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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.

Lots of large reservoirs have been built in the southwest mountainous areas of China, and the slope of reservoir shore is prone to landslides under complex geological conditions such as rainfall, reservoir water periodic fluctuation and earthquake. If the highway bridge foundation is located in the range of bank slope deformation or instability, huge lateral load may be generated on the bridge pier, thus endangering the foundation structure and the overall safety of the bridge. Taking the slope of Xiaojiang Bridge in Baihetan Reservoir as an example, this study applied GeoStudio to analyse the stability of bridge foundation slope under the combined condition of reservoir water fluctuation, rainfall and earthquake. As to the unstable slope under the combined rainfall condition of reservoir water fluctuation, the numerical method of Tsunami Balls (TB) was used to simulate the landslide dynamic process and evaluate the dynamic impact load of the bridge pier. The results show that the slope stability coefficient decreases due to the reservoir water fluctuation, which is the main factor affecting the slope stability. After seismic load is applied, the slope stability coefficient decreases sharply, while rainfall has limited influence on the stability coefficient. The impact load of the sliding body on the bridge pier increases first and then decreases with time, and the maximum impact load is 13890 kN, which appears after the maximum velocity of the sliding body. It is concluded that the stability of the bridge foundation slope on the bank of reservoir is reduced dramatically under the influence of reservoir water fluctuation, and the failure of the bridge foundation structure may be caused by the instability impact process of TB simulated sliding body. This study provides technical information for the disaster prevention and reduction and safe operation of large reservoir slopes and highway bridges.

Abstract The timely identification of individuals at high risk for peptic ulcers (PUs) is vital in preventing gastrointestinal bleeding after antiplatelet therapy. This study was designed to determine PU risk factors and develop a risk assessment model for PU detection in the general Chinese population. In a prospective dataset, clinical data from individuals undergoing gastroscopic evaluation between April 2019 and May 2022 were recorded. PUs were defined as mucosal defects exceeding 5 mm confirmed via gastroscopy. Participants were categorized into development (April 2019 to April 2021) and validation (May 2021 to May 2022) sets based on chronological order. LASSO-derived logistic regression analysis was employed to create a score, which was further validated via temporal validation. A total of 902 patients were ultimately enrolled, 204 (22.6%) of whom had PUs based on endoscopic findings. In the development cohort (n = 631), seven independent risk factors emerged: male sex (OR = 2.35, P = 0.002), white blood cell (WBC) count (OR = 1.16, P = 0.010), red blood cell (RBC) count (OR = 0.49, P

Abstract Quinoline‐based fibroblast activation protein (FAP) inhibitor (FAPI)‐based positron emission tomography (PET) imaging and radioligand therapy (RLT) are being investigated for use in a wide variety of diseases, and recent results have been promising. This review summarizes the current status of FAPI radiopharmaceuticals in PET imaging of malignant tumors and benign conditions and compares their diagnostic efficacy with 18F‐fluorodeoxyglucose. In addition, we summarize the previously published FAP‐targeted RLT data and discuss its current clinical use and future potential. Our qualitative summary can inform future research directions, medical guidelines, and optimal clinical decision‐making.

Clouds are an important component of weather systems and are difficult to effectively characterize using current climate models and estimation of radiative forcing. Due to the limitations in observational capabilities, it remains difficult to obtain high-spatiotemporal-resolution, continuous, and accurate observations of clouds. To overcome this issue, we propose a novel and practical combined retrieval method using millimeter-wave radar and lidar, which enables the microphysical properties of thin liquid water clouds, such as cloud droplet effective radius, number concentration, and liquid water content, to be retrieved. This method was utilized to analyze the clouds observed at the Shanghai World Expo Park and was validated through synchronous observations with a microwave radiometer. Furthermore, the most suitable extinction backscatter ratio was determined through sensitivity analysis. This study provides vertical distributions of cloud microphysical properties with a time resolution of 1 min and a spatial resolution of 30 m, demonstrating the scientific potential of this combined retrieval method.

Fibroblast activation protein (FAP) is among the most popular targets in nuclear medicine imaging and cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3 peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with 68Ga and 177Lu was assessed in several tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased tumor uptake, and decreased kidney accumulation. Our findings indicated that [68Ga]Ga-DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models, including pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [68Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction. In summary, we developed [68Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.

Based on the data from the mobile wind profile radar (MWPR) at Baoshan of Shanghai from July 2018 to June 2019, we have evaluated and analyzed the performance of MWPR in terms of acquisition rate, horizontal wind error and the reliability of wind data under six typical weather conditions. The main results are as follow. (1) The acquisition rate is most affected by turbulence intensity, followed by atmospheric temperature and humidity. It is obviously characterized by diurnal and seasonal variations. In the boundary layer, the acquisition rate in summer and autumn is higher than that in winter and spring. It also features high acquisition rate in afternoon and low acquisition rate in late night and early morning. In free atmosphere, the acquisition rate in winter and spring is higher than that in summer and autumn. Taking the acquisition rate of 80% as the operation admittance standards, the acquisition rate of MWPR within boundary layer reaches the standard. (2) Comparing with L-band radiosonde, the horizontal wind speeds detected by MWPR in all layers are relatively low. In low mode, 34.4% of the horizontal wind speed data are in the range of 2.0 m·s-1 to 6.0 m·s-1 lower. The wind direction deviation data which exceeds ±15åccounts for 48.9% of all the horizontal wind direction data. (3) Qualitative analysis shows that the directivity of vertical velocity detected by MWPR is reasonable. During heavy rainfall, the vertical velocity detected by MWPR is actually the sum of the falling velocity of precipitation particles and atmospheric turbulence velocity. The reliability of horizontal wind data from MWPR is highin typhoon, snowy and other weather days with the characteristic of strong atmospheric homogeneity. On the whole, MWPR can basically meet the needs of daily meteorological monitoring and services in terms of detection performance, but there still lies a certain gap between its wind measurement accuracy and operation admittance standards.

Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA concentrations in peripheral blood mononuclear cells (PBMCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) and to evaluate and validate the performance of the methodology. A prospective follow-up cohort study was conducted to determine whether intracellular concentrations were associated with adverse outcomes in renal transplants. Methods: PBMCs were prepared using the Ficoll separation technique and purified with erythrocyte lysis. The cells were counted using Sysmex XN-3100 and then packaged and frozen according to a 50 µL volume containing 1.0 × 106 cells. TAC and MPA were extracted using MagnaBeads and quantified using an LC-MS/MS platform. The chromatography was run on a reversed-phase Waters Acquity UPLC BEH C18 column (1.7 µm, 50 mm × 2.1 mm) for gradient elution separation with a total run time of 4.5 min and a flow rate of 0.3 mL/min. Mobile phases A and B were water and methanol, respectively, each containing 2 mM ammonium acetate and 0.1% formic acid. Renal transplant recipients receiving TAC and MPA in combination were selected for clinical validation and divided into two groups: a stable group and an adverse outcome group. The concentrations were dynamically monitored at 5, 7, 14, and 21 days (D5, D7, D14, and D21) and 1, 2, 3, and 6 months (M1, M2, M3, and M6) after operation. Results: Method performance validation was performed according to Food and Drug Administration guidelines, showing high specificity and sensitivity. The TAC and MPA calibration curves were linear (r2 = 0.9988 and r2 = 0.9990, respectively). Both intra-day and inter-day imprecision and inaccuracy were less than 15%. Matrix effects and recoveries were satisfactory. The TAC and MPA concentrations in 304 “real” PBMC samples from 47 renal transplant recipients were within the calibration curve range (0.12 to 16.40 ng/mL and 0.20 to 4.72 ng/mL, respectively). There was a weak correlation between PBMC-C0TAC and WB-C0TAC (p < 0.05), but no correlation was found for MPA. The level of immunosuppressive intra-patient variation (IPV) was higher in PBMC at 77.47% (55.06, 97.76%) than in WB at 34.61% (21.90, 49.85%). During the dynamic change in C0TAC, PBMC-C0TAC was in a fluctuating state, and no stable period was found. PBMC-C0TAC did not show a significant difference between the stable and adverse outcome group, but the level of the adverse outcome group was generally higher than that of the stable group. Conclusions: Compared with conventional therapeutic drug monitoring, the proposed rapid and sensitive method can provide more clinically reliable information on drug concentration at an active site, which has the potential to be applied to the clinical monitoring of intracellular immunosuppressive concentration in organ transplantation. However, the application of PBMC-C0TAC in adverse outcomes of renal transplant should be studied further.

ObjectiveProgrammed death-ligand 1 (PD-L1) expression status is a crucial index for identifying patients who will benefit from anti-programmed cell death protein 1 (PD-1)/PD-L1 therapy for non-small cell lung cancer (NSCLC). However, the concordance of Tumor Proportion Score (TPS) between biopsies and matched surgical specimens remains controversial. This study aims to evaluate the concordance of PD-L1 expression between image-guided percutaneous biopsies and matched surgical specimens.MethodWe evaluated 157 patients diagnosed with operable NSCLC on both surgical tissue sections and matched lung biopsies retrospectively. The patients underwent either regular computed tomography (CT)-guided biopsy (n = 82) or positron emission tomography (PET)/CT-guided biopsy (n = 75). The concordance between surgical specimens and lung biopsies for PD-L1 TPS was evaluated using Cohen’s kappa (κ) coefficient.ResultsImmunohistochemical expression of PD-L1 was evaluated in both surgical resected specimens and matched biopsies in the eligible 138 patients. The concordance rate of PD-L1 expression between surgical tissue sections and matched biopsies was fairly high at 84.1% (116/138), and the κ value was 0.73 (95% CI: 0.63–0.83, P < 0.001). The concordance rate was higher for tissue sections from PET/CT-guided biopsy than for tissue sections from CT-guided biopsy [88.6% (62/70, κ value: 0.81) vs 79.4% (54/68, κ value: 0.66)].ConclusionPD-L1 TPS was strongly concordant between surgical specimens and matched lung biopsies. Thus, the routine evaluation of PD-L1 expression in diagnostic percutaneous biopsies could be reliable for identifying patients who will benefit from anti-PD-1/PD-L1 immunotherapy.

Background: Patients with metastatic nasopharyngeal carcinoma (NPC) have heterogeneous survival outcomes. This study aimed to establish an effective prognostic nomogram for patients with NPC with distant metastases using easily determined factors.Methods: The nomogram was based on a retrospective study of 103 patients with metastatic NPC at the First Affiliated Hospital of Xiamen University during January 2009–March 2016. Nomogram performance was evaluated using a concordance index (C-index) and assessed using calibration plot. Bootstraps with 1,000 resamples were applied to these analyses.Results: In univariate and multivariate Cox proportional hazards model analyses, chemotherapy, metastatic liver involvement, number of tumor metastases, N stage and derived neutrophil–lymphocyte ratio correlated with overall survival (OS). The recurrence probability calibration curve indicated good agreement between nomogram-based predictions and actual observations. For OS predictions, the nomogram had a C-index of 0.824 (95% confidence interval, 0.74–0.91). The stratification by nomogram score of patients into different subgroups showed significant distinction.Conclusion: This novel nomogram comprises factors that are easily determined at most hospitals and can predict survival in patients with distant metastases of NPC. This model can precisely estimate the survival of individual patients and identify subgroups of patients requiring specific therapeutic strategies.