BACKGROUND The treatment of acute respiratory distress syndrome(ARDS)complicated by sepsis syndrome(SS)remains challenging.AIM To investigate whether combined adipose-derived mesenchymal-stem-cells(ADMSCs)-derived exo...BACKGROUND The treatment of acute respiratory distress syndrome(ARDS)complicated by sepsis syndrome(SS)remains challenging.AIM To investigate whether combined adipose-derived mesenchymal-stem-cells(ADMSCs)-derived exosome(EXAD)and exogenous mitochondria(mitoEx)protect the lung from ARDS complicated by SS.METHODS In vitro study,including L2 cells treated with lipopolysaccharide(LPS)and in vivo study including male-adult-SD rats categorized into groups 1(sham-operated-control),2(ARDS-SS),3(ARDS-SS+EXAD),4(ARDS-SS+mitoEx),and 5(ARDS-SS+EXAD+mitoEx),were included in the present study.RESULTS In vitro study showed an abundance of mitoEx found in recipient-L2 cells,resulting in significantly higher mitochondrial-cytochrome-C,adenosine triphosphate and relative mitochondrial DNA levels(P<0.001).The protein levels of inflammation[interleukin(IL)-1β/tumor necrosis factor(TNF)-α/nuclear factor-κB/toll-like receptor(TLR)-4/matrix-metalloproteinase(MMP)-9/oxidative-stress(NOX-1/NOX-2)/apoptosis(cleaved-caspase3/cleaved-poly(ADP-ribose)polymerase)]were significantly attenuated in lipopolysaccharide(LPS)-treated L2 cells with EXAD treatment than without EXAD treatment,whereas the protein expressions of cellular junctions[occluding/β-catenin/zonula occludens(ZO)-1/E-cadherin]exhibited an opposite pattern of inflam-mation(all P<0.001).Animals were euthanized by 72 h post-48 h-ARDS induction,and lung tissues were harvested.By 72 h,flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflam-matory cells(Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+)and albumin were lowest in group 1,highest in group 2,and significantly higher in groups 3 and 4 than in group 5(all P<0.0001),whereas arterial oxygen-saturation(SaO2%)displayed an opposite pattern of albumin among the groups.Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers(CD68+/γ-H2AX)displayed an identical pattern of SaO2%among the groups(all P<0.0001).The protein expressions of inflammatory(TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress(NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged(cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic(beclin-1/Atg-5/ratio of LC3B-II/LC3B-I)biomarkers exhibited a similar manner,whereas antioxidants[nuclear respiratory factor(Nrf)-1/Nrf-2]/cellular junctions(ZO-1/E-cadherin)/mitochondrial electron transport chain(complex I-V)exhibited an opposite manner of albumin among the groups(all P<0.0001).CONCLUSION Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.展开更多
Both platinum-based doublet chemotherapy(PBC) and epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer(NSCLC). In early studi...Both platinum-based doublet chemotherapy(PBC) and epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer(NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival(OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian(predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs(r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations(r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations(r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.展开更多
AIM:To identify risk factors predictive of intensive care unit(ICU) mortality in patients with ventilator-related pancreatitis.The clinical outcomes of patients with ventilator-related pancreatitis were compared with ...AIM:To identify risk factors predictive of intensive care unit(ICU) mortality in patients with ventilator-related pancreatitis.The clinical outcomes of patients with ventilator-related pancreatitis were compared with those of patients with pancreatitis-related respiratory failure as well as controls.METHODS:One hundred and forty-eight patients with respiratory failure requiring mechanical ventilation and concomitant acute pancreatitis were identified from a prospectively collected dataset of 9108 consecutive patients admitted with respiratory failure over a period of five years.Sixty patients met the criteria for ventilator-related pancreatitis,and 88(control patients),for pancreatitis-related respiratory failure.RESULTS:Mortality rate in ventilator-related pancreatitis was comparable to that in ICU patients without pancreatitis by case-control methodology(P=0.544).Multivariate logistic regression analysis identified low PaO2/FiO2(OR:1.032,95% CI:1.006-1.059,P=0.016) as an independent risk factor for mortality in patients with ventilator-related pancreatitis.The mortality rate in patients with ventilator-related pancreatitis was lower than that in patients with acute pancreatitis-related respiratory failure(P<0.001).CONCLUSION:We found that low PaO2/FiO2 was an independent clinical parameter predictive of ICU mortality in patients with ventilator-related pancreatitis.展开更多
Introduction:An increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma(NPC).However,targeted therapy-related oncogenic mutations have not been fully evaluated.This study aim...Introduction:An increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma(NPC).However,targeted therapy-related oncogenic mutations have not been fully evaluated.This study aimed to detect targeted therapy-related oncogenic mutations in NPC and to determine which targeted therapy might be potentially effective in treating NPC.Methods:By using the SNaPshot assay,a rapid detection method,19 mutation hotspots in 6 targeted therapy-related oncogenes were examined in 70 NPC patients.The associations between oncogenic mutations and clinicopathologic factors were analyzed.Results:Among 70 patients,12(17.1%) had mutations in 5 oncogenes:7(10.0%) had v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog(KIT) mutation,2(2.8%) had epidermal growth factor receptor(EGFR) mutation,1(1.4%) had phosphatidylinositol-4,5-bisphosphate 3-kinase,catalytic subunit alpha(PIK3CA) mutation,1(1.4%) had Kirsten rat sarcoma viral oncogene homolog(KRAS) mutation,and 1(1.4%) had simultaneous EGFR and v-Raf murine sarcoma viral oncogene homolog B1(BRAF) mutations.No significant differences were observed between oncogenic mutations and clinicopathologic characteristics.Additionally,these oncogenic mutations were not associated with tumor recurrence or metastasis.Conclusions:Oncogenic mutations are present in NPC patients.The efficacy of targeted drugs on patients with the related oncogenic mutations requires further validation.展开更多
Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor(EGFR)signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy.In this phase 3 study(Clin...Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor(EGFR)signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy.In this phase 3 study(ClinicalTrial.gov:NCT04028778),315 patients with treatment-naïve,EGFR-mutated,advanced non-small cell lung cancer(NSCLC)were randomized(1:1)to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle.At the prespecified final analysis of progression-free survival(PFS),a significant improvement in PFS was observed for the anlotinib arm over the placebo arm(hazards ratio[HR]=0.64,95%CI,0.48–0.80,P=0.003).Particularly,patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib.The incidence of grade 3 or higher treatment-emergent adverse events was 49.7%of the patients receiving gefitinib plus anlotinib versus 31.0%of the patients receiving gefitinib plus placebo.Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve,EGFR-mutated,advanced NSCLC,with a manageable safety profile.展开更多
Dear Editor,Programmed cell death 1 ligand 1(PD-L1)has been used as a biomarker for immune checkpoint inhibitors(ICIs)which exert durable efficacy in non-small cell lung cancer(NSCLC).^(1,2)However,many PD-L1-high pat...Dear Editor,Programmed cell death 1 ligand 1(PD-L1)has been used as a biomarker for immune checkpoint inhibitors(ICIs)which exert durable efficacy in non-small cell lung cancer(NSCLC).^(1,2)However,many PD-L1-high patients only marginally respond to,and PD-L1-low patients still benefit from,ICIs.^(3,4)展开更多
Nasopharyngeal carcinoma(NPC)is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa.To develop these comprehensive guidelines for the diagnosis and m...Nasopharyngeal carcinoma(NPC)is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa.To develop these comprehensive guidelines for the diagnosis and management of NPC,the Chinese Society of Clinical Oncology(CSCO)arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write,discuss,and revise the guidelines.Based on the findings of evidencebased medicine in China and abroad,domestic experts have iteratively developed these guidelines to provide proper management of NPC.Overall,the guidelines describe the screening,clinical and pathological diagnosis,staging and risk assessment,therapies,and follow-up of NPC,which aim to improve the management of NPC.展开更多
Indoleamine 2,3-dioxygenase 1(IDO1),the enzyme that catabolizes tryptophan(Trp)metabolism to promote regulatory T cells(Tregs)and suppress CD8+T cells,is regulated by several intrinsic signaling pathways.Here,we found...Indoleamine 2,3-dioxygenase 1(IDO1),the enzyme that catabolizes tryptophan(Trp)metabolism to promote regulatory T cells(Tregs)and suppress CD8+T cells,is regulated by several intrinsic signaling pathways.Here,we found that tobacco smoke,a major public health concern that kills 8 million people each year worldwide,induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo.The carcinogen nicotine-derived nitrosaminoketone(NNK)was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun,which has a binding site for the IDO1 promoter.The NNK receptorα7 nicotinic acetylcholine receptor(α7nAChR)was required for NNK-induced c-Jun activation and IDO1 upregulation.In A/J mice,NNK reduced CD8+T cells and increased Tregs.Clinically,smoker patients with non-small-cell lung cancer(NSCLC)exhibited high IDO1 levels and low Trp/kynurenine(Kyn)ratios.In NSCLC patients,smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1.These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis,and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients,whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.展开更多
文摘BACKGROUND The treatment of acute respiratory distress syndrome(ARDS)complicated by sepsis syndrome(SS)remains challenging.AIM To investigate whether combined adipose-derived mesenchymal-stem-cells(ADMSCs)-derived exosome(EXAD)and exogenous mitochondria(mitoEx)protect the lung from ARDS complicated by SS.METHODS In vitro study,including L2 cells treated with lipopolysaccharide(LPS)and in vivo study including male-adult-SD rats categorized into groups 1(sham-operated-control),2(ARDS-SS),3(ARDS-SS+EXAD),4(ARDS-SS+mitoEx),and 5(ARDS-SS+EXAD+mitoEx),were included in the present study.RESULTS In vitro study showed an abundance of mitoEx found in recipient-L2 cells,resulting in significantly higher mitochondrial-cytochrome-C,adenosine triphosphate and relative mitochondrial DNA levels(P<0.001).The protein levels of inflammation[interleukin(IL)-1β/tumor necrosis factor(TNF)-α/nuclear factor-κB/toll-like receptor(TLR)-4/matrix-metalloproteinase(MMP)-9/oxidative-stress(NOX-1/NOX-2)/apoptosis(cleaved-caspase3/cleaved-poly(ADP-ribose)polymerase)]were significantly attenuated in lipopolysaccharide(LPS)-treated L2 cells with EXAD treatment than without EXAD treatment,whereas the protein expressions of cellular junctions[occluding/β-catenin/zonula occludens(ZO)-1/E-cadherin]exhibited an opposite pattern of inflam-mation(all P<0.001).Animals were euthanized by 72 h post-48 h-ARDS induction,and lung tissues were harvested.By 72 h,flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflam-matory cells(Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+)and albumin were lowest in group 1,highest in group 2,and significantly higher in groups 3 and 4 than in group 5(all P<0.0001),whereas arterial oxygen-saturation(SaO2%)displayed an opposite pattern of albumin among the groups.Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers(CD68+/γ-H2AX)displayed an identical pattern of SaO2%among the groups(all P<0.0001).The protein expressions of inflammatory(TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress(NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged(cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic(beclin-1/Atg-5/ratio of LC3B-II/LC3B-I)biomarkers exhibited a similar manner,whereas antioxidants[nuclear respiratory factor(Nrf)-1/Nrf-2]/cellular junctions(ZO-1/E-cadherin)/mitochondrial electron transport chain(complex I-V)exhibited an opposite manner of albumin among the groups(all P<0.0001).CONCLUSION Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.
文摘Both platinum-based doublet chemotherapy(PBC) and epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer(NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival(OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian(predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs(r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations(r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations(r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.
文摘AIM:To identify risk factors predictive of intensive care unit(ICU) mortality in patients with ventilator-related pancreatitis.The clinical outcomes of patients with ventilator-related pancreatitis were compared with those of patients with pancreatitis-related respiratory failure as well as controls.METHODS:One hundred and forty-eight patients with respiratory failure requiring mechanical ventilation and concomitant acute pancreatitis were identified from a prospectively collected dataset of 9108 consecutive patients admitted with respiratory failure over a period of five years.Sixty patients met the criteria for ventilator-related pancreatitis,and 88(control patients),for pancreatitis-related respiratory failure.RESULTS:Mortality rate in ventilator-related pancreatitis was comparable to that in ICU patients without pancreatitis by case-control methodology(P=0.544).Multivariate logistic regression analysis identified low PaO2/FiO2(OR:1.032,95% CI:1.006-1.059,P=0.016) as an independent risk factor for mortality in patients with ventilator-related pancreatitis.The mortality rate in patients with ventilator-related pancreatitis was lower than that in patients with acute pancreatitis-related respiratory failure(P<0.001).CONCLUSION:We found that low PaO2/FiO2 was an independent clinical parameter predictive of ICU mortality in patients with ventilator-related pancreatitis.
基金supported in part by a grant from the National High Technology Research and Development Program of China(No.2012AA02A501)
文摘Introduction:An increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma(NPC).However,targeted therapy-related oncogenic mutations have not been fully evaluated.This study aimed to detect targeted therapy-related oncogenic mutations in NPC and to determine which targeted therapy might be potentially effective in treating NPC.Methods:By using the SNaPshot assay,a rapid detection method,19 mutation hotspots in 6 targeted therapy-related oncogenes were examined in 70 NPC patients.The associations between oncogenic mutations and clinicopathologic factors were analyzed.Results:Among 70 patients,12(17.1%) had mutations in 5 oncogenes:7(10.0%) had v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog(KIT) mutation,2(2.8%) had epidermal growth factor receptor(EGFR) mutation,1(1.4%) had phosphatidylinositol-4,5-bisphosphate 3-kinase,catalytic subunit alpha(PIK3CA) mutation,1(1.4%) had Kirsten rat sarcoma viral oncogene homolog(KRAS) mutation,and 1(1.4%) had simultaneous EGFR and v-Raf murine sarcoma viral oncogene homolog B1(BRAF) mutations.No significant differences were observed between oncogenic mutations and clinicopathologic characteristics.Additionally,these oncogenic mutations were not associated with tumor recurrence or metastasis.Conclusions:Oncogenic mutations are present in NPC patients.The efficacy of targeted drugs on patients with the related oncogenic mutations requires further validation.
基金funded by the Chinese National Natural Science Foundation Project(Grant No.82173101,82373262,82241232,82272789,82102864)Guangzhou Basic and Applied Basic Research Foundation(2024A04J4082)partly funded by the 308 Clinical Research Foundation of Sun Yat-sen University Cancer Center.
文摘Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor(EGFR)signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy.In this phase 3 study(ClinicalTrial.gov:NCT04028778),315 patients with treatment-naïve,EGFR-mutated,advanced non-small cell lung cancer(NSCLC)were randomized(1:1)to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle.At the prespecified final analysis of progression-free survival(PFS),a significant improvement in PFS was observed for the anlotinib arm over the placebo arm(hazards ratio[HR]=0.64,95%CI,0.48–0.80,P=0.003).Particularly,patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib.The incidence of grade 3 or higher treatment-emergent adverse events was 49.7%of the patients receiving gefitinib plus anlotinib versus 31.0%of the patients receiving gefitinib plus placebo.Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve,EGFR-mutated,advanced NSCLC,with a manageable safety profile.
基金supported by the Key Project of the National Natural Science Foundation of China(81830093)the National Key Research and Development Program of China(2022YFA1103900,2020YFA0803300)+2 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS,2022-RC310-05,2021-RC310-003)the CAMS Initiative for Innovative Medicine(2021-/2M-1-021,2022-12M-2-001,2021-1-/2M-012)the National Natural Science Foundation of China(82073092,82273076).
文摘Dear Editor,Programmed cell death 1 ligand 1(PD-L1)has been used as a biomarker for immune checkpoint inhibitors(ICIs)which exert durable efficacy in non-small cell lung cancer(NSCLC).^(1,2)However,many PD-L1-high patients only marginally respond to,and PD-L1-low patients still benefit from,ICIs.^(3,4)
文摘Nasopharyngeal carcinoma(NPC)is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa.To develop these comprehensive guidelines for the diagnosis and management of NPC,the Chinese Society of Clinical Oncology(CSCO)arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write,discuss,and revise the guidelines.Based on the findings of evidencebased medicine in China and abroad,domestic experts have iteratively developed these guidelines to provide proper management of NPC.Overall,the guidelines describe the screening,clinical and pathological diagnosis,staging and risk assessment,therapies,and follow-up of NPC,which aim to improve the management of NPC.
基金supported by the Key Project of the National Natural Science Foundation of China(81830093)the National Key Research and Development Program of China(2020YFA0803300)+3 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS2021-RC310-003,2020-RC310-002)the CAMS Initiative for Innovative Medicine(2021-1-I2M-012,2021-I2M-1-021)the National Natural Science Foundation of China(81802796,82073092).
文摘Indoleamine 2,3-dioxygenase 1(IDO1),the enzyme that catabolizes tryptophan(Trp)metabolism to promote regulatory T cells(Tregs)and suppress CD8+T cells,is regulated by several intrinsic signaling pathways.Here,we found that tobacco smoke,a major public health concern that kills 8 million people each year worldwide,induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo.The carcinogen nicotine-derived nitrosaminoketone(NNK)was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun,which has a binding site for the IDO1 promoter.The NNK receptorα7 nicotinic acetylcholine receptor(α7nAChR)was required for NNK-induced c-Jun activation and IDO1 upregulation.In A/J mice,NNK reduced CD8+T cells and increased Tregs.Clinically,smoker patients with non-small-cell lung cancer(NSCLC)exhibited high IDO1 levels and low Trp/kynurenine(Kyn)ratios.In NSCLC patients,smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1.These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis,and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients,whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.
