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  1. Article ; Online: In vitro and in vivo identification of clinically approved drugs that modify ACE2 expression

    Sanju Sinha / Kuoyuan Cheng / Alejandro A Schäffer / Kenneth Aldape / Eyal Schiff / Eytan Ruppin

    Molecular Systems Biology, Vol 16, Iss 7, Pp n/a-n/a (2020)

    2020  

    Abstract: Abstract The COVID‐19 pandemic caused by SARS‐CoV‐2 has been a global health challenge. Angiotensin‐converting enzyme 2 (ACE2) is the host receptor for SARS‐CoV‐2 entry. Recent studies have suggested that patients with hypertension and diabetes treated ... ...

    Abstract Abstract The COVID‐19 pandemic caused by SARS‐CoV‐2 has been a global health challenge. Angiotensin‐converting enzyme 2 (ACE2) is the host receptor for SARS‐CoV‐2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID‐19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2‐upregulating drugs, while antineoplastic agents are enriched for ACE2‐downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID‐19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.
    Keywords angiotensin I‐converting enzyme 2 ; coronavirus disease 2019 ; dexamethasone ; drug‐modifying ACE2 expression ; severe acute respiratory syndrome coronavirus 2 ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

    Lipika R. Pal / Kuoyuan Cheng / Nishanth Ulhas Nair / Laura Martin-Sancho / Sanju Sinha / Yuan Pu / Laura Riva / Xin Yin / Fiorella Schischlik / Joo Sang Lee / Sumit K. Chanda / Eytan Ruppin

    iScience, Vol 25, Iss 5, Pp 104311- (2022)

    2022  

    Abstract: Summary: Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic ...

    Abstract Summary: Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal and synthetic dosage lethal (SL/SDL) partners of such altered host genes. Pursuing this disparate antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL/SDL with altered host genes. The predicted SL/SDL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. We further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming noninfected healthy cells.
    Keywords Drugs ; Virology ; Synthetic biology ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Author Correction

    Sanju Sinha / Karina Barbosa / Kuoyuan Cheng / Mark D. M. Leiserson / Prashant Jain / Anagha Deshpande / David M. Wilson / Bríd M. Ryan / Ji Luo / Ze’ev A. Ronai / Joo Sang Lee / Aniruddha J. Deshpande / Eytan Ruppin

    Nature Communications, Vol 13, Iss 1, Pp 1-

    A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

    2022  Volume 1

    Keywords Science ; Q
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Identification of drugs associated with reduced severity of COVID-19 – a case-control study in a large population

    Ariel Israel / Alejandro A Schäffer / Assi Cicurel / Kuoyuan Cheng / Sanju Sinha / Eyal Schiff / Ilan Feldhamer / Ameer Tal / Gil Lavie / Eytan Ruppin

    eLife, Vol

    2021  Volume 10

    Abstract: Background: Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this ... ...

    Abstract Background: Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. Methods: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18 to 95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher’s exact test. False discovery rate was used to adjust for multiple testing. Results: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI [0.058 to 0.458], p<0.001), ezetimibe (OR=0.488, 95% CI [0.377 to 0.622], p<0.001), rosuvastatin (OR=0.673, 95% CI [0.596 to 0.758], p<0.001), flecainide (OR=0.301, 95% CI [0.118 to 0.641], p<0.001), and vitamin D (OR=0.869, 95% CI [0.792 to 0.954], p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization. Conclusions: Ubiquinone, ezetimibe, and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies. Funding: This research was supported in part by the Intramural Research Program of the National Institutes of ...
    Keywords SARS-CoV-2 ; disease severity ; retrospective study ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Genome‐scale metabolic modeling reveals SARS‐CoV‐2‐induced metabolic changes and antiviral targets

    Kuoyuan Cheng / Laura Martin‐Sancho / Lipika R Pal / Yuan Pu / Laura Riva / Xin Yin / Sanju Sinha / Nishanth Ulhas Nair / Sumit K Chanda / Eytan Ruppin

    Molecular Systems Biology, Vol 17, Iss 11, Pp n/a-n/a (2021)

    2021  

    Abstract: Abstract Tremendous progress has been made to control the COVID‐19 pandemic caused by the SARS‐CoV‐2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent ... ...

    Abstract Abstract Tremendous progress has been made to control the COVID‐19 pandemic caused by the SARS‐CoV‐2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical need. Viruses, including coronaviruses, are known to hijack host metabolism to facilitate viral proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published in vitro and human patient gene expression datasets on SARS‐CoV‐2 infection using genome‐scale metabolic modeling (GEM), revealing complicated host metabolism reprogramming during SARS‐CoV‐2 infection. We next applied the GEM‐based metabolic transformation algorithm to predict anti‐SARS‐CoV‐2 targets that counteract the virus‐induced metabolic changes. We successfully validated these targets using published drug and genetic screen data and by performing an siRNA assay in Caco‐2 cells. Further generating and analyzing RNA‐sequencing data of remdesivir‐treated Vero E6 cell samples, we predicted metabolic targets acting in combination with remdesivir, an approved anti‐SARS‐CoV‐2 drug. Our study provides clinical data‐supported candidate anti‐SARS‐CoV‐2 targets for future evaluation, demonstrating host metabolism targeting as a promising antiviral strategy.
    Keywords antiviral target ; genome‐scale metabolic modeling ; remdesivir ; RNAi screen ; SARS‐CoV‐2 ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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  6. Article ; Online: A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

    Sanju Sinha / Karina Barbosa / Kuoyuan Cheng / Mark D. M. Leiserson / Prashant Jain / Anagha Deshpande / David M. Wilson / Bríd M. Ryan / Ji Luo / Ze’ev A. Ronai / Joo Sang Lee / Aniruddha J. Deshpande / Eytan Ruppin

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 13

    Abstract: CRISPR-Cas9 gene editing can induce a p53 mediated damage response. Here the authors investigate the possibility of selection of pre-existing cancer driver mutations during CRISPR-Cas9 knockout based gene editing and identify KRAS mutants that may confer ...

    Abstract CRISPR-Cas9 gene editing can induce a p53 mediated damage response. Here the authors investigate the possibility of selection of pre-existing cancer driver mutations during CRISPR-Cas9 knockout based gene editing and identify KRAS mutants that may confer a selected advantage to edited cells.
    Keywords Science ; Q
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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  7. Article ; Online: Harnessing synthetic lethality to predict the response to cancer treatment

    Joo Sang Lee / Avinash Das / Livnat Jerby-Arnon / Rand Arafeh / Noam Auslander / Matthew Davidson / Lynn McGarry / Daniel James / Arnaud Amzallag / Seung Gu Park / Kuoyuan Cheng / Welles Robinson / Dikla Atias / Chani Stossel / Ella Buzhor / Gidi Stein / Joshua J. Waterfall / Paul S. Meltzer / Talia Golan /
    Sridhar Hannenhalli / Eyal Gottlieb / Cyril H. Benes / Yardena Samuels / Emma Shanks / Eytan Ruppin

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: Synthetic lethality (SL) offers a new precision oncology approach, which is based on targeting cancer-specific vulnerabilities across the whole genome, going beyond cancer drivers. The authors develop an approach termed ISLE to identify clinically ... ...

    Abstract Synthetic lethality (SL) offers a new precision oncology approach, which is based on targeting cancer-specific vulnerabilities across the whole genome, going beyond cancer drivers. The authors develop an approach termed ISLE to identify clinically relevant SL interactions and use them for patient stratification and novel target identification.
    Keywords Science ; Q
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  8. Article ; Online: Harnessing synthetic lethality to predict the response to cancer treatment

    Joo Sang Lee / Avinash Das / Livnat Jerby-Arnon / Rand Arafeh / Noam Auslander / Matthew Davidson / Lynn McGarry / Daniel James / Arnaud Amzallag / Seung Gu Park / Kuoyuan Cheng / Welles Robinson / Dikla Atias / Chani Stossel / Ella Buzhor / Gidi Stein / Joshua J. Waterfall / Paul S. Meltzer / Talia Golan /
    Sridhar Hannenhalli / Eyal Gottlieb / Cyril H. Benes / Yardena Samuels / Emma Shanks / Eytan Ruppin

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: Synthetic lethality (SL) offers a new precision oncology approach, which is based on targeting cancer-specific vulnerabilities across the whole genome, going beyond cancer drivers. The authors develop an approach termed ISLE to identify clinically ... ...

    Abstract Synthetic lethality (SL) offers a new precision oncology approach, which is based on targeting cancer-specific vulnerabilities across the whole genome, going beyond cancer drivers. The authors develop an approach termed ISLE to identify clinically relevant SL interactions and use them for patient stratification and novel target identification.
    Keywords Science ; Q
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

    More links

    Kategorien

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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