The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor ...The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment.We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse models.Using single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy response.Mechanistically,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production.As a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity.Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on macrophages.Collectively,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.展开更多
A tunneling accelerometer is fabricated and characterized based on the extension of the silicon-glass anodic-bonding and deep etching releasing process provided by Peking University.The tunneling current under open lo...A tunneling accelerometer is fabricated and characterized based on the extension of the silicon-glass anodic-bonding and deep etching releasing process provided by Peking University.The tunneling current under open loop operation is tested in the air by HP4145B semiconductor analyzer,which verifies the presence of tunneling current and the exponential relationship between tunneling gap and tunneling current.The tunneling barrier is extrapolated to be from 1.182 to 2.177eV.The threshold voltages are tested to be 14～16V for most of the devices.The threshold voltages under -1,0,and +1g are tested,respectively,which shows the sensitivity of the accelerometer is about 87mV/g.展开更多
基金supported by the Chinese National Natural Science Foundation Project(82073396,82303807)the Guangzhou Key Research and Development Plan(202206010141)+1 种基金the China National Postdoctoral Program for Innovative Talents(BX20230444)the China Postdoctoral Science Foundation(2023M734032).
文摘The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment.We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse models.Using single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy response.Mechanistically,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production.As a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity.Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on macrophages.Collectively,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.
文摘A tunneling accelerometer is fabricated and characterized based on the extension of the silicon-glass anodic-bonding and deep etching releasing process provided by Peking University.The tunneling current under open loop operation is tested in the air by HP4145B semiconductor analyzer,which verifies the presence of tunneling current and the exponential relationship between tunneling gap and tunneling current.The tunneling barrier is extrapolated to be from 1.182 to 2.177eV.The threshold voltages are tested to be 14～16V for most of the devices.The threshold voltages under -1,0,and +1g are tested,respectively,which shows the sensitivity of the accelerometer is about 87mV/g.
