Publications by authors named "Marc Ferrer"

228 Publications

A platform of assays for the discovery of anti-Zika small-molecules with activity in a 3D-bioprinted outer-blood-retina model.

PLoS One 2022 18;17(1):e0261821. Epub 2022 Jan 18.

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America.

The global health emergency posed by the outbreak of Zika virus (ZIKV), an arthropod-borne flavivirus causing severe neonatal neurological conditions, has subsided, but there continues to be transmission of ZIKV in endemic regions. As such, there is still a medical need for discovering and developing therapeutical interventions against ZIKV. To identify small-molecule compounds that inhibit ZIKV disease and transmission, we screened multiple small-molecule collections, mostly derived from natural products, for their ability to inhibit wild-type ZIKV. As a primary high-throughput screen, we used a viral cytopathic effect (CPE) inhibition assay conducted in Vero cells that was optimized and miniaturized to a 1536-well format. Suitably active compounds identified from the primary screen were tested in a panel of orthogonal assays using recombinant Zika viruses, including a ZIKV Renilla luciferase reporter assay and a ZIKV mCherry reporter system. Compounds that were active in the wild-type ZIKV inhibition and ZIKV reporter assays were further evaluated for their inhibitory effects against other flaviviruses. Lastly, we demonstrated that wild-type ZIKV is able to infect a 3D-bioprinted outer-blood-retina barrier tissue model and disrupt its barrier function, as measured by electrical resistance. One of the identified compounds (3-Acetyl-13-deoxyphomenone, NCGC00380955) was able to prevent the pathological effects of the viral infection on this clinically relevant ZIKV infection model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261821PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765781PMC
January 2022

Child and adolescent depression and other mental health issues during lockdown and SARS-CoV-2/COVID-19 pandemic: A survey in school setting.

An Pediatr (Engl Ed) 2022 Jan 4;96(1):61-64. Epub 2021 Dec 4.

Unidad de Urgencias Pediátricas, Hospital Infantil Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.anpede.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642161PMC
January 2022

Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model.

Nat Commun 2021 12 15;12(1):7293. Epub 2021 Dec 15.

Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.
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http://dx.doi.org/10.1038/s41467-021-27488-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674335PMC
December 2021

Exploring the psychological impact of COVID-19 on adolescents with borderline personality disorder and their mothers: A focus group study.

Clin Child Psychol Psychiatry 2021 Dec 7:13591045211058318. Epub 2021 Dec 7.

Psychiatry Department, Vall d'Hebron University Hospital, Mental Health Network Biomedical Research Center (CIBERSAM), Barcelona, Spain.

The aim of this study was to explore the impact of the coronavirus pandemic on adolescents diagnosed with Borderline Personality Disorder (BPD) and their mothers. This exploratory study used a qualitative focus group approach. This study's sample group consisted in nine participants: five adolescents diagnosed with BPD and their four mothers. Patients were recruited from a specialized BPD outpatient unit of a university hospital psychiatry department. The results are divided into two main areas, the first regarding the lockdown period and the second examining the period of gradual relaxation of lockdown restrictions. The results show that the adolescents had difficulties in the management of their interpersonal relationships, especially in striking a balance between individual and family space, as well as in communication, cohesion, and family dynamics. During the COVID lockdown, adolescents experienced a stabilization of psychopathological symptoms, but these symptoms worsened when the lockdown restrictions were lifted. Nevertheless, they reported having learned and implemented self-care strategies. The findings are discussed in terms of both individual and family impact, shedding light on some of the challenges precipitated by the COVID-19 pandemic.
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http://dx.doi.org/10.1177/13591045211058318DOI Listing
December 2021

The humanized nanobody RBD-1-2G tolerates the spike N501Y mutation to neutralize SARS-CoV-2.

bioRxiv 2021 Oct 24. Epub 2021 Oct 24.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.

One-sentence Summary: A cost-effective, high-throughput, adaptable pipeline capable of identifying effective humanized nanobodies against SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.10.22.465476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562546PMC
October 2021

The Natural Product β-Escin Targets Cancer and Stromal Cells of the Tumor Microenvironment to Inhibit Ovarian Cancer Metastasis.

Cancers (Basel) 2021 Aug 4;13(16). Epub 2021 Aug 4.

Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA.

The high mortality of OvCa is caused by the wide dissemination of cancer within the abdominal cavity. OvCa cells metastasize to the peritoneum, which is covered by mesothelial cells, and invade into the underlying stroma, composed of extracellular matrices (ECM) and stromal cells. In a study using a three-dimensional quantitative high-throughput screening platform (3D-qHTS), we found that β-escin, a component of horse chestnut seed extract, inhibited OvCa adhesion/invasion. Here, we determine whether β-escin and structurally similar compounds have a therapeutic potential against OvCa metastasis. Different sources of β-escin and horse chestnut seed extract inhibited OvCa cell adhesion/invasion, both in vitro and in vivo. From a collection of 160 structurally similar compounds to β-escin, we found that cardiac glycosides inhibited OvCa cell adhesion/invasion and proliferation in vitro, and inhibited adhesion/invasion and metastasis in vivo. Mechanistically, β-escin and the cardiac glycosides inhibited ECM production in mesothelial cells and fibroblasts. The oral administration of β-escin inhibited metastasis in both OvCa prevention and intervention mouse models. Specifically, β-escin inhibited ECM production in the omental tumors. Additionally, the production of HIF1α-targeted proteins, lactate dehydrogenase A, and hexokinase 2 in omental tumors was blocked by β-escin. This study reveals that the natural compound β-escin has a therapeutic potential because of its ability to prevent OvCa dissemination by targeting both cancer and stromal cells in the OvCa tumor microenvironment.
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http://dx.doi.org/10.3390/cancers13163931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394501PMC
August 2021

Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.

EMBO Mol Med 2021 09 11;13(9):e13929. Epub 2021 Aug 11.

Experimental Nephrology, Department of Clinical Sciences, University of Barcelona, Barcelona, Spain.

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.
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http://dx.doi.org/10.15252/emmm.202113929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422079PMC
September 2021

Operationalizing the Use of Biofabricated Tissue Models as Preclinical Screening Platforms for Drug Discovery and Development.

SLAS Discov 2021 10 16;26(9):1164-1176. Epub 2021 Jul 16.

3D Tissue Bioprinting Laboratory (3DTBL), Division of Pre-clinical Innovation (DPI), National Center for Advancing Translational Sciences (NCATS), NIH, Rockville, MD, USA.

A wide range of complex in vitro models (CIVMs) are being developed for scientific research and preclinical drug efficacy and safety testing. The hope is that these CIVMs will mimic human physiology and pathology and predict clinical responses more accurately than the current cellular models. The integration of these CIVMs into the drug discovery and development pipeline requires rigorous scientific validation, including cellular, morphological, and functional characterization; benchmarking of clinical biomarkers; and operationalization as robust and reproducible screening platforms. It will be critical to establish the degree of physiological complexity that is needed in each CIVM to accurately reproduce native-like homeostasis and disease phenotypes, as well as clinical pharmacological responses. Choosing which CIVM to use at each stage of the drug discovery and development pipeline will be driven by a fit-for-purpose approach, based on the specific disease pathomechanism to model and screening throughput needed. Among the different CIVMs, biofabricated tissue equivalents are emerging as robust and versatile cellular assay platforms. Biofabrication technologies, including bioprinting approaches with hydrogels and biomaterials, have enabled the production of tissues with a range of physiological complexity and controlled spatial arrangements in multiwell plate platforms, which make them amenable for medium-throughput screening. However, operationalization of such 3D biofabricated models using existing automation screening platforms comes with a unique set of challenges. These challenges will be discussed in this perspective, including examples and thoughts coming from a laboratory dedicated to designing and developing assays for automated screening.
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http://dx.doi.org/10.1177/24725552211030903DOI Listing
October 2021

Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

PLoS One 2021 15;16(7):e0252048. Epub 2021 Jul 15.

Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Harvard University, Boston, Massachusetts, United States of America.

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252048PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282008PMC
October 2021

Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection.

bioRxiv 2021 Jun 24. Epub 2021 Jun 24.

The ongoing COVID-19 pandemic has highlighted the dearth of approved drugs to treat viral infections, with only ∼90 FDA approved drugs against human viral pathogens. To identify drugs that can block SARS-CoV-2 replication, extensive drug screening to repurpose approved drugs is underway. Here, we screened ∼18,000 drugs for antiviral activity using live virus infection in human respiratory cells. Dose-response studies validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these drug candidates are 16 nucleoside analogs, the largest category of clinically used antivirals. This included the antiviral Remdesivir approved for use in COVID-19, and the nucleoside Molnupirivir, which is undergoing clinical trials. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral, and we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogs synergistically inhibits SARS-CoV-2 infection in vitro and in vivo suggesting a clinical path forward.
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http://dx.doi.org/10.1101/2021.06.24.449811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240684PMC
June 2021

Discovery and Optimization of a 4-Aminopiperidine Scaffold for Inhibition of Hepatitis C Virus Assembly.

J Med Chem 2021 07 29;64(13):9431-9443. Epub 2021 Jun 29.

Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

The majority of FDA-approved HCV therapeutics target the viral replicative machinery. An automated high-throughput phenotypic screen identified several small molecules as potent inhibitors of hepatitis C virus replication. Here, we disclose the discovery and optimization of a 4-aminopiperidine (4AP) scaffold targeting the assembly stages of the HCV life cycle. The original screening hit (1) demonstrates efficacy in the HCVcc assay but does not show potency prior to or during viral replication. Colocalization and infectivity studies indicate that the 4AP chemotype inhibits the assembly and release of infectious HCV. Compound 1 acts synergistically with FDA-approved direct-acting antiviral compounds Telaprevir and Daclatasvir, as well as broad spectrum antivirals Ribavirin and cyclosporin A. Following an SAR campaign, several derivatives of the 4AP series have been identified with increased potency against HCV, reduced toxicity, as well as improved and ADME properties.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00696DOI Listing
July 2021

Identification of Small Molecule Inhibitors of a Mir155 Transcriptional Reporter in Th17 Cells.

Sci Rep 2021 06 1;11(1):11498. Epub 2021 Jun 1.

Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, 20850, USA.

MicroRNA miR-155 is an important regulatory molecule in the immune system and is highly expressed and functional in Th17 cells, a subset of CD4 T helper cells which are key players in autoimmune diseases. Small molecules that can modulate miR-155 may potentially provide new therapeutic avenues to inhibit Th17 cell-mediated autoimmune diseases. Here, we present a novel high-throughput screening assay using primary T cells from genetically engineered Mir155 reporter mice, and its use to screen libraries of small molecules to identify novel modulators of Th17 cell function. We have discovered a chemical series of (E)-1-(phenylsulfonyl)-2-styryl-1H-benzo[d] imidazoles as novel down-regulators of Mir155 reporter and cytokine expression in Th17 cells. In addition, we found that FDA approved antiparasitic agents belonging to the 'azole' family also down-regulate Mir155 reporter and cytokine expression in Th17 cells, and thus could potentially be repurposed to treat Th17-driven immunopathologies.
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http://dx.doi.org/10.1038/s41598-021-90944-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169650PMC
June 2021

Modeling SARS-CoV-2 and Influenza Infections and Antiviral Treatments in Human Lung Epithelial Tissue Equivalents.

bioRxiv 2021 May 12. Epub 2021 May 12.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third coronavirus in less than 20 years to spillover from an animal reservoir and cause severe disease in humans. High impact respiratory viruses such as pathogenic beta-coronaviruses and influenza viruses, as well as other emerging respiratory viruses, pose an ongoing global health threat to humans. There is a critical need for physiologically relevant, robust and ready to use, cellular assay platforms to rapidly model the infectivity of emerging respiratory viruses and discover and develop new antiviral treatments. Here, we validate human alveolar and tracheobronchial tissue equivalents and assess their usefulness as assay platforms in the context of live SARS-CoV-2 and influenza A virus infections. We establish the cellular complexity of two distinct tracheobronchial and alveolar epithelial air liquid interface (ALI) tissue models, describe SARS-CoV-2 and influenza virus infectivity rates and patterns in these ALI tissues, the viral-induced cytokine production as it relates to tissue-specific disease, and demonstrate the pharmacologically validity of these lung epithelium models as antiviral drug screening assay platforms.
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http://dx.doi.org/10.1101/2021.05.11.443693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132232PMC
May 2021

Pharmacological activation of STING blocks SARS-CoV-2 infection.

Sci Immunol 2021 05;6(59)

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia PA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection. To identify potent antiviral innate immune agonists, we screened a panel of 75 microbial ligands that activate diverse signaling pathways and identified cyclic dinucleotides (CDNs), canonical STING agonists, as antiviral. Since CDNs have poor bioavailability, we tested the small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B.1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. Our study provides evidence that activation of STING may represent a promising therapeutic strategy to control SARS-CoV-2.
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http://dx.doi.org/10.1126/sciimmunol.abi9007DOI Listing
May 2021

Integration of the and Dimensional Systems for Personality Disorders Into a Unified Taxonomy With Non-overlapping Traits.

Front Psychiatry 2021 6;12:591934. Epub 2021 Apr 6.

Institute of Neuroscience, Hospital Clinic, Barcelona, Spain.

The promise of replacing the diagnostic categories of personality disorder with a better-grounded system has been only partially met. We still need to understand whether our main dimensional taxonomies, those of the , 11th Revision () and the , Fifth Edition (), are the same or different, and elucidate whether a unified structure is possible. We also need truly independent pathological domains, as they have shown unacceptable overlap so far. To inquire into these points, the Personality Inventory for (PID-5) and the Personality Inventory for (PiCD) were administered to 677 outpatients. Disattenuated correlation coefficients between 0.84 and 0.93 revealed that both systems share four analogous traits: negative affectivity, detachment, dissociality/antagonism, and disinhibition. These traits proved scalar equivalence too, such that scores in the two questionnaires are roughly interchangeable. These four domains plus psychoticism formed a theoretically consistent and well-fitted five-factor structure, but they overlapped considerably, thereby reducing discriminant validity. Only after the extraction of a general personality disorder factor (g-PD) through bifactor analysis, we could attain a comprehensive model bearing mutually independent traits.
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http://dx.doi.org/10.3389/fpsyt.2021.591934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055818PMC
April 2021

Identification of Small-Molecule Inhibitors of Human Inositol Hexakisphosphate Kinases by High-Throughput Screening.

ACS Pharmacol Transl Sci 2021 Apr 3;4(2):780-789. Epub 2021 Mar 3.

Lieber Institute for Brain Development, Baltimore, Maryland 21205, United States.

Inositol hexakisphosphate kinases (IP6Ks) catalyze pyrophosphorylation of inositol hexakisphosphate (IP6) into inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7), which is involved in numerous areas of cell physiology including glucose homeostasis, blood coagulation, and neurological development. Inhibition of IP6Ks may be effective for the treatment of Type II diabetes, obesity, metabolic complications, thrombosis, and psychiatric disorders. We performed a high-throughput screen (HTS) of 158 410 compounds for IP6K1 inhibitors using a previously developed ADP-Glo Max assay. Of these, 1206 compounds were found to inhibit IP6K1 kinase activity by more than 25%, representing a 0.8% hit rate. Structural clustering analysis of HTS-active compounds, which were confirmed in the dose-response testing using the same kinase assay, revealed diverse clusters that were feasible for future structure-activity relationship (SAR) optimization to potent IP6K inhibitors. Medicinal chemistry SAR efforts in three chemical series identified potent IP6K1 inhibitors which were further validated in an orthogonal LC-MS IP7 analysis. The effects of IP6K1 inhibitors on cellular IP7 levels were further confirmed and were found to correlate with cellular IP6K1 binding measured by a high-throughput cellular thermal shift assay (CETSA).
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http://dx.doi.org/10.1021/acsptsci.0c00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033760PMC
April 2021

[Child and adolescent depression and other mental health issues during lockdown and SARS-CoV-2/COVID-19 pandemic: A survey in school setting].

An Pediatr (Engl Ed) 2020 Oct 3. Epub 2020 Oct 3.

Unidad de Urgencias Pediátricas, Hospital Infantil Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, España. Electronic address:

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http://dx.doi.org/10.1016/j.anpedi.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532745PMC
October 2020

Isolating and targeting the real-time plasticity and malignant properties of epithelial-mesenchymal transition in cancer.

Oncogene 2021 04 19;40(16):2884-2897. Epub 2021 Mar 19.

The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus (CU AMC), Aurora, Colorado, USA.

Epithelial-mesenchymal transition (EMT) is a driving force in promoting malignant cancer, including initiation, growth, and metastasis. EMT is a dynamic process that can undergo a mesenchymal-epithelial transition (MET) and partial transitions between both phenotypes, termed epithelial-mesenchymal plasticity (EMP). In cancer, the acquisition of EMP results in a spectrum of phenotypes, promoting tumor cell heterogeneity and resistance to standard of care therapy. Here we describe a real-time fluorescent dual-reporter for vimentin and E-cadherin, biomarkers of the mesenchymal and epithelial cell phenotypes, respectively. Stable dual-reporter cell lines generated from colorectal (SW620), lung (A549), and breast (MDA-MB-231) cancer demonstrate a spectrum of EMT cell phenotypes. We used the dual-reporter to isolate the quasi epithelial, epithelial/mesenchymal, and mesenchymal phenotypes. Although EMT is a dynamic process, these isolated quasi-EMT-phenotypes remain stable to spontaneous EMP in the absence of stimuli and during prolonged cell culture. However, the quasi-EMT phenotypes can readily be induced to undergo EMT or MET with growth factors or small molecules. Moreover, isolated EMT phenotypes display different tumorigenic properties and are morphologically and metabolically distinct. 3D high-content screening of ~23,000 compounds using dual-reporter mesenchymal SW620 tumor organoids identified small molecule probes that modulate EMT, and a subset of probes that effectively induced MET. The tools, probes, and models described herein provide a coherent mechanistic understanding of mesenchymal cell plasticity. Future applications utilizing this technology and probes are expected to advance our understanding of EMT and studies aimed at therapeutic strategies targeting EMT.
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http://dx.doi.org/10.1038/s41388-021-01728-2DOI Listing
April 2021

A high-throughput screening to identify small molecules that suppress huntingtin promoter activity or activate huntingtin-antisense promoter activity.

Sci Rep 2021 03 17;11(1):6157. Epub 2021 Mar 17.

Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of huntingtin (HTT). While there are currently no disease-modifying treatments for HD, recent efforts have focused on the development of nucleotide-based therapeutics to lower HTT expression. As an alternative to siRNA or oligonucleotide methods, we hypothesized that suppression of HTT expression might be accomplished by small molecules that either (1) directly decrease HTT expression by suppressing HTT promoter activity or (2) indirectly decrease HTT expression by increasing the promoter activity of HTT-AS, the gene antisense to HTT that appears to inhibit expression of HTT. We developed and employed a high-throughput screen for modifiers of HTT and HTT-AS promoter activity using luminescent reporter HEK293 cells; of the 52,041 compounds tested, we identified 898 replicable hits. We used a rigorous stepwise approach to assess compound toxicity and the capacity of the compounds to specifically lower huntingtin protein in 5 different cell lines, including HEK293 cells, HD lymphoblastoid cells, mouse primary neurons, HD iPSCs differentiated into cortical-like neurons, and HD hESCs. We found no compounds which were able to lower huntingtin without lowering cell viability in all assays, though the potential efficacy of a few compounds at non-toxic doses could not be excluded. Our results suggest that more specific targets may facilitate a small molecule approach to HTT suppression.
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http://dx.doi.org/10.1038/s41598-021-85279-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969751PMC
March 2021

Transitioning from a coronary to a critical cardiovascular care unit: trends over the past three decades.

Eur Heart J Acute Cardiovasc Care 2020 Jul 16. Epub 2020 Jul 16.

Heart Institute, Hospital Universitari Germans Trias i Pujol, Spain.

Background: Coronary care units were established in the 1960s to reduce acute-phase mortality in acute coronary syndrome. In the 21st century, the original coronary care unit concept has evolved into an intensive cardiovascular care unit. The aim of this study was to analyse trend changes in characteristics and mortality of patients admitted to a coronary care unit over the past three decades.

Method: Between February 1989 and December 2017, a total of 18,334 patients was consecutively admitted to the coronary care unit of a university hospital in Barcelona. Data were analysed in five time frames: 1989-1994, 1995-1999, 2000-2004, 2005-2009 and 2010-2017. We analysed demographic profile, diagnoses at admission and trend changes in mortality across periods.

Results: During the periods, the patients' ages and comorbidities increased. Diagnoses at admission have evolved. Acute coronary syndrome cases declined from the first to the last period (72.6% vs. 62.8%) while heart failure (6.0% vs. 8.6%) and malignant arrhythmias (0.8% vs. 4.0%) increased significantly. Overall, coronary care unit mortality decreased 34% from the first to the last period (6.8% vs. 4.5%, P<0.001). Furthermore, the cause of death has changed, those due to acute coronary syndrome declining (66.7% vs. 45.5%), and death from malignant arrhythmias increasing (1.9% vs. 16.2%) from the first to the last period.

Conclusions: Although acute coronary syndrome remained the main diagnosis, heart failure and arrhythmias have increased. Despite the aging and comorbidities, overall mortality in the coronary care unit decreased by 34% in the past three decades. Deaths due to acute coronary syndrome have declined, whereas those due to malignant arrhythmias have increased.
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http://dx.doi.org/10.1177/2048872620936038DOI Listing
July 2020

Transitioning from a coronary to a critical cardiovascular care unit: trends over the past three decades.

Eur Heart J Acute Cardiovasc Care 2020 Jul 16. Epub 2020 Jul 16.

Heart Institute, Hospital Universitari Germans Trias i Pujol, Spain.

Background: Coronary care units were established in the 1960s to reduce acute-phase mortality in acute coronary syndrome. In the 21st century, the original coronary care unit concept has evolved into an intensive cardiovascular care unit. The aim of this study was to analyse trend changes in characteristics and mortality of patients admitted to a coronary care unit over the past three decades.

Method: Between February 1989 and December 2017, a total of 18,334 patients was consecutively admitted to the coronary care unit of a university hospital in Barcelona. Data were analysed in five time frames: 1989-1994, 1995-1999, 2000-2004, 2005-2009 and 2010-2017. We analysed demographic profile, diagnoses at admission and trend changes in mortality across periods.

Results: During the periods, the patients' ages and comorbidities increased. Diagnoses at admission have evolved. Acute coronary syndrome cases declined from the first to the last period (72.6% vs. 62.8%) while heart failure (6.0% vs. 8.6%) and malignant arrhythmias (0.8% vs. 4.0%) increased significantly. Overall, coronary care unit mortality decreased 34% from the first to the last period (6.8% vs. 4.5%, P<0.001). Furthermore, the cause of death has changed, those due to acute coronary syndrome declining (66.7% vs. 45.5%), and death from malignant arrhythmias increasing (1.9% vs. 16.2%) from the first to the last period.

Conclusions: Although acute coronary syndrome remained the main diagnosis, heart failure and arrhythmias have increased. Despite the aging and comorbidities, overall mortality in the coronary care unit decreased by 34% in the past three decades. Deaths due to acute coronary syndrome have declined, whereas those due to malignant arrhythmias have increased.
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http://dx.doi.org/10.1177/2048872620936038DOI Listing
July 2020

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer.

Cancers (Basel) 2020 Dec 15;12(12). Epub 2020 Dec 15.

Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.
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http://dx.doi.org/10.3390/cancers12123784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765376PMC
December 2020

Trends in Short- and Long-Term ST-Segment-Elevation Myocardial Infarction Prognosis Over 3 Decades: A Mediterranean Population-Based ST-Segment-Elevation Myocardial Infarction Registry.

J Am Heart Assoc 2020 10 15;9(20):e017159. Epub 2020 Oct 15.

Heart Institute Hospital Universitari Germans Trias i Pujol Badalona Spain.

Background Coronary artery disease remains a major cause of death despite better outcomes of ST-segment-elevation myocardial infarction (STEMI). We aimed to analyze data from the Ruti-STEMI registry of in-hospital, 28-day, and 1-year events in patients with STEMI over the past 3 decades in Catalonia, Spain, to assess trends in STEMI prognosis. Methods and Results Between February 1989 and December 2017, a total of 7589 patients with STEMI were admitted consecutively. Patients were grouped into 5 periods: 1989 to 1994 (period 1), 1995 to 1999 (period 2), 2000 to 2004 (period 3), 2005 to 2009 (period 4), and 2010 to 2017 (period 5). We used Cox regression to compare 28-day and 1-year STEMI mortality and in-hospital complication trends across these periods. Mean patient age was 61.6±12.6 years, and 79.3% were men. The 28-day all-cause mortality declined from period 1 to period 5 (10.4% versus 6.0%; <0.001), with a 40% reduction after multivariable adjustment (hazard ratio [HR], 0.6; 95% CI, 0.46-0.80; <0.001). One-year all-cause mortality declined from period 1 to period 5 (11.7% versus 9.0%; =0.001), with a 24% reduction after multivariable adjustment (HR, 0.76; 95% CI, 0.60-0.98; =0.036). A significant temporal reduction was observed for in-hospital complications including postinfarct angina (-78%), ventricular tachycardia (-57%), right ventricular dysfunction (-48%), atrioventricular block (-45%), pericarditis (-63%), and free wall rupture (-53%). Primary ventricular fibrillation showed no significant downslope trend. Conclusions In-hospital STEMI complications and 28-day and 1-year mortality rates have dropped markedly in the past 30 years. Reducing ischemia-driven primary ventricular fibrillation remains a major challenge.
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http://dx.doi.org/10.1161/JAHA.120.017159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763375PMC
October 2020

Therapeutic responses to in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair.

Sci Transl Med 2020 09;12(560)

Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.

Dysbiosis of the skin microbiota is increasingly implicated as a contributor to the pathogenesis of atopic dermatitis (AD). We previously reported first-in-human safety and clinical activity results from topical application of the commensal skin bacterium for the treatment of AD in 10 adults and 5 children older than 9 years of age. Here, we examined the potential mechanism of action of treatment and its impact on children with AD less than 7 years of age, the most common age group for children with AD. In 15 children with AD, treatment was associated with amelioration of disease severity, improvement in epithelial barrier function, reduced burden on the skin, and a reduction in topical steroid requirements without severe adverse events. Our observed response rates to treatment were greater than those seen in historical placebo control groups in prior AD studies. Skin improvements and colonization by persisted for up to 8 months after cessation of treatment. Analyses of cellular scratch assays and the MC903 mouse model of AD suggested that production of sphingolipids by , cholinergic signaling, and flagellin expression may have contributed to therapeutic impact through induction of a TNFR2-mediated epithelial-to-mesenchymal transition. These results suggest that a randomized, placebo-controlled trial of treatment in individuals with AD is warranted and implicate commensals in the maintenance of the skin epithelial barrier.
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http://dx.doi.org/10.1126/scitranslmed.aaz8631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571514PMC
September 2020

Short- and Long-Term Mortality Trends in STEMI-Cardiogenic Shock over Three Decades (1989-2018): The Ruti-STEMI-Shock Registry.

J Clin Med 2020 Jul 27;9(8). Epub 2020 Jul 27.

Heart Institute, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.

Aims: Cardiogenic shock (CS) is an ominous complication of ST-elevation myocardial infarction (STEMI), despite the recent widespread use of reperfusion and invasive management. The Ruti-STEMI-Shock registry analysed the prevalence of and 30-day and 1-year mortality rates in ST-elevation myocardial infarction (STEMI) complicated by CS (STEMI-CS) over the last three decades.

Methods And Results: From February 1989 to December 2018, 493 STEMI-CS patients were consecutively admitted in a well-defined geographical area of ~850,000 inhabitants. Patients were classified into six five-year periods based on their year of admission. STEMI-CS mortality trends were analysed at 30 days and 1 year across the six strata. Cox regression analyses were performed for comparisons. Mean age was 67.5 ± 11.7 years; 69.4% were men. STEMI-CS prevalence did not decline from period 1 to 6 (7.1 vs. 6.2%, = 0.218). Reperfusion therapy increased from 22.5% in 1989-1993 to 85.4% in 2014-2018. Thirty-day all-cause mortality declined from period 1 to 6 (65% vs. 50.5%, < 0.001), with a 9% reduction after multivariable adjustment (HR: 0.91; 95% CI: 0.84-0.99; = 0.024). One-year all-cause mortality declined from period 1 to 6 (67.5% vs. 57.3%, = 0.001), with an 8% reduction after multivariable adjustment (HR: 0.92; 95% CI: 0.85-0.99; = 0.030). Short- and long-term mortality trends in patients aged ≥ 75 years remained ~75%.

Conclusions: Short- and long-term STEMI-CS-related mortality declined over the last 30 years, to ~50% of all patients. We have failed to achieve any mortality benefit in STEMI-CS patients over 75 years of age.
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http://dx.doi.org/10.3390/jcm9082398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465647PMC
July 2020

A 3D biofabricated cutaneous squamous cell carcinoma tissue model with multi-channel confocal microscopy imaging biomarkers to quantify antitumor effects of chemotherapeutics in tissue.

Oncotarget 2020 Jul 7;11(27):2587-2596. Epub 2020 Jul 7.

Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA.

Cutaneous squamous cell carcinoma (cSCC) causes approximately 10,000 deaths annually in the U. S. Current therapies are largely ineffective against metastatic and locally advanced cSCC. There is a need to identify novel, effective, and less toxic small molecule cSCC therapeutics. We developed a 3-dimensional bioprinted skin (3DBPS) model of cSCC tumors together with a microscopy assay to test chemotherapeutic effects in tissue. The full thickness SCC tissue model was validated using hematoxylin and eosin (H&E) and immunohistochemical histological staining, confocal microscopy, and cDNA microarray analysis. A nondestructive, 3D fluorescence confocal imaging assay with tdTomato-labeled A431 SCC and ZsGreen-labeled keratinocytes was developed to test efficacy and general toxicity of chemotherapeutics. Fluorescence-derived imaging biomarkers indicated that 50% of cancer cells were killed in the tissue after 1μM 5-Fluorouracil 48-hour treatment, compared to a baseline of 12% for untreated controls. The imaging biomarkers also showed that normal keratinocytes were less affected by treatment (11% killed) than the untreated tissue, which had no significant killing effect. Data showed that 5-Fluorouracil selectively killed cSCC cells more than keratinocytes. Our 3DBPS assay platform provides cellular-level measurement of cell viability and can be adapted to achieve nondestructive high-throughput screening (HTS) in bio-fabricated tissues.
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http://dx.doi.org/10.18632/oncotarget.27570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343636PMC
July 2020

Transitioning from a coronary to a critical cardiovascular care unit: trends over the past three decades.

Eur Heart J Acute Cardiovasc Care 2020 Jul 16:2048872620936038. Epub 2020 Jul 16.

Heart Institute, Hospital Universitari Germans Trias i Pujol, Spain.

Background: Coronary care units were established in the 1960s to reduce acute-phase mortality in acute coronary syndrome. In the 21st century, the original coronary care unit concept has evolved into an intensive cardiovascular care unit. The aim of this study was to analyse trend changes in characteristics and mortality of patients admitted to a coronary care unit over the past three decades.

Method: Between February 1989 and December 2017, a total of 18,334 patients was consecutively admitted to the coronary care unit of a university hospital in Barcelona. Data were analysed in five time frames: 1989-1994, 1995-1999, 2000-2004, 2005-2009 and 2010-2017. We analysed demographic profile, diagnoses at admission and trend changes in mortality across periods.

Results: During the periods, the patients' ages and comorbidities increased. Diagnoses at admission have evolved. Acute coronary syndrome cases declined from the first to the last period (72.6% vs. 62.8%) while heart failure (6.0% vs. 8.6%) and malignant arrhythmias (0.8% vs. 4.0%) increased significantly. Overall, coronary care unit mortality decreased 34% from the first to the last period (6.8% vs. 4.5%, <0.001). Furthermore, the cause of death has changed, those due to acute coronary syndrome declining (66.7% vs. 45.5%), and death from malignant arrhythmias increasing (1.9% vs. 16.2%) from the first to the last period.

Conclusions: Although acute coronary syndrome remained the main diagnosis, heart failure and arrhythmias have increased. Despite the aging and comorbidities, overall mortality in the coronary care unit decreased by 34% in the past three decades. Deaths due to acute coronary syndrome have declined, whereas those due to malignant arrhythmias have increased.
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http://dx.doi.org/10.1177/2048872620936038DOI Listing
July 2020

KIF11 and KIF15 mitotic kinesins are potential therapeutic vulnerabilities for malignant peripheral nerve sheath tumors.

Neurooncol Adv 2020 Jul 4;2(Suppl 1):i62-i74. Epub 2020 Jan 4.

Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias & Pujol Research Institute (IGTP), Badalona, Barcelona, Spain.

Background: Malignant peripheral nerve sheath tumor (MPNST) constitutes the leading cause of neurofibromatosis type 1-related mortality. MPNSTs contain highly rearranged hyperploid genomes and exhibit a high division rate and aggressiveness. We have studied in vitro whether the mitotic kinesins KIF11, KIF15, and KIF23 have a functional role in maintaining MPNST cell survival and can represent potential therapeutic vulnerabilities.

Methods: We studied the expression of kinesin mRNAs and proteins in tumors and cell lines and used several in vitro functional assays to analyze the impact of kinesin genetic suppression (KIF15, KIF23) and drug inhibition (KIF11) in MPNST cells. We also performed in vitro combined treatments targeting KIF11 together with other described MPNST targets.

Results: The studied kinesins were overexpressed in MPNST samples. KIF15 and KIF23 were required for the survival of MPNST cell lines, which were also more sensitive than benign control fibroblasts to the KIF11 inhibitors ispinesib and ARRY-520. Co-targeting KIF11 and BRD4 with ARRY-520 and JQ1 reduced MPNST cell viability, synergistically killing a much higher proportion of MPNST cells than control fibroblasts. In addition, genetic suppression of conferred an increased sensitivity to KIF11 inhibitors alone or in combination with JQ1.

Conclusions: The mitotic spindle kinesins KIF11 and KIF15 and the cytokinetic kinesin KIF23 play a clear role in maintaining MPNST cell survival and may represent potential therapeutic vulnerabilities. Although further in vivo evidences are still mandatory, we propose a simultaneous suppression of KIF11, KIF15, and BRD4 as a potential therapy for MPNSTs.
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http://dx.doi.org/10.1093/noajnl/vdz061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317059PMC
July 2020

Personality Disorders in the ICD-11: Spanish Validation of the PiCD and the SASPD in a Mixed Community and Clinical Sample.

Assessment 2021 04 25;28(3):759-772. Epub 2020 Jun 25.

University of Kentucky, Lexington, KY, USA.

The International Classification of Diseases-11th revision (ICD-11) classification of personality disorders is the official diagnostic system that is used all over the world, and it has recently been renewed. However, as yet very few data are available on its performance. This study examines the Personality Inventory for ICD-11 (PiCD), which assesses the personality domains of the system, and the Standardized Assessment of Severity of Personality Disorder (SASPD), which determines severity. The Spanish versions of the questionnaires were administered to a community ( = 2,522) and a clinical sample ( = 797). Internal consistency was adequate in the PiCD (α = .75 to .84) but less so in the SASPD (α = .64 and .73). Factor analyses suggested a unidimensional or bidimensional structure for severity, while revealing that the personality trait qualifiers are organized into four factors: negative affectivity, detachment, dissociality, and a bipolar domain of disinhibition-anankastia. The mutual relationships between traits and severity were analyzed, as well as the ability of the whole system to identify clinical subjects. Although further improvements are required, the results generally support the use of the PiCD and the SASPD and help substantiate the new ICD-11 taxonomy that underlies them.
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http://dx.doi.org/10.1177/1073191120936357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961637PMC
April 2021

Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model.

Cancers (Basel) 2020 Jun 21;12(6). Epub 2020 Jun 21.

Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence.
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http://dx.doi.org/10.3390/cancers12061645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352549PMC
June 2020
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