Objectives:Thyroid cancer(THCA)is the most common malignant tumor in endocrine system and the incidence has been increasing worldwide.And the number of patients dying from THCA has also gradually risen because the inc...Objectives:Thyroid cancer(THCA)is the most common malignant tumor in endocrine system and the incidence has been increasing worldwide.And the number of patients dying from THCA has also gradually risen because the incidence continues to increase,so the mechanisms related to effective targets is necessary to improve the survival.This study was to preliminarily investigate the effects of the COL4A2 gene on the regulation of thyroid cancer(THCA)cell proliferation and the associated pathways.Methods:Bioinformatics analysis revealed that COL4A2 was closely associated with cancer development.COL4A2 expression in THCA tissues was analyzed using immunohistochemistry,and survival information was determined via Kaplan-Meier curves.The expression of COL4A2 and AKT pathway-related genes were analyzed using qPCR and western blot analyses.Colony formation as well as CCK-8 assays exhibited the cell proliferation level and cell activity,respectively.Downstream of COL4A2 was identified by Gene set enrichment analysis(GSEA).The effects of the COL4A2 and AKT pathways on THCA tumor growth in vivo were determined using a mouse model.Results:Bioinformatics analysis exhibited that COL4A2 plays a significant role in cancer and that the AKT pathway is downstream of COL4A2.THCA patients with high COL4A2 expression had shorter recurrence-free survival.Upregulation of COL4A2 gene expression in 2 THCA cell lines promoted tumor cell growth and activity.The use of AKT pathway blockers also restrained the growth and activity of the 2 THCA cell lines.The use of AKT pathway blockers reduced tumor volume and mass and prolonged mouse survival.Conclusions:COL4A2 can promote the growth as well as development of THCA through the AKT pathway and COL4A2 could be used as a target for THCA.展开更多
Patients with refractory metastatic triple-negative breast cancer(mTNBC)and symptomatic brain metastases have poor prognosis and are challenging to treat.The addition of an programmed cell death-1(PD-1)/programmed cel...Patients with refractory metastatic triple-negative breast cancer(mTNBC)and symptomatic brain metastases have poor prognosis and are challenging to treat.The addition of an programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1)inhibitor(pembrolizumab or atezolizumab)to first line chemotherapy has prolonged survivals in mTNBC patients with PD-L1-positive tumor and/or tumor-infiltrating immune cells.The clinical effi-cacy of the chemoimmunotherapy combination in patients with refractory mTNBC,especially brain metastasis,is unknown.Co-amplification of PD-L1,PD-L2,and Janus kinase 2(PD-L1/PD-L2/JAK2)genes(PDJ amplification)is associated with high PD-L1 protein expression and a 65-87%response rate to PD-1/PD-L1 inhibitors in patients with lymphomas.But the utility of PDJ amplification as a biomarker predictive of response to PD-1/PD-L1 in-hibitors is unknown for mTNBC patients.Here,we report a 46-year-old woman who had rapid tumor progression in the brain and lung within 3 months after chemotherapy,neurosurgery,and gamma knife stereotactic radio-surgery for brain metastasis.Next-generation sequencing of her brain metastasis specimen revealed 9 copies of PDJ amplification and a tumor mutational burden of 5 mutations per megabase.Although high PDJ mRNA ex-pression levels were detected,PD-L1 protein expression was negative on tumor cells and 10%on tumor-associated immune cells.After the debulking brain tumor resection,she received pembrolizumab monotherapy,whole brain radiation,and then atezolizumab and nab-paclitaxel with good intracranial and extracranial responses for>16 months.To the best of our knowledge,this is the first report that PDJ amplification is associated with durable clin-ical response to the PD-1/PD-L1 inhibitor-containing,multidisciplinary management in a patient with refractory,PD-L1 protein-negative,PDJ-amplified mTNBC.Further study is warranted to understand the underlying mech-anism and validate PDJ amplification as a biomarker for clinical response to PD-1/PD-L1 inhibitor-containing therapy in patients with mTNBC.展开更多
Comprehensive Summary Currently,CRISPR/Cas9 technology has found widespread applications across various domains.However,the utility of CRISPR/Cas9 is encumbered by issues pertaining to its reliability and safety,prima...Comprehensive Summary Currently,CRISPR/Cas9 technology has found widespread applications across various domains.However,the utility of CRISPR/Cas9 is encumbered by issues pertaining to its reliability and safety,primarily stemming from the uncontrolled activity of the system.Therefore,the design and development of CRISPR/Cas9 systems with controllable activity is of paramount importance.Biotin,characterized by its small molecular weight,and streptavidin,distinguished by its substantial spatial steric hindrance,can be harnessed as an ideal OFF switch(termed a"bioactivity brake")due to their interaction characteristics.In this work,we present a strategy that employs the streptavidin-biotin interaction as a"brake system"for CRISPR/Cas9,effectively allowing for the shutdown of the enzymatic activity of CRISPR/Cas9.展开更多
DNA 5-formylcytosine(5fC)is a prominent epigenetic modification within biological systems.Recent investigations have shed light on its pivotal role in governing cell fate,gene expression,and disease pathways.However,o...DNA 5-formylcytosine(5fC)is a prominent epigenetic modification within biological systems.Recent investigations have shed light on its pivotal role in governing cell fate,gene expression,and disease pathways.However,our comprehension of the precise control of the 5f site structure to influence its functionality remains limited.In this study,we have successfully achieved precise control over 5fc activity by harnessing the interaction between streptavidin and biotin.This research underscores the potential application of interactions between biomacromolecules and small molecules in advancing the field of DNA epigenetic functional regulation.展开更多
文摘Objectives:Thyroid cancer(THCA)is the most common malignant tumor in endocrine system and the incidence has been increasing worldwide.And the number of patients dying from THCA has also gradually risen because the incidence continues to increase,so the mechanisms related to effective targets is necessary to improve the survival.This study was to preliminarily investigate the effects of the COL4A2 gene on the regulation of thyroid cancer(THCA)cell proliferation and the associated pathways.Methods:Bioinformatics analysis revealed that COL4A2 was closely associated with cancer development.COL4A2 expression in THCA tissues was analyzed using immunohistochemistry,and survival information was determined via Kaplan-Meier curves.The expression of COL4A2 and AKT pathway-related genes were analyzed using qPCR and western blot analyses.Colony formation as well as CCK-8 assays exhibited the cell proliferation level and cell activity,respectively.Downstream of COL4A2 was identified by Gene set enrichment analysis(GSEA).The effects of the COL4A2 and AKT pathways on THCA tumor growth in vivo were determined using a mouse model.Results:Bioinformatics analysis exhibited that COL4A2 plays a significant role in cancer and that the AKT pathway is downstream of COL4A2.THCA patients with high COL4A2 expression had shorter recurrence-free survival.Upregulation of COL4A2 gene expression in 2 THCA cell lines promoted tumor cell growth and activity.The use of AKT pathway blockers also restrained the growth and activity of the 2 THCA cell lines.The use of AKT pathway blockers reduced tumor volume and mass and prolonged mouse survival.Conclusions:COL4A2 can promote the growth as well as development of THCA through the AKT pathway and COL4A2 could be used as a target for THCA.
文摘Patients with refractory metastatic triple-negative breast cancer(mTNBC)and symptomatic brain metastases have poor prognosis and are challenging to treat.The addition of an programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1)inhibitor(pembrolizumab or atezolizumab)to first line chemotherapy has prolonged survivals in mTNBC patients with PD-L1-positive tumor and/or tumor-infiltrating immune cells.The clinical effi-cacy of the chemoimmunotherapy combination in patients with refractory mTNBC,especially brain metastasis,is unknown.Co-amplification of PD-L1,PD-L2,and Janus kinase 2(PD-L1/PD-L2/JAK2)genes(PDJ amplification)is associated with high PD-L1 protein expression and a 65-87%response rate to PD-1/PD-L1 inhibitors in patients with lymphomas.But the utility of PDJ amplification as a biomarker predictive of response to PD-1/PD-L1 in-hibitors is unknown for mTNBC patients.Here,we report a 46-year-old woman who had rapid tumor progression in the brain and lung within 3 months after chemotherapy,neurosurgery,and gamma knife stereotactic radio-surgery for brain metastasis.Next-generation sequencing of her brain metastasis specimen revealed 9 copies of PDJ amplification and a tumor mutational burden of 5 mutations per megabase.Although high PDJ mRNA ex-pression levels were detected,PD-L1 protein expression was negative on tumor cells and 10%on tumor-associated immune cells.After the debulking brain tumor resection,she received pembrolizumab monotherapy,whole brain radiation,and then atezolizumab and nab-paclitaxel with good intracranial and extracranial responses for>16 months.To the best of our knowledge,this is the first report that PDJ amplification is associated with durable clin-ical response to the PD-1/PD-L1 inhibitor-containing,multidisciplinary management in a patient with refractory,PD-L1 protein-negative,PDJ-amplified mTNBC.Further study is warranted to understand the underlying mech-anism and validate PDJ amplification as a biomarker for clinical response to PD-1/PD-L1 inhibitor-containing therapy in patients with mTNBC.
基金the National Natural Science Foundation of China(Nos.22177089,21721005,92153303,22037004,22177088)the Fundamental Research Funds for the Central Universities(2042023kf0204)Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(Grant No.ZNJC202309).
文摘Comprehensive Summary Currently,CRISPR/Cas9 technology has found widespread applications across various domains.However,the utility of CRISPR/Cas9 is encumbered by issues pertaining to its reliability and safety,primarily stemming from the uncontrolled activity of the system.Therefore,the design and development of CRISPR/Cas9 systems with controllable activity is of paramount importance.Biotin,characterized by its small molecular weight,and streptavidin,distinguished by its substantial spatial steric hindrance,can be harnessed as an ideal OFF switch(termed a"bioactivity brake")due to their interaction characteristics.In this work,we present a strategy that employs the streptavidin-biotin interaction as a"brake system"for CRISPR/Cas9,effectively allowing for the shutdown of the enzymatic activity of CRISPR/Cas9.
基金the National Natural Science Foundation of China(Nos.22177089,21721005,92153303,22037004,22177088)the Fundamental Research Funds for the Central Universities(2042021kf0211)Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(Grant No.ZNJC202309).
文摘DNA 5-formylcytosine(5fC)is a prominent epigenetic modification within biological systems.Recent investigations have shed light on its pivotal role in governing cell fate,gene expression,and disease pathways.However,our comprehension of the precise control of the 5f site structure to influence its functionality remains limited.In this study,we have successfully achieved precise control over 5fc activity by harnessing the interaction between streptavidin and biotin.This research underscores the potential application of interactions between biomacromolecules and small molecules in advancing the field of DNA epigenetic functional regulation.
