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Astrid Hagelkruys

Other affiliations: Medical University of Vienna
Bio: Astrid Hagelkruys is an academic researcher from Austrian Academy of Sciences. The author has contributed to research in topics: Medicine & Biology. The author has an hindex of 11, co-authored 23 publications receiving 1774 citations. Previous affiliations of Astrid Hagelkruys include Medical University of Vienna.

Papers
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Book ChapterDOI
TL;DR: This chapter summarizes the current state of knowledge of individual nuclear HDAC family members in development and tumorigenesis, their contribution to the hallmarks of cancer, and the involvement of HDACfamily members in different types of human malignancies.
Abstract: Traditionally, cancer has been regarded to originate from genetic alterations such as mutations, deletions, rearrangements as well as gene amplifications, leading to abnormal expression of tumor suppressor genes and oncogenes. An increasing body of evidence indicates that in addition to changes in DNA sequence, epigenetic alterations contribute to cancer initiation and progression. In contrast to genetic mutations, epigenetic changes are reversible and therefore an attractive target for cancer therapy. Many epi-drugs such as histone deacetylase (HDAC) inhibitors showed anticancer activity in cell culture and animal models of carcinogenesis. Recently, the two HDAC inhibitors suberoylanilide hydroxamic acid (SAHA, Vorinostat) and Romidepsin (Depsipeptide, FK228) were FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL). Although HDAC inhibitors are potent anticancer agents, these compounds act against several HDAC family members potentially resulting in numerous side effects. This stems from the fact that HDACs play crucial roles in a variety of biological processes including cell cycle progression, proliferation, differentiation, and development. Consistently, mice deficient in single HDACs mostly exhibit severe phenotypes. Therefore, it is necessary to specify the cancer-relevant HDACs in a given tumor type in order to design selective inhibitors that target only cancer cells without affecting normal cells. In this chapter, we summarize the current state of knowledge of individual nuclear HDAC family members in development and tumorigenesis, their contribution to the hallmarks of cancer, and the involvement of HDAC family members in different types of human malignancies.

108 citations

Journal ArticleDOI
TL;DR: New findings on redundant and unique functions ofHDAC1 and HDAC2 as regulators of proliferation and tumorigenesis are discussed and potential implications for applications of HDAC inhibitors as therapeutic drugs are discussed.
Abstract: Histone deacetylases (HDACs) are negative regulators of gene expression and have been implicated in tumorigenesis and tumor progression. Therefore, HDACs are promising targets for antitumor drugs. However, the relevant isoforms of the 18 members encompassing HDAC family have not been identified. Studies utilizing either gene targeting or knockdown approaches reveal both specific and redundant functions of the closely related class I deacetylases HDAC1 and HDAC2 in the control of proliferation and differentiation. Combined ablation of HDAC1 and HDAC2 in different cell types led to a severe proliferation defects or enhanced apoptosis supporting the idea that both enzymes are relevant targets for tumor therapy. In a recent study on the role of HDAC1 in teratoma formation we have reported a novel and surprising function of HDAC1 in tumorigenesis. In this tumor model HDAC1 attenuates proliferation during teratoma formation. In the present work we discuss new findings on redundant and unique functions of HDAC1 and HDAC2 as regulators of proliferation and tumorigenesis and potential implications for applications of HDAC inhibitors as therapeutic drugs.

101 citations

Journal ArticleDOI
TL;DR: Simultaneous ablation of HDAC1 and HDAC2 or single deletion of Hdac3 severely impairs cell cycle progression in all proliferating cell types indicating that these class I deacetylases are promising targets for small molecule inhibitors as anti-tumor drugs.
Abstract: The Rpd3-like members of the class I lysine deacetylase family are important regulators of chromatin structure and gene expression and have pivotal functions in the control of proliferation, differentiation and development. The highly related class I deacetylases HDAC1 and HDAC2 have partially overlapping but also isoform-specific roles in diverse biological processes, whereas HDAC3 and HDAC8 have unique functions. This review describes the role of class I KDACs in the regulation of transcription as well as their non-transcriptional functions, in particular their contributions to splicing, mitosis/meiosis, replication and DNA repair. During the past years, a number of mouse loss-of-function studies provided new insights into the individual roles of class I deacetylases in cell cycle control, differentiation and tumorigenesis. Simultaneous ablation of HDAC1 and HDAC2 or single deletion of Hdac3 severely impairs cell cycle progression in all proliferating cell types indicating that these class I deacetylases are promising targets for small molecule inhibitors as anti-tumor drugs.

89 citations

Journal ArticleDOI
TL;DR: The data indicate that HDAC1 and HDAC2 have a common function in maintaining proper chromatin structures and show that Hdac2 has a unique role by controlling the fate of neural progenitors during normal brain development.
Abstract: The histone deacetylases HDAC1 and HDAC2 are crucial regulators of chromatin structure and gene expression, thereby controlling important developmental processes. In the mouse brain, HDAC1 and HDAC2 exhibit different developmental stage- and lineage-specific expression patterns. To examine the individual contribution of these deacetylases during brain development, we deleted different combinations of Hdac1 and Hdac2 alleles in neural cells. Ablation of Hdac1 or Hdac2 by Nestin-Cre had no obvious consequences on brain development and architecture owing to compensation by the paralog. By contrast, combined deletion of Hdac1 and Hdac2 resulted in impaired chromatin structure, DNA damage, apoptosis and embryonic lethality. To dissect the individual roles of HDAC1 and HDAC2, we expressed single alleles of either Hdac1 or Hdac2 in the absence of the respective paralog in neural cells. The DNA-damage phenotype observed in double knockout brains was prevented by expression of a single allele of either Hdac1 or Hdac2. Strikingly, Hdac1(-/-)Hdac2(+/-) brains showed normal development and no obvious phenotype, whereas Hdac1(+/-)Hdac2(-/-) mice displayed impaired brain development and perinatal lethality. Hdac1(+/-)Hdac2(-/-) neural precursor cells showed reduced proliferation and premature differentiation mediated by overexpression of protein kinase C, delta, which is a direct target of HDAC2. Importantly, chemical inhibition or knockdown of protein kinase C delta was sufficient to rescue the phenotype of neural progenitor cells in vitro. Our data indicate that HDAC1 and HDAC2 have a common function in maintaining proper chromatin structures and show that HDAC2 has a unique role by controlling the fate of neural progenitors during normal brain development.

76 citations


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Journal ArticleDOI
TL;DR: The vascular endothelium is an active paracrine, endocrine, and Endothelial cell infection and endotheliitis in COVID-19 and recruitment of immune cells can result in widespread endothelial dysfunction associated with apoptosis.

4,855 citations

01 Jan 2020
TL;DR: Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

4,408 citations

Journal ArticleDOI
TL;DR: The basic virology of SARS-CoV-2 is described, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety. In this Review, we describe the basic virology of SARS-CoV-2, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses. We summarize current knowledge of clinical, epidemiological and pathological features of COVID-19, as well as recent progress in animal models and antiviral treatment approaches for SARS-CoV-2 infection. We also discuss the potential wildlife hosts and zoonotic origin of this emerging virus in detail. In this Review, Shi and colleagues summarize the exceptional amount of research that has characterized acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) since this virus has swept around the globe. They discuss what we know so far about the emergence and virology of SARS-CoV-2 and the pathogenesis and treatment of COVID-19.

2,904 citations

Journal ArticleDOI
TL;DR: Key cell entry mechanisms of SARS-CoV-2 that potentially contribute to the immune evasion, cell infectivity, and wide spread of the virus are identified using biochemical and pseudovirus entry assays and the potency and evasiveness are highlighted.
Abstract: A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.

2,450 citations

Journal ArticleDOI
Carly G. K. Ziegler, Samuel J. Allon, Sarah K. Nyquist, Ian M. Mbano1, Vincent N. Miao, Constantine N. Tzouanas, Yuming Cao2, Ashraf S. Yousif3, Julia Bals3, Blake M. Hauser4, Blake M. Hauser3, Jared Feldman4, Jared Feldman3, Christoph Muus5, Christoph Muus4, Marc H. Wadsworth, Samuel W. Kazer, Travis K. Hughes, Benjamin Doran, G. James Gatter3, G. James Gatter5, G. James Gatter6, Marko Vukovic, Faith Taliaferro7, Faith Taliaferro5, Benjamin E. Mead, Zhiru Guo2, Jennifer P. Wang2, Delphine Gras8, Magali Plaisant9, Meshal Ansari, Ilias Angelidis, Heiko Adler, Jennifer M.S. Sucre10, Chase J. Taylor10, Brian M. Lin4, Avinash Waghray4, Vanessa Mitsialis11, Vanessa Mitsialis7, Daniel F. Dwyer11, Kathleen M. Buchheit11, Joshua A. Boyce11, Nora A. Barrett11, Tanya M. Laidlaw11, Shaina L. Carroll12, Lucrezia Colonna13, Victor Tkachev7, Victor Tkachev4, Christopher W. Peterson13, Christopher W. Peterson14, Alison Yu7, Alison Yu15, Hengqi Betty Zheng15, Hengqi Betty Zheng13, Hannah P. Gideon16, Caylin G. Winchell16, Philana Ling Lin7, Philana Ling Lin16, Colin D. Bingle17, Scott B. Snapper7, Scott B. Snapper11, Jonathan A. Kropski10, Jonathan A. Kropski18, Fabian J. Theis, Herbert B. Schiller, Laure-Emmanuelle Zaragosi9, Pascal Barbry9, Alasdair Leslie19, Alasdair Leslie1, Hans-Peter Kiem13, Hans-Peter Kiem14, JoAnne L. Flynn16, Sarah M. Fortune4, Sarah M. Fortune3, Sarah M. Fortune5, Bonnie Berger6, Robert W. Finberg2, Leslie S. Kean4, Leslie S. Kean7, Manuel Garber2, Aaron G. Schmidt3, Aaron G. Schmidt4, Daniel Lingwood3, Alex K. Shalek, Jose Ordovas-Montanes, Nicholas E. Banovich, Alvis Brazma, Tushar J. Desai, Thu Elizabeth Duong, Oliver Eickelberg, Christine S. Falk, Michael Farzan20, Ian A. Glass, Muzlifah Haniffa, Peter Horvath, Deborah T. Hung, Naftali Kaminski, Mark A. Krasnow, Malte Kühnemund, Robert Lafyatis, Haeock Lee, Sylvie Leroy, Sten Linnarson, Joakim Lundeberg, Kerstin B. Meyer, Alexander V. Misharin, Martijn C. Nawijn, Marko Nikolic, Dana Pe'er, Joseph E. Powell, Stephen R. Quake, Jay Rajagopal, Purushothama Rao Tata, Emma L. Rawlins, Aviv Regev, Paul A. Reyfman, Mauricio Rojas, Orit Rosen, Kourosh Saeb-Parsy, Christos Samakovlis, Herbert B. Schiller, Joachim L. Schultze, Max A. Seibold, Douglas P. Shepherd, Jason R. Spence, Avrum Spira, Xin Sun, Sarah A. Teichmann, Fabian J. Theis, Alexander M. Tsankov, Maarten van den Berge, Michael von Papen, Jeffrey A. Whitsett, Ramnik J. Xavier, Yan Xu, Kun Zhang 
28 May 2020-Cell
TL;DR: The data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.

1,911 citations