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Abstract Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.

During long-duration dynamic loads, such as wind loads or seismic effects, the internal temperature and pressure of a damping cylinder escalate rapidly, which induce shifts in the mechanical attributes of viscous fluid dampers (VFDs). This study investigated the mechanical performance of VFD considering the coupling effects of temperature and pressure under long-duration loads. First, we analyzed the mechanical and energy-dissipation performances of the dampers based on the dynamic mechanical tests considering different loading frequencies, displacement amplitude, and loading cycles. The experimental results indicated that both temperature and pressure influenced the output of the dampers, and in the sealed environment of the damper pip, temperature and pressure exerted mutual influence. Furthermore, the relationship between the damping coefficient and temperature–pressure coupling effects was obtained. Subsequently, an improved mathematical model for the mechanical performance of a gap-type VFD was proposed by considering the macroscopic energy balance of the entire fluid within the damper. Finally, the accuracy of the mathematical model for VFD under long-duration dynamic loads was validated by comparing the computational results with the experimental data.

In this study, we investigated the effects of Cu doping on the performance of CoFeSiB amorphous microwires as the core of a fluxgate magnetometer. The noise performance of fluxgate sensors primarily depends on the crystal structure of constituent materials. CoFeSiB amorphous microwires with varying Cu doping ratios were prepared using melt-extraction technology. The microstructure of microwire configurations was observed using transmission electron microscopy, and the growth of nanocrystalline was examined. Additionally, the magnetic performance of the microwire and the noise of the magnetic fluxgate sensors were tested to establish the relationship between Cu-doped CoFeSiB amorphous wires and sensor noise performance. The results indicated that Cu doping triggers a positive mixing enthalpy and the reduced difference in the atomic radius that enhances the degree of nanocrystalline formation within the system; differential scanning calorimetry analysis indicates that this is due to Cu doping reducing the glass formation capacity of the system. In addition, Cu doping affects the soft magnetic properties of amorphous microwires, with 1% low-doping samples exhibiting better soft magnetic properties. This phenomenon is likely the result of the interaction between nanocrystalline organization and magnetic domains. Furthermore, a Cu doping ratio of 1% yields the best noise performance, aligning with the trend observed in the material’s magnetic properties. Therefore, to reduce the noise of the CoFeSiB amorphous wire sensor, the primary goal should be to reduce microscopic defects in amorphous alloys and enhance soft magnetic properties. Cu doping is a superior preparation method which facilitates control over preparation conditions, ensuring the formation of stable amorphous wires with consistent performance.

As an important part of the national political system, government audits play a significant role in supervising and restricting enterprises. Since 2010, the National Audit Office of China has repeatedly disclosed the problems regarding enterprises’ M&A to prevent the loss of state-owned assets. This study takes listed companies controlled by the central enterprises of A-shares from 2008 to 2018 as a sample to investigate the impact of government audit supervision on M&A. We find that government audit supervision reduces the number and scale of M&As. Further research shows that government audits can reduce enterprises’ M&A premiums and affect payment methods. Finally, government audits significantly improve the short- and long-term performance of M&As. These findings show that Chinese government audits positively affect corporate governance, curbing M&As that damage enterprise interests. This study provides micro-level evidence of the governance effect of government audits on the scientific decision-making of enterprises.

The luminal-to-basal transition in mammary epithelial cells (MECs) is accompanied by changes in epithelial cell lineage plasticity; however, the underlying mechanism remains elusive. Here, we report that deficiency of Frmd3 inhibits mammary gland lineage development and induces stemness of MECs, subsequently leading to the occurrence of triple-negative breast cancer. Loss of Frmd3 in PyMT mice results in a luminal-to-basal transition phenotype. Single-cell RNA sequencing of MECs indicated that knockout of Frmd3 inhibits the Notch signaling pathway. Mechanistically, FERM domain-containing protein 3 (FRMD3) promotes the degradation of Disheveled-2 by disrupting its interaction with deubiquitinase USP9x. FRMD3 also interrupts the interaction of Disheveled-2 with CK1, FOXK1/2, and NICD and decreases Disheveled-2 phosphorylation and nuclear localization, thereby impairing Notch-dependent luminal epithelial lineage plasticity in MECs. A low level of FRMD3 predicts poor outcomes for breast cancer patients. Together, we demonstrated that FRMD3 is a tumor suppressor that functions as an endogenous activator of the Notch signaling pathway, facilitating the basal-to-luminal transformation in MECs. [ABSTRACT FROM AUTHOR]