The past decade has seen an unprecedented increase in our understanding of the biology and etiology of head and neck squamous cell carcinomas(HNSCC).Genome-wide sequencing projects have identified a number of recurren...The past decade has seen an unprecedented increase in our understanding of the biology and etiology of head and neck squamous cell carcinomas(HNSCC).Genome-wide sequencing projects have identified a number of recurrently mutated genes,including unexpected alterations in the NOTCH pathway and chromatin related genes.Gene-expression profiling has identified 4 distinct genetic subtypes which show some parallels to lung squamous cell carcinoma biology.The identification of the human papilloma virus as one causative agent in a subset of oropharyngeal cancers and their association with a favorable prognosis has opened up avenues for new therapeutic strategies.The expanding knowledge of the underlying molecular abnormalities in this once very poorly understood cancer should allow for increasingly rational clinical trial design and improved patient outcomes.展开更多
Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial,and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied.Here we inspected sex differenc...Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial,and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied.Here we inspected sex differences in SARS-CoV-2 infection,hospitalization,admission to the intensive care unit(ICU),sera inflammatory biomarker profiling,and single-cell RNA-sequencing(scRNA-seq)profiles across nasal,bronchoalveolar lavage fluid(BALF),and peripheral blood mononuclear cells(PBMCs)from COVID-19 patients with varying degrees of disease severities.Our propensity score-matching observations revealed that male individuals have a 29%elevated likelihood of SARS-CoV-2 positivity,with a hazard ratio(HR)1.32(95%confidence interval[Cl]1.18-1.48)for hospitalization and HR 1.51(95%Cl 1.24-1.84)for admission to ICU.Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers(C-reactive protein and procalcitonin).We found that SARS-CoV-2 entry factors,including ACE2,TMPRSS2,FURIN,and NRP1,have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19.We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples,which offers potential molecular mechanism for sex-biased susceptibility to viral infection.Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19.Mechanistically,monocyte-elevated expression of Toll-like receptor 7{TLR7)and Bruton tyrosine kinase{BTK)is associated with severe outcomes in males with COVID-19.In summary,these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.展开更多
基金We thank Dr.Nancy Lee for thoughtful discussions.T.A.C.was partially supported by the Adenoid Cystic Carcinoma Research Foundation(ACCRF)and a grant from the National Institutes of Health(R21 DE023229).
文摘The past decade has seen an unprecedented increase in our understanding of the biology and etiology of head and neck squamous cell carcinomas(HNSCC).Genome-wide sequencing projects have identified a number of recurrently mutated genes,including unexpected alterations in the NOTCH pathway and chromatin related genes.Gene-expression profiling has identified 4 distinct genetic subtypes which show some parallels to lung squamous cell carcinoma biology.The identification of the human papilloma virus as one causative agent in a subset of oropharyngeal cancers and their association with a favorable prognosis has opened up avenues for new therapeutic strategies.The expanding knowledge of the underlying molecular abnormalities in this once very poorly understood cancer should allow for increasingly rational clinical trial design and improved patient outcomes.
基金This work was supported by the National Institute of Aging(R01AG066707 and 3R01AG066707-01S1)the National Heart,Lung,and Blood Institute(R00HL138272)to F.C+1 种基金This work has been also supported in part by the VeloSano Pilot Program(Cleveland Clinic Taussig Cancer Institute)to F.C.and J.D.LThis work was partly supported by NIH P01 CA245705 and NIH R01 NS109742 to J.D.L.
文摘Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial,and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied.Here we inspected sex differences in SARS-CoV-2 infection,hospitalization,admission to the intensive care unit(ICU),sera inflammatory biomarker profiling,and single-cell RNA-sequencing(scRNA-seq)profiles across nasal,bronchoalveolar lavage fluid(BALF),and peripheral blood mononuclear cells(PBMCs)from COVID-19 patients with varying degrees of disease severities.Our propensity score-matching observations revealed that male individuals have a 29%elevated likelihood of SARS-CoV-2 positivity,with a hazard ratio(HR)1.32(95%confidence interval[Cl]1.18-1.48)for hospitalization and HR 1.51(95%Cl 1.24-1.84)for admission to ICU.Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers(C-reactive protein and procalcitonin).We found that SARS-CoV-2 entry factors,including ACE2,TMPRSS2,FURIN,and NRP1,have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19.We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples,which offers potential molecular mechanism for sex-biased susceptibility to viral infection.Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19.Mechanistically,monocyte-elevated expression of Toll-like receptor 7{TLR7)and Bruton tyrosine kinase{BTK)is associated with severe outcomes in males with COVID-19.In summary,these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.
