ABSTRACT
In addition to the angiotensinconverting enzyme 2 (ACE2), a number of host cell entry mediators have been identified for severe acute respiratory syndrome coronavirus2 (SARSCoV2), including transmembrane protease serine 4 (TMPRSS4). The authors have recently demonstrated the upregulation of TMPRSS4 in 11 different cancers, as well as its specific expression within the central nervous system using in silico tools. The present study aimed to expand the initial observations and, using immunohistochemistry, TMPRSS4 protein expression in the gastrointestinal (GI) tract and lungs was further mapped. Immunohistochemistry was performed on tissue arrays and lung tissues of patients with nonsmall cell lung cancer with concurrent coronavirus disease 2019 (COVID19) infection using TMPRSS4 antibody. The results revealed that TMPRSS4 was abundantly expressed in the oesophagus, stomach, small intestine, jejunum, ileum, colon, liver and pancreas. Moreover, the extensive TMPRSS4 protein expression in the lungs of a deceased patient with COVID19 with chronic obstructive pulmonary disease and bronchial carcinoma, as well in the adjacent normal tissue, was demonstrated for the first time, at least to the best of our knowledge. On the whole, the immunohistochemistry data of the present study suggest that TMPRSS4 may be implicated in the broader (pulmonary and extrapulmonary) COVID19 symptomatology; thus, it may be responsible for the tropism of this coronavirus both in the GI tract and lungs.
Subject(s)
COVID-19/pathology , Gastrointestinal Tract/pathology , Lung Neoplasms/pathology , Lung/pathology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/virology , Gastrointestinal Tract/virology , Humans , Immunohistochemistry , Lung/virology , Lung Neoplasms/complications , Male , Membrane Proteins/analysis , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/analysis , Virus InternalizationABSTRACT
BACKGROUND: Team-based learning (TBL) combines active and collaborative learning, while incorporating aspects of the flipped classroom approach and problem-based learning. The COVID-19 pandemic presented certain challenges in the delivery of TBL in class. In this study, we investigated the impact of TBL on the academic performance of final year Biomedical Sciences' undergraduate students in the context of an "Endocrine Disorders" study block. We did so by comparing the classical in-person approach and online delivery due to the COVID-19 pandemic. METHODS: A non-compulsory TBL session was introduced to the curriculum of this block, which followed the traditional 2-h lecture delivery. Comparative analysis was performed for the exam and coursework performance of students who attended the TBL sessions (online and in-person) and those that did not. RESULTS: Both cohorts of students who attended either in-person (n = 66) or online TBL sessions (n = 109) performed significantly better in their exams (p < 0.05) and a related coursework (p < 0.001 and p < 0.05, respectively) when compared to those that did not attend. For both these cohorts the exam mark distribution was much narrower compared to those that did not attend the TBL sessions where the majority of fails and "no shows" were recorded. CONCLUSIONS: Online and in-person TBL, can successfully supplement traditional lecture-based teaching and enhance the learning/performance, for complex medical subjects/topics. Our findings demonstrate that it is possible to deliver these sessions online with demonstrable benefit for students suggesting that there is greater flexibility in the use of TBL in higher education.
Subject(s)
COVID-19 , Educational Measurement , Group Processes , Humans , Pandemics , Problem-Based Learning , SARS-CoV-2 , StudentsABSTRACT
The pathophysiology of coronavirus disease 2019 (COVID19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARSCoV2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a widerepertoire of possible cell entry mediators that appear to colocalise in a cell and tissuespecific manner. The present study provides an overview of the 'canonical' SARSCoV2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin1, expanding on the involvement of novel candidates, including glucoseregulated protein 78, basigin, kidney injury molecule1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factorα convertase) and Tolllike receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARSCoV2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID19 warrants further investigation.
Subject(s)
COVID-19/metabolism , MicroRNAs/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/virology , Endoplasmic Reticulum Chaperone BiP/genetics , Endoplasmic Reticulum Chaperone BiP/metabolism , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/genetics , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Virus/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Viral TropismABSTRACT
[This corrects the article DOI: 10.1016/j.patter.2021.100269.].
ABSTRACT
Although a plethora of research articles on AI methods on COVID-19 medical imaging are published, their clinical value remains unclear. We conducted the largest systematic review of the literature addressing the utility of AI in imaging for COVID-19 patient care. By keyword searches on PubMed and preprint servers throughout 2020, we identified 463 manuscripts and performed a systematic meta-analysis to assess their technical merit and clinical relevance. Our analysis evidences a significant disparity between clinical and AI communities, in the focus on both imaging modalities (AI experts neglected CT and ultrasound, favoring X-ray) and performed tasks (71.9% of AI papers centered on diagnosis). The vast majority of manuscripts were found to be deficient regarding potential use in clinical practice, but 2.7% (n = 12) publications were assigned a high maturity level and are summarized in greater detail. We provide an itemized discussion of the challenges in developing clinically relevant AI solutions with recommendations and remedies.
ABSTRACT
Severe acute respiratory syndrome (SARS) coronavirus2 (SARSCoV2), the causative viral agent for the ongoing COVID19 pandemic, enters its host cells primarily via the binding of the SARSCoV2 spike (S) proteins to the angiotensinconverting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARSCoV2 S proteins, and enhance the viral infection of human small intestinal enterocytes. To date, a systematic analysis of TMPRSS4 in health and disease is lacking. In the present study, using in silico tools, the gene expression and genetic alteration of TMPRSS4 were analysed across numerous tumours and compared to controls. The observations were also expanded to the level of the central nervous system (CNS). The findings revealed that TMPRSS4 was overexpressed in 11 types of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, cervical squamous cell carcinoma, thyroid carcinoma, ovarian cancer, cancer of the rectum, pancreatic cancer, colon and stomach adenocarcinoma, uterine carcinosarcoma and uterine corpus endometrial carcinoma, whilst it was significantly downregulated in kidney carcinomas, acute myeloid leukaemia, skin cutaneous melanoma and testicular germ cell tumours. Finally, a high TMPRSS4 expression was documented in the olfactory tubercle, paraolfactory gyrus and frontal operculum, all brain regions which are associated with the sense of smell and taste. Collectively, these data suggest that TMPRSS4 may play a role in COVID19 symptomatology as another SARSCoV2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.
Subject(s)
COVID-19/enzymology , COVID-19/genetics , Membrane Proteins/genetics , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics , Virus Internalization , Brain/enzymology , COVID-19/virology , Central Nervous System/enzymology , Computer Simulation , Databases, Genetic , Female , Gastrointestinal Tract/enzymology , Gene Expression Profiling , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Male , Membrane Proteins/physiology , Neoplasms/enzymology , Neoplasms/genetics , Pandemics , Serine Endopeptidases/physiologyABSTRACT
Infection by the severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) is the causative agent of a new disease (COVID-19). The risk of severe COVID-19 is increased by certain underlying comorbidities, including asthma, cancer, cardiovascular disease, hypertension, diabetes, and obesity. Notably, exposure to hormonally active chemicals called endocrine-disrupting chemicals (EDCs) can promote such cardio-metabolic diseases, endocrine-related cancers, and immune system dysregulation and thus, may also be linked to higher risk of severe COVID-19. Bisphenol A (BPA) is among the most common EDCs and exerts its effects via receptors which are widely distributed in human tissues, including nuclear oestrogen receptors (ERα and ERß), membrane-bound oestrogen receptor (G protein-coupled receptor 30; GPR30), and human nuclear receptor oestrogen-related receptor gamma. As such, this paper focuses on the potential role of BPA in promoting comorbidities associated with severe COVID-19, as well as on potential BPA-induced effects on key SARS-CoV-2 infection mediators, such as angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Interestingly, GPR30 appears to exhibit greater co-localisation with TMPRSS2 in key tissues like lung and prostate, suggesting that BPA exposure may impact on the local expression of these SARS-CoV-2 infection mediators. Overall, the potential role of BPA on the risk and severity of COVID-19 merits further investigation.
ABSTRACT
Infection by the severe acute respiratory syndrome (SARS) coronavirus2 (SARSCoV2) is the cause of the new viral infectious disease (coronavirus disease 2019; COVID19). Emerging evidence indicates that COVID19 may be associated with a wide spectrum of neurological symptoms and complications with central nervous system (CNS) involvement. It is now wellestablished that entry of SARSCoV2 into host cells is facilitated by its spike proteins mainly through binding to the angiotensinconverting enzyme 2 (ACE2). Preclinical studies have suggested that neuropilin1 (NRP1), which is a transmembrane receptor that lacks a cytosolic protein kinase domain and exhibits high expression in the respiratory and olfactory epithelium, may also be implicated in COVID19 by enhancing the entry of SARSCoV2 into the brain through the olfactory epithelium. In the present study, we expand on these findings and demonstrate that the NRP1 is also expressed in the CNS, including olfactoryrelated regions such as the olfactory tubercles and paraolfactory gyri. This furthers supports the potential role of NRP1 as an additional SARSCoV2 infection mediator implicated in the neurologic manifestations of COVID19. Accordingly, the neurotropism of SARSCoV2 via NRP1expressing cells in the CNS merits further investigation.
Subject(s)
Central Nervous System/metabolism , Coronavirus Infections/metabolism , Neuropilin-1/metabolism , Pneumonia, Viral/metabolism , Receptors, Virus/metabolism , Betacoronavirus/physiology , Brain/metabolism , Brain/virology , COVID-19 , Central Nervous System/virology , Databases, Genetic , Humans , Pandemics , Receptors, Coronavirus , SARS-CoV-2ABSTRACT
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 , TranscriptomeABSTRACT
Severe acute respiratory syndrome (SARS) coronavirus2 (SARSCoV2) is the cause of a new disease (COVID19) which has evolved into a pandemic during the first half of 2020. Older age, male sex and certain underlying diseases, including cancer, appear to significantly increase the risk for severe COVID19. SARSCoV2 infection of host cells is facilitated by the angiotensinconverting enzyme 2 (ACE2), and by transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL). With the exception of ACE2, a systematic analysis of these two other SARSCoV2 infection mediators in malignancies is lacking. Here, we analysed genetic alteration, RNA expression, and DNA methylation of TMPRSS2 and CTSL across a wide spectrum of tumors and controls. TMPRSS2 was overexpressed in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma and uterine carcinosarcoma, with PRAD and READ exhibiting the highest expression of all cancers. CTSL was upregulated in lymphoid neoplasm diffuse large Bcell lymphoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lower grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, and thymoma. Hypomethylation of both genes was evident in most cases where they have been highly upregulated. We have expanded on our observations by including data relating to mutations and copy number alterations at pancancer level. The novel hypotheses that are stemming out of these data need to be further investigated and validated in large clinical studies.
Subject(s)
Betacoronavirus/pathogenicity , Biomarkers, Tumor/genetics , Cathepsin L/genetics , Coronavirus Infections/virology , Neoplasms/genetics , Opportunistic Infections/virology , Pneumonia, Viral/virology , Serine Endopeptidases/genetics , Virus Internalization , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/immunology , DNA Methylation , Databases, Genetic , Female , Host-Pathogen Interactions , Humans , Immunocompromised Host , Male , Neoplasms/enzymology , Neoplasms/immunology , Opportunistic Infections/enzymology , Opportunistic Infections/immunology , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/immunology , Risk Factors , SARS-CoV-2ABSTRACT
BACKGROUND: In women of reproductive age, polycystic ovary syndrome (PCOS) constitutes the most frequent endocrine disorder. Women with PCOS are considered to typically belong to an age and sex group which is at lower risk for severe COVID-19. MAIN BODY: Emerging data link the risk of severe COVID-19 with certain factors such as hyper-inflammation, ethnicity predisposition, low vitamin D levels, and hyperandrogenism, all of which have known direct associations with PCOS. Moreover, in this common female patient population, there is markedly high prevalence of multiple cardio-metabolic conditions, such as type 2 diabetes, obesity, and hypertension, which may significantly increase the risk for adverse COVID-19-related outcomes. This strong overlap of risk factors for both worse PCOS cardio-metabolic manifestations and severe COVID-19 should be highlighted for the clinical practice, particularly since women with PCOS often receive fragmented care from multiple healthcare services. Comprehensively informing women with PCOS regarding the potential risks from COVID-19 and how this may affect their management is also essential. CONCLUSION: Despite the immense challenges posed by the COVID-19 outbreak to the healthcare systems in affected countries, attention should be directed to maintain a high standard of care for complex patients such as many women with PCOS and provide relevant practical recommendations for optimal management in the setting of this fast moving pandemic.