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MeSH Disease

Human Phenotype

Transmission

Seroprevalence
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    Structure of human steroid 5α-reductase 2 with anti-androgen drug finasteride

    Authors: Qingpin Xiao; Lei Wang; Shreyas Supekar; Tao Shen; Heng Liu; Fei Ye; Junzhou Huang; Hao Fan; Zhiyi Wei; Cheng Zhang

    doi:10.21203/rs.3.rs-40159/v1 Date: 2020-07-04 Source: ResearchSquare

    Human steroid 5α-reductase 2 (SRD5α2) as a critical integral membrane enzyme in steroid metabolism catalyzes testosterone to dihydrotestosterone. Mutations on its gene have been linked to 5α-reductase deficiency and prostate cancer HP. Finasteride and dutasteride as SRD5α2 inhibitors are widely used anti-androgen drugs for benign prostate hyperplasia MESHD, which have recently been indicated in the treatment of COVID-19. The molecular mechanisms underlying enzyme catalysis and inhibition remained elusive for SRD5α2 and other eukaryotic integral membrane steroid reductases due to a lack of structural information. Here, we report a crystal structure of human SRD5α2 at 2.8 Å revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP-dihydrofinasteride in a largely enclosed binding cavity inside the membrane. Structural analysis together with computational and mutagenesis studies reveals molecular mechanisms for the 5α-reduction of testosterone and the finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region regulating the NADPH/NADP+ exchange. Mapping disease MESHD-causing mutations of SRD5α2 to our structure suggests molecular mechanisms for their pathological effects. Our results offer critical structural insights into the function of integral membrane steroid reductases and will facilitate drug development.

    Structural variability, expression profile and pharmacogenetics properties of TMPRSS2 gene as a potential target for COVID-19 therapy

    Authors: Aleksei Zarubin; Vadim Stepanov; Anton Markov; Nikita Kolesnikov; Andrey Marusin; Irina Khitrinskaya; Maria Swarovskaya; Sergey Litvinov; Natalia Ekomasova; Murat Dzhaubermezov; Nadezhda Maksimova; Aitalina Sukhomyasova; Olga Shtygasheva; Elza Khusnutdinova; Magomed Radjabov; Vladimir Kharkov

    doi:10.1101/2020.06.20.156224 Date: 2020-06-20 Source: bioRxiv

    The human serine protease TMPRSS2 gene is involved in the priming of the novel severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) proteins being one of the possible targets for COVID-19 therapy. TMPRSS2 gene is possibly co-expressed with SARS-CoV-2 cell receptor genes ACE2 and BSG, but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data of 76 human populations demonstrates that functionally significant missense mutation in exon 6/7 in TMPRSS2 gene, was found in many human populations in relatively high frequency, featuring region-specific distribution patterns. The frequency of the missense mutation encoded by the rs12329760, which previously was found to be associated with prostate cancer HP, is ranged between 10% and 63% being significantly higher in populations of Asian origin compared to European populations. In addition to SNPs, two copy numbers variants (CNV) were detected in the TMPRSS2 gene. Number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well studied drugs can downregulate the expression of TMPRSS2 in human cells, including Acetaminophen (Paracetamol) and Curcumin. Thus TMPRSS2 interaction with the SARS-CoV-2, its structural variability, gene-gene interactions, and expression regulation profiles, and pharmacogenomics properties characterize this gene as a potential target for COVID-19 therapy.

    TMPRSS2, required for SARS-CoV-2 entry, is downregulated in lung cells by enzalutamide, a prostate cancer HP therapeutic 

    Authors: Damien A. Leach; Ana-Maria Isac; Charlotte L. Bevan; Greg N. Brooke

    doi:10.21203/rs.3.rs-34503/v1 Date: 2020-06-09 Source: ResearchSquare

    The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer HP – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. In support of this new experimental data, analysis of existing datasets shows striking co- expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS- CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19. 

    Finding disease MESHD modules for cancer and COVID-19 in gene co-expression networks with the Core&Peel method

    Authors: Marta Lucchetta; Marco Pellegrini

    doi:10.1101/2020.05.27.118414 Date: 2020-05-27 Source: bioRxiv

    Diseases MESHD imply dysregulation of cells functions at several levels. The study of differentially expressed genes in case-control cohorts of patients is often the first step in understanding the details of the cells dysregulation. A further level of analysis is introduced by noticing that genes are organized in functional modules (often called pathways), thus their action and their dysregulation may be better understood by the identification of the modules most affected by the disease MESHD (aka disease MESHD modules, or active subnetworks). We describe how an algorithm based on the Core&Peel method developed originally for detecting protein complexes in PPI networks, can be adapted to detect disease MESHD modules in co-expression networks of genes. We first validate Core&Peel for the easier general task of functional module detection by comparison with 42 methods participating in the Disease MESHD Module Identification DREAM challenge of 2019. Next, we use four specific disease MESHD test cases (colorectal cancer, prostate HP cancer, asthma MESHD asthma HP and rheumatoid arthritis MESHD rheumatoid arthritis HP), four state-of-the-art algorithms (ModuleDiscoverer, Degas, KeyPathwayMiner and ClustEx), and several pathway databases to validate the proposed algorithm. Core&Peel is the only method able to find significant associations of the predicted disease MESHD module with known validated relevant pathways for all four diseases MESHD. Moreover for the two cancer data sets, Core&Peel detects further nine relevant pathways enriched in the predicted disease MESHD module, not discovered by the other methods used in the comparative analysis. Finally we apply Core&Peel, along with other methods, to explore the transcriptional response of human cells to SARS-CoV-2 infection MESHD, at a modular level, aiming at finding supporting evidence for drug repositioning efforts.

    Impact of anti-androgenic therapies on COVID-19: an observational study in male TRANS population from a COVID-19 regional centre of Lombardy (Italy)

    Authors: Stefano Duga; Rosanna Asselta; Massimo Lazzeri; Giorgio Guazzoni; Elena Azzolini; Nicolo Buffi; Vittorio Fasulo; Francesco Persico; Alberto Saita; Rodolfo Hurle; Giovanni Lughezzani; Paolo Casale

    doi:10.1101/2020.04.20.20068056 Date: 2020-04-24 Source: medRxiv

    There are gender TRANS differences in susceptibility and vulnerability to the Coronavirus disease MESHD 2019 (COVID-19). The S protein of coronaviruses facilitates viral entry into target cells and employs the host cellular serine protease TMPRSS2 for S protein priming. The TMPRSS2 gene expression is responsive to androgen stimulation and it could partially explain gender TRANS differences. We tested the hypothesis that men who received 5-Alpha reductase inhibitors (5ARIs) or androgen deprivation therapy (ADT) for prostate cancer HP could have a different susceptibility to COVID-19. We carried out an observational study on patients who were referred to our COVID-19 regional centre in Lombardy from 1st to 31st March 2020. Data from 421 patients, 137 women (32.54%) and 284 men (67.44%) with laboratory-confirmed COVID-19, were included in this report. Overall 84 patients died: 28 women (33.33%) and 56 men (66.67%). Among men, 12 patients (4.22%) reported assuming 5ARI treatment, and 6 were under ADT. Over 12 patients under 5ARIs, 3 (25%) died; 2 deaths MESHD (33%) were reported in patients under ADT. Our findings showed that only 4.22% of the overall population received 5ARI anti-androgen therapy, a percentage, which revealed to be significantly lower (P<0.0001) than what observed in Italian men aged TRANS more than 40 years (14.97%).

    Outcomes of the 2019 Novel Coronavirus in patients with or without a history of cancer - a multi-centre North London experience

    Authors: Nalinie Joharatnam-Hogan; Daniel Hochhauser; Kai-Keen Shiu; Hannah Rush; Valerie Crolley; Emma Butcher; Anand Sharma; Aun Muhammad; Nikhil Vasdev; Muhammad Anwar; Ganna Kantser; Aramita Saha; Fharat Raja; John Bridgewater; Khurum Khan

    doi:10.1101/2020.04.16.20061127 Date: 2020-04-17 Source: medRxiv

    Background Four months after the first known case of the 2019 novel coronavirus disease MESHD (COVID-19), on the 11th March 2020, the WHO declared the outbreak a pandemic and acknowledged the potential to overwhelm national healthcare systems. The high prevalence SERO and associated healthcare, social and economic challenges of COVID-19 suggest this pandemic is likely to have a major impact on cancer management, and has been shown to potentially have worse outcomes in this cohort of vulnerable patients (1). This study aims to compare the outcomes of reverse transcriptase polymerase chain reaction (RT-PCR) confirmed COVID-19 positive disease MESHD in patients with or without a history of cancer. Method: We retrospectively collected clinical, pathological and radiological characteristics and outcomes of COVID-19 RT-PCR positive cancer patients treated consecutively in four different North London hospitals (cohort A). Outcomes recorded included morbidity, mortality and length of hospital stay. All clinically relevant outcomes were then compared to consecutively admitted COVID-19 positive patients, without a history of cancer (cohort B), treated at the primary centre during the same time period (12th March- 7th April 2020). Results: A total of 52 electronic patient records during the study time period were reviewed. Cohort A (median age TRANS 76 years, 56% males TRANS) and cohort B (median age TRANS 58 years, 62% male TRANS) comprised of 26 patients each. With the exclusion of cancer, both had a median of 2 comorbidities. Within cohort A, the most frequent underlying cancer was colorectal (5/26) and prostate cancer HP (5/26), and 77% of patients in Cohort A had received previous anti-cancer therapy. The most common presenting symptoms were cough MESHD cough HP and pyrexia in both cohorts. Frequent laboratory findings included lymphopenia MESHD lymphopenia HP, anaemia and elevated CRP in both cohorts, whilst hypokalaemia, hypoalbuminaemia and hypoproteinaemia was predominantly seen amongst patients with cancer. Median duration of admission was 7 days in both cohorts. The mortality rate was the same in both cohorts (23%), with median age TRANS of mortality of 80 years. Of cancer patients who died, all were advanced stage, had been treated with palliative intent and had received anti-cancer therapy within 13 days of admission. Conclusion: Old age TRANS, late stage of cancer diagnosis and multiple co-morbidities adversely influence the outcome of patients with COVID-19 positive patients. Whilst extra caution is warranted in the administration of anti-cancer therapies pertaining to the risk of immune-suppression, this data does not demonstrate a higher risk to cancer patients compared to their non-cancer counterparts.

The ZB MED preprint Viewer preVIEW includes all COVID-19 related preprints from medRxiv and bioRxiv, from ChemRxiv, from ResearchSquare, from arXiv and from Preprints.org and is updated on a daily basis (7am CET/CEST).

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MeSH Disease
Human Phenotype
Transmission
Seroprevalence


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