Thermoelectric-Feedback Nanocomposite Hydrogel for Temperature-Synchronized Monitoring and Regulation in Accurate Photothermal Therapy.

Photothermal therapy (PTT) is a promising approach for tumor ablation and cancer treatment. However, controlling the therapeutic temperature during treatment remains challenging, and imprecise thermal regulation can harm adjacent healthy tissues, reduce therapeutic accuracy, and promote the thermotolerance of cellular phenotypes, potentially leading to tumor invasion and recurrence. Although existing methods provide basic temperature control by adjusting irradiation power and photothermal agent dosing, they lack real-time temperature monitoring and feedback control capabilities, underscoring the urgent need for more integrated and precise PTT systems. In this context, an innovative photothermoelectric (PTE) cobalt-infused chitosan (CS) nanocomposite hydrogel (PTE-Co@CS) is developed for precise temperature-regulated PTT, exhibiting desirable mechanical properties and exceptional biocompatibility. Enhanced by embedded nanoparticles, PTE-Co@CS demonstrates superior photothermal conversion efficiency compared with existing methods, while also featuring thermoelectric responsiveness and increased sensitivity to photostimuli. Its advantageous PTE response characteristics ensure a linear correlation between temperature shifts and resistance changes (e.g., R2 = 0.99919 at 0.5 W cm⁻2), enabling synchronized qualitative and quantitative control of PTT temperature through electrical signal monitoring. This allows for real-time monitoring and regulation during PTT, effectively addressing the issue of uncontrollable temperatures and improving therapeutic efficacy.

Tumor growth manifested in two-fifths of low-risk papillary thyroid microcarcinoma patients during active surveillance: data from a tertiary center in China.

Purpose: To assess tumor growth using tumor doubling rate (TDR) during active surveillance (AS) in China. Methods: Between January 2016 and June 2020, a total of 219 patients with low-risk papillary thyroid microcarcinoma (PTMC) (aged 23-75 years) were consecutively enrolled in the AS program. Results: Four sections of TDR, >0.5, 0.1~0.5, -0.1~0.1 and <-0.1, corresponded with four categories of tumor volume kinetics: rapid growth, slow growth, stable, and decreased size. We found that 10.5% of PTMCs exhibited rapid growth, 33.33% exhibited slow growth, 26.48% were stable, and 29.68% decreased in size. Tumor growth was associated with two factors: age and volume of PTMC at diagnosis. 85.72% of elderly patients (≥ 61 years old) had tumors that remained stable or even shrank and rapidly growing tumors were not found in them. When the volume was small (≤14.13 mm3), the proportion of rapid growth was high (41.67%), whereas when the volume was large (> 179.5 mm3), the proportion of non-growth was 68.75%. Conclusion: TDR may be a better metric for evaluating tumor growth in observational PTMCs. A certain proportion of PTMCs grow during the period of AS and tumor growth was associated with age and volume of PTMC at initial diagnosis. Therefore, how to block tumor growth during the AS period, especially for young patients and patients with early-stage PTMC (size ≤ 5 mm), will be a new challenge.

Molecular mechanism of miR-203a targeting Runx2 to regulate thiram induced-chondrocyte development.

Thiram is a kind of organic compound, which is commonly used for sterilization, insecticidal and deodorization in daily life. Its toxicology has been broadly studied. Recently, more and more microRNAs have been shown to participate in the regulation of cartilage development. However, the potential mechanism by which microRNA regulates chondrocyte growth is still unclear. Our experiments have demonstrated that thiram can hamper chondrocytes development and cause a significant increase in miR-203a content in vitro and in vivo trials. miR-203a mimic significantly decrease in mRNA and protein expression of Wnt4, Runx2, COL2A1, ß-catenin and ALP, and significantly enhance the mRNA and protein levels of GSK-3ß. It has been observed that overexpression of miR-203a hindered chondrocytes development. In addition, Runx2 was confirmed to be a direct target of miR-203a by dual luciferase report gene assay. Transfection of si-Runx2 into chondrocytes reveals that significant downregulation of genes is associated with cartilage development. Overall, these results suggest that overexpression of miR-203a inhibits the expression of Runx2. These findings are conducive to elucidate the mechanism of chondrocytes dysplasia induced by thiram and provide new research ideas for the toxicology of thiram.

Tumor microenvironment-activatable nanocatalysts with chemodynamic therapy and enhanced autophagy for specific treatment of oral squamous cell carcinoma.

Adjuvant therapy following surgery is imperative for enhancing the prognosis of patients with oral squamous cell carcinoma (OSCC) in the clinical setting. Nevertheless, challenges such as treatment resistance mediated by the tumor microenvironment (TME), systemic toxicity, and adverse side effects hinder the effectiveness of conventional adjuvant therapy. In this context, we introduce a novel nanocatalyst denoted as MnO2-x@HA-CCM (MnHA@CCM NC) designed specifically for treating OSCC. This nanocatalyst exerts targeted anti-tumor effects through TME-activatable chemodynamic therapy (CDT) and tumoricidal autophagy. The MnHA@CCM NCs exploit the biocompatibility of hyaluronic acid (HA) coating and the homologous targeting effect of cancer cell membrane (CCM) camouflage, ensuring safe in vivo delivery and specific accumulation at tumor sites. Following intracellular uptake, Fenton-like Mn2+ is generated by consuming glutathione (GSH) within the TME. Subsequently, Mn2+ catalyzes the overproduced H2O2 to generate reactive oxygen species (ROS), inducing cell apoptosis through mitochondrial damage. Additionally, phagocytized NCs and the resultant ROS accumulation in tumor cells elevate the autophagy flux, leading to autophagosome overload and consequent tumoricidal autophagy. Notably, normal cells without TME-catalytic CDT undergo mild protective autophagy to rebalance the stimulation of NCs. As a result, the TME-activatable MnHA@CCM NCs demonstrate a therapeutic efficacy in inhibiting cancer cell growth both in vitro and in vivo. This study presents a targeted treatment strategy for OSCC tumors while sparing normal cells, offering a potential alternative in the realm of adjuvant therapy.

Progressions of the correlation between lipid metabolism and immune infiltration characteristics in gastric cancer and identification of BCHE as a potential biomarker.

Background: Globally, gastric cancer (GC) is a category of prevalent malignant tumors. Its high occurrence and fatality rates represent a severe threat to public health. According to recent research, lipid metabolism (LM) reprogramming impacts immune cells' ordinary function and is critical for the onset and development of cancer. Consequently, the article conducted a sophisticated bioinformatics analysis to explore the potential connection between LM and GC. Methods: We first undertook a differential analysis of the TCGA queue to recognize lipid metabolism-related genes (LRGs) that are differentially expressed. Subsequently, we utilized the LASSO and Cox regression analyses to create a predictive signature and validated it with the GSE15459 cohort. Furthermore, we examined somatic mutations, immune checkpoints, tumor immune dysfunction and exclusion (TIDE), and drug sensitivity analyses to forecast the signature's immunotherapy responses. Results: Kaplan-Meier (K-M) curves exhibited considerably longer OS and PFS (p<0.001) of the low-risk (LR) group. PCA analysis and ROC curves evaluated the model's predictive efficacy. Additionally, GSEA analysis demonstrated that a multitude of carcinogenic and matrix-related pathways were much in the high-risk (HR) group. We then developed a nomogram to enhance its clinical practicality, and we quantitatively analyzed tumor-infiltrating immune cells (TIICs) using the CIBERSORT and ssGSEA algorithms. The low-risk group has a lower likelihood of immune escape and more effective in chemotherapy and immunotherapy. Eventually, we selected BCHE as a potential biomarker for further research and validated its expression. Next, we conducted a series of cell experiments (including CCK-8 assay, Colony formation assay, wound healing assay and Transwell assays) to prove the impact of BCHE on gastric cancer biological behavior. Discussion: Our research illustrated the possible consequences of lipid metabolism in GC, and we identified BCHE as a potential therapeutic target for GC. The LRG-based signature could independently forecast the outcome of GC patients and guide personalized therapy.

Redox-Activatable Magnetic Nanoarchitectonics for Self-Enhanced Tumor Imaging and Synergistic Photothermal-Chemodynamic Therapy.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy of the head and neck region associated with high recurrence rates and poor prognosis under current diagnostic and treatment methods. The development of nanomaterials that can improve diagnostic accuracy and therapeutic efficacy is of great importance for OSCC. In this study, a redox-activatable nanoarchitectonics is designed via the construction of dual-valence cobalt oxide (DV-CO) nanospheres, which can serve as a contrast agent for magnetic resonance (MR) imaging, and exhibit enhanced transverse and longitudinal relaxivities through the release and redox of Co3+ /Co2+ in an acidic condition with glutathione (GSH), resulting in self-enhanced T1 /T2 -weighted MR contrast. Moreover, DV-CO demonstrates properties of intracellular GSH-depletion and hydroxyl radicals (•OH) generation through a Fenton-like reaction, enabling strengthened chemodynamic (CD) effect. Additionally, DV-CO displays efficient near-infrared laser-induced photothermal (PT) effect, thereby exhibiting synergistic PT-CD therapy for suppressing OSCC tumor cells. It further investigates the tumor-specific self-enhanced MR imaging of DV-CO both in subcutaneous and orthotopic OSCC mouse models, and demonstrate the therapeutic effects of DV-CO in orthotopic OSCC mouse models. Overall, the in vitro and in vivo findings highlight the excellent theranositc potentials of DV-CO for OSCC and offer new prospects for future advancement of nanomaterials.

Global research trends on B7-H3 for cancer immunotherapy: A bibliometric analysis (2012-2022).

Immunotherapy has revolutionized cancer treatment. B7-H3 is a promising target for cancer immunotherapy (CI). The present study aimed to utilize bibliometric methods to assess the current research status and explore future trends in the use of B7-H3 for CI. We collected publications related to B7-H3/CI from the Clarivate Web of Science Core Collection database. VOSviewer, Microsoft Excel, the bibliometrix R package, and an online platform were used to conduct qualitative and visualized analyses of the literature. A total of 555 papers were analyzed, revealing a significant increase in annual publications since 2018. The most productive countries were China and the USA, and the leading institutions were Soochow University and Sichuan University. Zang and Ferrone were the most popular authors. Among the journals, Frontiers in Immunology had the highest number of papers, whereas Clinical Cancer Research was the most influential. Historical citation analysis reveals the development of B7-H3/CI. Top-cited papers and keyword analyses were performed to highlight current hotspots in the domain. Using cluster analysis, we classified all keywords into four clusters: "immunotherapy," "co-stimulatory molecule," "B7 family," and "PD-L1." Finally, Trends analysis suggested that future research might focus on "chimeric antigen receptor," "pathways," and "targeting B7-H3." This is the first bibliometric crosstalk analysis between B7-H3 and CI. Our study illustrates that the topic of B7-H3/CI is very popular and has great clinical implications and that the number of correlative publications will continue to increase. B7-H3-based CI may lead to new research trends.

Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis.

BACKGROUND: Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS: Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS: Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-ß/Smad expression, then promoted the development of GC. CONCLUSIONS: Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-ß/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

A novel 5-gene prognostic signature to improve risk stratification of cytogenetically normal acute myeloid leukemia.

PURPOSE: Prognostic prediction is a challenging task in cytogenetically normal acute myeloid leukemia (CN-AML) patients. In this study, we aimed at developing a novel prognostic signature to predict and stratify the survival of CN-AML patients. METHODS: Using a training dataset (GSE12417), 5-gene prognostic signature was established to predict survival of CN-AML patients. The prognostic performance of this prognostic signature was further validated in testing dataset (TCGA CN-AML cohort) and validation dataset (GSE6891 CN-AML cohort). RESULTS: In training, testing and validation datasets, the increased 5-gene risk score was significantly related with inferior overall survival (OS) of patients, and the area under the receiver operating characteristic curve (AUC) demonstrated that our prognostic signature had overall prediction accuracy. The excellent prognostic value of the 5-gene prognostic signature was also supported by the comparison with three previously proposed prognostic models. For the intermediate-risk CN-AML patients and the CN-AML patients with FLT3 or NPM1 mutation, our model could also well dichotomize them into two subgroups with distinct prognosis. Multivariate analysis demonstrated that 5-gene risk score was the only independent risk factor in TCGA CN-AML cohort. Nomogram including the 5-gene risk score performed well in predicting 1-year, 2-year and 3-year OS. CONCLUSION: In summary, our novel 5-gene prognostic signature facilitated the improvement in risk stratification of CN-AML patients.

Role of Fibrinogen in Type-2 Diabetes Mellitus with Diabetic Neuropathy and its Preliminary Mechanism.

INTRODUCTION: Diabetic peripheral neuropathy (DN) is the most common complication of type 2 diabetes mellitus (T2DM). OBJECTIVE: This study aimed to explore the role of fibrinogen (FIB) in T2DM neuropathy and its preliminary mechanism. METHODS: Ten male Sprague-Dawley rats were divided into a normal control group (NC group) and a T2DM neuropathy model group (DN group). The DN group was given a high-energy diet and streptozotocin, while the NC group was given a normal diet and a citric acid buffer. The expression levels of related proteins were analysed. RESULTS: Electrophysiology: Compared with the NC group, the conduction latency of the somatosensory-evoked potential and nerve conduction velocity was prolonged in the DN group, while the motor nerve action potential was decreased. As seen under a light microscope, the peripheral nerve fibres in the DN group were swollen, and the nerve fibres in the posterior funiculus of the spinal cord were loose or missing. Moreover, as seen under an electron microscope, the peripheral nerve demyelination of the DN group was severe, with microvascular blood coagulation, luminal stenosis, and collapse. Compared with the NC group, in the DN group, the expression of FIB was positively correlated with the expression of both ionised calcium-binding adaptor molecule-1 and glial fibrillary acidic protein. Compared with the NC group, in the DN group, the expression of platelet/endothelial cell adhesion molecule-1 and B-cell lymphoma 2 was negatively correlated. CONCLUSION: The increased concentration of FIB may be the cause of neuropathy, and its mechanism may be related to its promotion of inflammatory response, blood coagulation, and vascular stenosis.

Potential effective diagnostic biomarker in patients with primary and metastatic small intestinal neuroendocrine tumors.

Background: Small intestinal neuroendocrine tumors (SI-NETs) are the most common malignant tumors of the small intestine, with many patients presenting with metastases and their incidence increasing. We aimed to find effective diagnostic biomarkers for patients with primary and metastatic SI-NETs that could be applied for clinical diagnosis. Methods: We downloaded GSE65286 (training set) and GSE98894 (test set) from the GEO database and performed differential gene expression analysis to obtain differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs). The functions and pathways involved in these genes were further explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. In addition, a global regulatory network involving dysregulated genes in SI-NETs was constructed based on RNAInter and TRRUST v2 databases, and the diagnostic power of hub genes was identified by receiver operating characteristic curve (ROC). Results: A total of 2,969 DEGs and DElncRNAs were obtained in the training set. Enrichment analysis revealed that biological processes (BPs) and KEGG pathways were mainly associated with cancer. Based on gene set enrichment analysis (GSEA), we obtained five BPs (cytokinesis, iron ion homeostasis, mucopolysaccharide metabolic process, platelet degranulation and triglyceride metabolic process) and one KEGG pathway (ppar signaling pathway). In addition, the core set of dysregulated genes obtained included MYL9, ITGV8, FGF2, FZD7, and FLNC. The hub genes were upregulated in patients with primary SI-NETs compared to patients with metastatic SI-NETs, which is consistent with the training set. Significantly, the results of ROC analysis showed that the diagnostic power of the hub genes was strong in both the training and test sets. Conclusion: In summary, we constructed a global regulatory network in SI-NETs. In addition, we obtained the hub genes including MYL9, ITGV8, FGF2, FZD7, and FLNC, which may be useful for the diagnosis of patients with primary and metastatic SI-NETs.

A biomimetic nanoplatform for customized photothermal therapy of HNSCC evaluated on patient-derived xenograft models.

Cancer cell membrane (CCM) derived nanotechnology functionalizes nanoparticles (NPs) to recognize homologous cells, exhibiting translational potential in accurate tumor therapy. However, these nanoplatforms are majorly generated from fixed cell lines and are typically evaluated in cell line-derived subcutaneous-xenografts (CDX), ignoring the tumor heterogeneity and differentiation from inter- and intra- individuals and microenvironments between heterotopic- and orthotopic-tumors, limiting the therapeutic efficiency of such nanoplatforms. Herein, various biomimetic nanoplatforms (CCM-modified gold@Carbon, i.e., Au@C-CCM) were fabricated by coating CCMs of head and neck squamous cell carcinoma (HNSCC) cell lines and patient-derived cells on the surface of Au@C NP. The generated Au@C-CCMs were evaluated on corresponding CDX, tongue orthotopic xenograft (TOX), immune-competent primary and distant tumor models, and patient-derived xenograft (PDX) models. The Au@C-CCM generates a photothermal conversion efficiency up to 44.2% for primary HNSCC therapy and induced immunotherapy to inhibit metastasis via photothermal therapy-induced immunogenic cell death. The homologous CCM endowed the nanoplatforms with optimal targeting properties for the highest therapeutic efficiency, far above those with mismatched CCMs, resulting in distinct tumor ablation and tumor growth inhibition in all four models. This work reinforces the feasibility of biomimetic NPs combining modular designed CMs and functional cores for customized treatment of HNSCC, can be further extended to other malignant tumors therapy.

Endothelial anthrax toxin receptor 2 plays a protective role in liver fibrosis.

Hepatocellular carcinoma is one of the leading cancers worldwide and is a potential consequence of fibrosis. Therefore, the identification of key cellular and molecular mechanisms involved in liver fibrosis is an important goal for the development of new strategies to control liver-related diseases. Here, single-cell RNA sequencing data (GSE136103 and GES181483) of clinical liver non-parenchymal cells were analyzed to identify cellular and molecular mechanisms of liver fibrosis. The proportion of endothelial subpopulations in cirrhotic livers was significantly higher than that in healthy livers. Gene ontology and gene set enrichment analysis of differentially expressed genes in the endothelial subgroups revealed that extracellular matrix (ECM)-related pathways were significantly enriched. Since anthrax toxin receptor 2 (ANTXR2) interacts with the ECM, the expression of ANTXR2 in the liver endothelium was analyzed. ANTXR2 expression in the liver endothelium of wild-type (WT) mice significantly decreased after a 4-time sequential injection of carbon tetrachloride (CCl4) to induce liver fibrosis. Next, conditional knockout mice selectively lacking Antxr2 in endothelial cells were generated. After endothelial-specific Antxr2 knockout mice were subjected to the CCl4 model, the degree of liver fibrosis in the knockout group was significantly more severe than that in the control group. In addition, ANTXR2 in human umbilical vein endothelial cells promoted matrix metalloproteinase 2 (MMP2) activation to degrade the ECM in vitro. Finally, endothelial-specific overexpression of Antxr2 alleviated the development of liver fibrosis following adeno-associated virus treatment. Collectively, these results suggested that endothelial ANTXR2 plays a protective role in liver fibrosis. This function of ANTXR2 may be achieved by promoting MMP2 activation to degrade the ECM.

STAT1 is associated with NK cell dysfunction by downregulating NKG2D transcription in chronic HBV-infected patients.

PURPOSE: Natural killer (NK) cells are key players in the immune system, however, the exact mechanism of NK cell dysfunction during HBV infection remains poorly defined. METHODS: Hepatitis B envelope antigen-negative (HBeAg-, n = 19) chronic hepatitis B infection (CHB) patients, HBeAg-positive (HBeAg+, n = 20) CHB patients, HBV-related hepatocellular carcinoma (HBV-HCC, n = 12) patients and healthy blood donors (HD, n = 20), were enrolled in our study. The phenotype and function of the corresponding NK cells of these subjects were then determined. NK cells were cocultured with HBV to assess whether HBV influences the activation of STAT1. Receptors, proliferation, apoptosis rate, and cytotoxicity of NK-92 cells were detected after STAT1 overexpression and knockdown. The relationship between STAT1 and NKG2D promoter was determined by luciferase assay. RESULTS: The levels of NKG2D and STAT1 were the lowest in the HBV-HCC group compared with the HD group, followed by the HBeAg+ group and then the HBeAg- group, respectively. Interestingly, STAT1 levels were positively correlated with NKG2D expression and HBeAg status. Furthermore, STAT1 directly bound to the NKG2D promoter to regulate the transcription and expression of NKG2D. Finally, the results also suggested that knockdown of STAT1 can inhibit proliferation, increase apoptosis rate of NK-92 cells and impair cytotoxicity of NK-92 cells. CONCLUSION: STAT1 is correlated with NK cell dysfunction by downregulating NKG2D transcription in HBV-infected patients. Our findings demonstrate that STAT1 is an important and positive regulator of NK cells, which could provide a potential immunotherapy target for CHB.

Minimizing adverse effects of Cerenkov radiation induced photodynamic therapy with transformable photosensitizer-loaded nanovesicles.

BACKGROUND: Photodynamic therapy (PDT) is a promising antitumor strategy with fewer adverse effects and higher selectivity than conventional therapies. Recently, a series of reports have suggested that PDT induced by Cerenkov radiation (CR) (CR-PDT) has deeper tissue penetration than traditional PDT; however, the strategy of coupling radionuclides with photosensitizers may cause severe side effects. METHODS: We designed tumor-targeting nanoparticles (131I-EM@ALA) by loading 5-aminolevulinic acid (ALA) into an 131I-labeled exosome mimetic (EM) to achieve combined antitumor therapy. In addition to playing a radiotherapeutic role, 131I served as an internal light source for the Cerenkov radiation (CR). RESULTS: The drug-loaded nanoparticles effectively targeted tumors as confirmed by confocal imaging, flow cytometry, and small animal fluorescence imaging. In vitro and in vivo experiments demonstrated that 131I-EM@ALA produced a promising antitumor effect through the synergy of radiotherapy and CR-PDT. The nanoparticles killed tumor cells by inducing DNA damage and activating the lysosome-mitochondrial pathways. No obvious abnormalities in the hematology analyses, blood biochemistry, or histological examinations were observed during the treatment. CONCLUSIONS: We successfully engineered a nanocarrier coloaded with the radionuclide 131I and a photosensitizer precursor for combined radiotherapy and PDT for the treatment of breast cancer.

Multi-antitumor therapy and synchronous imaging monitoring based on exosome.

BACKGROUND: Tumor-derived exosomes (TEX) have shown great potential for drug delivery and tumor targeting. Here, we developed a novel multi-drug loaded exosomes nanoprobe for combined antitumor chemotherapy and photodynamic therapy, and monitoring the drug delivery capabilities with pre-targeting technique. METHODS: TEX of human colorectal cancer HCT116 was prepared, and Doxorubicin and the photodynamic therapy agent 5-aminolevulinic acid (ALA) were loaded and named as TEX@DOX@ALA. Tumor uptake was first examined using fluorescence imaging of the fluorescent dye Cy5 (TEX@DOX@ALA@Cy5). Visualization of exosome aggregation in tumor were realized by positron-emission tomography/computed tomography (PET/CT) with pre-targeting technique. Tumor-bearing mice were first injected with TEX@DOX@ALA labeled with azide (N3) (TEX@DOX@ALA@N3), and then 68Ga-(2,2'-((6-amino-1-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) hexan-2-yl) azanediyl) diacetic acid-dibenzocyclooctyne (68Ga-L-NETA-DBCO) was injected after 24 h for PET/CT imaging via in vivo click chemistry. For the antitumor therapy with photodynamic and/or chemotherapy, seven groups of tumor-bearing mice with different therapy were monitored, and the tumor size, animal weight and the survival time were recorded. Furthermore, the samples of blood and interested tissues (heart, lung, liver, kidney, and spleen) were harvested for hematological analysis and H&E staining. RESULTS: The drug loading process did not influence the structure or the function of the HCT116 TEX membranes. In a fluorescence imaging experiment, higher fluorescence could be seen in tumor after TEX@DOX@ALA@Cy5 injected, and reached the highest signal at 24 h. From PET/CT images with subcutaneous and orthotopic colon tumor-bearing mice, clear radioactivity could be seen in tumors, which suggested the successes of TEX accumulation in tumors. TEX@DOX@ALA group with photodynamic therapy and chemotherapy had the best tumor inhibition effect compared with the other groups, with the longest survival time (36 days, 37.5%). No significant damage was found on histological observation and the blood biochemical analysis, which suggested the safety of the multi-drug loaded exosomes. CONCLUSIONS: We successfully engineered an exosome-based nanoprobe integrating PET imaging components and therapeutic drugs. This drug-loaded exosome system may effectively target tumors and enable synergistic chemotherapeutic and photodynamic antitumor effects.

Dopamine receptor D2 antagonism normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Currently there is no effective treatment for liver fibrosis, which is one of the main histological determinants of non-alcoholic steatohepatitis (NASH). While Hippo/YAP (Yes-associated protein) signaling is essential for liver regeneration, its aberrant activation frequently leads to fibrosis and tumorigenesis. Unravelling "context-specific" contributions of YAP in liver repair might help selectively bypass fibrosis and preserve the pro-regenerative YAP function in hepatic diseases. METHODS: We used murine liver fibrosis and minipig NASH models, and liver biopsies from patients with cirrhosis. Single-cell RNA-sequencing (scRNA-Seq) was performed, and a G-protein-coupled receptor (GPCR) ligand screening system was used to identify cell-selective YAP inhibitors. RESULTS: YAP levels in macrophages are increased in the livers of humans and mice with liver fibrosis. The increase in type I interferon and attenuation of hepatic fibrosis observed in mice specifically lacking Yap1 in myeloid cells provided further evidence for the fibrogenic role of macrophage YAP. ScRNA-Seq further showed that defective YAP pathway signaling in macrophages diminished a fibrogenic vascular endothelial cell subset that exhibited profibrotic molecular signatures such as angiocrine CTGF and VCAM1 expression. To specifically target fibrogenic YAP in macrophages, we utilized a GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocked YAP in macrophages but not hepatocytes. Genetic and pharmacological targeting of macrophage DRD2 attenuated liver fibrosis. In a large animal (minipig) NASH model recapitulating human pathology, the DRD2 antagonist blocked fibrosis and restored hepatic architecture. CONCLUSIONS: DRD2 antagonism selectively targets YAP-dependent fibrogenic crosstalk between macrophages and CTGF+VCAM1+ vascular niche, promoting liver regeneration over fibrosis in both rodent and large animal models. LAY SUMMARY: Fibrosis in the liver is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes. Our study demonstrates that a macrophage-specific deficiency in Yes-associated protein (YAP) attenuates liver fibrosis. Dopamine receptor D2 (DRD2) antagonism selectively blocks YAP in macrophages and thwarts liver fibrosis in both rodent and large animal models, and thus holds potential for the treatment of NASH.

The decreased platelet-to-lymphocyte ratio could predict a good prognosis in patients with oligometastatic colorectal cancer: a single-center cohort retrospective study.

BACKGROUND: Inflammation markers have an important effect on tumor proliferation, invasion, and metastasis. Oligometastatic disease (OMD) is an intermediate state between widespread metastases and locally confined disease, where curative strategies may be effective for some patients. We aimed to explore the predictive value of inflammatory markers in patients with oligometastatic colorectal cancer (OMCC) and build a nomogram to predict the prognosis of these patients. METHODS: Two hundred nine patients with OMCC were retrospectively collected in this study. The Kaplan-Meier survival curves and Cox regression analysis were used to estimate overall survival (OS) and progression-free survival (PFS). A multivariate Cox analysis model was utilized to establish the nomogram. The concordance index (C-index), calibration curve, and receiver operating characteristics (ROC) were established to verify the validity and accuracy of the prediction model. RESULTS: According to the multivariate analysis, decreased platelet-to-lymphocyte ratio (PLR) might independently improve OS in patients with OMCC (HR = 2.396, 95% CI 1.391-4.126, P = 0.002). Metastases of extra-regional lymph nodes indicated poor OS (HR = 2.472, 95% CI 1.247-4.903, P = 0.010). While the patients with early N stage had better OS (HR = 4.602, 95% CI 2.055-10.305, P = 0.001) and PFS (HR = 2.100, 95% CI 1.364-3.231, P = 0.007). Primary tumor resection (HR = 0.367, 95% CI 0.148-0.908, P = 0.030) and lower fibrinogen (HR = 2.254, 95% CI 1.246-4.078, P = 0.007) could significantly prolong the OS in patients with OMCC. PLR, metastases of extra-regional lymph nodes, N stage, primary tumor resection, and fibrinogen were used to make up the nomogram. The C-index and area under the curve (AUC) of the ROC in nomogram were 0.721 and 0.772 respectively for OS, showed good consistency between predictive probability of OS and actual survival. CONCLUSIONS: Decreased PLR could predict a good prognosis in patients with OMCC. The nomogram including inflammatory factors and clinicopathological markers was credible and accurate to predict survivals in patients with OMCC.

Protective mechanism of Erigeron breviscapus injection on blood-brain barrier injury induced by cerebral ischemia in rats.

This study investigates the protective effect of Erigeron breviscapus injection, a classic traditional Chinese medicine most typically used by Chinese minority to treat stroke, on cerebral ischemia-reperfusion injury and the related signaling pathways. Use network pharmacology methods to study the relationship between E. breviscapus (Vant.) Hand-Mazz. and ischemic stroke, predict the mechanism and active ingredients of E. breviscapus (Vant.) Hand-Mazz. in improving ischemic stroke disease. We study the protective effect of E. breviscapus injection on blood-brain barrier (BBB) injuries induced by cerebral ischemia in rats by regulating the ROS/RNS-MMPs-TJs signaling pathway. The rat model of focal cerebral ischemia-reperfusion injury has been prepared using the wire-suppository method. Firstly, the efficacy of E. breviscapus injection, Scutellarin and 3,5-dicaffeoylquinic acid in protecting BBB injury caused by cerebral ischemia has been evaluated. Secondly, the following two methods have been used to study the mechanism of E. breviscapus injection in regulating the ROS/RNS-MMPS-TJS signaling pathway: real-time PCR and western blot for the determination of iNOS, MMP-9, claudin-5, occludin, ZO-1 mRNA and protein expression in brain tissue. We find that PI3K-Akt signaling pathway predicted by network pharmaology affects the blood-brain barrier function, so we chose the blood-brain barrier-related MMP-9, claudin-5, iNOS, occludin and ZO-1 proteins are used for research. The results of our research show that 3 drugs can reduce the rate of cerebral infarction in rats, relieve the abnormal neuroethology of rats, reduce the degree of brain tissue lesion, increase the number of the Nissl corpuscle cells and repair the neuron ultrastructure in injured rats. At the same time, it can obviously reduce the ultrastructure damage of the BBB in rats. All three drugs significantly reduced the content of Evans blue in the ischemic brain tissue caused by cerebral ischemia in rats with BBB injury. In addition, E. breviscapus injection, Scutellarin and 3,5-dicaffeoylquinic acid can decrease the protein expression of iNOS and MMP-9 in rat ischemic brain tissue. In addition, 3,5-dicaffeoylquinic acid can increase the protein expression of claudin-5. We conclude that E. breviscapus injection, Scutellarin and 3,5-dicaffeoylquinic acid have obvious therapeutic effects on BBB and neuron injury induced by cerebral ischemia in rats. Our results from studying the mechanism of action show that E. breviscapus injection and Scutellarin inhibited the activation of MMP-9 by inhibiting the synthesis of iNOS, 3,5-dicaffeoylquinic acid inhibits the expression and activation of MMP-9 by inhibiting the activation of iNOS and reducing the generation of free radicals, thus reducing the degradation of important cytoskeleton connexin claudin-5 in the tight junction (TJ) structure by inhibiting the expression and activation of MMP-9. Finally BBB structure integrity was protected.

Predicting the Survival Probability of Neuroendocrine Tumor Populations: Developing and Evaluating a New Predictive Nomogram.

PURPOSE: The purpose of this study was to develop and initially validate a nomogram model in order to predict the 3-year and 5-year survival rates of neuroendocrine tumor patients. METHODS: Accordingly, 348 neuroendocrine tumor patients were enrolled as study objects, of which 244 (70%) patients were included in the training set to establish the nomogram model, while 104 (30%) patients were included in the validation set to verify the robustness of the model. First, the variables related to the survival rate were determined by univariable analysis. In addition, variables that were sufficiently significant were selected for constructing the nomogram model. Furthermore, the concordance index (C-index), receiver operating characteristic (ROC), and calibration curve analysis were used to evaluate the performance of the proposed nomogram model. The survival analysis was then used to evaluate the return to survival probability as well as the indicators of constructing the nomogram model. RESULTS: According to the multivariable analysis, lymphatic metastasis, international normalized ratio (INR), prothrombin time (PT), tumor differentiation, and the number of tumor metastases were found to be independent predictors of survival rate. Moreover, the C-index results demonstrated that the model was robust in both the training set (0.891) and validation set (0.804). In addition, the ROC results further verified the robustness of the model either in the training set (AUC = 0.823) or training set (AUC = 0.768). Furthermore, the calibration curve results showed that the model can be used to predict the 3-year and 5-year survival probability of neuroendocrine tumor patients. Meaningfully, five variables were found: lymphatic metastasis (p = 0.0095), international standardized ratio (p = 0.024), prothrombin time (p = 0.0036), tumor differentiation (p = 0.0026), and the number of tumor metastases (p = 0.00096), which were all significantly related to the 3-year and 5-year survival probability of neuroendocrine tumor patients. CONCLUSION: In summary, a nomogram model was constructed in this study based on five variables (lymphatic metastasis, international normalized ratio (INR), prothrombin time (PT), tumor differentiation, and number of tumor metastases), which was shown to predict the survival probability of patients with neuroendocrine tumors. Additionally, the proposed nomogram exhibited good ability in predicting survival probability, which may be easily adopted for clinical use.