The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions:insights from a single-arm,phase II trial

Immune checkpoint inhibitors targeting the programmed cell death-1(PD-1)protein significantly improve survival in patients with advanced non-small-cell lung cancer(NSCLC),but its impact on early-stage ground-glass opacity(GGO)lesions remains unclear.This is a single-arm,phase II trial(NCT04026841)using Simon’s optimal two-stage design,of which 4 doses of sintilimab(200 mg per 3 weeks)were administrated in 36 enrolled multiple primary lung cancer(MPLC)patients with persistent high-risk(Lung-RADS category 4 or had progressed within 6 months)GGOs.The primary endpoint was objective response rate(ORR).T/B/NK-cell subpopulations,TCR-seq,cytokines,exosomal RNA,and multiplexed immunohistochemistry(mIHC)were monitored and compared between responders and non-responders.Finally,two intent-to-treat(ITT)lesions(pure-GGO or GGO-predominant)showed responses(ORR:5.6%,2/36),and no patients had progressive disease(PD).No grade 3-5 TRAEs occurred.The total response rate considering two ITT lesions and three non-intent-to-treat(NITT)lesions(pure-solid or solid-predominant)was 13.9%(5/36).The proportion of CD8^(+)T cells,the ratio of CD8^(+)/CD4^(+),and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time.Correspondingly,the mIHC analysis showed more CD8^(+)T cells infiltrated in responders.Besides,responders’cytokine concentrations of EGF and CTLA-4 increased during treatment.The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders.Collectively,PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns.Such effects were associated with specific T-cell re-distribution,EGF/CTLA-4 cytokine compensation,and regulation of metabolism pathways.

Asian,regional,and national burdens of respiratory tract cancers and associated risk factors from 1990 to 2019:A systematic analysis for the global burden of disease study 2019

Background:Respiratory cancer is the leading cause of cancer-related deaths worldwide,but its statistics vary between the East and West.This study aimed to estimate the burdens of tracheal,bronchus,and lung(TBL)cancer and larynx cancer and their attributable risks from 1990 to 2019 in Asia,and at regional and national levels.Methods:This research evaluated the incidence,mortality,years lived with disability,years of life lost,and disability-adjusted life years(DALYs)for respiratory tract cancers using the Global Burden of Diseases,Injuries,and Risk Factors Study(GBD)2019 database.Age-standardized rates were calculated for TBL cancer from 1990 to 2019,adjusted for smoking and socio-demographic index(SDI).Deaths from TBL cancer and larynx cancer attributable to each risk factor were estimated for 33 Asian countries.Results:The age-standardized incidence and death rates for TBL cancer in Asia declined from 2010 to 2019,while the incidence rate of larynx cancer increased.Smoking was the leading specific risk factor for deaths from both TBL and larynx cancers.The burden of TBL cancer in Asian countries was influenced by SDI and smoking,particularly among males in Central Asia.Deaths,DALYs,and incidences of larynx cancer in East Asia had not changed significantly over the past 30 years,but showed slight downward trends in males and both sexes combined,and an upward trend in females in recent years.Conclusions:The past decade saw increases in numbers of incident cases and deaths from TBL cancer and larynx cancer in Asia.SDI and smoking were the main factors influencing the disease burden of TBL cancer in Asian countries.This study highlights the need for tailored cancer control programs to address the burden of respiratory tract cancers in different Asian countries.

Comparison of nonhuman primates identified the suitable model for COVID-19

Identification of a suitable nonhuman primate(NHP)model of COVID-19 remains challenging.Here,we characterized severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in three NHP species:Old World monkeys Macaca mulatta(M.mulatta)and Macaca fascicularis(M.fascicularis)and New World monkey Callithrix jacchus(C.jacchus).Infected M.mulatta and M.fascicularis showed abnormal chest radiographs,an increased body temperature and a decreased body weight.Viral genomes were detected in swab and blood samples from all animals.Viral load was detected in the pulmonary tissues of M.mulatta and M.fascicularis but not C.jacchus.Furthermore,among the three animal species,M.mulatta showed the strongest response to SARS-CoV-2,including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues.Collectively,these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M.mulatta as the most suitable for modeling COVID-19.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys

Neurological manifestations are frequently reported in the COVID-19 patients.Neuromechanism of SARS-CoV-2 remains to be elucidated.In this study,we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19.In rhesus monkey,SARS-CoV-2 invades the CNS primarily via the olfactory bulb.Thereafter,viruses rapidly spread to functional areas of the central nervous system,such as hippocampus,thalamus,and medulla oblongata.The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons,microglia,and astrocytes in the CNS.Consistently,SARS-CoV-2 infects neuro-derived SK-N-SH,glial-derived U251,and brain microvascular endothelial cells in vitro.To our knowledge,this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model,which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.

Three doses of prototypic SARS-CoV-2 inactivated vaccine induce cross-protection against its variants of concern

Variants are globally emerging very quickly following pandemic prototypic SARS-CoV-2.To evaluate the cross-protection of prototypic SARS-CoV-2 vaccine against its variants,we vaccinated rhesus monkeys with three doses of prototypic SARS-CoV-2 inactivated vaccine,followed by challenging with emerging SARS-CoV-2 variants of concern(VOCs).