Serum IL-24 combined with CA125 as screening and prognostic biomarkers for NSCLC.

Noninvasive and effective methods for early screening of non-small cell lung cancer (NSCLC) still need to be developed. At present, a reasonable conclusion is that a combination of tumor markers is a superior predictor of screening. Cytokines, as important regulators of cancer development, have great potential for the screening and prognosis of NSCLC. This study screened novel biomarkers related to the early screening and prognosis of NSCLC. In the present study, the biological significance and immunoregulation of interleukin-24 (IL-24) were analyzed based on The Cancer Genome Atlas data. Next, 150 serum samples from initially treated patients with NSCLC and 70 controls were collected, and we obtained pathological sections from 60 patients with NSCLC. The ELISA and immunohistochemistry results showed the differential expression of IL-24 and carbohydrate antigen 125 (CA125). The results show that IL-24 is an important tumor suppressor in NSCLC that helps to improve the poor prognosis of these patients. A significantly negative correlation between IL-24 and CA125 levels was also found. Notably, serum IL-24 levels were significantly negatively correlated with the TNM stage of patients with NSCLC, consistent with an important role for tumor suppressors in NSCLC. The receiver operating characteristic curve analysis showed that a combination of IL-24 and CA125 was an effective panel for discriminating patients with NSCLC from HD, and individuals with other lung diseases. Serum IL-24 and CA125 levels were identified as independent prognostic markers for NSCLC. The IL-24 and CA125 panel exhibited good performance in the screening of NSCLC.

Gallic acid ameliorates endometrial hyperplasia through the inhibition of the PI3K/AKT pathway and the down-regulation of cyclin D1 expression.

BACKGROUND: Gallic acid (GA) is an organic compound with phenolic properties that occurs naturally and can be found in Guizhi Fuling capsules, showcasing a wide range of biological functionalities. PURPOSE: The objective of this study was to examine the influence of GA on endometrial hyperplasia (EH) and elucidate its underlying mechanism. METHODS: Initially, the induction of EH was achieved by administering estradiol to mice via continuous subcutaneous injection for a duration of 21 days. Concurrently, GA treatment was administered, and subsequently, the uterine tissue structure was assessed using hematoxylin and eosin (H&E) staining. Following this, the proliferation of human endometrial cells treated by GA was determined utilizing the CCK-8 method. Furthermore, network pharmacology and single-cell-RNA-seq data were employed to identify the target of GA action. In addition, we will employ immunofluorescence (IF), immunohistochemistry (IHC), flow cytometry, western blot and RT-qPCR methodologies to investigate the impact of GA on the expression level of cyclin D1, PI3K, p-PI3K, AKT, p-AKT. RESULTS: GA treatment ameliorated histopathological alterations in the uterus and suppress proliferation. Estradiol stimulation can activate the PI3K/AKT pathway, leading to up-regulation of cyclin D1 expression, whereas GA treatment results in down-regulation of its expression. CONCLUSIONS: The expression of cyclin D1 is down-regulated by GA through the inhibition of the PI3K/AKT pathway, effectively mitigating estradiol-induced EH in mice.

Evaluating the Impact of Cl2•- Generation on Antibiotic-Resistance Contamination Removal via UV/Peroxydisulfate.

The removal of antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARGs) using sulfate anion radical (SO4•-)-based advanced oxidation processes has gained considerable attention recently. However, immense uncertainties persist in technology transfer. Particularly, the impact of dichlorine radical (Cl2•-) generation during SO4•--mediated disinfection on ARB/ARGs removal remains unclear, despite the Cl2•- concentration reaching levels notably higher than those of SO4•- in certain SO4•--based procedures applied to secondary effluents, hospital wastewaters, and marine waters. The experimental results of this study reveal a detrimental effect on the disinfection efficiency of tetracycline-resistant Escherichia coli (Tc-ARB) during SO4•--mediated treatment owing to Cl2•- generation. Through a comparative investigation of the distinct inactivation mechanisms of Tc-ARB in the Cl2•-- and SO4•--mediated disinfection processes, encompassing various perspectives, we confirm that Cl2•- is less effective in inducing cellular structural damage, perturbing cellular metabolic activity, disrupting antioxidant enzyme system, damaging genetic material, and inducing the viable but nonculturable state. Consequently, this diminishes the disinfection efficiency of SO4•--mediated treatment owing to Cl2•- generation. Importantly, the results indicate that Cl2•- generation increases the potential risk associated with the dark reactivation of Tc-ARB and the vertical gene transfer process of tetracycline-resistant genes following SO4•--mediated disinfection. This study underscores the undesired role of Cl2•- for ARB/ARGs removal during the SO4•--mediated disinfection process.

Traditional Chinese Medicine Shi-Bi-Man ameliorates psoriasis via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation.

BACKGROUND: Psoriasis is a chronic inflammatory genetic disease, mainly manifesting in the skin. Conventional therapies, such as glucocorticosteroids and corticosteroids, have adverse effects that limit drug use. Hence, it is imperative to identify a new therapeutic strategy that exhibits a favorable safety profile. Shi-Bi-Man (SBM) is a safe herbal supplement sourced from various natural plants, including ginseng, angelica sinensis, polygonum multiflorum, and aloe vera. PURPOSE: We aimed to find a potential treatment for psoriasis and investigate the underlying mechanism through which SBM alleviates psoriatic-like skin inflammation in mice. METHODS: We investigated the effects of supplementing with SBM through intragastric administration or smear administration in a murine model of imiquimod-induced psoriasis. The changes in body weight and Psoriasis Area and Severity Index (PASI) score were recorded throughout the entire process. Additionally, we used hematoxylin-eosin staining to observe the skin structure and performed single-cell RNA sequencing to explore the underlying mechanism of SBM in influencing the psoriasis-like phenotype. Immunofluorescence was conducted to verify our findings. Furthermore, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to investigate the impact of Tetrahydroxy stilbene glycoside (TSG) on the expression levels of IL23 in HaCaT cells. RESULTS: SBM remarkably alleviated the psoriasis-like phenotype by inhibiting IL-23/Th17 cell axis. Single-cell RNA sequencing analysis revealed a decrease in the expression of Il17 and Il23 in keratinocytes and T cells, concomitant with a reduction in the proportion of Th17 cells. Meanwhile, the activation of endothelial cells was inhibited, accompanied by a decrease in the expression of Cxcl16. In vitro, the addition of TSG to HaCaT cells resulted in significant suppression of IL23 expression stimulated by tumor necrosis factor-alpha (TNF-α).

Targeting Senescent Alveolar Epithelial Cells Using Engineered Mesenchymal Stem Cell-Derived Extracellular Vesicles To Treat Pulmonary Fibrosis.

Type 2 alveolar epithelial cell (AEC2) senescence is crucial to the pathogenesis of pulmonary fibrosis (PF). The nicotinamide adenine dinucleotide (NAD+)-consuming enzyme cluster of differentiation 38 (CD38) is a marker of senescent cells and is highly expressed in AEC2s of patients with PF, thus rendering it a potential treatment target. Umbilical cord mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) have emerged as a cell-free treatment with clinical application prospects in antiaging and antifibrosis treatments. Herein, we constructed CD38 antigen receptor membrane-modified MSC-EVs (CD38-ARM-MSC-EVs) by transfecting MSCs with a lentivirus loaded with a CD38 antigen receptor-CD8 transmembrane fragment fusion plasmid to target AEC2s and alleviate PF. Compared with MSC-EVs, the CD38-ARM-MSC-EVs engineered in this study showed a higher expression of the CD38 antigen receptor and antifibrotic miRNAs and targeted senescent AEC2s cells highly expressing CD38 in vitro and in naturally aged mouse models after intraperitoneal administration. CD38-ARM-MSC-EVs effectively restored the NAD+ levels, reversed the epithelial-mesenchymal transition phenotype, and rejuvenated senescent A549 cells in vitro, thereby mitigating multiple age-associated phenotypes and alleviating PF in aged mice. Thus, this study provides a technology to engineer MSC-EVs and support our CD38-ARM-MSC-EVs to be developed as promising agents with high clinical potential against PF.

The dual function of cGAS-STING signaling axis in liver diseases.

Numerous liver diseases, such as nonalcoholic fatty liver disease, hepatitis, hepatocellular carcinoma, and hepatic ischemia-reperfusion injury, have been increasingly prevalent, posing significant threats to global health. In recent decades, there has been increasing evidence linking the dysregulation of cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING)-related immune signaling to liver disorders. Both hyperactivation and deletion of STING can disrupt the immune microenvironment dysfunction, exacerbating liver disorders. Consequently, there has been a surge in research investigating medical agents or mediators targeting cGAS-STING signaling. Interestingly, therapeutic manipulation of the cGAS-STING pathway has yielded inconsistent and even contradictory effects on different liver diseases due to the distinct physiological characteristics of intrahepatic cells that express and respond to STING. In this review, we comprehensively summarize recent advancements in understanding the dual roles of the STING pathway, highlighting that the benefits of targeting STING signaling depend on the specific types of target cells and stages of liver injury. Additionally, we offer a novel perspective on the suitability of STING agonists and antagonists for clinical assessment. In conclusion, STING signaling remains a highly promising therapeutic target, and the development of STING pathway modulators holds great potential for the treatment of liver diseases.

Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.

Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.

The double-edged role of neutrophil heterogeneity in inflammatory diseases and cancers.

Neutrophils are important immune cells act as the body's first line of defense against infection and respond to diverse inflammatory cues. Many studies have demonstrated that neutrophils display plasticity in inflammatory diseases and cancers. Clarifying the role of neutrophil heterogeneity in inflammatory diseases and cancers will contribute to the development of novel treatment strategies. In this review, we have presented a review on the development of the understanding on neutrophil heterogeneity from the traditional perspective and a high-resolution viewpoint. A growing body of evidence has confirmed the double-edged role of neutrophils in inflammatory diseases and tumors. This may be due to a lack of precise understanding of the role of specific neutrophil subsets in the disease. Thus, elucidating specific neutrophil subsets involved in diseases would benefit the development of precision medicine. Thusly, we have summarized the relevance and actions of neutrophil heterogeneity in inflammatory diseases and cancers comprehensively. Meanwhile, we also discussed the potential intervention strategy for neutrophils. This review is intended to deepen our understanding of neutrophil heterogeneity in inflammatory diseases and cancers, while hold promise for precise treatment of neutrophil-related diseases.

SARS-CoV-2 Omicron BA.5.2-infection and COVID-19 in persons with chronic myeloid leukaemia.

OBJECTIVE: A SARS-CoV-2 Omicron (BA.5.2) epidemic began in China in December, 2022 following stopping the zero COVID policy. METHODS: We studied features of the epidemic in 1,121 persons with chronic myeloid leukaemia (CML). RESULTS: 1103 (98%) were in chronic, 10 in accelerated and 8 in acute phases. 834 (74%) became infected almost all of whom met criteria for COVID-19. The most common symptoms were fever (91%), cough (90%) and fatigue (82%). 42 infected persons were asymptomatic. Most people quarantined at home and self-medicated. 22 were hospitalized for COVID-19. At admission 5 had mild, 14, moderate and 3, severe/critical disease according to World Health Organization (WHO) criteria. 5 received respiratory assistance, 3 were admitted to the intensive care unit (ICU) and 1 in accelerated phase died from COVID-19. Co-variates associated with a risk of COVID-19 in SARS-CoV-2-infected subjects include age ≥ 65 years, higher education level and imatinib therapy. CONCLUSION: In conclusion, most SARS-CoV-2 Omicron BA.5.2 infections in persons with CML resulted in COVID-19 most of which cases are mild with only 1 death.

Construction and evaluation of a gated high-resolution neural network for automatic brain metastasis detection and segmentation.

OBJECTIVES: To construct and evaluate a gated high-resolution convolutional neural network for detecting and segmenting brain metastasis (BM). METHODS: This retrospective study included craniocerebral MRI scans of 1392 patients with 14,542 BMs and 200 patients with no BM between January 2012 and April 2022. A primary dataset including 1000 cases with 11,686 BMs was employed to construct the model, while an independent dataset including 100 cases with 1069 BMs from other hospitals was used to examine the generalizability. The potential of the model for clinical use was also evaluated by comparing its performance in BM detection and segmentation to that of radiologists, and comparing radiologists' lesion detecting performances with and without model assistance. RESULTS: Our model yielded a recall of 0.88, a dice similarity coefficient (DSC) of 0.90, a positive predictive value (PPV) of 0.93 and a false positives per patient (FP) of 1.01 in the test set, and a recall of 0.85, a DSC of 0.89, a PPV of 0.93, and a FP of 1.07 in dataset from other hospitals. With the model's assistance, the BM detection rates of 4 radiologists improved significantly, ranging from 5.2 to 15.1% (all p < 0.001), and also for detecting small BMs with diameter ≤ 5 mm (ranging from 7.2 to 27.0%, all p < 0.001). CONCLUSIONS: The proposed model enables accurate BM detection and segmentation with higher sensitivity and less time consumption, showing the potential to augment radiologists' performance in detecting BM. CLINICAL RELEVANCE STATEMENT: This study offers a promising computer-aided tool to assist the brain metastasis detection and segmentation in routine clinical practice for cancer patients. KEY POINTS: • The GHR-CNN could accurately detect and segment BM on contrast-enhanced 3D-T1W images. • The GHR-CNN improved the BM detection rate of radiologists, including the detection of small lesions. • The GHR-CNN enabled automated segmentation of BM in a very short time.

Microfluidic synthesis of fibronectin-coated polydopamine nanocomplexes for self-supplementing tumor microenvironment regulation and MR imaging-guided chemo-chemodynamic-immune therapy.

Development of nanomedicines to overcome the hindrances of tumor microenvironment (TME) for tumor theranostics with alleviated side effects remains challenging. We report here a microfluidic synthesis of artesunate (ART)-loaded polydopamine (PDA)/iron (Fe) nanocomplexes (NCs) coated with fibronectin (FN). The created multifunctional Fe-PDA@ART/FN NCs (FDRF NCs) with a mean size of 161.0 â€‹nm exhibit desired colloidal stability, monodispersity, r1 relaxivity (4.96 â€‹mM-1s-1), and biocompatibility. The co-delivery of the Fe2+ and ART enables enhanced chemodynamic therapy (CDT) through improved intracellular reactive oxygen species generation via a cycling reaction between Fe3+ and Fe2+ caused by the Fe3+-mediated glutathione oxidation and Fe2+-mediated ART reduction/Fenton reaction for self-supplementing TME regulation. Likewise, the combination of ART-mediated chemotherapy and the Fe2+/ART-regulated enhanced CDT enables noticeable immunogenic cell death, which can be collaborated with antibody-mediated immune checkpoint blockade to exert immunotherapy having significant antitumor immunity. The combined therapy improves the efficacy of primary tumor therapy and tumor metastasis inhibition by virtue of FN-mediated specific targeting of FDRF NCs to tumors with highly expressed αvß3 integrin and can be guided through the Fe(III)-rendered magnetic resonance (MR) imaging. The developed FDRF NCs may be regarded as an advanced nanomedicine formulation for chemo-chemodynamic-immune therapy of different tumor types under MR imaging guidance.

Paeonol ameliorates endometrial hyperplasia in mice via inhibiting PI3K/AKT pathway-related ferroptosis.

BACKGROUND: Paeonol (Pae) is one of the active ingredients from components of Guizhi Fuling Capsule, a traditional Chinese medicine widely used for the treatment of women's diseases, which exhibits various biological and pharmacological activities. PURPOSE: The objective of this study was to investigate the molecular mechanism underlying the role of Pae in protecting against endometrial hyperplasia (EH). METHODS: CCK-8 assay was performed to detect the effect of Pae on cell proliferation. Hematoxylin and eosin (H&E) staining was performed to evaluate uterine tissue structure. A network pharmacology study was performed to search the disease targets. Single-cell transcriptome analysis was performed with uterine tissues from 3 healthy donors and 3 EH patients on 10X Genomics platform. Changes in lipid peroxidation were detected by the MDA reaction. IHC assay, Western blot, immunofluorescence and RT-qPCR were used to study the effects of estradiol and Pae on the expression levels of GPX4, PI3K, AKT, p-PI3K, p-AKT in mice. RESULTS: Pae treatment resulted in a decrease in cell viability of endometrial epithelial cells. Loss of uterus weight and morphology changes were observed in mice. In addition, Fe iron concentration and MDA levels increased, while the expression of GPX4, p-PI3K and p-AKT diminished. CONCLUSIONS: Pae exhibited obvious alleviative activity in estradiol-induced mice via PI3K/AKT signaling pathway-regulated ferroptosis.

Long Noncoding RNA lncNDEPD1 Regulates PD-1 Expression via miR-3619-5p in CD8+ T Cells.

Therapies targeting programmed cell death protein 1 (PD-1) have gained great success in patients with multiple types of cancer. The regulatory mechanisms underlying PD-1 expression have been extensively explored. However, the impact of long noncoding RNAs on PD-1 expression remains elusive. In this study, we identified the Notch1/lncNDEPD1 axis, which plays a critical role in PD-1 expression in human CD8+ T cells. RNA sequencing and quantitative reverse transcription PCR data showed that lncNDEPD1 was upregulated in activated T cells, especially in PD-1high subsets. Fluorescence in situ hybridization demonstrated that lncNDEPD1 was localized in the cytoplasm. A mechanistic study showed that lncNDEPD1 could bind with miR-3619-5p and PDCD1 mRNA to prevent PDCD1 mRNA degradation and then upregulate PD-1 expression. A chromatin immunoprecipitation assay showed that Notch1 directly binds to the promoter of lncNDEPD1 instead of PDCD1 Furthermore, chimeric Ag receptor T cells expressing lncNDEPD1-specific short hairpin RNAs were generated. Chimeric Ag receptor T cells with decreased lncNDEPD1 expression showed enhanced tumoricidal effects when PD-L1 was present. Our work uncovered a new regulatory mechanism of PD-1 expression and thus provided a potential target to decrease PD-1 without affecting T cell function.

Advances in ameliorating inflammatory diseases and cancers by andrographolide: Pharmacokinetics, pharmacodynamics, and perspective.

Andrographolide, a well-known natural lactone having a range of pharmacological actions in traditional Chinese medicine. It has long been used to cure a variety of ailments. In this review, we cover the pharmacokinetics and pharmacological activity of andrographolide which supports its further clinical application in cancers and inflammatory diseases. Growing evidence shows a good therapeutic effect in inflammatory diseases, including liver diseases, joint diseases, respiratory system diseases, nervous system diseases, heart diseases, inflammatory bowel diseases, and inflammatory skin diseases. As a result, the effects of andrographolide on immune cells and the processes that underpin them are discussed. The preclinical use of andrographolide to different organs in response to malignancies such as colorectal, liver, gastric, breast, prostate, lung, and oral cancers has also been reviewed. In addition, several clinical trials of andrographolide in inflammatory diseases and cancers have been summarized. This review highlights recent advances in ameliorating inflammatory diseases as well as cancers by andrographolide and its analogs, providing a new perspective for subsequent research of this traditional natural product.

Activated AMPK by metformin protects against fibroblast proliferation during pulmonary fibrosis by suppressing FOXM1.

Pulmonary fibrosis (PF) is a progressive and devastating lung disease of unknown etiology, excessive fibroblast proliferation serves as a key event to promote PF. Transcription factor forkhead box M1 (FOXM1) is not only a well-known proto-oncogene, but also an essential driver of cell proliferation. Recently, 5'-AMP-activated protein kinase (AMPK) is reported to reduce the incidence of PF. However, it remains elusive whether have an underlying relationship between AMPK and FOXM1 in fibroblast proliferation-mediated PF. Here, the progression of lung fibroblast proliferation and the expression levels of AMPK and FOXM1 were observed by intratracheally instilled of bleomycin (BLM) and intraperitoneal injection of metformin in C57BL/6 J mice. Meanwhile, human fetal lung fibroblast1 (HFL1) cells were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C, or FOXM1 depletion by transfected small interfering RNA (siRNA) to unveil roles of AMPK, FOXM1 and the link between them on platelet-derived growth factor (PDGF)-induced fibroblast proliferation. Our results demonstrated that AMPK activated by metformin could down-regulate FOXM1 and alleviate BLM-induced mouse PF model. In vitro, activation of AMPK attenuated PDGF-induced fibroblast proliferation accompanied by the down-regulation of FOXM1. In contrast, inhibition of AMPK enhanced PDGF-induced fibroblast proliferation along with activating FOXM1. These findings suggest that AMPK can ameliorate the progression of fibroblast proliferation during PF via suppressing the expression of FOXM1 and provide new insight into seek PF treatment approaches.

Re-Du-Ning injection ameliorates LPS-induced lung injury through inhibiting neutrophil extracellular traps formation.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases and could occur in severe COVID-19 patients. Re-Du-Ning injection (RDN) is a tradition Chinese medicine preparation which has been clinically used for treatment of respiratory diseases including COVID-19. PURPOSE: To elucidate the potential mechanisms of RDN for the treatment of ALI. METHODS: Female C57BL/6J mice were used to establish ALI model by intraperitoneal injection 10 mg/kg LPS, and RDN injection was intraperitoneally administered with the dose of 5 and 10 ml/kg. The cytokines were measured by ELISA and qPCR. The data related to NETs were analyzed by ELISA, immunofluorescence, Western blotting and network pharmacological approach. RESULTS: RDN robustly alleviated LPS-induced ALI. Meanwhile, RDN downregulated the expression of pro-inflammatory cytokines, such as IL-1ß, IL-6 and TNF-α. Specifically, RDN treatment inhibited the formation of neutrophil extracellular traps (NETs) and remarkably suppressed the protein of PAD4. The active compound from RDN decreased the phosphorylation of ERK1/2. CONCLUSION: These findings demonstrate that RDN ameliorates LPS-induced ALI through suppressing MAPK pathway to inhibit the formation of NETs.

Identification and characterization of prognosis-related genes in the tumor microenvironment of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the main pathological subtype of esophageal cancer with high incidence and mortality. Immune and stromal cells in the tumor microenvironment (TME) profoundly affect the development of ESCC. METHODS: In this study, we used the ESTIMATE algorithm to calculate the immune and stromal scores of ESCC samples in The Cancer Genome Atlas (TCGA) database. Next, we used the R package limma to identify differentially expressed genes (DEGs) from high- versus low-immune/stromal score groups and these DEGs were further utilized to analyze the functional annotations, protein-protein interaction (PPI) networks and overall survival of patients with ESCC. Finally, we identified the biological roles of core gene C3AR1 in the TME of ESCC using the TCGA database and in vitro experiments. RESULTS: We obtained the immune and stromal scores of ESCC samples and further evaluated the impact of these scores on the prognosis and clinical parameters of patients with ESCC. Next, we identified 410 DEGs from high- versus low-immune/stromal score groups and to gain better understanding of the biological functions and characteristics of DEGs. Among these DEGs, 69 were correlated with the overall survival of patients with ESCC and C3AR1 was identified as a core gene for the regulation of most genes in the network. We found that C3AR1 was positively correlated with M2 macrophages and immune inhibitory molecules (T-cell immunoglobulin and mucin domain 3 (TIM-3), programmed cell death-1 (PD-1)), but not with M1 macrophages. We also observed a higher expression of CD163 and CD206, which were the markers for M2 macrophages in the TLQP-21 TFA (the agonist of C3AR1)groups than in the control groups. CONCLUSION: Based on the ESTIMATE algorithm, we obtained and characterized prognosis-related genes in the TME of ESCC samples from the TCGA database. We have further revealed that C3AR1 may cause an immunosuppressive microenvironment by affecting the polarization of macrophages to M2 phenotype and lead to the progression of ESCC, which indicates that C3AR1 may be a potential target for immunotherapy.

Core-Shell Tecto Dendrimers Enable Enhanced Tumor MR Imaging through an Amplified EPR Effect.

Development of nanoplatforms that can amplify the passive tumor targeting effect based on enhanced permeability and retention (EPR) effect is crucial for precision cancer nanomedicine applications. Herein, we present the development of core-shell tecto dendrimers (CSTDs) as a platform for enhanced tumor magnetic resonance (MR) imaging through an amplified EPR effect. In this work, poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5) were decorated with ß-cyclodextrin (CD) and then assembled with G3 PAMAM dendrimers premodified with adamantane (Ad) via supramolecular recognition of CD and Ad. The formed G5-CD/Ad-G3 CSTDs were conjugated with tetraazacyclododecane tetraacetic acid (DOTA)-Gd(III) chelators and further acetylated to neutralize the remaining CSTD periphery amines. We reveal that the formed CSTD.NHAc-DOTA(Gd) (CSTD-D-Gd) complexes have a narrow size distribution and satisfactory colloidal stability, and are cytocompatible within the concentration range studied. Compared to the single dendrimer counterpart of G5.NHAc-DOTA(Gd) (G5-D-Gd) complexes, the CSTD-D-Gd complexes with a higher molecular weight and volume possess a longer rotation correlation time, hence having a longitudinal relaxivity (r1) of 7.34 mM-1 s-1, which is 1.5 times larger than that of G5-D-Gd complexes (4.92 mM-1 s-1). More importantly, the CSTD-D-Gd complexes display better permeability in the three-dimensional (3D) cell spheroids in vitro through fluorescence imaging and a more significant EPR effect for improved tumor MR imaging in vivo than the G5-DOTA-Gd complexes. The generated CSTD-D-Gd complexes may be adopted for enhanced tumor MR imaging through an amplified passive EPR effect and also be further extended for different cancer theranostic applications.

Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi Fuling Capsule (GFC) is a classical traditional Chinese medicine officially recorded in Synopsis of the Golden Chamber and has long been used to treat gynecological diseases in China. However, scientific evidence for the anti-endometrial hyperplasia potential of GFC used in traditional medicine is lacking. AIM OF THE STUDY: This study evaluated whether GFC protects against endometrial hyperplasia and its potential mechanism in mice. METHODS AND MATERIALS: We used estrogen (estradiol) to induce endometrial hyperplasia in mice. C57BL/6 mice were treated with estradiol subcutaneously for 21 days, and GFC (75 mg/kg and 150 mg/kg) was given intragastric administration from the first day of the modeling. H&E staining is used to evaluate endometrial tissue structure change. Malondialdehyde was measured to explore lipid peroxidation. Western blot, immunohistochemistry and immunofluorescence were performed to observe the expressions of GPX4, p62, Keap1 and NRF2. RESULTS: The degree of ferroptosis in endometrial tissue of patients with endometrial hyperplasia was lower than normal endometrial tissue. In addition, ferroptosis inducer imidazole ketone erastin could improve endometrial hyperplasia in mice. Interestingly, GFC significantly alleviated endometrial hyperplasia through triggering ferroptosis. Furthermore, GFC inhibited p62-Keap1-NRF2 pathway in estradiol-induced endometrial hyperplasia model. CONCLUSIONS: GFC may attenuate estrogen-induced endometrial hyperplasia in mice through triggering ferroptosis via inhibiting p62-Keap1-NRF2 pathway. These findings suggest that GFC might act as a promising traditional Chinese medicine to treat endometrial hyperplasia.

[Progress in CT and MRI of preoperative T staging of laryngeal carcinoma].

The T stage of laryngeal carcinoma is directly related to the choice of surgical, and CT and MRI are useful tools to assess staging of laryngeal carcinoma preoperatively. In this review, current status and progress of CT and MRI in preoperative T staging of laryngeal carcinoma were summarized. Conventional CT and MRI still have limitations in the evaluation of preoperative T staging of laryngeal carcinoma, however DECT, DWI and other technologies can provide more useful information. The limitation of this article is that CT and MRI are not compared with other examination methods.