bims-myxlip Biomed News
on Myxoid liposarcoma
Issue of 2021‒01‒17
sixteen papers selected by
Laura Mannarino
Mario Negri Institute


  1. Diabetes Metab Syndr Obes. 2021 ;14 67-83
    Jakab J, Miškić B, Mikšić Š, Juranić B, Ćosić V, Schwarz D, Včev A.
      Obesity is recognized as a severe threat to overall human health and is associated with type 2 diabetes mellitus, dyslipidemia, hypertension, and cardiovascular diseases. Abnormal expansion of white adipose tissue involves increasing the existing adipocytes' cell size or increasing the number through the differentiation of new adipocytes. Adipogenesis is a process of proliferation and differentiation of adipocyte precursor cells in mature adipocytes. As a key process in determining the number of adipocytes, it is a possible therapeutic approach for obesity. Therefore, it is necessary to identify the molecular mechanisms involved in adipogenesis that could serve as suitable therapeutic targets. Reducing bodyweight is regarded as a major health benefit. Limited efficacy and possible side effects and drug interactions of available anti-obesity treatment highlight a constant need for finding novel efficient and safe anti-obesity ingredients. Numerous studies have recently investigated the inhibitory effects of natural products on adipocyte differentiation and lipid accumulation. Possible anti-obesity effects of natural products include the induction of apoptosis, cell-cycle arrest or delayed progression, and interference with transcription factor cascade or intracellular signaling pathways during the early phase of adipogenesis.
    Keywords:  adipogenesis; anti-obesity treatment; bioactive molecules; signaling pathways; transcriptional cascades
    DOI:  https://doi.org/10.2147/DMSO.S281186
  2. J Surg Oncol. 2021 Jan 14.
    Subramaniam S, Callahan J, Bressel M, Hofman MS, Mitchell C, Hendry S, Vissers FL, Van der Hiel B, Patel D, Van Houdt WJ, Tseng WW, Gyorki DE.
      BACKGROUND: The role of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS).METHODS: Patients with the above histological subtypes in three participating institutions with preoperative 18 F-FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse-free survival (RFS) and overall survival (OS) were also studied.
    RESULTS: Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2-33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (rs  = 0.40, p = .002). Increasing SUVmax was associated with worse RFS (p = .003) and OS (p = .003).
    CONCLUSION: There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior.
    Keywords:  PET scan; retroperitoneal; soft tissue tumor
    DOI:  https://doi.org/10.1002/jso.26379
  3. DNA Repair (Amst). 2021 Jan 07. pii: S1568-7864(20)30296-2. [Epub ahead of print]98 103036
    Malakoti F, Alemi F, Younesi S, Majidinia M, Yousefi B, Morovat P, Khelghati N, Maleki M, Karimian A, Asemi Z.
      The DNA damage response (DDR) pathway's primary purpose is to maintain the genome structure's integrity and stability. A great deal of effort has done to understand the exact molecular mechanisms of non-coding RNAs, such as lncRNA, miRNAs, and circRNAs, in distinct cellular and genomic processes and cancer progression. In this regard, the ncRNAs possible regulatory role in DDR via modulation of key components expression and controlling repair signaling pathway activation is validated. Therefore, in this article, we will discuss the latest developments of ncRNAs contribution in different aspects of DNA repair through regulation of ATM-ATR, P53, and other regulatory signaling pathways.
    Keywords:  ATM; ATR; DNA damage; DNA repair; Noncoding RNA
    DOI:  https://doi.org/10.1016/j.dnarep.2020.103036
  4. Cancer Med. 2021 Jan 15.
    Felix A, Berlanga P, Toulmonde M, Landman-Parker J, Dumont S, Vassal G, Le Deley MC, Gaspar N.
      BACKGROUND: Optimal Phase-II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined.OBJECTIVES: Recurrent/refractory ES phase-I/II trials analysis to improve trials design.
    METHODS: Comprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e-cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase-I or Phase-II).
    RESULTS: The 146 trials identified (77 phase-I/II, 67 phase-II, and 2 phase-II/III) tested targeted (34%), chemo- (23%), immune therapies (19%), or combined therapies (24%). Twenty-three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single-arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression-free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%-25% and 20%-50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3-14.7) and 7.6 months (5-30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%-30%), 4.5 (1.3-10), and 16.6 months (6.9-30), respectively.
    CONCLUSION: This review supports the need to develop the international randomized phase-II trials across all age ranges with PFS as primary endpoint.
    Keywords:  Ewing sarcoma; new cancer therapies; phase-I/II trials; trial design
    DOI:  https://doi.org/10.1002/cam4.3712
  5. J Exp Clin Cancer Res. 2021 Jan 09. 40(1): 27
    Tocci P, Blandino G, Bagnato A.
      The rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.
    Keywords:  Endothelin-1 receptors; G protein‐coupled receptor; Mutant TP53; YAP; β-arrestin1
    DOI:  https://doi.org/10.1186/s13046-021-01827-8
  6. Front Genet. 2020 ;11 607428
    Yue X, Bai C, Xie D, Ma T, Zhou PK.
      DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a member of the phosphatidylinositol 3-kinase related kinase family, which can phosphorylate more than 700 substrates. As the core enzyme, DNA-PKcs forms the active DNA-PK holoenzyme with the Ku80/Ku70 heterodimer to play crucial roles in cellular DNA damage response (DDR). Once DNA double strand breaks (DSBs) occur in the cells, DNA-PKcs is promptly recruited into damage sites and activated. DNA-PKcs is auto-phosphorylated and phosphorylated by Ataxia-Telangiectasia Mutated at multiple sites, and phosphorylates other targets, participating in a series of DDR and repair processes, which determine the cells' fates: DSBs NHEJ repair and pathway choice, replication stress response, cell cycle checkpoints, telomeres length maintenance, senescence, autophagy, etc. Due to the special and multi-faceted roles of DNA-PKcs in the cellular responses to DNA damage, it is important to precisely regulate the formation and dynamic of its functional complex and activities for guarding genomic stability. On the other hand, targeting DNA-PKcs has been considered as a promising strategy of exploring novel radiosensitizers and killing agents of cancer cells. Combining DNA-PKcs inhibitors with radiotherapy can effectively enhance the efficacy of radiotherapy, offering more possibilities for cancer therapy.
    Keywords:  DNA damage response; DNA repair; DNA-PKcs; genomic instability; radiosensitization
    DOI:  https://doi.org/10.3389/fgene.2020.607428
  7. Am J Transl Res. 2020 ;12(12): 7693-7701
    Li X, Wang G, Cai Z, Sun W.
      There are more than 100 sarcoma subtypes, each of which is uncommon and challenging to diagnose. Most patients with locally advanced and unresectable sarcomas are still treated with cytotoxic chemotherapy and have low long-term survival. Therefore, novel therapeutic methods are needed to improve the prognosis of patients with sarcomas. Immunotherapy is increasingly recognized as have an essential role in the treatment of malignant tumors. Emerging strategies, such as immune checkpoint inhibitors, vaccines, and adoptive cell therapies have been investigated for the treatment of sarcomas. Advances in these immunotherapies have provided a better understanding of how immuno-oncology can be best applied to the treatment of sarcomas, including their potential as adjuvant therapies in combination strategies. In this review, we discuss the immune microenvironment and how it relates to immunoresponsiveness, focusing on the advances in immunotherapy (immune checkpoint inhibitors, vaccines and adoptive cell therapies), the use of which will hopefully lead to improved outcomes for patients with sarcomas.
    Keywords:  Tumor immune microenvironment; adoptive cell therapy; clinical significance; immune checkpoint inhibitor; vaccine
  8. Semin Cancer Biol. 2021 Jan 06. pii: S1044-579X(20)30282-0. [Epub ahead of print]
    Guo L, Lee YT, Zhou Y, Huang Y.
      Drug resistance, either intrinsic or acquired, represents a major hurdle to achieving optimal therapeutic outcomes during cancer treatment. In addition to acquisition of resistance-conferring genetic mutations, accumulating evidence suggests an intimate involvement of the epigenetic machinery in this process as well. Recent studies have revealed that epigenetic reprogramming, such as altered expression or relocation of DNA/histone modulators accompanied with chromatin structure remodeling, can lead to transcriptional plasticity in tumor cells, thereby driving their transformation towards a persistent state. These "persisters" represent a pool of slow-growing cells that can either re-expand when treatment is discontinued or acquire permanent resistance. Targeting epigenetic reprogramming or plasticity represents a new strategy to prevent the emergence of drug-refractory populations and to enable more consistent clinical responses. With the growing numbers of drugs or drug candidates developed to target epigenetic regulators, more and more epigenetic therapies are under preclinical evaluation, early clinical trials or approved by FDA as single agent or in combination with existing antitumor drugs. In this review, we highlight latest discoveries in the mechanistic understanding of epigenetically-induced drug resistance. In parallel, we discuss the potential of combining epigenetic drugs with existing anticancer regimens as a promising strategy for overcoming cancer drug resistance.
    Keywords:  3D chromatin organization; DNA methylation; Epigenome; cancer; drug resistance; epigenetic reprogramming; histone modifications
    DOI:  https://doi.org/10.1016/j.semcancer.2020.12.022
  9. BMC Cancer. 2021 Jan 12. 21(1): 58
    Wang Y, Li J, Shao C, Tang X, Du Y, Xu T, Zhao Z, Hu H, Sheng Y, Hu C, Xi Y.
      BACKGROUND: Autophagy-related genes (ARGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of ARGs and their clinical significance in sarcoma patients is lacking.METHODS: Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed ARGs (DEARGs) were determined by matching the DEG and HADb gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEARGs was conducted, and associations with tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for disease-free survival (DFS), were established and validated in an independent set.
    RESULTS: In total, 84 DEARGs and two clusters were identified. TME scores, five immune checkpoints, and several types of immune cells were found to be significantly different between two clusters. Two prognostic signatures incorporating DEARGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.818 and 0.747 for the OS and DFS nomograms, respectively.
    CONCLUSION: This comprehensive analyses of the ARG landscape in sarcoma showed novel ARGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy.
    Keywords:  Autophagy-related genes; Immune cell; Immune checkpoint; Prognosis; Sarcoma
    DOI:  https://doi.org/10.1186/s12885-020-07596-5
  10. Pharm Res. 2021 Jan 12.
    Mayeuf-Louchart A.
      The presence of glycogen in the brown adipose tissue (BAT) has been described 60 years ago. However, the role of this energetic storage in brown adipocytes has been long time underestimated. We have recently shown that during brown adipocyte differentiation in the embryo, glycogen accumulates and is degraded by glycophagy, a dynamic essential for lipid droplets biogenesis. Recent studies have shown that the storage and degradation of triglycerides in BAT are not essential for the activation of BAT in response to cold exposure in adults, and that glycogen can compensate for their absence. In this review, we report the recent advances related to the importance of glycogen in brown adipocytes.
    Keywords:  brown adipose tissue; cold exposure; glycogen; glycophagy; lipid droplet; lipolysis
    DOI:  https://doi.org/10.1007/s11095-020-02979-6
  11. Cancer Lett. 2021 Jan 12. pii: S0304-3835(21)00002-1. [Epub ahead of print]
    Gala K, Khattar E.
      Long non-coding RNAs (lncRNAs) are known to regulate various biological processes including cancer. Cancer cells possess limitless replicative potential which is attained by telomere length maintenance while normal somatic cells have a limited lifespan because their telomeres shorten with every cell division ultimately triggering replicative senescence. Two lncRNAs have been observed to play a key role in telomere length maintenance. First is the lncRNA TERC (telomerase RNA component) which functions as a template for telomeric DNA synthesis in association with telomerase reverse transcriptase (TERT) which serves as the catalytic component. Together they constitute the telomerase complex which functions as a reverse transcriptase to elongate telomeres. Second lncRNA that helps in regulating telomere length is the telomeric repeat-containing RNA (TERRA) which is transcribed from the subtelomeric region and extends to the telomeric region. TERC and TERRA exhibit important functions in cancer with implications in precision oncology. In this review, we discuss various aspects of these important lncRNAs in humans and their role in cancer along with recent advancements in their anticancer therapeutic application.
    Keywords:  Alternative lengthening of telomeres; TERC; TERRA; Telomerase; Telomere
    DOI:  https://doi.org/10.1016/j.canlet.2020.12.036
  12. J Pathol. 2021 Jan 11.
    Kannan S, Lock I, Ozenberger BB, Jones KB.
      Sarcoma comprises a group of malignancies that includes over one hundred individual disease entities. Type-specific genetic events initiate each tumor, occurring within a specific cellular context or circumstance. All sarcomas share a relationship with mesenchymal tissues of origin. Conceptual models for each specific route towards sarcomagenesis have developed over the years as clinical, cellular, and increasing molecular observations have advanced hypotheses to be tested in the forward or reverse direction in experimental systems, often genetically engineered model organisms. This review considers the history of these discoveries in the context of technologies available at the time each was made and provides a comprehensive summary of the current knowledge of sarcoma genetics, including characteristic translocations, oncogene activation and loss of tumor suppressor gene events, and their putative cells of origin. Also considered are the interrelatedness of molecular clinical observations and genetic experiments in model systems to move this field of knowledge forward, as well as their implications for diagnostic and therapeutic paradigms for sarcoma. This article is protected by copyright. All rights reserved.
    Keywords:  bone; cell of origin; epigenetics; genetics; mouse model; sarcoma; soft-tissue; transformation
    DOI:  https://doi.org/10.1002/path.5617
  13. Dev Biol. 2021 Jan 08. pii: S0012-1606(21)00004-X. [Epub ahead of print]
    Szulzewsky F, Holland EC, Vasioukhin V.
      YAP1 is a transcriptional co-activator whose activity is controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and regeneration, YAP1 has also prominent functions in cancer initiation, aggressiveness, metastasis, and therapy resistance. In this review we are discussing the molecular functions of YAP1 and its roles in cancer, with a focus on the different mechanisms of de-regulation of YAP1 activity in human cancers, including inactivation of upstream Hippo pathway tumor suppressors, regulation by intersecting pathways, miRNAs, and viral oncogenes. We are also discussing new findings on the function and biology of the recently identified family of YAP1 gene fusions, that constitute a new type of activating mutation of YAP1 and that are the likely oncogenic drivers in several subtypes of human cancers. Lastly, we also discuss different strategies of therapeutic inhibition of YAP1 functions.
    Keywords:  Cancer; Gene fusions; Hippo signaling pathway; YAP1; YAP1 fusion
    DOI:  https://doi.org/10.1016/j.ydbio.2020.12.018
  14. Proc Natl Acad Sci U S A. 2021 Jan 05. pii: e2004077118. [Epub ahead of print]118(1):
    Fritsch C, Gout JF, Haroon S, Towheed A, Chung C, LaGosh J, McGann E, Zhang X, Song Y, Simpson S, Danthi PS, Benayoun BA, Wallace D, Thomas K, Lynch M, Vermulst M.
      Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.
    Keywords:  DNA damage; genotoxic stress; mutagenesis; transcription error
    DOI:  https://doi.org/10.1073/pnas.2004077118
  15. Saudi J Biol Sci. 2021 Jan;28(1): 628-634
    Aboul-Soud MAM, Alzahrani AJ, Mahmoud A.
      Background: Pharmacogenetics is involved in customizing therapy according to the genetic makeup of an individual, and is applicable for chemotherapy, radiotherapy as well as targeted therapy. Drug metabolizing enzymes (DMEs) involving both phase I, and phase II reactions are widely studied. Our study was involved in whole exome sequencing (WES) of cancer patients, followed by analysis for identifying key variations in DMEs, and associated transporters that have a potential impact on treatment outcome.Methodology: A total of 181 solid tumor patients at stage >/= III were subjected to WES by the SureSelectXT Human All Exon V6 + UTR library preparation kit, and sequencing in the Illumina NextSeq 550 system. Bioinformatics analysis involved use of GATK pipeline, and the variants were further assessed for population frequency, functional impact with annovar insilico algorithms. Further variant information from significant DMEs, and transporters were extracted and analyzed with PharmGKB to assess level of evidence and infer their impact on the pathways involved in drug response.
    Results: The total study cohort of 181 solid tumor patients included 60 males, and 121 females respectively. Among DMEs, deleterious mutation in dihydropyrimidine dehydrogenase (DPYD; rs67376798), solute carrier organic anion transporter family member 1B1 (SLCO1B1*5), and cytochrome P450 2D6 (CYP2D6*10) associated with metabolism of anticancer drugs was detected to be in high frequency of 26%, 21% and 25% respectively.
    Conclusion: Our analysis detected variations in both phase I and phase II DMEs, as well as associated transporter genes which has been documented to reduce drug efficacy, as well as cause grade 3 and 4 toxicity. Our study reiterates the significance of pharmacogenomics in stratifying patients for appropriate therapy regimen focused at better treatment outcome and quality of life.
    Keywords:  Cancer; Chemotherapy; Circulating tumor DNA; Pharmacogenomics; Single nucleotide polymorphisms; Whole exome sequencing
    DOI:  https://doi.org/10.1016/j.sjbs.2020.10.052
  16. Cell Rep. 2021 Jan 12. pii: S2211-1247(20)31613-2. [Epub ahead of print]34(2): 108624
    Schlein C, Fischer AW, Sass F, Worthmann A, Tödter K, Jaeckstein MY, Behrens J, Lynes MD, Kiebish MA, Narain NR, Bussberg V, Darkwah A, Jespersen NZ, Nielsen S, Scheele C, Schweizer M, Braren I, Bartelt A, Tseng YH, Heeren J, Scheja L.
      Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic. Using metabolic and lipidomic approaches, we show that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of BAT involution. By transcriptional control of lipogenesis-related enzymes, ChREBP determines the abundance and composition of both storage and membrane lipids known to regulate organelle turnover and function. Notably, ChREBP deficiency and pharmacological inhibition of lipogenesis during thermoneutral adaptation preserved mitochondrial mass and thermogenic capacity of BAT independently of mitochondrial biogenesis. In conclusion, we establish lipogenesis as a potential therapeutic target to prevent loss of BAT thermogenic capacity as seen in adult humans.
    Keywords:  ChREBP; brown adipose tissue; cardiolipins; de novo lipogenesis; energy expenditure; fatty acid synthesis; fatty acids; lipidome; mitochondria; mitophagy; non-shivering thermogenesis; phospholipids; thermoneutrality; triacylglycerols; whitening
    DOI:  https://doi.org/10.1016/j.celrep.2020.108624