simon Rauber, Armin Atzinger, Rahul Agarwal, Theresa Ida Götz, Alina Soare, Michael Cordes, Olaf Prante, Christina Bergmann, Arnd Kleyer, Philipp Ritt, Simone Maschauer, Peter Hennig, Johannes Toms, Markus Köhner, Bernhard Manger, John H Stone, Uwe Haberkorn, Tobias Baeuerle, Jörg H W Distler, Abbas Agaimy, Torsten Kuwert, Georg Schett, Andreas Ramming
Journal: Annals of the Rheumatic Diseases (2020)

Objectives To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG 4 -related disease. Methods In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG 4 -related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68 Ga-FAP inhibitor (FAPI)-04), 18 F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18 F-FDG and 68 Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. Results Using combination of 68 Ga-FAPI-04 and 18 F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG 4 -related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18 F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG 4 + cells in histology, while 68 Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. Conclusion FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG 4 -related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG 4 -related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
Acute Aortic Syndromes: New Insights From IRAD and GenTAC Registries
Authors: Kim Eagle
Journal: Circulation (2013)

In his presentation entitled “Acute Aortic Syndromes: New Insights from IRAD and GenTAC Registries”, Dr. Eagle will review the latest in the approaches to diagnosis and treatment of acute aortic syndromes and thoracic aortic disease. In particular, new insights as to the underlying causes of aortic syndromes, the optimal use of biomarkers, and the evolving role of genetics as it relates to diagnosis and screening will be emphasized. In addition, recent advances in best medical and interventional therapy for thoracic aortic disease will be discussed. Finally, Dr. Eagle will discuss where translational and imaging research advances are likely to shape the future care for patients with or at risk for thoracic aortic disease.
Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [<sup>18</sup>F]fluoromethyl-(1,2-<sup>2</sup>H<sub>4</sub>)-choline
Authors: Suraiya Dubash, Marianna Inglese, Francesco Mauri, Kasia Kozlowski, Pritesh Trivedi, Mubarik Arshad, Amarnath Challapalli, Tara Barwick, Adil Al-Nahhas, Rex Stanbridge, Conrad Lewanski, Matthew Berry, Frances Bowen, Eric O. Aboagye
Journal: Theranostics (2020)

Purpose:The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous.Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy.However, non-invasive methods to assess this phenomenon in patients are limited.We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [ 18 F]fluoromethyl-(1,2-2 H 4 ) choline ([ 18 F]D4-FCH) and positron emission tomography/computed tomography (PET/CT).Experimental design: [ 18 F]D4- ) was administered intravenously to 17 newly diagnosed NSCLC patients.PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants.Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) scans.Results: Oxidation of [ 18 F]D4-FCH to [ 18 F]D4-fluorobetaine was suppressed (48.58±0.31%parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer.Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed.[ 18 F]D4-FCH-derived uptake (SUV 60max ) in index primary lesions (n=17) ranged between 2.87-10.13;lower than that of [ 18 F]FDG .Mathematical modelling demonstrated net irreversible uptake of [ 18 F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression.Conclusions: [ 18 F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.
Comparison of Urologist- vs Gastroenterologist-Directed Extracorporeal Shock Wave Lithotripsy for Pancreaticolithiasis
Authors: Isaac L. Jaben, Gregory A. Coté, Erin Forster, Robert A. Moran, Kent A. Broussard, Norman Scott, Peter B. Cotton, Thomas Keane, B. Joseph Elmunzer
Journal: Clinical Gastroenterology and Hepatology (2020)
Microbiome in Sjögren’s syndrome: here we are
Authors: Taco A van der Meulen, Arjan Vissink, Hendrika Bootsma, Fred K L Spijkervet, Frans G M Kroese
Journal: Annals of the Rheumatic Diseases (2020)

Manasson et al 1 wrote an interesting review on what is known with regard to the application of microbiome research for diagnostic and research purposes within autoimmunity and rheumatology. The authors focused this review on the connection between the microbiome and rheumatoid arthritis (RA) as for long it has been presumed that microbiota are contributors to the development and progression of RA. Besides RA, the review also discussed microbiome studies in systemic lupus erythematosus (SLE) and systemic sclerosis. Remarkably, no attention was paid by Manasson et al to the potential involvement of the microbiome in Sjogren’s syndrome (SS). SS is the second most prevalent systemic rheumatic autoimmune disease after RA and the potential involvement of the microbiome in SS-patients is yet also extensively reported. The current knowledge on the relationship between the human microbiome and SS reveals possible pathogenic mechanisms and forms a basis for future treatment options through influencing the microbiome. Thus, the current knowledge on the SS–microbiome connection is an important addition to the review of Manasson et al .1

Thus far, all studies that compared the gut microbiome of SS patients with healthy or population controls have shown that the composition of the gut microbiome in SS patients differs from controls.2–7 Mandl et al 3 found that severe intestinal …
pH-responsive DNA nanomicelles for chemo-gene Synergetic Therapy of Anaplastic Large Cell Lymphoma
Authors: Yuwei Li, Shuzhen Yue, Jingyu Cao, Chengzhan Zhu, Yixiu Wang, Xin Hai, Weiling Song, Sai Bi
Journal: Theranostics (2020)

Chemo-gene therapy is an emerging synergetic modality for the treatment of cancers. Herein, we developed pH-responsive multifunctional DNA nanomicelles (DNMs) as delivery vehicles for controllable release of doxorubicin (Dox) and anaplastic lymphoma kinase (ALK)-specific siRNA for the chemo-gene synergetic therapy of anaplastic large cell lymphoma (ALCL). Methods: DNMs were synthesized by performing in situ rolling circle amplification (RCA) on the amphiphilic primer-polylactide (PLA) micelles, followed by functionalization of pH-responsive triplex DNA via complementary base pairing. The anticancer drug Dox and ALK-specific siRNA were co-loaded to construct Dox/siRNA/DNMs for chemo-gene synergetic cancer therapy. When exposed to the acidic microenvironment (pH below 5.0), C-G·C+ triplex structures were formed, leading to the release of Dox and siRNA for gene silencing to enhance the chemosensitivity in ALCL K299 cells. The chemo-gene synergetic anticancer effect of Dox/siRNA/DNMs on ALCL was evaluated in vitro and in vivo. Results: The pH-responsive DNMs exhibited good monodispersity at different pH values, good biocompatibility, high drug loading capacity, and excellent stability even in the human serum. With the simultaneous release of anticancer drug Dox and ALK-specific siRNA in response to pH in the tumor microenvironment, the Dox/siRNA/DNMs demonstrated significantly higher treatment efficacy for ALCL compared with chemotherapy alone, because the silencing of ALK gene expression mediated by siRNA increased the chemosensitivity of ALCL cells. From the pathological analysis of tumor tissue, the Dox/siRNA/DNMs exhibited the superiority in inhibiting tumor growth, low toxic side effects and good biosafety. Conclusion: DNMs co-loaded with Dox and ALK-specific siRNA exhibited significantly enhanced apoptosis of ALCL K299 cells in vitro and effectively inhibited tumor growth in vivo without obvious toxicity, providing a potential strategy in the development of nanomedicines for synergetic cancer therapy.
Abstract 10565: Effective Treatment of Diabetic Cardiomyopathy With a Selective Beta3-Adrenergic Receptor Antagonist, but Not Beta1-Adrenergic Receptor Blocker in a Murine Model
Authors: Yixi Liu, Heng-Jie Cheng, Zhe Chen, Leanne Groban, Dalane Kitzman, Donald A McClain, Che Ping Cheng
Journal: Circulation (2019)

Background: Diabetic cardiomyopathy (DCM) leads to the progressive decline in cardiac function- increasing risk for heart failure (HF). Both down-regulation of β1-adrenergic receptors (AR) and up-r...
Elective extra corporeal membrane oxygenation for high-risk rigid bronchoscopy
Authors: Emmanuel Martinod, Ana-Maria Portela, Yurdagül Uzunhan, Olivia Freynet, Salam Abou Taam, Florent Vinas, Stephane Dominique, Yacine Tandjaoui-Lambiotte, Manuel Otero-Lopez, Elie Zogheib, Guillaume Lebreton
Journal: Thorax (2020)

The use of extracorporeal membrane oxygenation for high-risk rigid bronchoscopy has been reported in few urgent cases. We report our experience with this approach which was planned electively in five cases on 202 procedures (2.5%). It was proposed because of the potential inability to ventilate the lungs using conventional techniques due to extensive tracheobronchial lesions or the risk of major intraoperative bleeding related to disease characteristics. There were no intraoperative complications and postoperative course was favourable in all patients. With a maximum follow-up of 3 years and 7 months, all patients are alive with no tracheostomy despite major morbidities.
Improving the Efficacy of Liver Cancer Immunotherapy: The Power of Combined Preclinical and Clinical Studies
Authors: Gen‐Sheng Feng, Kaisa L. Hanley, Yan Liang, Xiaoxue Lin
Journal: Hepatology (2020)

Hepatocellular carcinoma (HCC) is a most deadly malignant disease worldwide, with no effective mechanism-based therapy available. Therefore, following the "miracle" outcomes seen in a few patients at the advanced stages of melanoma or lung cancer, the immune checkpoint inhibitors (ICIs) immediately entered clinical trials for advanced HCC patients without pre-clinical studies. Emerging data of clinical studies showed manageable toxicity and safety but limited therapeutic benefit to HCC patients, suggesting low response rate. Thus, one urgent issue is how to convert the liver tumors from cold to hot and responsive, which may rely on in-depth mechanistic studies in animal models and large scale data analysis in human patients. One ongoing approach is to design combinatorial treatment of different ICIs with other reagents and modalities. Indeed, a phase 3 clinical trial showed that combination of atezolizumab and bevacizumab achieved better overall and progression-free survival rates than sorafenib in unresectable HCC. This review highlights the value of animal models and the power of combining pre-clinical and clinical studies in efforts to improve HCC immunotherapy.
Prevalence and clinical characterization of cancer patients with asymptomatic SARS-CoV-2 infection history
Authors: Jianping Bi, Yongping Lin, Ran Zhong, Guowu Jiang, Vivek Verma, Hongwei Shi, Jianfu Li, Xianli Tong, Yanping Li, Desheng Hu, Wenhua Liang, Guang Han, Jianxing He
Journal: Journal of Infection (2020)
Pulsed Inhaled Nitric Oxide (NO) Improves Exercise Tolerance in Severe Chronic Obstructive Pulmonary Disease (COPD) Patients with Pulmonary Hypertension (PH)
Authors: B. Hajian, B. Shivalkar, J. Leemans, C. Van Holsbeke, W. Vos, J. De Backer, K. Sartoris, D. Quinn, A. Hufkins, P. Parizel, J. Cluckers, W. De Backer
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma
Authors: Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Manjie Xing, Xuewen Ong, Takayuki Hoshii, Genki Usui, Motoaki Seki, Yasunobu Mano, Bahityar Rahmutulla, Teru Kanda, Takayoshi Suzuki, Sun Young Rha, Tetsuo Ushiku, Masashi Fukayama, Patrick Tan, Atsushi Kaneda
Journal: Nature Genetics (2020)
A Single Center Analysis of Clofarabine Use Prior to Bone Marrow Transplantation in Patients with Relapsed/Refractory Acute Myeloid Leukemia
Authors: Caleb J Scheckel, Jeffrey Alan Betcher, Lisa Sproat, Nandita Khera, James L. Slack, Jose F. Leis, Pierre Noel, Raoul Tibes, Lanyu Mi, Jeanne Palmer
Journal: Blood (2017)
THU0112 Anaemia in rheumatoid arthritis
Authors: P Athanassiou, E Griva, I Kostoglou-Athanassiou, P Konstantopoulou, S Papazoglou, D Rontogianni, G Vezyroglou, T Kontomerkos
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Rheumatoid arthritis (RA) is accompanied by haematological abnormalities. It is well known that anaemia in RA may have plural aetiology, however no correlation has been performed between anaemia and the morphology of blood cell precursors in the bone marrow in RA. <h3>Objectives</h3> The aim was to investigate the aetiology of anaemia in RA by analysing blood, bone marrow aspirate and bone marrow biopsy findings. <h3>Methods</h3> RA patients were included in the study, n = 51, aged 58.7 ± 1.2 (range 17–85) years. None of the patients was taking any disease modifying agents and 26 were newly diagnosed and had never taken any treatment for RA, duration of disease of the remaining being 9.1 ± 1.8 (range 0.5–35) years. In all patients antinuclear antibodies, anti-dsDNA antibodies and serum rheumatoid factor were measured. Haematocrit, haemoglobin, MCV, MCH, MCHC, serum iron, serum ferritin, serum iron-binding capacity, serum folate and vitamin B12 levels were also measured and indirect and direct Coombs' test was performed. In all patients a bone marrow aspirate was obtained and a bone marrow biopsy was performed. <h3>Results</h3> In 51 RA patients haemoglobin levels were 11.3+0.2 g/dl (mean ± SEM), haematocrit 35.0 ± 0.6%, MCV 80.5 ± 1.4 fl, MCH 25.9 ± 0.5 pg, MCHC 32.0 ± 0.1%, serum iron levels 72.9 ± 4.8 ?g/dl, serum iron-binding capacity 343.4 ± 7.4 ?g/dl, ferritin levels 119.5 ± 23.1 ?g/dl, folate 12.4 ± 1.9 ng/ml and vitamin B12 levels 722.6 ± 301.3 pg/ml. In 32 of 51 patients with haemoglobin 12 g/dl, hyperplasia of red blood cell precursors was noted in 12, megaloblastoid alterations in 4 and erythroblastic islets in 2 patients. No correlation was observed between the presence or absence of anaemia and the dysplastic alterations in the blood cell precursors in the bone marrow in the RA patients studied. <h3>Conclusion</h3> The aetiology of anaemia in RA patients seems to be multifactorial. Dysplastic alterations in blood cell precursors were noted in all the groups of RA patients, irrespective of the presence of anaemia, indicating either that inflammatory cytokines may affect the microenvironment of the bone marrow in RA or that in RA the stem cell in the bone marrow is defective being implicated in the pathogenesis of the disease.
Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients
Authors: Franziska Karl, Andrej Stoll, Romy Böttcher-Loschinski, Martin Böttcher, Rebecca Baur, Benedikt Jacobs, Simon Völkl, Regina Jitschin, Wolf Rösler, Andreas Mackensen, Dimitrios Mougiakakos
Journal: Leukemia (2020)
Hepatitis B Virus Screening and Management for Patients With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update
Authors: Jessica P. Hwang, Jordan J. Feld, Sarah P. Hammond, Su H. Wang, Devena E. Alston-Johnson, Donna R. Cryer, Dawn L. Hershman, Andrew P. Loehrer, Anita L. Sabichi, Banu E. Symington, Norah Terrault, Melisa L. Wong, Mark R. Somerfield, Andrew S. Artz
Journal: Journal of Clinical Oncology (2020)

This Provisional Clinical Opinion update presents a clinically pragmatic approach to hepatitis B virus (HBV) screening and management.All patients anticipating systemic anticancer therapy should be tested for HBV by 3 tests-hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) total immunoglobulin (Ig) or IgG, and antibody to hepatitis B surface antigen-but anticancer therapy should not be delayed. Findings of chronic HBV (HBsAg-positive) or past HBV (HBsAg-negative and anti-HBc-positive) infection require HBV reactivation risk assessment.Patients with chronic HBV receiving any systemic anticancer therapy should receive antiviral prophylactic therapy through and for minimum 12 months following anticancer therapy. Hormonal therapy alone should not pose a substantial risk of HBV reactivation in patients with chronic HBV receiving hormonal therapy alone; these patients may follow noncancer HBV monitoring and treatment guidance. Coordination of care with a clinician experienced in HBV management is recommended for patients with chronic HBV to determine HBV monitoring and long-term antiviral therapy after completion of anticancer therapy.Patients with past HBV infection undergoing anticancer therapies associated with a high risk of HBV reactivation, such as anti-CD20 monoclonal antibodies or stem-cell transplantation, should receive antiviral prophylaxis during and for minimum 12 months after anticancer therapy completion, with individualized management thereafter. Careful monitoring may be an alternative if patients and providers can adhere to frequent, consistent follow-up so antiviral therapy may begin at the earliest sign of reactivation. Patients with past HBV undergoing other systemic anticancer therapies not clearly associated with a high risk of HBV reactivation should be monitored with HBsAg and alanine aminotransferase during cancer treatment; antiviral therapy should commence if HBV reactivation occurs.Additional information is available at www.asco.org/supportive-care-guidelines.
ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming
Authors: Fei Li, Qiuyue Yuan, Wei Di, Xinyi Xia, Zhuang Liu, Ninghui Mao, Lin Li, Chunfeng Li, Juan He, Yunguang Li, Wangxin Guo, Xiaoyu Zhang, Yiqin Zhu, Rebiguli Aji, Shangqian Wang, Xinyuan Tong, Hongbin Ji, Ping Chi, Brett Carver, Yong Wang, Yu Chen, Dong Gao
Journal: Journal of Clinical Investigation (2020)

Although cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early-stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer proluminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we found that ERG was highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibited those cells' normal plasticity to transdifferentiate into a basal lineage, and ERG superseded PTEN loss, which favored basal differentiation. ERG KO disrupted prostate cell luminal differentiation, whereas AR KO had no such effects. Trp63 is a known master regulator of the prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG bound and inhibited the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG, in its fundamental role in lineage differentiation in prostate cancer initiation, orchestrated chromatin interactions and regulated prostate cell lineage toward a proluminal program.
039 Shoulder rotation strength changes from preseason to midseason: a cohort study of 292 youth elite handball players without shoulder problems
Authors: Behnam Liaghat, Jesper Bencke, Mette Kreutzfeldt Zebis, Henrik Sørensen, Grethe Myklebust, Niels Wedderkopp, Martin Lind, Merete Møller
Journal: British Journal of Sports Medicine (2021)