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1.
Sci Adv ; 8(6): eabk2691, 2022 02 11.
Article in English | MEDLINE | ID: covidwho-1685473

ABSTRACT

Upon virus infection, CD8+ T cell accumulation is tightly controlled by simultaneous proliferation and apoptosis. However, it remains unclear how TCR signal coordinates these events to achieve expansion and effector cell differentiation. We found that T cell-specific deletion of nuclear helicase Dhx9 led to impaired CD8+ T cell survival, effector differentiation, and viral clearance. Mechanistically, Dhx9 acts as the key regulator to ensure LCK- and CD3ε-mediated ZAP70 phosphorylation and ERK activation to protect CD8+ T cells from apoptosis before proliferative burst. Dhx9 directly regulates Id2 transcription to control effector CD8+ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and Id2 transcription, respectively. Dhx9 expression is predominantly increased in effector CD8+ T cells of COVID-19 patients. Therefore, we revealed a previously unknown regulatory mechanism that Dhx9 protects activated CD8+ T cells from apoptosis and ensures effector differentiation to promote antiviral immunity independent of nuclear sensor function.


Subject(s)
Antiviral Agents/pharmacology , Arenaviridae Infections/prevention & control , CD8-Positive T-Lymphocytes/immunology , COVID-19/prevention & control , DEAD-box RNA Helicases/metabolism , Immunity, Innate , Neoplasm Proteins/metabolism , Animals , Arenaviridae Infections/immunology , Arenaviridae Infections/metabolism , Arenaviridae Infections/pathology , COVID-19/immunology , COVID-19/metabolism , COVID-19/pathology , Cell Differentiation , DEAD-box RNA Helicases/genetics , Humans , Lymphocyte Activation , Lymphocytic choriomeningitis virus/physiology , Mice , Neoplasm Proteins/genetics , SARS-CoV-2/physiology , Virus Replication
2.
J Immunol ; 208(1): 74-84, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1534334

ABSTRACT

ORAI1 and stromal interaction molecule 1 (STIM1) are the critical mediators of store-operated Ca2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca2+ signaling, STIM1 is also involved in regulation of the type I IFN (IFN-I) response. To examine their potential role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated ORAI1 and STIM1 knockout human HEK293-angiotensin-converting enzyme 2 cells and checked their responses. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection as a result of enhanced IFN-I response. On the contrary, ORAI1 deletion induced high susceptibility to SARS-CoV-2 infection. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca2+ concentration and severe impairment in tonic IFN-I signaling. Transcriptome analysis showed downregulation of multiple antiviral signaling pathways in ORAI1 knockout cells, likely because of reduced expression of the Ca2+-dependent transcription factors of the AP-1 family and MEF2C Accordingly, modulation of homeostatic Ca2+ concentration by pretreatment with ORAI1 blocker or agonist could influence baseline IFNB expression and resistance to SARS-CoV-2 infection in a human lung epithelial cell line. Our results identify a novel role of ORAI1-mediated Ca2+ signaling in regulating the tonic IFN-I levels, which determine host resistance to SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Interferon Type I/metabolism , Lung/immunology , Neoplasm Proteins/metabolism , ORAI1 Protein/metabolism , Respiratory Mucosa/metabolism , SARS-CoV-2/physiology , Stromal Interaction Molecule 1/metabolism , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Calcium Signaling , Clustered Regularly Interspaced Short Palindromic Repeats , Disease Resistance , Disease Susceptibility , Gene Expression Profiling , HEK293 Cells , Humans , Lung/virology , MEF2 Transcription Factors/genetics , Neoplasm Proteins/genetics , ORAI1 Protein/genetics , Stromal Interaction Molecule 1/genetics , Transcription Factor AP-1/genetics
3.
Int J Lab Hematol ; 43(6): 1325-1333, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1462811

ABSTRACT

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy. Coronavirus disease 2019 (COVID-19) infection correlates with MM features. This study aimed to identify MM prognostic biomarkers with potential association with COVID-19. METHODS: Differentially expressed genes (DEGs) in five MM data sets (GSE47552, GSE16558, GSE13591, GSE6477, and GSE39754) with the same expression trends were screened out. Functional enrichment analysis and the protein-protein interaction network were performed for all DEGs. Prognosis-associated DEGs were screened using the stepwise Cox regression analysis in the cancer genome atlas (TCGA) MMRF-CoMMpass cohort and the GSE24080 data set. Prognosis-associated DEGs associated with COVID-19 infection in the GSE164805 data set were also identified. RESULTS: A total of 98 DEGs with the same expression trends in five data sets were identified, and 83 DEGs were included in the protein-protein interaction network. Cox regression analysis identified 16 DEGs were associated with MM prognosis in the TCGA cohort, and only the cytochrome c oxidase subunit 6C (COX6C) gene (HR = 1.717, 95% CI 1.231-2.428, p = .002) and the nucleotide-binding oligomerization domain containing 2 (NOD2) gene (HR = 0.882, 95% CI 0.798-0.975, p = .014) were independent factors related to MM prognosis in the GSE24080 data set. Both of them were downregulated in patients with mild COVID-19 infection compared with controls but were upregulated in patients with severe COVID-19 compared with patients with mild illness. CONCLUSIONS: The NOD2 and COX6C genes might be used as prognostic biomarkers in MM. The two genes might be associated with the development of COVID-19 infection.


Subject(s)
COVID-19/genetics , Computational Biology/methods , Gene Expression Profiling , Multiple Myeloma/genetics , SARS-CoV-2 , COVID-19/mortality , Datasets as Topic , Electron Transport Complex IV/genetics , Gene Expression Regulation, Neoplastic , Gene Expression Regulation, Viral , Gene Ontology , Humans , Kaplan-Meier Estimate , Microarray Analysis , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Nod2 Signaling Adaptor Protein/genetics , Prognosis , Proportional Hazards Models , Protein Interaction Maps/genetics
4.
J Virol ; 95(24): e0059621, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1443352

ABSTRACT

Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus life cycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1's crucial role to the biogenesis of pan-flavivirus replication organelles. IMPORTANCE Cellular factors are critical in all facets of viral lifecycles, where overlapping interactions between the virus and host can be exploited as possible avenues for the development of antiviral therapeutics. Using a genome-wide CRISPR knockout screening approach to identify novel cellular factors important for flavivirus replication we identified RACK1 as a pro-viral host factor for both mosquito- and tick-borne flaviviruses in addition to SARS-CoV-2. Using an innovative flavivirus protein expression system, we demonstrate for the first time the impact of the loss of RACK1 on the formation of viral replication factories known as 'vesicle packets' (VPs). In addition, we show that RACK1 can interact with numerous flavivirus NS1 proteins as a potential mechanism by which VP formation can be induced by the former.


Subject(s)
CRISPR-Cas Systems , Flavivirus/genetics , Neoplasm Proteins/genetics , Receptors for Activated C Kinase/genetics , Virus Replication , A549 Cells , Aedes , Animals , COVID-19 , Chlorocebus aethiops , Culicidae , Dengue Virus/genetics , Genome-Wide Association Study , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , RNA, Small Interfering/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Vero Cells , West Nile virus/genetics , Zika Virus/genetics , Zika Virus Infection/virology
5.
J Med Virol ; 93(9): 5350-5357, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1384240

ABSTRACT

PARP14 and PARP9 play a key role in macrophage immune regulation. SARS-CoV-2 is an emerging viral disease that triggers hyper-inflammation known as a cytokine storm. In this study, using in silico tools, we hypothesize about the immunological phenomena of molecular mimicry between SARS-CoV-2 Nsp3 and the human PARP14 and PARP9. The results showed an epitope of SARS-CoV-2 Nsp3 protein that contains consensus sequences for both human PARP14 and PARP9 that are antigens for MHC Classes 1 and 2, which can potentially induce an immune response against human PARP14 and PARP9; while its depletion causes a hyper-inflammatory state in SARS-CoV-2 patients.


Subject(s)
COVID-19/immunology , Coronavirus Papain-Like Proteases/chemistry , Cytokine Release Syndrome/immunology , Neoplasm Proteins/chemistry , Poly(ADP-ribose) Polymerases/chemistry , SARS-CoV-2/immunology , Amino Acid Sequence , Binding Sites , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Computer Simulation , Consensus Sequence , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Gene Expression , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Macrophages/immunology , Macrophages/virology , Molecular Docking Simulation , Molecular Mimicry , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/immunology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sequence Alignment , Sequence Homology, Amino Acid , Thermodynamics
6.
Bioengineered ; 12(1): 4054-4069, 2021 12.
Article in English | MEDLINE | ID: covidwho-1348035

ABSTRACT

During the pandemic of the coronavirus disease 2019, there exist quite a few studies on angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 infection, while little is known about ACE2 in hepatocellular carcinoma (HCC). The detailed mechanism among ACE2 and HCC still remains unclear, which needs to be further investigated. In the current study with a total of 6,926 samples, ACE2 expression was downregulated in HCC compared with non-HCC samples (standardized mean difference = -0.41). With the area under the curve of summary receiver operating characteristic = 0.82, ACE2 expression showed a better ability to differentiate HCC from non-HCC. The mRNA expression of ACE2 was related to the age, alpha-fetoprotein levels and cirrhosis of HCC patients, and it was identified as a protected factor for HCC patients via Kaplan-Meier survival, Cox regression analyses. The potential molecular mechanism of ACE2 may be relevant to catabolic and cell division. In all, decreasing ACE2 expression can be seen in HCC, and its protective role for HCC patients and underlying mechanisms were explored in the study.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Carcinoma, Hepatocellular/genetics , Liver Cirrhosis/genetics , Liver Neoplasms/genetics , Neoplasm Proteins/genetics , Receptors, Virus/genetics , alpha-Fetoproteins/genetics , Age Factors , Aged , Angiotensin-Converting Enzyme 2/metabolism , Area Under Curve , COVID-19/virology , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Databases, Genetic , Datasets as Topic , Female , Gene Expression Regulation, Neoplastic , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/mortality , Liver Cirrhosis/pathology , Liver Neoplasms/diagnosis , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Proteins/classification , Neoplasm Proteins/metabolism , Protective Factors , Protein Interaction Mapping , ROC Curve , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Survival Analysis , alpha-Fetoproteins/metabolism
7.
J Virol ; 95(15): e0032721, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1305507

ABSTRACT

The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domains; previously C6orf106) was identified as a proviral factor for Hendra virus infection and was recently characterized to function as an inhibitor of type I interferon expression. Here, we have utilized transcriptome sequencing (RNA-seq) to define cellular pathways regulated by ILRUN in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of Caco-2 cells. We find that inhibition of ILRUN expression by RNA interference alters transcription profiles of numerous cellular pathways, including upregulation of the SARS-CoV-2 entry receptor ACE2 and several other members of the renin-angiotensin aldosterone system. In addition, transcripts of the SARS-CoV-2 coreceptors TMPRSS2 and CTSL were also upregulated. Inhibition of ILRUN also resulted in increased SARS-CoV-2 replication, while overexpression of ILRUN had the opposite effect, identifying ILRUN as a novel antiviral factor for SARS-CoV-2 replication. This represents, to our knowledge, the first report of ILRUN as a regulator of the renin-angiotensin-aldosterone system (RAAS). IMPORTANCE There is no doubt that the current rapid global spread of COVID-19 has had significant and far-reaching impacts on our health and economy and will continue to do so. Research in emerging infectious diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is growing rapidly, with new breakthroughs in the understanding of host-virus interactions to assist with the development of innovative and exciting therapeutic strategies. Here, we present the first evidence that modulation of the human protein-coding gene ILRUN functions as an antiviral factor for SARS-CoV-2 infection, likely through its newly identified role in regulating the expression of SARS-CoV-2 entry receptors ACE2, TMPRSS2, and CTSL. These data improve our understanding of biological pathways that regulate host factors critical to SARS-CoV-2 infection, contributing to the development of antiviral strategies to deal with the current SARS-CoV-2 pandemic.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/metabolism , Down-Regulation , Gene Expression Regulation, Enzymologic , Neoplasm Proteins/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Caco-2 Cells , Cathepsin L/biosynthesis , Cathepsin L/genetics , Chlorocebus aethiops , Humans , Neoplasm Proteins/genetics , Renin-Angiotensin System , SARS-CoV-2/genetics , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Vero Cells
8.
Int J Mol Sci ; 22(13)2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1304669

ABSTRACT

Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with dual pathogenesis, Human papillomavirus (HPV)-associated and HPV-independent, with a poorly explored molecular landscape. We aimed to summarize the findings of the series analyzing molecular hallmarks of this neoplasm. In January 2021, we conducted a comprehensive literature search using Pubmed Medline and Scopus to identify publications focused on genomic profiling of VSCC. Observational studies, including both prospective and retrospective designs, evaluating molecular alterations in VSCC were deemed eligible. A total of 14 studies analyzing 749 VSCC were identified. The study series were heterogeneous in HPV testing and sequencing strategies, included small sets of tumors and cancer genes, and commonly lacked survival analysis. Only one extensive targeted next-generation sequencing-based study comprised a large cohort of 280 VSCC. The mutated genes, their number, and frequencies were highly variable between the series. Overall, TP53 and CDKN2A, followed by PIK3CA, HRAS, and PTEN, were the most frequently studied and mutated genes. Mutations involved in the PI3K/AKT/mTOR pathway, including TP53, HRAS, KRAS, and PIK3CA, have been consistently reported across the studies. However, the role of individual mutations or pathways in the development of VSCC remains unclear. In conclusion, heterogeneity and the small sample size of available molecular series contribute to a limited view of the molecular landscape of VSCC. Large-scale genome- or exome-wide studies with robust HPV testing are necessary to improve the molecular characterization of VSCC.


Subject(s)
Carcinoma, Squamous Cell/genetics , Mutation , Neoplasm Proteins/genetics , Vulvar Neoplasms/genetics , Carcinoma, Squamous Cell/metabolism , Female , Humans , Neoplasm Proteins/metabolism , Vulvar Neoplasms/metabolism
9.
Int J Biol Sci ; 17(8): 1925-1939, 2021.
Article in English | MEDLINE | ID: covidwho-1266906

ABSTRACT

Background: Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) allow entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells and play essential roles in cancer therapy. However, the functions of ACE2 and TMPRSS2 in kidney cancer remain unclear, especially as kidneys are targets for SARS-CoV-2 infection. Methods: UCSC Xena project, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases (GSE30589 and GSE59185) were searched for gene expression in human tissues, gene expression data, and clinical information. Several bioinformatics methods were utilized to analyze the correlation between ACE2 and TMPRSS2 with respect to the prognosis of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP). Results: ACE2 expression was significantly upregulated in tumor tissue, while its downregulation was associated with low survival in KIRC and KIRP patients. TMPRSS2 was downregulated in KIRC and KIRP, and its expression was not correlated with patient survival. According to clinical risk factor-based prediction models, ACE2 exhibits predictive accuracy for kidney cancer prognosis and is correlated with metabolism and immune infiltration. In an animal model, ACE2 expression was remarkably downregulated in SARS-CoV-2-infected cells compared to in the control. Conclusion: ACE2 expression is highly correlated with various metabolic pathways and is involved in immune infiltration.it plays a crucial role than TMPRSS2 in diagnosing and prognosis of kidney cancer patients. The overlap in ACE2 expression between kidney cancer and SARS-CoV-2 infection suggests that patients with KIRC or KIRP are at high risk of developing serious symptoms.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/complications , Carcinoma, Renal Cell/complications , Kidney Neoplasms/complications , Receptors, Virus/biosynthesis , SARS-CoV-2 , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/mortality , Chlorocebus aethiops , Down-Regulation , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/immunology , Kidney Neoplasms/metabolism , Kidney Neoplasms/mortality , Lymphocytes, Tumor-Infiltrating/immunology , Male , Middle Aged , Models, Animal , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Organ Specificity , Prognosis , Proportional Hazards Models , Receptors, Virus/genetics , Renin-Angiotensin System/physiology , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Serine Endopeptidases/physiology , Tissue Array Analysis , Vero Cells
10.
J Med Virol ; 93(9): 5350-5357, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1206838

ABSTRACT

PARP14 and PARP9 play a key role in macrophage immune regulation. SARS-CoV-2 is an emerging viral disease that triggers hyper-inflammation known as a cytokine storm. In this study, using in silico tools, we hypothesize about the immunological phenomena of molecular mimicry between SARS-CoV-2 Nsp3 and the human PARP14 and PARP9. The results showed an epitope of SARS-CoV-2 Nsp3 protein that contains consensus sequences for both human PARP14 and PARP9 that are antigens for MHC Classes 1 and 2, which can potentially induce an immune response against human PARP14 and PARP9; while its depletion causes a hyper-inflammatory state in SARS-CoV-2 patients.


Subject(s)
COVID-19/immunology , Coronavirus Papain-Like Proteases/chemistry , Cytokine Release Syndrome/immunology , Neoplasm Proteins/chemistry , Poly(ADP-ribose) Polymerases/chemistry , SARS-CoV-2/immunology , Amino Acid Sequence , Binding Sites , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Computer Simulation , Consensus Sequence , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Gene Expression , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Macrophages/immunology , Macrophages/virology , Molecular Docking Simulation , Molecular Mimicry , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/immunology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sequence Alignment , Sequence Homology, Amino Acid , Thermodynamics
11.
Head Neck Pathol ; 15(4): 1409-1414, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1122819

ABSTRACT

NUT carcinoma (NUT-C) is a relatively new malignancy that was recently listed in the 4th edition of the WHO Classification of Head and Neck Tumors in 2017. NUT carcinoma is a rare, aggressive, poorly differentiated carcinoma genetically defined by chromosomal rearrangement of the nuclear protein in testis (NUTM1) gene. The prognosis is extremely poor, with a mean survival < 1 year. Recent publications suggest a multimodality treatment approach. In the existing literature, only a few reports of sinonasal NUT-C have been reported. Sinonasal NUT-C is considered a very rare entity, but because of its recent inclusion as a head and neck malignancy, its true prevalence is unknown. We report the case of a 56-year-old woman with NUT-C of the sinonasal cavities. In the case reported, the coexistence of Coronavirus disease 2019 (COVID-19)-related nasal congestion delayed the diagnosis of NUT-C. Clinical presentation, diagnosis and treatment modalities are discussed together with a review of the literature.


Subject(s)
COVID-19/complications , Delayed Diagnosis , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Paranasal Sinus Neoplasms , Squamous Cell Carcinoma of Head and Neck , Female , Humans , Middle Aged , Mutation , Pandemics , Paranasal Sinus Neoplasms/diagnosis , Paranasal Sinus Neoplasms/genetics , Paranasal Sinus Neoplasms/pathology , Paranasal Sinus Neoplasms/therapy , Prognosis , Squamous Cell Carcinoma of Head and Neck/diagnosis , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/therapy
12.
Int J Mol Med ; 46(3): 949-956, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-676301

ABSTRACT

Severe acute respiratory syndrome (SARS) coronavirus­2 (SARS­CoV­2) enters into human host cells via mechanisms facilitated mostly by angiotensin­converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). New loss of smell (anosmia/hyposmia) is now recognized as a COVID­19 related symptom, which may be caused by SARS­CoV­2 infection and damage of the olfactory receptor (OR) cells in the nasal neuro­epithelium and/or central involvement of the olfactory bulb. ORs are also expressed peripherally (e.g., in tissues of the gastrointestinal and respiratory systems) and it is possible that their local functions could also be impaired by SARS­CoV­2 infection of these tissues. Using Gene Expression Profiling Interactive Analysis, The Cancer Genome Atlas, Genotype­Tissue Expression, cBioPortal and Shiny Methylation Analysis Resource Tool, we highlight the expression of peripheral ORs in both healthy and malignant tissues, and describe their co­expression with key mediators of SARS­CoV­2 infection, such as ACE2 and TMPRSS2, as well as cathepsin L (CTSL; another cellular protease mediating SARS­CoV­2 infection of host cells). A wide expression profile of peripheral ORs was noted, particularly in tissues such as the prostate, testis, thyroid, brain, liver, kidney and bladder, as well as tissues with known involvement in cardio­metabolic disease (e.g., the adipose tissue, pancreas and heart). Among these, OR51E2, in particular, was significantly upregulated in prostate adenocarcinoma (PRAD) and co­expressed primarily with TMPRSS2. Functional networks of this OR were further analysed using the GeneMANIA interactive tool, showing that OR51E2 interacts with a plethora of genes related to the prostate. Further in vitro and clinical studies are clearly required to elucidate the role of ORs, both at the olfactory level and the periphery, in the context of COVID­19.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Anosmia/etiology , COVID-19/complications , Neoplasm Proteins/genetics , Receptors, Odorant/genetics , Serine Endopeptidases/genetics , Anosmia/genetics , COVID-19/genetics , Gene Expression Profiling , Gene Regulatory Networks , Genomics , Humans , Male , Neoplasms/genetics , Prostatic Neoplasms/genetics , SARS-CoV-2/isolation & purification , Transcriptome
13.
Med Hypotheses ; 144: 110009, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-611692

ABSTRACT

The outbreak of Novel Coronavirus 2019 (COVID-19) represents a global threat to the public healthcare. The viral spike (S) glycoprotein is the key molecule for viral entry through interaction with angiotensin converting enzyme 2 (ACE2) receptor molecules present on the cell membranes. Moreover, it has been established that COVID-19 interacts and infects brain cells in humans via ACE2. Therefore in the light of these known facts we hypothesized that viral S protein molecule may bind to the other overexpressed receptor molecules in glioma cells and may play some role in glioma tumorogenesis. Thus we leverage docking analysis (HEX and Z-DOCK) between viral S protein and epidermal growth factor receptors (EGFR), vascular endothelial growth factor receptors (VEGFR) and hepatocyte growth factor receptors (HGFR/c-MET) to investigate the oncogenic potential of COVID-19. Our findings suggested higher affinity of Viral S protein towards EGFR and VEGFR. Although, the data presented is preliminary and need to be validated further via molecular dynamics studies, however it paves platform to instigate further investigations on this aspect considering the aftermath of COVID-19 pandemic in oncogenic perspective.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Brain Neoplasms/etiology , COVID-19/complications , Glioma/etiology , Neoplasm Proteins/metabolism , Proto-Oncogene Proteins c-met/metabolism , Receptors, Vascular Endothelial Growth Factor/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Brain/virology , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cell Transformation, Neoplastic , ErbB Receptors/chemistry , ErbB Receptors/metabolism , Glioma/genetics , Glioma/metabolism , Humans , Models, Molecular , Molecular Docking Simulation , Neoplasm Proteins/genetics , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Protein Binding , Protein Conformation , Proto-Oncogene Proteins c-met/chemistry , Receptors, Vascular Endothelial Growth Factor/chemistry , SARS-CoV-2/metabolism , Up-Regulation
14.
Med Hypotheses ; 144: 109987, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-592474

ABSTRACT

In 2019, a new coronavirus (SARS CoV2) infecting humans has emerged in Wuhan, China which caused an unprecedented pandemic involving at least 185 countries infecting 2.5 million people till date. This virus is transmitted directly or indirectly through the upper aerodigestive tract. As it is evident from the recent studies that SARS-CoV-2 requires host enzyme Furin to activate receptor binding domain of its S protein and host Angiotensin Convertase Enzyme 2 (ACE2) is required as binding receptor, facilitating the entry of virus into the host cell. Evidence from literature shows that oral cancer tissues as well as paracarcinoma tissue exhibit higher expression of both Furin and ACE2, giving rise to the hypothesis that patients with oral cancer have higher chances of SARS CoV2 infection. It is also hypothesised that there will be increased severity of disease due to facilitated entry of the virus into the cells. Therefore, we suggest oral cancer patients require extra attention during COVID-19 pandemic and re-evaluation of current treatment paradigms in oral oncology is also needed.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , COVID-19/virology , Furin/metabolism , Mouth Neoplasms/virology , Neoplasm Proteins/metabolism , Receptors, Virus/physiology , SARS-CoV-2/physiology , Virus Internalization , Angiotensin-Converting Enzyme 2/biosynthesis , Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , COVID-19/prevention & control , Disease Susceptibility , Furin/genetics , Gene Expression Regulation, Neoplastic , Humans , Models, Biological , Mouth Neoplasms/genetics , Mouth Neoplasms/metabolism , Neoplasm Proteins/genetics , Pandemics , Protein Binding , Receptors, Virus/biosynthesis , Receptors, Virus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Up-Regulation
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