Skin reaction or dermatological toxicities induced by immunotherapy is common.It usually manifests skin rash or erythema and can be cured by skin lotion or steroid.Nivolumab,a human IgG4 programmed cell death protein ...Skin reaction or dermatological toxicities induced by immunotherapy is common.It usually manifests skin rash or erythema and can be cured by skin lotion or steroid.Nivolumab,a human IgG4 programmed cell death protein 1(PD-1)inhibitor,blocks T cells activation preventing signal and allows the immune system to clear cancer cells.Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA,with less than 10%unusual skin reaction,like sensory neuropathy,peeling skin,erythema multiforme,vitiligo,and psoriasis.Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity.The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies,but the risk of side effects may be high.We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy.The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events.Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.展开更多
Crizotinib,a small molecular tyrosine kinase inhibitor,manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase(EML4-ALK...Crizotinib,a small molecular tyrosine kinase inhibitor,manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase(EML4-ALK)rearrangements.ALK gene point mutation is the primary mechanism of acquired crizotinib resistance;however,the intrinsic mechanism is not fully understood.Here,we report a patient with a low mutant allele fraction(MAF)of EML4-ALK rearrangement,who experienced primary resistance to crizotinib treatment.The patient was a 66-year-old Chinese man,who had a history of metastatic lung cancer and was treated with first-and third-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR TKIs).After 14 months of osimertinib treatment,his disease progressed,and next-generation sequencing was performed from a liquid biopsy of the patient’s blood.An EML4-ALK rearrangement was found and crizotinib was administered.The patient’s lung lesions continued to progress after one month of crizotinib treatment,and pemetrexed-bevacizumab was initiated.After two cycles of chemotherapy,the metastatic cancers shrunk,and the patient maintained stable disease at his last follow-up.EML4-ALK rearrangements can happen in patients with EGFR-positive NSCLC,after acquired resistance to EGFR TKI treatment.The EGFR T790M and C797G mutations occur in cis is a critical mechanism of resistance to osimertinib therapy.The MAF of EML4-ALK rearrangements in cancer cells might be a predictive factor for crizotinib treatment.展开更多
Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progre...Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor(EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor Ⅷ(C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic(RGD) integrin-binding motif that engages α_vβ_5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin α_vβ_3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of α_vβ_3 and α_vβ_5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of α_vβ_3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4^+ and/or CD8^+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies.展开更多
With the discovery of the two-dimensional(2D) MXene, it shows a great application potential in the field of electromagnetic interference(EMI) shielding, but the mechanical brittleness and easy oxidation of MXene limit...With the discovery of the two-dimensional(2D) MXene, it shows a great application potential in the field of electromagnetic interference(EMI) shielding, but the mechanical brittleness and easy oxidation of MXene limit its wide application. For this reason, a double crosslinking strategy is provided to solve the above problems in a nacre-like “brick-mortar” layered MXene/cellulose nanofiber(MXene/CNF) film.Typically, the film was firstly suffered by dopamine modification, then was further reinforced by secondary Ca^(2+)bridging, so as to obtain excellent mechanical properties and antioxidative EMI shielding performance. Comparing with the single crosslinking, the double crosslinking strategy reveals a higher efficiency in improving the mechanical property. The mechanical strength and toughness of the double crosslinking MXene/CNF film can increase to 142.2 MPa and 9.48 MJ/m^(3), respectively. More importantly, while achieving good mechanical properties, the MXene composite film still holds a very stable EMI shielding performance of more than 44.6 dB when suffering from the oxidation treatment of hightemperature annealing, showing excellent anti-oxidation ability and environment tolerance. Therefore,this work provides a universal but effective double crosslinking strategy to solve the mechanical brittleness and easy oxidation of MXene-based composites, thus showing a huge potential in flexible EMI shielding applications.展开更多
The rapid improvement in the running speed,transmission efficiency,and power density of miniaturized devices means that multifunctional flexible composites with excellent thermal management capability and high electro...The rapid improvement in the running speed,transmission efficiency,and power density of miniaturized devices means that multifunctional flexible composites with excellent thermal management capability and high electromagnetic interference(EMI)shielding performance are urgently required.Here,inspired by the fibrous pathways of the human nervous system,a“core–sheath”fibers structured strategy was proposed to prepare thermoplastic polyurethane/polydopamine/carbon nanotube(TPU/PDA/CNT)composites film with thermal management capability and EMI shielding performance.Firstly,TPU@PDA@CNT fibers with CNT shell were prepared by a facile polydopamine-assisted coating on electrospun TPU fibers.Subsequently,TPU/PDA/CNT composites with three-dimensional(3D)fibrous CNT“tracks”are obtained by a hot-pressing process,where CNTs distributed on adjacent fibers are compactly contacted.The fabricated TPU/PDA/CNT composites exhibit a high in-plane thermal conductivity(TC)of 9.6 W/(m·K)at low CNT loading of 7.6 wt.%.In addition,it also presents excellent mechanical properties and excellent EMI shielding effectiveness of 48.3 dB as well as multi-source driven thermal management capabilities.Hence,this study provides a simple yet scalable technique to prepare composites with advanced thermal management and EMI shielding performance to develop new-generation wireless communication technologies and portable intelligent electronic devices.展开更多
A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC...A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC)patients without pretreatment.This study presents the prespecifiedfinal analysis of overall survival(OS)and biomarkers utilizing circulating tumor DNA(ctDNA)and tissuebased sequencing.Additionally,the analysis revealed a higher median overall survival(OS,23.8 months)in the toripalimab group than that in the control group(17.0 months).(HR=0.69,95%CI:0.57-0.93,nominal P=0.01).This survival benefit was particularly notable in the nonsquamous subgroup.As thefirst phase 3 study to perform both baseline tissue whole-exome sequencing(WES)and peripheral blood ctDNA testing,we investigated efficacy predictive biomarkers based on both tissue and ctDNA,Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden,as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment.Furthermore,a ctDNA response observed on cycle 3 day 1,was associated with improved clinical outcomes for patients treated with the combination therapy.In conclusion,Toripalimab plus chemotherapy yields significant improvements in OS as afirst-line treatment.The study highlights the utility of ctDNA as a proxy for tumor tissue,providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.展开更多
文摘Skin reaction or dermatological toxicities induced by immunotherapy is common.It usually manifests skin rash or erythema and can be cured by skin lotion or steroid.Nivolumab,a human IgG4 programmed cell death protein 1(PD-1)inhibitor,blocks T cells activation preventing signal and allows the immune system to clear cancer cells.Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA,with less than 10%unusual skin reaction,like sensory neuropathy,peeling skin,erythema multiforme,vitiligo,and psoriasis.Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity.The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies,but the risk of side effects may be high.We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy.The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events.Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.
文摘Crizotinib,a small molecular tyrosine kinase inhibitor,manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase(EML4-ALK)rearrangements.ALK gene point mutation is the primary mechanism of acquired crizotinib resistance;however,the intrinsic mechanism is not fully understood.Here,we report a patient with a low mutant allele fraction(MAF)of EML4-ALK rearrangement,who experienced primary resistance to crizotinib treatment.The patient was a 66-year-old Chinese man,who had a history of metastatic lung cancer and was treated with first-and third-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR TKIs).After 14 months of osimertinib treatment,his disease progressed,and next-generation sequencing was performed from a liquid biopsy of the patient’s blood.An EML4-ALK rearrangement was found and crizotinib was administered.The patient’s lung lesions continued to progress after one month of crizotinib treatment,and pemetrexed-bevacizumab was initiated.After two cycles of chemotherapy,the metastatic cancers shrunk,and the patient maintained stable disease at his last follow-up.EML4-ALK rearrangements can happen in patients with EGFR-positive NSCLC,after acquired resistance to EGFR TKI treatment.The EGFR T790M and C797G mutations occur in cis is a critical mechanism of resistance to osimertinib therapy.The MAF of EML4-ALK rearrangements in cancer cells might be a predictive factor for crizotinib treatment.
基金Supported by a grant from Medical Technology Research Center for Health Development of China National Health and Family Planning Commission(No.W2012FZ007)
文摘Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor(EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor Ⅷ(C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic(RGD) integrin-binding motif that engages α_vβ_5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin α_vβ_3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of α_vβ_3 and α_vβ_5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of α_vβ_3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4^+ and/or CD8^+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies.
基金financially supported by the National Key R&D Program of China(No.2019YFA0706802)the National Natural Science Foundation of China(Nos.51903223 and 12072325)the Key Technologies R&D Program of Henan Province(No.212102210302)。
文摘With the discovery of the two-dimensional(2D) MXene, it shows a great application potential in the field of electromagnetic interference(EMI) shielding, but the mechanical brittleness and easy oxidation of MXene limit its wide application. For this reason, a double crosslinking strategy is provided to solve the above problems in a nacre-like “brick-mortar” layered MXene/cellulose nanofiber(MXene/CNF) film.Typically, the film was firstly suffered by dopamine modification, then was further reinforced by secondary Ca^(2+)bridging, so as to obtain excellent mechanical properties and antioxidative EMI shielding performance. Comparing with the single crosslinking, the double crosslinking strategy reveals a higher efficiency in improving the mechanical property. The mechanical strength and toughness of the double crosslinking MXene/CNF film can increase to 142.2 MPa and 9.48 MJ/m^(3), respectively. More importantly, while achieving good mechanical properties, the MXene composite film still holds a very stable EMI shielding performance of more than 44.6 dB when suffering from the oxidation treatment of hightemperature annealing, showing excellent anti-oxidation ability and environment tolerance. Therefore,this work provides a universal but effective double crosslinking strategy to solve the mechanical brittleness and easy oxidation of MXene-based composites, thus showing a huge potential in flexible EMI shielding applications.
基金supported by the National Natural Science Foundation of China(Nos.21704096,51703217,and 12072325)the Natural Science Foundation of Henan Province(No.20A430028).
文摘The rapid improvement in the running speed,transmission efficiency,and power density of miniaturized devices means that multifunctional flexible composites with excellent thermal management capability and high electromagnetic interference(EMI)shielding performance are urgently required.Here,inspired by the fibrous pathways of the human nervous system,a“core–sheath”fibers structured strategy was proposed to prepare thermoplastic polyurethane/polydopamine/carbon nanotube(TPU/PDA/CNT)composites film with thermal management capability and EMI shielding performance.Firstly,TPU@PDA@CNT fibers with CNT shell were prepared by a facile polydopamine-assisted coating on electrospun TPU fibers.Subsequently,TPU/PDA/CNT composites with three-dimensional(3D)fibrous CNT“tracks”are obtained by a hot-pressing process,where CNTs distributed on adjacent fibers are compactly contacted.The fabricated TPU/PDA/CNT composites exhibit a high in-plane thermal conductivity(TC)of 9.6 W/(m·K)at low CNT loading of 7.6 wt.%.In addition,it also presents excellent mechanical properties and excellent EMI shielding effectiveness of 48.3 dB as well as multi-source driven thermal management capabilities.Hence,this study provides a simple yet scalable technique to prepare composites with advanced thermal management and EMI shielding performance to develop new-generation wireless communication technologies and portable intelligent electronic devices.
基金supported by National key R&D program of China(2022YFC2505000)to J.WNSFC general program(82272796)NSFC special program(82241229)to J.W+1 种基金CAMS Innovation Fund for Medical Sciences(CIFMS 20adjuvant-I2M-1-009)to J.W,CAMS Key Laboratory of Translational Research on Lung Cancer(2018PT31035)to J.WAiyou foundation(KY201701)to J.W,CAMS Innovation Fund for Medical Sciences(2021-1-I2M-012)to Z.W.Beijing Natural Science Foundation(7222144)to J.Z,NSFC program(82303969)to J.Z.
文摘A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC)patients without pretreatment.This study presents the prespecifiedfinal analysis of overall survival(OS)and biomarkers utilizing circulating tumor DNA(ctDNA)and tissuebased sequencing.Additionally,the analysis revealed a higher median overall survival(OS,23.8 months)in the toripalimab group than that in the control group(17.0 months).(HR=0.69,95%CI:0.57-0.93,nominal P=0.01).This survival benefit was particularly notable in the nonsquamous subgroup.As thefirst phase 3 study to perform both baseline tissue whole-exome sequencing(WES)and peripheral blood ctDNA testing,we investigated efficacy predictive biomarkers based on both tissue and ctDNA,Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden,as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment.Furthermore,a ctDNA response observed on cycle 3 day 1,was associated with improved clinical outcomes for patients treated with the combination therapy.In conclusion,Toripalimab plus chemotherapy yields significant improvements in OS as afirst-line treatment.The study highlights the utility of ctDNA as a proxy for tumor tissue,providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.
