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  1. Article: Management of Acute Appendicitis During the COVID-19 Pandemic: A Single-Centre Retrospective Cohort Study.

    Afzal, Zeeshan / Bukhari, Ishtiyaq / Kumar, Sumit / Deeknah, Abdulqudus / Lei, Winnie / Mitrasinovic, Stefan / Chan, Onton / Francis, Francesca E / Satheesan, Kanagasingham S

    Cureus

    2023  Volume 15, Issue 4, Page(s) e37193

    Abstract: Background: During the coronavirus disease 2019 (COVID-19) pandemic, the management of acute appendicitis shifted towards non-operative management in the United Kingdom (UK). The open approach was recommended over the laparoscopic approach due to the ... ...

    Abstract Background: During the coronavirus disease 2019 (COVID-19) pandemic, the management of acute appendicitis shifted towards non-operative management in the United Kingdom (UK). The open approach was recommended over the laparoscopic approach due to the risk of aerosol generation and subsequent contamination. The aim of this study was to compare the overall management and surgical outcomes of the patients treated for acute appendicitis before and during the COVID-19 pandemic.
    Materials and methods: We performed a retrospective cohort study at a single district general hospital in the UK. We compared the management and outcome of the patients diagnosed with acute appendicitis before the pandemic, from March to August 2019, and during the pandemic, from March to August 2020. We looked at the patient demographics, methods of diagnosis, management, and surgical outcomes for these patients. The primary outcome of the study was the 30-day readmission rate. Secondary outcomes included length of stay and post-operative complications.
    Results: Over the period of six months, a total of 179 patients were diagnosed with acute appendicitis in 2019 (Pre-COVID-19 pandemic, from March 1, 2019, to August 31, 2019) versus 152 in 2020 (during the COVID-19 pandemic, from March 1, 2020, to August 31, 2020). For the 2019 cohort, the mean age of the patients was 33 (range 6-86 years), 52% (n=93) were female, and the mean BMI was 26 (range 14-58). For the 2020 cohort, the mean age was 37 (range 4-93 years), 48% (n=73) of the patients were female, and the mean BMI was 27 (range 16-53). At the first presentation, in 2019, 97.2% of the patients (174 out of 179) received surgical treatment compared to 70.4% (107 out of 152) in 2020. Three per cent of the patients (n=5) were managed conservatively in 2019 (two out these failed conservative management) as compared to 29.6% (n=45) in 2020 (21 of these failed conservative management). Pre-pandemic, only 32.4% (n= 57, ultrasound (US) scan: 11, computer tomography (CT) scan): 45, both US and CT: 1) of the patients received imaging to confirm the diagnosis as compared to 53.3% during pandemic (n=81, US scan: 12, CT scan: 63, both US and CT: 6). Overall, the CT to US ratio increased. We found that during 2019, 91.5% (n=161/176) of the patients who received surgical treatment went through laparoscopic surgery as compared to only 74.2% (n=95/128) in 2020 (p<0.0001). Postoperative complications occurred in 5.1% (n=9/176) of the surgical patients in 2019 as compared to 12.5% (n=16/128) in 2020 (p<0.033). The mean length of hospital stay in 2019 was 2.9 days (range 1-11) versus 4.5 days in 2020 (range 1-57) (p<0.0001). The 30-day readmission rate was 4.5% (8/179) versus 19.1% (29/152) (p<0.0001). The 90-day mortality rate was zero for both cohorts.
    Conclusion: Our study shows that the management of acute appendicitis changed due to the COVID-19 pandemic. More patients went through imaging, especially CT scans for diagnosis and received non-operative management with antibiotics only. The open surgical approach became more common during the pandemic. This was associated with longer lengths of hospital stay, more readmissions, and an increase in postoperative complications.
    Language English
    Publishing date 2023-04-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2747273-5
    ISSN 2168-8184
    ISSN 2168-8184
    DOI 10.7759/cureus.37193
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Current and prospective computational approaches and challenges for developing COVID-19 vaccines.

    Hwang, Woochang / Lei, Winnie / Katritsis, Nicholas M / MacMahon, Méabh / Chapman, Kathryn / Han, Namshik

    Advanced drug delivery reviews

    2021  Volume 172, Page(s) 249–274

    Abstract: SARS-CoV-2, which causes COVID-19, was first identified in humans in late 2019 and is a coronavirus which is zoonotic in origin. As it spread around the world there has been an unprecedented effort in developing effective vaccines. Computational methods ... ...

    Abstract SARS-CoV-2, which causes COVID-19, was first identified in humans in late 2019 and is a coronavirus which is zoonotic in origin. As it spread around the world there has been an unprecedented effort in developing effective vaccines. Computational methods can be used to speed up the long and costly process of vaccine development. Antigen selection, epitope prediction, and toxicity and allergenicity prediction are areas in which computational tools have already been applied as part of reverse vaccinology for SARS-CoV-2 vaccine development. However, there is potential for computational methods to assist further. We review approaches which have been used and highlight additional bioinformatic approaches and PK modelling as in silico methods which may be useful for SARS-CoV-2 vaccine design but remain currently unexplored. As more novel viruses with pandemic potential are expected to arise in future, these techniques are not limited to application to SARS-CoV-2 but also useful to rapidly respond to novel emerging viruses.
    MeSH term(s) Animals ; B-Lymphocytes/drug effects ; B-Lymphocytes/immunology ; COVID-19/genetics ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19 Vaccines/administration & dosage ; COVID-19 Vaccines/genetics ; COVID-19 Vaccines/immunology ; Computational Biology/methods ; Computational Biology/trends ; Drug Development/methods ; Drug Development/trends ; Epitopes/genetics ; Epitopes/immunology ; Gene Expression Profiling/methods ; Gene Expression Profiling/trends ; Humans ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism
    Chemical Substances COVID-19 Vaccines ; Epitopes
    Language English
    Publishing date 2021-02-06
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 639113-8
    ISSN 1872-8294 ; 0169-409X
    ISSN (online) 1872-8294
    ISSN 0169-409X
    DOI 10.1016/j.addr.2021.02.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification of SARS-CoV-2-induced pathways reveals drug repurposing strategies.

    Han, Namshik / Hwang, Woochang / Tzelepis, Konstantinos / Schmerer, Patrick / Yankova, Eliza / MacMahon, Méabh / Lei, Winnie / M Katritsis, Nicholas / Liu, Anika / Felgenhauer, Ulrike / Schuldt, Alison / Harris, Rebecca / Chapman, Kathryn / McCaughan, Frank / Weber, Friedemann / Kouzarides, Tony

    Science advances

    2021  Volume 7, Issue 27

    Abstract: The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, ... ...

    Abstract The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.
    MeSH term(s) Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/pathology ; COVID-19/virology ; Drug Repositioning ; Humans ; Neural Networks, Computer ; Proguanil/pharmacology ; Proguanil/therapeutic use ; SARS-CoV-2/immunology ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/physiology ; Sulfasalazine/pharmacology ; Virus Replication/drug effects ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; Sulfasalazine (3XC8GUZ6CB) ; Proguanil (S61K3P7B2V)
    Language English
    Publishing date 2021-06-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abh3032
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics.

    Boned Del Río, Isabel / Young, Lucy C / Sari, Sibel / Jones, Greg G / Ringham-Terry, Benjamin / Hartig, Nicole / Rejnowicz, Ewa / Lei, Winnie / Bhamra, Amandeep / Surinova, Silvia / Rodriguez-Viciana, Pablo

    Proceedings of the National Academy of Sciences of the United States of America

    2019  Volume 116, Issue 27, Page(s) 13330–13339

    Abstract: Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps ... ...

    Abstract Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps for RAF activation but the precise mechanisms and dynamics remain unclear. A ternary complex comprised of SHOC2, MRAS, and PP1 (SHOC2 complex) functions as a RAF S259 holophosphatase and gain-of-function mutations in SHOC2, MRAS, and PP1 that promote complex formation are found in Noonan syndrome. Here we show that SHOC2 complex-mediated S259 RAF dephosphorylation is critically required for growth factor-induced RAF heterodimerization as well as for MEK dissociation from BRAF. We also uncover SHOC2-independent mechanisms of RAF and ERK pathway activation that rely on N-region phosphorylation of CRAF. In DLD-1 cells stimulated with EGF, SHOC2 function is essential for a rapid transient phase of ERK activation, but is not required for a slow, sustained phase that is instead driven by palmitoylated H/N-RAS proteins and CRAF. Whereas redundant SHOC2-dependent and -independent mechanisms of RAF and ERK activation make SHOC2 dispensable for proliferation in 2D, KRAS mutant cells preferentially rely on SHOC2 for ERK signaling under anchorage-independent conditions. Our study highlights a context-dependent contribution of SHOC2 to ERK pathway dynamics that is preferentially engaged by KRAS oncogenic signaling and provides a biochemical framework for selective ERK pathway inhibition by targeting the SHOC2 holophosphatase.
    MeSH term(s) CRISPR-Associated Protein 9 ; CRISPR-Cas Systems ; Cell Line, Tumor ; Gene Editing ; Gene Knockout Techniques ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Signaling System ; Phosphorylation ; Protein Multimerization ; raf Kinases/chemistry ; raf Kinases/metabolism ; ras Proteins/metabolism
    Chemical Substances Intracellular Signaling Peptides and Proteins ; MRAS protein, human ; SHOC2 protein, human ; raf Kinases (EC 2.7.11.1) ; CRISPR-Associated Protein 9 (EC 3.1.-) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2019-06-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1902658116
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers.

    Jones, Greg G / Del Río, Isabel Boned / Sari, Sibel / Sekerim, Aysen / Young, Lucy C / Hartig, Nicole / Areso Zubiaur, Itziar / El-Bahrawy, Mona A / Hynds, Rob E / Lei, Winnie / Molina-Arcas, Miriam / Downward, Julian / Rodriguez-Viciana, Pablo

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 2532

    Abstract: Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by ... ...

    Abstract Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.
    MeSH term(s) Animals ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Female ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; MAP Kinase Signaling System ; Male ; Mice, Knockout ; Mice, Nude ; Mutation ; Neoplasm Transplantation ; Protein Kinase Inhibitors/pharmacology ; Protein Multimerization ; raf Kinases/antagonists & inhibitors ; raf Kinases/genetics ; raf Kinases/metabolism ; ras Proteins/metabolism
    Chemical Substances Intracellular Signaling Peptides and Proteins ; Protein Kinase Inhibitors ; SHOC2 protein, human ; raf Kinases (EC 2.7.11.1) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2019-06-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-10367-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies

    Han, Namshik / Hwang, Woochang / Tzelepis, Kostas / Schmerer, Patrick / Yankova, Eliza / MacMahon, Meabh / Lei, Winnie / Katritsis, Nicholas M / Liu, Anika / Schuldt, Alison / Harris, Rebecca / Chapman, Kathryn / McCaughan, Frank / Weber, Friedemann / Kouzarides, Tony

    bioRxiv

    Abstract: The global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced ...

    Abstract The global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein (SIP) network, based on disease signatures defined by COVID-19 multi-omic datasets(Bojkova et al., 2020; Gordon et al., 2020), and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials(Clinicaltrials.gov, 2020) testifying to the validity of the approach. Using artificial neural network analysis we classified these 200 drugs into 9 distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (130) and immune response (70). A subset of drugs implicated in viral replication were tested in cellular assays and two (proguanil and sulfasalazine) were shown to inhibit replication. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.
    Keywords covid19
    Language English
    Publishing date 2020-08-25
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.08.24.265496
    Database COVID19

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  7. Article ; Online: Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies

    Han, Namshik / Hwang, Woochang / Tzelepis, Konstantinos / Schmerer, Patrick / Yankova, Eliza / MacMahon, Méabh / Lei, Winnie / Katritsis, Nicholas M / Liu, Anika / Schuldt, Alison / Harris, Rebecca / Chapman, Kathryn / McCaughan, Frank / Weber, Friedemann / Kouzarides, Tony

    bioRxiv

    Abstract: The global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced ...

    Abstract The global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein (SIP) network, based on disease signatures defined by COVID-19 multi-omic datasets(Bojkova et al., 2020; Gordon et al., 2020), and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials(Clinicaltrials.gov, 2020) testifying to the validity of the approach. Using artificial neural network analysis we classified these 200 drugs into 9 distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (130) and immune response (70). A subset of drugs implicated in viral replication were tested in cellular assays and two (proguanil and sulfasalazine) were shown to inhibit replication. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.
    Keywords covid19
    Publisher BioRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.08.24.265496
    Database COVID19

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