Background:C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons.However,its function is still not clear.We established C1ql3-deficient rats to investigate the role of C...Background:C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons.However,its function is still not clear.We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain.Methods:C1ql3 knockout(KO)rats were generated using CRISPR/Cas9.C1ql3 KO was determined by polymerase chain reaction(PCR),DNA sequencing,and western blot-ting.Microglia morphology and cytokine expression with or without lipopolysaccha-ride(LPS)stimulus were analyzed using immunohistochemistry and real-time PCR.The brain structure changes in KO rats were examined using magnetic resonance imaging.Neuronal architecture alteration was analyzed by performing Golgi staining.Behavior was evaluated using the open field test,Morris water maze test,and Y maze test.Results:C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia,whereas C1ql3 KO did not in-fluence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10.C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation.The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats.C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density.C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory.Conclusions:C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation,resulting in hyperactive behavior and impaired short memory in rats,which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.展开更多
Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT045...Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.展开更多
基金The present work was supported by the National Natural Science Foundation(31970508)the National Key Research and Development Program of China(2022YFF0710702).
文摘Background:C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons.However,its function is still not clear.We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain.Methods:C1ql3 knockout(KO)rats were generated using CRISPR/Cas9.C1ql3 KO was determined by polymerase chain reaction(PCR),DNA sequencing,and western blot-ting.Microglia morphology and cytokine expression with or without lipopolysaccha-ride(LPS)stimulus were analyzed using immunohistochemistry and real-time PCR.The brain structure changes in KO rats were examined using magnetic resonance imaging.Neuronal architecture alteration was analyzed by performing Golgi staining.Behavior was evaluated using the open field test,Morris water maze test,and Y maze test.Results:C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia,whereas C1ql3 KO did not in-fluence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10.C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation.The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats.C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density.C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory.Conclusions:C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation,resulting in hyperactive behavior and impaired short memory in rats,which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.
文摘Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.
