Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling.

Craniopharyngiomas (CPs), particularly Adamantinomatous Craniopharyngiomas (ACPs), often exhibit a heightened risk of postoperative recurrence and severe complications of the endocrine and hypothalamic function. The primary objective of this study is to investigate potential novel targeted therapies within the microenvironment of ACP tumors. Cancer-Associated Fibroblasts (CAFs) were identified in the craniopharyngioma microenvironment, notably in regions characterized by cholesterol clefts, wet keratin, ghost cells, and fibrous stroma in ACPs. CAFs, alongside ghost cells, basaloid-like epithelium cells and calcifications, were found to secrete PROS1 and GAS6, which can activate AXL receptors on the surface of tumor epithelium cells, promoting immune suppression and tumor progression in ACPs. Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

First Potassium Fluoroaluminate Ionic Exchanger for Rapid and Selective Removal of Sr2+ with High Capacity.

90 Sr, as a typical artificial radionuclide, poses a serious threat to human health and the ecological environment. The selective removal of this radionuclide from industrial nuclear waste is crucial for our environment. Here we report a novel potassium fluoroaluminate, K2 [(AlF5 )H2 O], which was synthesized by a simple low-temperature one-step method. It adopts a 1D AlF6 -chain structure, which consists of exchangeable potassium ions in between the infinite chains of octahedral Al centers. As a remarkable inorganic ionic exchanger, K2 [(AlF5 )H2 O] has a high chemical stability (resistance of pH=~3-12) and thermal stability (≥~300 °C). It possesses an excellent adsorption selectivity (Kd =~6.1×104  mL ⋅ g-1 ) and a maximum adsorption capacity of qm =~120.32 mg ⋅ g-1 for Sr2+ . Importantly, it still keep a very good selectivity for Sr2+ ions even in the presence of competing Na+ , Mg2+ and Ca2+ aqueous solutions. K2 [(AlF5 )H2 O] is the first example of fluoroaluminate ionic exchange materials that can capture Sr2+ . This result opens up a new way to design and synthesize inorganic ionic exchangers for the selective removal of Sr2+ ions from radioactive waste water.

Benchmarking Supervised and Self-Supervised Learning Methods in A Large Ultrasound Muti-task Images Dataset.

Deep learning in ultrasound(US) imaging aims to construct foundational models that accurately reflect the modality's unique characteristics. Nevertheless, the limited datasets and narrow task types have restricted this field in recent years. To address these challenges, we introduce US-MTD120K, a multi-task ultrasound dataset with 120,354 real-world two-dimensional images. This dataset covers three standard plane recognition and two diagnostic tasks in ultrasound imaging, providing a rich basis for model training and evaluation. We detail the data collection, distribution, and labelling processes, ensuring a thorough understanding of the dataset's structure. Furthermore, we conduct extensive benchmark tests on 27 state-of-the-art methods from both supervised and self-supervised learning(SSL) perspectives. In the realm of supervised learning, we analyze the sensitivity of two main feature computation methods to ultrasound images at the representational level, highlighting that models which judiciously constrain global feature computation could potentially serve as a viable analytical approach for US image analysis. In the context of self-supervised learning, we delved into the modelling process of self-supervised learning models for medical images and proposed an improvement strategy, named MoCo-US, a solution that addresses the excessive reliance on pretext task design from the input side. It achieves competitive performance with minimal pretext task design and enhances other SSL methods simply. The dataset and the code will be available at https://github.com/JsongZhang/CDOA-for-UMTD.

Lung Ultrasound Assessment of Lung Hyperinflation in Patients with Stable COPD: An Effective Diagnostic Tool.

Purpose: To evaluate the degree of lung hyperinflation (LH) in patients with stable chronic obstructive pulmonary disease (COPD) by lung ultrasound score (LUS) and assess its value. Patients and Methods: We conducted a study of 149 patients with stable COPD and 100 healthy controls recruited by the Second Affiliated Hospital of Fujian Medical University. The pleural sliding displacement (PSD) was measured, the sliding of the pleura in different areas was observed, and LUS was calculated from both of them. The diaphragm excursion (DE), residual capacity (RV), total lung capacity (TLC), inspiratory capacity (IC) and functional residual capacity (FRC) were measured. We described the correlation between ultrasound indicators and pulmonary function indicators reflecting LH. Multiple linear regression analysis was used. The ROC curves of LUS and DE were drawn to evaluate their diagnostic efficacy, and De Long method was used for comparison. Results: (1) The LUS of patients with stable COPD were positively correlated with RV, TLC, RV/TLC and FRC and negatively correlated with IC and IC/TLC (r1=0.72, r2=0.41, r3=0.72, r4=0.70, r5=-0.56, r6=-0.65, P < 0.001). The correlation was stronger than that between DE at maximal deep inspiration and the corresponding pulmonary function indices (r1=-0.41, r2=-0.26, r3=-0.40, r4=-0.43, r5=0.30, r6=0.37, P < 0.001). (2) Multiple linear regression analysis showed that LUS were significantly correlated with IC/TLC and RV/TLC. (3) With IC/TLC<25% and RV/TLC>60% as the diagnostic criterion of severe LH, the areas under the ROC curves of LUS and DE at maximal deep inspiration for diagnosing severe LH were 0.914 and 0.385, 0.845 and 0.543, respectively (P < 0.001). Conclusion: The lung ultrasound score is an important parameter for evaluating LH. LUS is better than DE at maximal deep inspiration for diagnosing severe LH and is expected to become an effective auxiliary tool for evaluating LH.

Evaluation of extravascular lung water and cardiac function in normal vaginal delivery by intrapartum bedside ultrasound.

BACKGROUND: Healthy parturients may experience pulmonary edema and disturbed cardiac function during labor. We aimed to evaluate the extravascular lung water (EVLW), intravascular volume, and cardiac function of normal parturients during spontaneous vaginal delivery by bedside ultrasound. And to explore the correlation between EVLW and intravascular volume, cardiac function. METHODS: This was a prospective observational study including 30 singleton-term pregnant women undergoing spontaneous vaginal delivery. Bedside ultrasound was performed at the early labor, the end of the second stage of labor, 2 and 24 h postpartum, and 120 scanning results were recorded. EVLW was evaluated by the echo comet score (ECS) obtained by the 28-rib interspaces technique. Inferior vena cava collapsibility index (IVC-CI), left ventricle ejection fraction, right ventricle fractional area change, left and right ventricular E/A ratio, and left and right ventricular index of myocardial performance (LIMP and RIMP) were measured. Measurements among different time points were compared, and the correlations between ECS and other measurements were analyzed. RESULTS: During the spontaneous vaginal delivery of healthy pregnant women, 2 had a mild EVLW increase at the early labor, 8 at the end of the second stage of labor, 13 at 2 h postpartum, and 4 at 24 h postpartum (P < 0.001). From the early labor to 24 h postpartum, ECS first increased and then decreased, reaching its peak at 2 h postpartum (P < 0.001). IVC-CI first decreased and then increased, reaching its minimum at the end of the second stage of labor (P < 0.001). RIMP exceeded the cut-off value of 0.43 at the end of the second stage of labor. ECS was weakly correlated with IVC-CI (r=-0.373, P < 0.001), LIMP (r = 0.298, P = 0.022) and RIMP (r = 0.211, P = 0.021). CONCLUSIONS: During spontaneous vaginal delivery, the most vital period of perinatal care is between the end of the second stage of labor and 2 h postpartum, because the risk of pulmonary edema is higher and the right ventricle function may decline. IVC-CI can be used to evaluate maternal intravascular volume. The increase in EVLW may be related to the increase in intravascular volume and the decrease in ventricular function.

[Degradation of Ciprofloxacin by Activating Peroxymonosulfate with Sludge Biochar].

Sludge biochar(BC), which was prepared by the pyrolysis of waste-activated sludge at 450℃, was applied for peroxymonosulfate(PMS) activation to construct a BC/PMS system for ciprofloxacin(CIP) degradation. The physical and chemical properties of BC were studied using scanning electron microscopy(SEM), an energy dispersive spectrometer(EDS), a Fourier transform infrared spectrometer(FTIR), X-ray diffraction(XRD), a Zeta potential analyzer, and electron paramagnetic resonance spectroscopy(EPR). The effects of BC dosage, PMS dosage, initial pH value, and inorganic anions on CIP removal in the BC/PMS system were investigated. Further, the degradation mechanism of the BC/PMS system was speculated through the free radical quenching experiment and X-ray photoelectron spectroscopy(XPS) analysis. The results showed that the CIP degradation rate was 49.09% at a BC dosage of 1.0 g·L-1, PMS of 3.0 mmol·L-1, CIP of 20 mg·L-1, and pH of 6.0 in 120 min. SO42- and NO3- had no obvious effect on the removal of CIP in the BC/PMS system, whereas HCO3- and Cl-could inhibit CIP degradation significantly. The CIP removal in the BC/PMS system was attributed to the common function of the radical pathway dominated by ·OH and SO4-· and the non-radical pathway dominated by 1O2. The CIP degradation pathway mainly included piperazine ring opening and hydroxylation reaction.

The molecular mechanisms of glycosaminoglycan biosynthesis regulating chondrogenesis and endochondral ossification.

Disorders of chondrocyte differentiation and endochondral osteogenesis are major underlying factors in skeletal developmental disorders, including tibial dysplasia (TD), osteoarthritis (OA), chondrodysplasia (ACH), and multiple epiphyseal dysplasia (MED). Understanding the cellular and molecular pathogenesis of these disorders is crucial for addressing orthopedic diseases resulting from impaired glycosaminoglycan synthesis. Glycosaminoglycan is a broad term that refers to the glycan component of proteoglycan macromolecules. It is an essential component of the cartilage extracellular matrix and plays a vital role in various biological processes, including gene transcription, signal transduction, and chondrocyte differentiation. Recent studies have demonstrated that glycosaminoglycan biosynthesis plays a regulatory role in chondrocyte differentiation and endochondral osteogenesis by modulating various growth factors and signaling molecules. For instance, glycosaminoglycan is involved in mediating pathways such as Wnt, TGF-ß, FGF, Ihh-PTHrP, and O-GlcNAc glycosylation, interacting with transcription factors SOX9, BMPs, TGF-ß, and Runx2 to regulate chondrocyte differentiation and endochondral osteogenesis. To propose innovative approaches for addressing orthopedic diseases caused by impaired glycosaminoglycan biosynthesis, we conducted a comprehensive review of the molecular mechanisms underlying chondrocyte glycosaminoglycan biosynthesis, which regulates chondrocyte differentiation and endochondral osteogenesis. Our analysis considers the role of genes, glycoproteins, and associated signaling pathways during chondrogenesis and endochondral ossification.

Machine learning radiomics of magnetic resonance imaging predicts recurrence-free survival after surgery and correlation of LncRNAs in patients with breast cancer: a multicenter cohort study.

BACKGROUND: Several studies have indicated that magnetic resonance imaging radiomics can predict survival in patients with breast cancer, but the potential biological underpinning remains indistinct. Herein, we aim to develop an interpretable deep-learning-based network for classifying recurrence risk and revealing the potential biological mechanisms. METHODS: In this multicenter study, 1113 nonmetastatic invasive breast cancer patients were included, and were divided into the training cohort (n = 698), the validation cohort (n = 171), and the testing cohort (n = 244). The Radiomic DeepSurv Net (RDeepNet) model was constructed using the Cox proportional hazards deep neural network DeepSurv for predicting individual recurrence risk. RNA-sequencing was performed to explore the association between radiomics and tumor microenvironment. Correlation and variance analyses were conducted to examine changes of radiomics among patients with different therapeutic responses and after neoadjuvant chemotherapy. The association and quantitative relation of radiomics and epigenetic molecular characteristics were further analyzed to reveal the mechanisms of radiomics. RESULTS: The RDeepNet model showed a significant association with recurrence-free survival (RFS) (HR 0.03, 95% CI 0.02-0.06, P < 0.001) and achieved AUCs of 0.98, 0.94, and 0.92 for 1-, 2-, and 3-year RFS, respectively. In the validation and testing cohorts, the RDeepNet model could also clarify patients into high- and low-risk groups, and demonstrated AUCs of 0.91 and 0.94 for 3-year RFS, respectively. Radiomic features displayed differential expression between the two risk groups. Furthermore, the generalizability of RDeepNet model was confirmed across different molecular subtypes and patient populations with different therapy regimens (All P < 0.001). The study also identified variations in radiomic features among patients with diverse therapeutic responses and after neoadjuvant chemotherapy. Importantly, a significant correlation between radiomics and long non-coding RNAs (lncRNAs) was discovered. A key lncRNA was found to be noninvasively quantified by a deep learning-based radiomics prediction model with AUCs of 0.79 in the training cohort and 0.77 in the testing cohort. CONCLUSIONS: This study demonstrates that machine learning radiomics of MRI can effectively predict RFS after surgery in patients with breast cancer, and highlights the feasibility of non-invasive quantification of lncRNAs using radiomics, which indicates the potential of radiomics in guiding treatment decisions.

Performance of two-dimensional shear wave elastography for detecting advanced liver fibrosis and cirrhosis in patients with biliary atresia: a systematic review and meta-analysis.

BACKGROUND: Two-dimensional shear wave elastography (2D-SWE) has been proposed for detecting liver fibrosis in biliary atresia. OBJECTIVES: To assess the performance of 2D-SWE for detecting advanced liver fibrosis and cirrhosis in patients with biliary atresia. MATERIALS AND METHODS: Five electronic databases were searched to identify studies investigating the performance of 2D-SWE for diagnosing liver fibrosis in biliary atresia in children. We constructed the summary receiver operating characteristic (SROC) curves of 2D-SWE for detecting advanced liver fibrosis and cirrhosis, and then calculated the area under the SROC curves (AUROCs). RESULTS: Six studies with 470 patients (ages 55 days to 6.6 years) were included. The median correlation coefficient of 2D-SWE with pathological liver fibrosis stages was 0.779 (range: 0.443‒0.813). The summary AUROCs for advanced liver fibrosis and cirrhosis were 0.929 and 0.883, respectively. The summary sensitivity and specificity of 2D-SWE for advanced liver fibrosis were 88% (95% confidence interval [CI]: 80‒94%) and 85% (95% CI: 77‒91%) with I values of 0% and 45.6%, respectively, and for cirrhosis were 80% (95% CI: 72‒87%) and 82% (95% CI: 77‒86%) with I values of 12.9% and 0%, respectively. The diagnostic odds ratio (DOR) of 2D-SWE for advanced liver fibrosis and cirrhosis were 40.3 (95% CI: 18.2‒89.4) and 18.9 (95% CI: 11.2‒31.7), respectively. For preoperative detection of cirrhosis, the pooled AUROC, sensitivity, specificity, and DOR based on the four 2D-SWE studies were 0.877, 79% (95% CI: 71‒86%), 82% (95% CI: 77‒86%), and 17.58 (95% CI: 10.35‒29.85), respectively. CONCLUSIONS: Results show that 2D-SWE has potential as a non-invasive tool for detecting advanced liver fibrosis and cirrhosis in patients with biliary atresia.

Biotin-decorated hollow gold nanoshells for dual-modal imaging-guided NIR-II photothermal and radiosensitizing therapy toward breast cancer.

Radiotherapy (RT) is dominantly used in breast cancer therapy but is facing fierce side effects because of the limited difference between tumor and normal tissues in response to ionizing radiation. Herein, we construct a core-shell nanoparticle of UiO-66-NH2@AuNS. Then the solid gold shell was etched into hollow AuNS (HAuNS) and further modified with biotin-PEG-SH (PEG-bio) to obtain HAuNS@PEG-bio. HAuNS@PEG-bio demonstrates effective near infrared II (NIR-II) region photothermal therapy (PTT) performance, and the increase of temperature at the tumor site promotes the blood circulation to alleviate the hypoxia in the tumor microenvironment (TME). Meanwhile, HAuNS exhibits strong X-ray absorption and deposition ability due to the high atomic coefficient of elemental Au (Z = 79) and hollowed-out structure. Through the dual radiosensitization of the high atomic coefficient of Au and the hypoxia alleviation from PTT of HAuNS, the breast cancer cells could undergo immunogenic cell death (ICD) to activate the immune response. At the in vivo level, HAuNS@PEG-bio performs NIR-II photothermal, radiosensitization, and ICD therapies through cellular targeting, guided by infrared heat and CT imaging. This work highlights that the constructed biotin-decorated hollow gold nanoshell has a promising potential as a diagnostic and treatment integration reagents for the breast cancer.

FMO2 ameliorates nonalcoholic fatty liver disease by suppressing ER-to-Golgi transport of SREBP1.

BACKGROUND AND AIMS: NAFLD comprises a spectrum of liver disorders with the initial abnormal accumulation of lipids in hepatocytes called NAFL, progressing to the more serious NASH in a subset of individuals. Our previous study revealed that global flavin-containing monooxygenase 2 (FMO2) knockout causes higher liver weight in rats. However, the role of FMO2 in NAFLD remains unclear. Herein, we aimed to determine the function and mechanism of FMO2 in liver steatosis and steatohepatitis. APPROACH AND RESULTS: The expression of FMO2 was significantly downregulated in patients with NAFL/NASH and mouse models. Both global and hepatocyte-specific knockout of FMO2 resulted in increased lipogenesis and severe hepatic steatosis, inflammation, and fibrosis, whereas FMO2 overexpression in mice improved NAFL/NASH. RNA sequencing showed that hepatic FMO2 deficiency is associated with impaired lipogenesis in response to metabolic challenges. Mechanistically, FMO2 directly interacts with SREBP1 at amino acids 217-296 competitively with SREBP cleavage-activating protein (SCAP) and inhibits SREBP1 translocation from the endoplasmic reticulum (ER) to the Golgi apparatus and its subsequent activation, thus suppressing de novo lipogenesis (DNL) and improving NAFL/NASH. CONCLUSIONS: In hepatocytes, FMO2 is a novel molecule that protects against the progression of NAFL/NASH independent of enzyme activity. FMO2 impairs lipogenesis in high-fat diet-induced or choline-deficient, methionine-deficient, amino acid-defined high-fat diet-induced steatosis, inflammation, and fibrosis by directly binding to SREBP1 and preventing its organelle translocation and subsequent activation. FMO2 thus is a promising molecule for targeting the activation of SREBP1 and for the treatment of NAFL/NASH.

CD45- erythroid progenitor cells promote lymph node metastasis in gastric cancer by inducing a hybrid epithelial/mesenchymal state in lymphatic endothelial cells.

BACKGROUND AND AIMS: Specific mechanisms of lymph node (LN) metastasis in early-stage gastric cancer (GC) have not been elucidated. The role of anemia, a vital clinical feature of GC, in LN metastasis is also unclear. Since the number of erythroid progenitor cells (EPCs) is increased in chronic anemia, we investigated its association with LN metastasis in GC. METHODS: Flow cytometry and immunofluorescence analyses were performed to sort and study EPCs from the circulation and tumors of patients with stage I-III GC. The effect of these EPCs on the activation of T and B cells and on the functions of lymphatic endothelial cells (LECs) was determined, and their ability to promote LN metastasis was evaluated using a footpad-popliteal LN metastasis model based on two human adenocarcinoma GC cell lines in nude mice. The prognostic value of EPCs was also analyzed. RESULTS: The proportion of CD45- EPCs was higher in the mononuclear cells in the circulation, tumors, and LNs of GC patients with LN metastasis (N+) than in those of GC patients without LN metastasis (N0). In N+ patients, CD45- EPCs were more abundant in metastatic LNs than in non-metastatic LNs. Lymphatic vessel endothelial hyaluronan receptor 1 immunoreactivity in tumors revealed that CD45- EPCs were positively associated with nodal stages and lymph vessel density. Furthermore, CD45- EPCs increased LEC proliferation and migration through their S100A8/A9 heterodimer-induced hybrid epithelial/mesenchymal (E/M) state; however, they did not influence the invasion and tubulogenesis of LECs or T and B cell proliferation. CD45- EPCs promoted LN metastasis in vivo; the S100A8/A9 heterodimer mimicked this phenomenon. Finally, CD45- EPCs predicted the overall and disease-free survival of stage I-III GC patients after radical resection. CONCLUSIONS: The CD45- EPCs accumulated in GC tissues and metastatic LNs and promoted LN metastasis via the S100A8/9-induced hybrid E/M state of LECs, which was the specific mechanism of LN metastasis in the early stages of GC.

Impact of three surgical approaches on the therapeutic efficacy of intraventricular craniopharyngiomas: a single-center retrospective analysis.

This study aimed to investigate the therapeutic efficacy of three different surgical approaches for the treatment of intraventricular craniopharyngiomas (IVCs). The three surgical approaches investigated in this study were the endoscopic endonasal approach (EEA), pterional trans-lamina terminalis approach (PTA), and interhemispheric trans-lamina terminalis approach (ITA). Patient demographics, preoperative symptoms, endocrine and hypothalamic status, tumor characteristics, and surgical outcomes were analyzed and compared among the different surgical groups. A total of 31 patients with IVCs were included in the analysis, with 12 patients in the EEA group, 8 patients in the ITA group, and 11 patients in the PTA group. The mean follow-up time was 39 ± 23 months. Statistical analysis of the data revealed significant differences in the gross total resection (GTR) rate among the three surgical groups (P = 0.033). The GTR rate for the EEA group was 100%, that for the ITA group was 88%, and that for the PTA group was 64%, which was the lowest rate observed. After surgery, only 8.3% of the patients in the EEA group did not experience new postoperative hypopituitarism, while the percentages in the ITA and PTA groups were 75% and 73%, respectively (P = 0.012). Finally, we found that postoperative hypopituitarism may be related to the transection of the pituitary stalk during the operation (P = 0.020). Based on the results of this study, we recommend using the EEA and the ITA instead of the PTA for the surgical resection of IVCs. Furthermore, the appropriate surgical approach should be selected based on the tumor's growth pattern.

High Curvature PEDOT:PSS Transport Layer Toward Enhanced Perovskite Light-Emitting Diodes.

The rapidly developed metal halide perovskite light-emitting diodes (PeLEDs) are considered as a promising candidate for next-generation display and illumination, but the unbalanced charge transport is still a hard-treat case to restrict its efficiency and operational stability. Here, a high curvature PEDOT:PSS transport layer is demonstrated via the self-assembly island-like structures by the incorporation of alkali metal salts. Benefiting from the dielectric confinement effect of the high curvature surface, the modified CsPbBr3 -based PeLEDs present a 2.1 times peak external quantum efficiency (EQE) from 6.75% to 14.23% and a 3.3 times half lifetime (T50 ) from 3.96 to 13.01 h. Besides, the PeLEDs show high luminance up to 44834 cd m-2 . Evidently, this work may provide a deep insight into the structure-activity relationship between the micro-structures at the PEDOT:PSS/perovskite interface and the performance of PeLEDs, and crack the codes for ameliorating the performance of PeLEDs via interfacial micro-structured regulation.

Enhancement of CAR-T cell activity against cholangiocarcinoma by simultaneous knockdown of six inhibitory membrane proteins.

BACKGROUND: Existing treatments for cholangiocarcinoma have poor efficacy. However, chimeric antigen receptor-T (CAR-T) cells are emerging as a potential therapeutic strategy. Solid tumors possess multiple adverse factors in an immunosuppressive microenvironment that impair CAR-T cell infiltration and function. This study aimed to improve the function of CAR-T cells through knock down immune checkpoints and immunosuppressive molecular receptors. METHODS: We evaluated the expression of epidermal growth factor receptor (EGFR) and B7 homolog 3 protein (B7H3) antigens in cholangiocarcinoma tissues using immunohistochemistry and screened specific immune checkpoints in the cholangiocarcinoma microenvironment via flow cytometry. Subsequently, we engineered CAR-T cells targeting EGFR and B7H3 antigens. We simultaneously knocked down immune checkpoints and immunosuppressive molecular receptors in CAR-T cells by constructing two clusters of small hairpin RNAs and evaluated the engineered CAR-T cells for antitumor activity both in vitro, using tumor cell lines and cholangiocarcinoma organoid models, and in vivo, using humanized mouse models. RESULTS: We observed high expression of EGFR and B7H3 antigens in cholangiocarcinoma tissues. EGFR-CAR-T and B7H3-CAR-T cells demonstrated specific anti-tumor activity. We found an abundance of programmed cell death protein 1 (PD-1), T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and T cell immunoglobulin and ITIM domain (Tigit) on infiltrated CD8+ T cells in the cholangiocarcinoma microenvironment. We then decreased the expression of these 3 proteins on the surface of CAR-T cells, named PTG-scFV-CAR-T cells. Furthermore, we knocked-down the expression of transforming growth factor beta receptor (TGFßR), interleukin-10 receptor (IL-10R), and interleukin-6 receptor (IL-6R) of PTG-scFV-CAR-T cells. Those cells, named PTG-T16R-scFV-CAR-T cells, potently killed tumor cells in vitro and promoted apoptosis of tumor cells in a cholangiocarcinoma organoid model. Finally, the PTG-T16R-scFv-CAR-T cells showed greater inhibitory effect on tumor growth in vivo, and were superior in prolonging the survival of mice. CONCLUSIONS: Our results revealed that PTG-T16R-scFV-CAR-T cells with knockdown of sextuplet inhibitory molecules exhibited strong immunity against cholangiocarcinoma and long-term efficacy both in vitro and in vivo. This strategy provides an effective and personalized immune cell therapy against cholangiocarcinoma.

Identification of the potential TLR7 antagonists by virtual screening and experimental validation.

Toll-like receptor 7 (TLR7) is highly expressed in dendritic cells (DCs) and B cells, and its aberrant activation can promote disease progression in systemic lupus erythematosus (SLE). We utilized structure-based virtual screening and experimental validation to screen natural products from TargetMol for potential TLR7 antagonists. Our results of molecular docking and molecular dynamics simulation showed that Mogroside V (MV) strongly interacted with TLR7, with stable open-TLR7-MV and close-TLR7-MV complexes. Furthermore, in vitro experiments demonstrated that MV significantly inhibited B cell differentiation in a concentration-dependent manner. In addition to TLR7, we also revealed a strong interaction of MV with all TLRs, including TLR4. The above results suggested that MV might be a potential TLR7 antagonist deserving of further study.

Kinetically and thermodynamically controlled one-pot growth of gold nanoshells with NIR-II absorption for multimodal imaging-guided photothermal therapy.

Since the successful clinical trial of AuroShell for photothermal therapy, there is currently intense interest in developing gold-based core-shell structures with near-infrared (NIR) absorption ranging from NIR-I (650-900 nm) to NIR-II (900-1700 nm). Here, we propose a seed-mediated successive growth approach to produce gold nanoshells on the surface of the nanoscale metal-organic framework (NMOF) of UiO-66-NH2 (UiO = the University of Oslo) in one pot. The key to this strategy is to modulate the proportion of the formaldehyde (reductant) and its regulator / oxidative product of formic acid to harness the particle nucleation and growth rate within the same system. The gold nanoshells propagate through a well-oriented and controllable diffusion growth pattern (points → facets → octahedron), which has not been identified. Most strikingly, the gold nanoshells prepared hereby exhibit an exceedingly broad and strong absorption in NIR-II with a peak beyond 1300 nm and outstanding photothermal conversion efficiency of 74.0%. Owing to such superior performance, these gold nanoshells show promising outcomes in photoacoustic (PA), computed tomography (CT), and photothermal imaging-guided photothermal therapy (PTT) for breast cancer, as demonstrated both in vitro and in vivo.

Immune gene patterns and characterization of the tumor immune microenvironment associated with cancer immunotherapy efficacy.

Although immunotherapy has revolutionized cancer management, most patients do not derive benefits from it. Aiming to explore an appropriate strategy for immunotherapy efficacy prediction, we collected 6251 patients' transcriptome data from multicohort population and analyzed the data using a machine learning algorithm. In this study, we found that patients from three immune gene clusters had different overall survival when treated with immunotherapy (P < 0.001), and that these clusters had differential states of hypoxia scores and metabolism functions. The immune gene score showed good immunotherapy efficacy prediction (AUC was 0.737 at 20 months), which was well validated. The immune gene score, tumor mutation burden, and long non-coding RNA score were further combined to build a tumor immune microenvironment signature, which correlated more strongly with overall survival (AUC, 0.814 at 20 months) than when using a single variable. Thus, we recommend using the characterization of the tumor immune microenvironment associated with immunotherapy efficacy via a multi-omics analysis of cancer.

Efficiency and mechanism of the degradation of ciprofloxacin by the oxidation of peroxymonosulfate under the catalysis of a Fe3O4/N co-doped sludge biochar.

A novel and recyclable composite material, Fe3O4/N co-doped sludge biochar (FNBC), was developed from original sludge biochar (BC) and found to have excellent stability and superior catalytic capacity during the ciprofloxacin (CIP) degradation under the action of peroxymonosulfate (PMS). In the FNBC/PMS system, an approximately complete removal of CIP was achieved within 60 min under the condition of 1.0 g/L FNBC, 3.0 mM PMS, and 20 mg/L CIP, which was about 2.08 times of that in BC/PMS system (48.01%). Besides, FNBC/PMS system could effectively remove CIP under the influence of wide pH (2.0-10.0) or inorganic ions compared with BC/PMS system. Moreover, it was found that there were radical produced under the effect of Fe element, defects, functional groups, pyridinic N and pyrrolic N and non-radical caused by graphitic N, carbon atoms next to the iron atoms and better adsorption capacity in the FNBC/PMS system. It was observed that the contribution of hydroxyl radical (•OH), sulfate radical (SO4•-) and singlet oxygen (1O2), which were the main reactive oxygen species, during the CIP degradation, were 75.80%, 11.49% and 10.26%, respectively. Furthermore, total organic carbon (TOC) variation was analyzed and the degradation pathway of CIP was speculated. The application of this material could combine the recycling of sludge with the effective degradation of refractory organic pollutant, providing an environmentally friendly and economic method.