Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour–node–metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies. Head and neck squamous cell carcinomas (HNSCCs) originate from the mucosal epithelium in the oral cavity, pharynx and larynx and are commonly associated with viral infection and tobacco use. This Primer provides an overview of the epidemiology, pathogenesis and treatment of HNSCCs of different aetiologies and the effects of the cancer and its treatment on patient quality of life.

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Head and neck squamous cell carcinoma

The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.

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Mechanisms of SARS-CoV-2 entry into cells.

I. Introduction A FUNCTIONAL relationship between cell growth and the initiation and progression of events associated with differentiation has been a fundamental question challenging developmental biologists for more than a century. In the case of bone, as observed with other cells and tissue, the relationship of growth and differentiation must be maintained and stringently regulated, both during development and throughout the life of the organism, to support tissue remodeling. For many years, bone was defined anatomically and examined largely in a descriptive manner by ultrastructural analysis and by biochemical and histochemical methods. These studies provided the basis for our understanding of bone tissue organization and orchestration of the progressive recruitment, proliferation, and differentiation of the various cellular components of bone tissue. Now, complemented by an increased knowledge of molecular mechanisms that are associated with and regulate expression of genes encoding phenotypic compone...

Molecular mechanism mediating proliferation, defferentiation interralationships during progressie development of the osteoblast phenotype

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19

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COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis.

Radiographic Predictors for Malignant Transformation of Inverted Papilloma

High prevalence of persistent smell loss and qualitative smell dysfunction during the COVID-19 pandemic in the United States: urgent need for clinical trials.

Olfactory dysfunction (OD) is associated with both post‐viral and inflammatory etiologies such as COVID‐19 and chronic rhinosinusitis/rhinitis (CRS/R) respectively, to result in reduced quality of life (QoL). However, the former typically induces a sudden‐onset OD while the latter has a gradual presentation. This study aims to establish and compare health utility values (HUVs) and olfactory‐specific QoL measurements between patients with COVID‐19 and CRS/R related OD.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/lio2.921

Impact of COVID‐19 versus chronic rhinosinusitis/rhinitis associated olfactory dysfunction on health utility and quality of life

Cancer development, cell survival, and therapeutic resistance have recently been linked to a small sub-population of cells expressing stem cell genes, and capable of reproducing the cancer cell population, called cancer stem cells (CSC). CK2 (formerly casein kinase II) has emerged as a key signal serine/threonine kinase that modulates diverse signal cascades that regulate cell fate and growth. We previously showed that CK2 is aberrantly expressed and activated in head and neck squamous cell carcinomas (HNSCC). Concomitant inactivation of tumor suppressor TAp73, along with mutation of related family member TP53, is also often observed, but the relationship between CK2, TAp73 inactivation, and CSC is unknown. Here, we observed that classical stem cell genes NANOG, SOX2, and OCT4, are overexpressed in HNSCC with inactivated TAp73 and mtTP53. Inhibition of CK2 by pharmacologic inhibitors or siRNA increased TAp73 mRNA and protein expression, while inhibiting CSC gene expression and the SP. Conversely, knockdown of TAp73 increased CSC gene expression and the SP. Bioinformatic analysis identified a single predicted CK2 threonine phosphorylation site (T27) within the N-terminal transactivation domain of TAp73. Nuclear CK2 and TAp73 interaction, confirmed by co-immunoprecipitation, was attenuated by CK2 inhibitor, or a T27A point-mutation of the predicted CK2 threonine phospho-acceptor site of TAp73. Furthermore, T27A mutation attenuated TAp73 phosphorylation, while enhancing its function in repressing CSC gene expression, and SP cells. Novel CK2 inhibitor CX-4945 inhibited CSC related SP cells, clonogenic survival, and spheroid formation, identifying CK2 modulation of tumor suppressor TAp73 as a potential target for inhibition of CSCs. Our study reveals a novel regulatory mechanism whereby aberrant CK2-mediated inactivation of TAp73 tumor suppressor function promotes key CSC genes and phenotype. Supported by NIDCD intramural project ZIA-DC-00073 Citation Format: Hai Lu, Carol H. Yan, Yansong Bian, Zhong Chen, Carter Van Waes. CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1925. doi:10.1158/1538-7445.AM2014-1925

Abstract 1925: CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer

Chronic rhinosinusitis (CRS) is a common inflammatory disease of the sinonasal cavity that affects millions of individuals worldwide. The complex pathophysiology of CRS remains poorly understood, with emerging evidence implicating the orchestration between diverse immune and epithelial cell types in disease progression. We applied single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to both dissociated and intact, freshly isolated sinonasal human tissues to investigate the cellular and molecular heterogeneity of CRS with and without nasal polyp formation compared to non-CRS control samples. Our findings reveal a mechanism for macrophage-eosinophil recruitment into the nasal mucosa, systematic dysregulation of CD4+ and CD8+ T cells, and enrichment of mast cell populations to the upper airway tissues with intricate interactions between mast cells and CD4 T cells. Additionally, we identify immune-epithelial interactions and dysregulation, particularly involving understudied basal progenitor cells and Tuft chemosensory cells. We further describe a distinct basal cell differential trajectory in CRS patients with nasal polyps (NP), and link it to NP formation through immune-epithelial remodeling. By harnessing stringent patient tissue selection and advanced technologies, our study unveils novel aspects of CRS pathophysiology, and sheds light onto both intricate immune and epithelial cell interactions within the disrupted CRS tissue microenvironment and promising targets for therapeutic intervention. These findings expand upon existing knowledge of nasal inflammation and provide a comprehensive resource towards understanding the cellular and molecular mechanisms underlying this uniquely complex disease entity, and beyond.

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Carol H. Yan

Papers

Radiographic Predictors for Malignant Transformation of Inverted Papilloma

High prevalence of persistent smell loss and qualitative smell dysfunction during the COVID-19 pandemic in the United States: urgent need for clinical trials.

Impact of COVID‐19 versus chronic rhinosinusitis/rhinitis associated olfactory dysfunction on health utility and quality of life

Abstract 1925: CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer

Immune-Epithelial Dynamics and Tissue Remodeling in Chronically Inflamed Nasal Epithelium via Multi-scaled Transcriptomics