ß-Glucuronidase-triggered reaction for fluorometric and colorimetric dual-mode assay based on the in situ formation of silicon nanoparticles.

BACKGROUND: ß-Glucuronidase (GUS) is considered as a promising biomarker for primary cancer. Thus, the reliable detection of GUS has great practical significance in the discovery and diagnosis of cancer. Compared with traditional organic probes, silicon nanoparticles (Si NPs) have emerged as robust optical nanomaterials due to their facile preparation, superior photobleaching resistance and excellent biocompatibility. However, most nanomaterials-based methods only output a single signal which is easily influenced by external factors in complex systems. Hence, developing nanomaterial-based multi-signal optical assays for highly sensitive GUS determination is still urgently desired. RESULTS: In this study, we developed a simple and efficient one-step method for the in situ preparation of yellow color and yellow-green fluorescent Si NPs. This was achieved by combining 3-[2-(2-aminoethylamino) ethylamino] propyl-trimethoxysilane with p-aminophenol (AP) in an aqueous solution. The obtained Si NPs showed yellow-green fluorescence at 535 nm when excited at 380 nm, while also exhibiting an absorption peak at a wavelength of 490 nm. Taking inspiration from the easy synthesis step regulated by AP, which is generated through the hydrolysis of 4-aminophenyl ß-D-glucuronide catalyzed by GUS, we constructed a direct fluorometric and colorimetric dual-mode method to measure GUS activity. The developed fluorometric and colorimetric sensing platform showed high sensitivity and accuracy with detection limits for GUS determination as low as 0.0093 and 0.081 U/L, respectively. SIGNIFICANCE: This study provides a facile dual-mode fluorometric and colorimetric approach for determination of GUS activity based on novel Si NPs for the first time. This designed sensing approach was successfully employed for the quantification of GUS in human serum samples and screening of GUS inhibitors, indicating the feasibility and potential applications in clinical cancer diagnosis and anti-cancer drug discovery.

Near-Infrared Dual-Modal Sensing of Force and Temperature in Total Knee Replacement Using Mechanoluminescent Phosphor of Sr3 Sn2 O7 : Nd, Yb.

Knee replacement surgery confronts challenges including patient dissatisfaction and the necessity for secondary procedures. A key requirement lies in dual-modal measurement of force and temperature of artificial joints during postoperative monitoring. Here, a novel non-toxic near-infrared (NIR) phosphor Sr3 Sn2 O7 :Nd, Yb, is designed to realize the dual-modal measurement. The strategy is to entail phonon-assisted upconversion luminescence (UCL) and trap-controlled mechanoluminescence (ML) in a single phosphor well within the NIR biological transmission window. The phosphor is embedded in medical bone cement forming a smart joint in total knee replacements illustrated as a proof-of-concept. The sensing device can be charged in vitro by a commercial X-ray source with a safe dose rate for ML, and excited by a low power 980 nm laser for UCL. It attains impressive force and temperature sensing capabilities, exhibiting a force resolution of 0.5% per 10 N, force detection threshold of 15 N, and a relative temperature sensitive of up to 1.3% K-1 at 309 K. The stability against humidity and thermal shock together with the robustness of the device are attested. This work introduces a novel methodological paradigm, paving the way for innovative research to enhance the functionality of artificial tissues and joints in living organisms.

HSP90a promotes the resistance to oxaliplatin in HCC through regulating IDH1-induced cell competition.

Though burgeoning research manifests that cell competition, an essential selection and quality control mechanism for maintaining tissue or organ growth and homeostasis in multicellular organisms, is closely related to tumorigenesis and development, the mechanism of cell competition associated with tumor drug resistance remains elusive. In the study, we uncovered that oxaliplatin-resistant hepatocellular carcinoma (HCC) cells exhibit a pronounced competitive advantage against their sensitive counterparts, which is related to lipid takeover of resistant cells from sensitive cells. Of note, such lipid takeover is dependent on the existence of isocitrate dehydrogenase 1 (IDH1) in resistant HCC cells. Mechanistically, IDH1 activity is regulated by heat shock protein 90 alpha (HSP90α) through binding with each other, which orchestrates the expressions of lipid metabolic enzymes and lipid accumulation in resistant HCC cells. Our results suggest that HCC cell competition-driven chemoresistance can be regulated by HSP90α/IDH1-mediated lipid metabolism, which may serve as a promising target for overcoming drug resistance in HCC.

Identification of Fasudil as a collaborator to promote the anti-tumor effect of lenvatinib in hepatocellular carcinoma by inhibiting GLI2-mediated hedgehog signaling pathway.

Lenvatinib is a frontline tyrosine kinase inhibitor for patients with advanced hepatocellular carcinoma (HCC). However, just 25% of patients benefit from the treatment, and acquired resistance always develops. To date, there are neither effective medications to combat lenvatinib resistance nor accurate markers that might predict how well a patient would respond to the lenvatinib treatment. Thus, novel strategies to recognize and deal with lenvatinib resistance are desperately needed. In the current study, a robust Lenvatinib Resistance index (LRi) model to predict lenvatinib response status in HCC was first established. Subsequently, five candidate drugs (Mercaptopurine, AACOCF3, NU1025, Fasudil, and Exisulind) that were capable of reversing lenvatinib resistance signature were initially selected by performing the connectivity map (CMap) analysis, and fasudil finally stood out by conducting a series of cellular functional assays in vitro and xenograft mouse model. Transcriptomics revealed that the co-administration of lenvatinib and fasudil overcame lenvatinib resistance by remodeling the hedgehog signaling pathway. Mechanistically, the feedback activation of EGFR by lenvatinib led to the activation of the GLI2-ABCC1 pathway, which supported the HCC cell's survival and proliferation. Notably, co-administration of lenvatinib and fasudil significantly inhibited IHH, the upstream switch of the hedgehog pathway, to counteract GLI2 activation and finally enhance the effectiveness of lenvatinib. These findings elucidated a novel EGFR-mediated mechanism of lenvatinib resistance and provided a practical approach to overcoming drug resistance in HCC through meaningful drug repurposing strategies.

Small Extracellular Vesicles Derived from Altered Peptide Ligand-Loaded Dendritic Cell Act as A Therapeutic Vaccine for Spinal Cord Injury Through Eliciting CD4+ T cell-Mediated Neuroprotective Immunity.

The balance among different CD4+ T cell subsets is crucial for repairing the injured spinal cord. Dendritic cell (DC)-derived small extracellular vesicles (DsEVs) effectively activate T-cell immunity. Altered peptide ligands (APLs), derived from myelin basic protein (MBP), have been shown to affect CD4+ T cell subsets and reduce neuroinflammation levels. However, the application of APLs is challenging because of their poor stability and associated side effects. Herein, it is demonstrate that DsEVs can act as carriers for APL MBP87-99 A91 (A91-DsEVs) to induce the activation of 2 helper T (Th2) and regulatory T (Treg) cells for spinal cord injury (SCI) in mice. These stimulated CD4+ T cells can efficiently "home" to the lesion area and establish a beneficial microenvironment through inducing the activation of M2 macrophages/microglia, inhibiting the expression of inflammatory cytokines, and increasing the release of neurotrophic factors. The microenvironment mediated by A91-DsEVs may enhance axon regrowth, protect neurons, and promote remyelination, which may support the recovery of motor function in the SCI model mice. In conclusion, using A91-DsEVs as a therapeutic vaccine may help induce neuroprotective immunity in the treatment of SCI.

Multi-Slice CT Features Predict Pathological Risk Classification in Gastric Stromal Tumors Larger Than 2 cm: A Retrospective Study.

BACKGROUND: The Armed Forces Institute of Pathology (AFIP) had higher accuracy and reliability in prognostic assessment and treatment strategies for patients with gastric stromal tumors (GSTs). The AFIP classification is frequently used in clinical applications. But the risk classification is only available for patients who are previously untreated and received complete resection. We aimed to investigate the feasibility of multi-slice MSCT features of GSTs in predicting AFIP risk classification preoperatively. METHODS: The clinical data and MSCT features of 424 patients with solitary GSTs were retrospectively reviewed. According to pathological AFIP risk criteria, 424 GSTs were divided into a low-risk group (n = 282), a moderate-risk group (n = 72), and a high-risk group (n = 70). The clinical data and MSCT features of GSTs were compared among the three groups. Those variables (p < 0.05) in the univariate analysis were included in the multivariate analysis. The nomogram was created using the rms package. RESULTS: We found significant differences in the tumor location, morphology, necrosis, ulceration, growth pattern, feeding artery, vascular-like enhancement, fat-positive signs around GSTs, CT value in the venous phase, CT value increment in the venous phase, longest diameter, and maximum short diameter (all p < 0.05). Two nomogram models were successfully constructed to predict the risk of GSTs. Low- vs. high-risk group: the independent risk factors of high-risk GSTs included the location, ulceration, and longest diameter. The area under the receiver operating characteristic curve (AUC) of the prediction model was 0.911 (95% CI: 0.872-0.951), and the sensitivity and specificity were 80.0% and 89.0%, respectively. Moderate- vs. high-risk group: the morphology, necrosis, and feeding artery were independent risk factors of a high risk of GSTs, with an AUC value of 0.826 (95% CI: 0.759-0.893), and the sensitivity and specificity were 85.7% and 70.8%, respectively. CONCLUSIONS: The MSCT features of GSTs and the nomogram model have great practical value in predicting pathological AFIP risk classification between high-risk and non-high-risk groups before surgery.

Electrothermal Water-Gas Shift Reaction at Room Temperature with a Silicomolybdate-Based Palladium Single-Atom Catalyst.

The water-gas shift (WGS) reaction is often conducted at elevated temperature and requires energy-intensive separation of hydrogen (H2 ) from methane (CH4 ), carbon dioxide (CO2 ), and residual carbon monoxide (CO). Designing processes to decouple CO oxidation and H2 production provides an alternative strategy to obtain high-purity H2 streams. We report an electrothermal WGS process combining thermal oxidation of CO on a silicomolybdic acid (SMA)-supported Pd single-atom catalyst (Pd1 /CsSMA) and electrocatalytic H2 evolution. The two half-reactions are coupled through phosphomolybdic acid (PMA) as a redox mediator at a moderate anodic potential of 0.6 V (versus Ag/AgCl). Under optimized conditions, our catalyst exhibited a TOF of 1.2 s-1 with turnover numbers above 40 000 mol CO 2 ${{_{{\rm CO}{_{2}}}}}$ molPd -1 achieving stable H2 production with a purity consistently exceeding 99.99 %.

HSF1 is involved in immunotherapeutic response through regulating APOJ/STAT3-mediated PD-L1 expression in hepatocellular carcinoma.

Hepatocellular cancer (HCC) is a serious illness with high prevalence and mortality throughout the whole world. For advanced HCC, immunotherapy is somewhat impactful and encouraging. Nevertheless, a substantial proportion of patients with advanced HCC are still unable to achieve a durable response, owing to heterogeneity from clonal variability and differential expression of the PD-1/PD-L1 axis. Recently, heat shock factor 1 (HSF1) is recognized as an important component of tumor immunotherapeutic response as well as related to PD-L1 expression in cancer. However, the mechanism of HSF1 regulating PD-L1 in cancer, especially in HCC, is still not fully clear. In this study, we observed the significantly positive correlation between HSF1 expression and PD-L1 expression in HCC samples; meanwhile combination expressions of HSF1 and PD-L1 served as the signature for predicting prognosis of patients with HCC. Mechanistically, HSF1 upregulated PD-L1 expression by inducing APOJ expression and activating STAT3 signaling pathway in HCC. In addition, we explored further the potential values of targeting the HSF1-APOJ-STAT3 axis against CD8+ T cells-mediated cancer cells cytotoxicity. These findings unveiled the important involvement of HSF1 in regulating PD-L1 expression in HCC as well as provided a novel invention component for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade.

Nucleotide sugar transporter SLC35A2 is involved in promoting hepatocellular carcinoma metastasis by regulating cellular glycosylation.

PURPOSE: Recently, aberrant glycosylation has been recognized to be relate to malignant behaviors of cancer and outcomes of patients with various cancers. SLC35A2 plays an indispensable role on glycosylation as a nucleotide sugar transporter. However, effects of SLC35A2 on malignant behaviors of cancer cells and alteration of cancer cells surface glycosylation profiles are still not fully understood, particularly in hepatocellular carcinoma (HCC). Hence, from a glycosylation perspective, we investigated the effects of SLC35A2 on metastatic behaviors of HCC cells. METHODS: SLC35A2 expression in clinical samples and HCC cells was examined by immunohistochemical staining or Western blot/quantitative PCR and was regulated by RNA interference or vectors-mediated transfection. Effects of SLC35A2 expression alteration on metastatic behaviors and membrane glycan profile of HCC cells were observed by using respectively invasion, migration, cell adhesion assay, in vivo lung metastatic nude mouse model and lectins microarray. Co-location among proteins in HCC cells was observed by fluorescence microscope and detected by an in vitro co-immunoprecipitation assay. RESULTS: SLC35A2 was upregulated in HCC tissues, and is associated with poor prognosis of HCC patients. SLC35A2 expression alteration significantly affected the invasion, adhesion, metastasis and membrane glycan profile and led to the dysregulated expressions or glycosylation of cell adhesion-related molecules in HCC cells. Mechanistically, the maintenance of SLC35A2 activity is critical for the recruitment of the key galactosyltransferase B4GalT1, which is responsible for complex glycoconjugate and lactose biosynthesis, to Golgi apparatus in HCC cells. CONCLUSION: SLC35A2 plays important roles in promoting HCC metastasis by regulating cellular glycosylation modification and inducing the cell adhesive ability of HCC cells.

Multislice Computed Tomographic Manifestation of Transient Hepatic Attenuation Difference in the Left Lobe of the Liver: A Retrospective Study.

INTRODUCTION: Transient hepatic attenuation differences (THAD) are areas of high parenchymal enhancement observed during the hepatic arterial phase on computed tomography (CT). THAD in the left lobe of the liver can lead to surgical complications. METHODS: A retrospective study was conducted on patients who underwent multislice computed tomography (MSCT) examination of the upper abdomen to understand the morphology, distribution, and causes of THAD and their correlation with hepatic artery variation. RESULTS: Among 179 cases, 65 and 114 belonged to diseased and normal groups, respectively. THAD as observed in MSCT demonstrated various shapes: lobe/segment (127 cases; 70.9%), irregular sheet (31; 17.3%), strip shape (9; 5.02%), arc/semicircle (7; 3.9%), and segment + flaky (5; 2.79%). THAD were found to be caused by liver tumor (32.3%), hepatic inflammatory lesions (6.15%), biliary tract diseases (13.8%), perihepatic disease compression (9.23%), portal vein obstructive disease (1.53%), and lesion in left hepatic lobe with hepatic artery variation (29.2%). THAD exhibited variation in distribution in the left lobe of the liver. Among 114 cases, THAD in 18 (15.7%) cases were observed in the S2 segment, six (5.26%) in the S3 segment, and 90 (78.9%) in multiple segments of the liver, that is, 50 cases in S2 and S3 segments and 40 cases in S2, S3, and S4 segments. The hepatic artery of 179 cases was of various types based on Hiatt classification: 57 cases of Hiatt I (31%), 65 cases of Hiatt II (37%), 11 cases of Hiatt III (6%), 17 cases of Hiatt IV (10%), 7 cases of Hiatt V (4%), 12 cases of large left hepatic artery (7%), 6 cases of right hepatic artery originating from the celiac trunk (3%), and 4 cases (2%) of superior mesenteric artery originating from the celiac trunk. CONCLUSION: THAD can occur as a result of specific pathological causes and hence should be considered as a diagnostic sign in liver pathologies.