Verteporfin synergizes the efflcacy of anti-PD-1 in cholangiocarcinoma

Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA.The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis.This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1(PD-1)in CCA mouse model.Methods:We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro,including both intrahepatic CCA and extrahepatic CCA cells.We examined the in vitro effect of verteporfin on cell proliferation,apoptosis,and stemness.We evaluated the in vivo efflcacy of verteporfin,anti-PD-1,and a combination of both in subcutaneous CCA mouse model.Results:Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion.Nevertheless,verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation,decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers(all P<0.05).The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.Conclusions:Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.

Microsphere-assisted hyperspectral imaging:super-resolution,non-destructive metrology for semiconductor devices

As semiconductor devices shrink and their manufacturing processes advance,accurately measuring in-cell critical dimensions(CD)becomes increasingly crucial.Traditional test element group(TEG)measurements are becoming inadequate for representing the fine,repetitive patterns in cell blocks.Conventional non-destructive metrology technologies like optical critical dimension(OCD)are limited due to their large spot diameter of approximately 25μm,which impedes their efficacy for detailed in-cell structural analysis.Consequently,there is a pressing need for small-spot and non-destructive metrology methods.To address this limitation,we demonstrate a microsphere-assisted hyperspectral imaging(MAHSI)system,specifically designed for small spot optical metrology with super-resolution.Utilizing microsphere-assisted super-resolution imaging,this system achieves an optical resolution of 66 nm within a field of view of 5.6μm×5.6μm.This approach effectively breaks the diffraction limit,significantly enhancing the magnification of the system.The MAHSI system incorporating hyperspectral imaging with a wavelength range of 400–790 nm,enables the capture of the reflection spectrum at each camera pixel.The achieved pixel resolution,which is equivalent to the measuring spot size,is 14.4 nm/pixel and the magnification is 450X.The MAHSI system enables measurement of local uniformity in critical areas like corners and edges of DRAM cell blocks,areas previously challenging to inspect with conventional OCD methods.To our knowledge,this approach represents the first global implementation of microsphere-assisted hyperspectral imaging to address the metrology challenges in complex 3D structures of semiconductor devices.

Integrated NLRP3,AIM2,NLRC4,Pyrin inflammasome activation and assembly drive PANoptosis

Inflammasomes are important sentinels of innate immune defense;they sense pathogens and induce the cell death of infected cells,playing key roles in inflammation,development,and cancer.Several inflammasome sensors detect and respond to specific pathogen-and damage-associated molecular patterns(PAMPs and DAMPs,respectively)by forming a multiprotein complex with the adapters ASC and caspase-1.During disease,cells are exposed to several PAMPs and DAMPs,leading to the concerted activation of multiple inflammasomes.However,the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown.Here,we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death,and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome.Furthermore,NLRP3,AIM2,NLRC4,and Pyrin were determined to be members of a large multiprotein complex,along with ASC,caspase-1,caspase-8,and RIPK3,and this complex drove PANoptosis.Furthermore,this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes.Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages.Collectively,our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors,which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators.The discovery of critical interactions among NLRP3,AIM2,NLRC4,and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-,AIM2-,NLRC4-and Pyrin-mediated diseases.

“假难民请滚开” 也门难民惹怒韩国居民

在以碧水沙滩闻名于世的韩国旅游胜地济州岛，李香（Lee Hyang）很生气。让她愤怒如斯的是500多名来自也门的逃难者。他们成功逃离战火纷飞的家园，试图寻找一个安稳的居住和工作地。