Histone deacetylase 8 promotes innate antiviral immunity through deacetylation of RIG-I.

Histone deacetylates family proteins have been studied for their function in regulating viral replication by deacetylating non-histone proteins. RIG-I (Retinoic acid-inducible gene I) is a critical protein in RNA virus-induced innate antiviral signaling pathways. Our previous research showed that HDAC8 (histone deacetylase 8) involved in innate antiviral immune response, but the underlying mechanism during virus infection is still unclear. In this study, we showed that HDAC8 was involved in the regulation of vesicular stomatitis virus (VSV) replication. Over-expression of HDAC8 inhibited while knockdown promoted VSV replication. Further exploration demonstrated that HDAC8 interacted with and deacetylated RIG-I, which eventually lead to enhance innate antiviral immune response. Collectively, our data clearly demonstrated that HDAC8 inhibited VSV replication by promoting RIG-I mediated interferon production and downstream signaling pathway.

Consensus statement on extracellular vesicles in liquid biopsy for advancing laboratory medicine.

Extracellular vesicles (EVs) represent a diverse class of nanoscale membrane vesicles actively released by cells. These EVs can be further subdivided into categories like exosomes and microvesicles, based on their origins, sizes, and physical attributes. Significantly, disease-derived EVs have been detected in virtually all types of body fluids, providing a comprehensive molecular profile of their cellular origins. As a result, EVs are emerging as a valuable addition to liquid biopsy techniques. In this collective statement, the authors share their current perspectives on EV-related research and product development, with a shared commitment to translating this newfound knowledge into clinical applications for cancer and other diseases, particularly as disease biomarkers. The consensus within this document revolves around the overarching recognition of the merits, unresolved questions, and existing challenges surrounding EVs. This consensus manuscript is a collaborative effort led by the Committee of Exosomes, Society of Tumor Markers, Chinese anti-Cancer Association, aimed at expediting the cultivation of robust scientific and clinically applicable breakthroughs and propelling the field forward with greater swiftness and efficacy.

circ_0000592 facilitates the progression of esophageal squamous cell carcinoma via miR-155-5p/FZD5 axis.

Esophageal squamous cell carcinoma (ESCC) is one of the gastrointestinal malignancies with high prevalence and poor prognosis. Previous reports suggested that circular ribose nucleic acids might exert regulatory functions in ESCC. This study aims to explore the role of circ_0000592 in ESCC progression, providing novel insights into the diagnosis and therapeutic avenues for ESCC. The GSE131969 data set was utilized to assess circ_0000592 expression in ESCC. The validation was performed in the tumorous tissues of ESCC patients (n = 80) and human-immortalized ESCC cell lines. The correlation between circ_0000592 expression and prognosis was analyzed. The impact of circ_0000592 on ESCC cell activity was evaluated through downregulating circ_0000592, as well as encompassing cell viability, migration, and invasion abilities. The downstream pathway of circ_0000592 was explored by binding site prediction from the TargetScan database, followed by in vitro and in vivo experiments. An in vivo xenograft tumor model was established to highlight the role of circ_0000592 in ESCC. Patients with ESCC exhibited higher circ_0000592 expression levels compared to noncancerous patients, which were associated with reduced survival time, higher TNM stage, and increased lymph node metastasis. The circ_0000592 downregulation suppressed cell viability, migration, and invasion abilities in vitro. Mechanistically, circ_0000592 countered the inhibitory effects on the target gene Frizzled 5 (FZD5) through interactions with miR-155-5p. The overexpression of miR-155-5p curtailed the luciferase activity of circ_0000592 in ESCC cells, inhibiting downstream molecule FZD5 protein expression and subsequently mitigating the detrimental consequences of escalated circ_0000592 expression in ESCC cells. Consistently, circ_0000592 downregulation curbed proliferation and metastasis of ESCC tumors in vivo. In summary, circ_0000592 promoted the progress of ESCC by counteracting the inhibitory impact on FZD5 through its interaction with miR-155-5p. Together, our findings highlighted circ_0000592 as a prospective therapeutic target for ESCC.

The clinical regimens and cell membrane camouflaged nanodrug delivery systems in hematologic malignancies treatment.

Hematologic malignancies (HMs), also referred to as hematological or blood cancers, pose significant threats to patients as they impact the blood, bone marrow, and lymphatic system. Despite significant clinical strategies using chemotherapy, radiotherapy, stem cell transplantation, targeted molecular therapy, or immunotherapy, the five-year overall survival of patients with HMs is still low. Fortunately, recent studies demonstrate that the nanodrug delivery system holds the potential to address these challenges and foster effective anti-HMs with precise treatment. In particular, cell membrane camouflaged nanodrug offers enhanced drug targeting, reduced toxicity and side effects, and/or improved immune response to HMs. This review firstly introduces the merits and demerits of clinical strategies in HMs treatment, and then summarizes the types, advantages, and disadvantages of current nanocarriers helping drug delivery in HMs treatment. Furthermore, the types, functions, and mechanisms of cell membrane fragments that help nanodrugs specifically targeted to and accumulate in HM lesions are introduced in detail. Finally, suggestions are given about their clinical translation and future designs on the surface of nanodrugs with multiple functions to improve therapeutic efficiency for cancers.

Radiation-primed TGF-ß trapping by engineered extracellular vesicles for targeted glioblastoma therapy.

The poor outcome of glioblastoma multiforme (GBM) treated with immunotherapy is attributed to the profound immunosuppressive tumor microenvironment (TME) and the lack of effective delivery across the blood-brain barrier. Radiation therapy (RT) induces an immunogenic antitumor response that is counteracted by evasive mechanisms, among which transforming growth factor-ß (TGF-ß) activation is the most prominent factor. We report an extracellular vesicle (EV)-based nanotherapeutic that traps TGF-ß by expressing the extracellular domain of the TGF-ß type II receptor and targets GBM by decorating the EV surface with RGD peptide. We show that short-burst radiation dramatically enhanced the targeting efficiency of RGD peptide-conjugated EVs to GBM, while the displayed TGF-ß trap reversed radiation-stimulated TGF-ß activation in the TME, offering a synergistic effect in the murine GBM model. The combined therapy significantly increased CD8+ cytotoxic T cells infiltration and M1/M2 macrophage ratio, resulting in the regression of tumor growth and prolongation of overall survival. These results provide an EV-based therapeutic strategy for immune remodeling of the GBM TME and eradication of therapy-resistant tumors, further supporting its clinical translation.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via avß3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

Manganese dioxide nanoparticles provoke inflammatory damage in BV2 microglial cells via increasing reactive oxygen species to activate the p38 MAPK pathway.

With the widespread use of manganese dioxide nanoparticles (nano MnO2), health hazards have also emerged. The inflammatory damage of brain tissues could result from nano MnO2, in which the underlying mechanism is still unclear. During this study, we aimed to investigate the role of ROS-mediated p38 MAPK pathway in nano MnO2-induced inflammatory response in BV2 microglial cells. The inflammatory injury model was established by treating BV2 cells with 2.5, 5.0, and 10.0 µg/mL nano MnO2 suspensions for 12 h. Then, the reactive oxygen species (ROS) scavenger (20 nM N-acetylcysteine, NAC) and the p38 MAPK pathway inhibitor (10 µM SB203580) were used to clarify the role of ROS and the p38 MAPK pathway in nano MnO2-induced inflammatory lesions in BV2 cells. The results indicated that nano MnO2 enhanced the expression of pro-inflammatory cytokines IL-1ß and TNF-α, elevated intracellular ROS levels and activated the p38 MAPK pathway in BV2 cells. Controlling intracellular ROS levels with NAC inhibited p38 MAPK pathway activation and attenuated the inflammatory response induced by nano MnO2. Furthermore, inhibition of the p38 MAPK pathway with SB203580 led to a decrease in the production of inflammatory factors (IL-1ß and TNF-α) in BV2 cells. In summary, nano MnO2 can induce inflammatory damage by increasing intracellular ROS levels and further activating the p38 MAPK pathway in BV2 microglial cells.

Emerging Strategies to Overcome Current CAR-T Therapy Dilemmas - Exosomes Derived from CAR-T Cells.

Adoptive T cells immunotherapy, specifically chimeric antigen receptor T cells (CAR-T), has shown promising therapeutic efficacy in the treatment of hematologic malignancies. As extensive research on CAR-T therapies has been conducted, various challenges have emerged that significantly hampered their clinical application, including tumor recurrence, CAR-T cell exhaustion, and cytokine release syndrome (CRS). To overcome the hurdles of CAR-T therapy in clinical treatment, cell-free emerging therapies based on exosomes derived from CAR-T cells have been developed as an effective and promising alternative approach. In this review, we present CAR-T cell-based therapies for the treatment of tumors, including the features and benefits of CAR-T therapies, the limitations that exist in this field, and the measures taken to overcome them. Furthermore, we discuss the notable benefits of utilizing exosomes released from CAR-T cells in tumor treatment and anticipate potential issues in clinical trials. Lastly, drawing from previous research on exosomes from CAR-T cells and the characteristics of exosomes, we propose strategies to overcome these restrictions. Additionally, the review discusses the plight in large-scale preparation of exosome and provides potential solutions for future clinical applications.

Synthesis of compounds based on the active domain of cabotegravir and their application in inhibiting tumor cells activity.

Structural modification based on existing drugs, which ensures the safety of marketed drugs, is an essential approach in developing new drugs. In this study, we modified the structure of cabotegravir by introducing the front alkyne on the core structure through chemical reaction, resulting in the synthesis of 9 compounds resembling 1,2,3-triazoles. The potential of these new cabotegravir derivatives as tumor suppressors in gastrointestinal tumors was investigated. Based on the MTT experiment, most compounds showed a reduction in the viability of KYSE30 and HCT116 cells. Notably, derivatives 5b and 5h exhibited the most significant inhibitory effects. To further explore the effects of derivatives 5b and 5h on gastrointestinal tumors, KYSE30 cells were chosen as a representative cell line. Both derivatives can effectively curtail the migration and invasion capabilities of KYSE30 cells and induce apoptosis in a dose-dependent manner. We further demonstrated these derivatives induce cell apoptosis in KYSE30 cells by inhibiting the expression of Stat3 protein and Smad2/3 protein. Based on the above results, we suggest they show promise in developing drugs for esophageal squamous cell carcinoma.

Circ_0023990 Promotes the Proliferation, Invasion, and Glycolysis of Esophageal Squamous Cell Carcinoma Cells Via Targeting miR-6884-5p/PAK1 Axis.

Circular RNAs are emerging players in human cancers, including esophageal squamous cell carcinoma (ESCC). Herein, we assessed the expression level of circ_0023990 and explored the molecular mechanisms of circ_0023990 in ESCC. circ_0023990, miR-6884-5p, and PAK1 expressions in ESCC tissues and cells were detected by quantitative real-time polymerase chain reaction and western blot. ESCC cells were transfected with different constructs to alter the expression of circ_0023990, miR-6884-5p, and PAK1. The effect of circ_0023990 on the proliferation, invasion, and glycolysis of ESCC cells was observed. The interaction between circ_0023990 and miR-6884-5p and between miR-6884-5p and PAK1 were explored. A mouse model of ESCC was established to study the in vivo effect of circ_0023990 knockdown on tumor formation.The expression levels of circ_0023990 was upregulated in ESCC tissues and cells. Inhibiting circ_0023990 suppressed the proliferation, invasion, and glycolysis of ESCC cells. circ_0023990 might target miR-6884-5p and consequently modulate the expression and activity of PAK1. Knockdown of circ_0023990 led to significantly reduced tumor volume and weight in mice with ESCC.These findings overall suggest an oncogenic role of circ_0023990 in ESCC. Future research is warranted to confirm the expression pattern and clinical significance of circ_0023990 in ESCC.

Spindle and kinetochore-related complex subunit 3 has a protumour function in osteosarcoma by activating the Notch pathway.

Increasing expression of spindle and kinetochore-related complex subunit 3 (SKA3) is related to the progression of multiple malignancies. However, the role of SKA3 in osteosarcoma remains unexplored. The present study aimed to investigate the relevance of SKA3 in osteosarcoma. Preliminarily, SKA3 expression in osteosarcoma was assessed through The Cancer Genome Atlas (TCGA) analysis, which revealed high levels of SKA3 transcripts in osteosarcoma tissues. Subsequent examination of clinical tissues confirmed the abundant expression of SKA3 in osteosarcoma. Downregulation of SKA3 expression in osteosarcoma cell lines resulted in repressive effects on cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), while upregulation of SKA3 expression had the opposite effect. Gene set enrichment analysis (GSEA) revealed that the Notch pathway is enriched in SKA3 high groups based on different expressed genes from the TCGA data. Further investigation showed that the levels of Notch1, Notch1 intracellular domain (NICD1), hairy and enhancer of split 1 (HES1), and hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) were downregulated in SKA3-silenced osteosarcoma cells, and upregulated in SKA3-overexpressed osteosarcoma cells. Activation of the Notch pathway by increasing NICD1 expression reversed the antitumour effects induced by SKA3 silencing, while deactivation of the Notch pathway diminished the protumour effects induced by SKA3 overexpression. Moreover, SKA3-silenced osteosarcoma cells exhibited a reduced capacity for xenograft formation in nude mice. In conclusion, SKA3 plays a cancer-enhancing role in osteosarcoma through its effect on the Notch pathway. Reducing the expression of SKA3 could be a potential therapeutic approach for treating osteosarcoma.

Engineered mRNA Delivery Systems for Biomedical Applications.

Messenger RNA (mRNA)-based therapeutic strategies have shown remarkable promise in preventing and treating a staggering range of diseases. Optimizing the structure and delivery system of engineered mRNA has greatly improved its stability, immunogenicity, and protein expression levels, which has led to a wider range of uses for mRNA therapeutics. Herein, a thorough analysis of the optimization strategies used in the structure of mRNA is first provided and delivery systems are described in great detail. Furthermore, the latest advancements in biomedical engineering for mRNA technology, including its applications in combatting infectious diseases, treating cancer, providing protein replacement therapy, conducting gene editing, and more, are summarized. Lastly, a perspective on forthcoming challenges and prospects concerning the advancement of mRNA therapeutics is offered. Despite these challenges, mRNA-based therapeutics remain promising, with the potential to revolutionize disease treatment and contribute to significant advancements in the biomedical field.

Codelivery of CuS and DOX into Deep Tumors with Size and Charge-Switchable PAMAM Dendrimers for Chemo-photothermal Therapy.

Accurate targeting of therapeutic agents to specific tumor tissues, especially via deep tumor penetration, has been an effective strategy in cancer treatments. Here, we described a flexible nanoplatform, pH-responsive zwitterionic acylsulfonamide betaine-functionalized fourth-generation PAMAM dendrimers (G4-AB), which presented multiple advantages for chemo-photothermal therapy, including template synthesis of ultrasmall copper sulfide (CuS) nanoparticles and further encapsulation of doxorubicin (DOX) (G4-AB-DOX/CuS), long-circulating performance by a relatively large size and zwitterionic surface in a physiological environment, combined size shrinkage, and charge conversions via pH-responsive behavior in an acidic tumor microenvironment (TME). Accordingly, high tumor penetration and positive cell uptake for CuS and DOX have been determined, which triggered an excellent combination treatment under near-infrared irradiation in comparison to the monochemotherapy system and irresponsive chemo-photothermal system. Our study represented great promise in constructing multifunctional carriers for the effective delivery of photothermal nanoparticles and drugs in chemo-photothermal therapy.

[Effectiveness of dorsal perforator flap of cross-finger proper digital artery in treatment of high-pressure injection injuries of the finger].

Objective: To investigate the effectiveness of dorsal perforator flap of cross-finger proper digital artery in the treatment of finger soft tissue defect caused by high-pressure injection injury. Methods: Between July 2011 and June 2020, 14 cases of finger soft tissue defect caused by high-pressure injection injury were repaired with dorsal perforator flap of cross-finger proper digital artery. All patients were male, with a mean age of 36 years (range, 22-56 years). The defects were located on the index finger in 8 cases, middle finger in 4 cases, and ring finger in 2 cases. The causes of injury include 8 cases of emulsion paint injection, 4 cases of oil paint injection, and 2 cases of cement injection. The time from injury to debridement was 2-8 hours, with a mean time of 4.5 hours. The soft tissue defects sized from 4.0 cm×1.2 cm to 6.0 cm×2.0 cm. The flaps sized from 4.5 cm×1.5 cm to 6.5 cm×2.5 cm. The donor site of the flap was repaired with skin graft. The pedicle was cut off at 3 weeks after operation, and followed by functional exercise. Results: All flaps and skin grafts at donor sites survived, and the wounds healed by first intention. Twelve patients were followed-up 16-38 months (mean, 22.6 months). The texture and appearance of all flaps were satisfactory. The color and texture of the flaps were similar to those of the surrounding tissues. The two-point discrimination of the flap was 10-12 mm, with a mean of 11.5 mm. There were different degrees of cold intolerance at the end of the affected fingers. At last follow-up, the finger function was evaluated according to the Upper Extremity Functional Evaluation Standard set up by Hand Surgery Branch of Chinese Medical Association, 3 cases were excellent, 8 cases were good, and 1 case was poor. Conclusion: The dorsal perforator flap of cross-finger proper digital artery can effectively repair finger soft tissue defect caused by high-pressure injection injury. The operation was simple, and the appearance and function of the finger recover well.

Mesenchymal stromal cell-derived magnetic nanovesicles for enhanced skin retention and hair follicle growth.

BACKGROUND AIMS: Extracellular vesicles and exosome-mimetic nanovesicles (NVs) derived from mesenchymal stromal cells (MSCs) have emerged as promising to promote hair growth. However, short local skin retention after subcutaneous administration hinders their clinical applications. METHODS: In this study, we prepared magnetic nanovesicles (MNVs) from iron oxide nanoparticle-incorporated MSCs. MNVs contained more therapeutic growth factors than NVs derived from naive MSCs, and their localization and internalization were manipulated by external magnetic field. RESULTS: Following the subcutaneous injection of MNVs into a mouse model of depilation-induced hair regeneration, the magnetic attraction increased their skin retention. Then, the cellular proliferation and ß-catenin signaling in hair follicles (HF) were markedly enhanced by MNV injection and magnetic field application. Furthermore, an acceleration of HF growth was revealed by histological analysis. CONCLUSIONS: The proposed strategy can enhance the therapeutic potential of MSC-derived NVs for hair regeneration and other dermatological diseases.

Selective activation of TGFß signaling by P. gingivalis-mediated upregulation of GARP aggravates esophageal squamous cell carcinoma.

Aberrant TGFß signaling plays critical roles in the progression of multiple cancers; however, the functional mechanism of this signaling network in the infectious milieu of Esophageal Squamous Cell Carcinoma (ESCC) remains largely unknown. In this study, by using global transcriptomic analysis, we found that Porphyromonas gingivalis infection increased TGFß secretion and promoted the activation of TGFß/Smad signaling in cultured cells and in clinical ESCC samples. Furthermore, we demonstrated for the first time that P. gingivalis enhanced the expression of Glycoprotein A repetitions predominant (GARP), thereby activating TGFß/Smad signaling. Moreover, the increased GARP expression and the subsequent TGFß activation was partially dependent on the fimbriae (FimA) of P. gingivalis. Intriguingly, eliminating P. gingivalis, inhibiting TGFß, or silencing GARP led to a decreased phosphorylation of Smad2/3, the central mediator of TGFß signaling, as well as an attenuated malignant phenotype of ESCC cells, indicating that the activation of TGFß signaling could be an adverse prognostic factor of ESCC. Consistently, our clinical data demonstrated that the phosphorylation of Smad2/3 and the expression of GARP were positively correlated to the poor prognosis of ESCC patients. Lastly, using xenograft models, we found that P. gingivalis infection remarkably activated TGFß signaling and subsequently enhanced the tumor growth and lung metastasis. Collectively, our study indicated that TGFß/Smad signaling mediates the oncogenic function of P. gingivalis in ESCC, which is augmented by the expression of GARP. Therefore, targeting either P. gingivalis or GARP-TGFß signaling could be a potential treatment strategy for patients with ESCC.

The combined effect and mechanism of antiangiogenic drugs and PD-L1 inhibitor on cell apoptosis in triple negative breast cancer.

Background: Breast cancer is the most common cancer worldwide, and triple-negative breast cancer (TNBC) has the worst prognosis. Standard systemic treatment includes chemotherapy and immunotherapy. Poly ADP-ribose polymerase (PARP) inhibitors are considered in breast cancer (BRCA) susceptibility genes mutated tumors. The role of antiangiogenic drugs is controversial. Immunotherapy with immune checkpoint inhibitor is now a standard of care for TNBC in the US, but its use in combination with anlotinib, an inhibitor of angiogenesis, on TNBC cells was never investigated. Methods: We tested the effects of anlotinib and programmed cell death-ligand 1 (PD-L1) inhibitor on the proliferation, apoptosis, migration, and invasion of MDA-MB-468 and BT-549 TNBC cells through 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assays, cell apoptosis assay, wound healing and transwell matrix assays, and verified whether the combination of the two drugs had synergistic effect. Western blotting was used to detect the effect of anlotinib and PD-L1 inhibitor on the protein expression levels of PI3K, p-PI3K, AKT, p-AKT, Bcl-xl in MDA-MB-468 and BT-549 cells. The effects of anlotinib, PD-L1 inhibitor and the combination of the two drugs on the transplanted tumor of TNBC mice were tested by animal experiments. Results: Anlotinib and PD-L1 inhibitor inhibited the proliferation and promote cell apoptosis of MDA-MB-468 and BT-549 cells, and the combination demonstrated the synergetic effect. Anlotinib and PD-L1 inhibitor inhibited cell migration and invasion, and the effect was strongest in the combination group. Both anlotinib and PD-L1 inhibitor reduced the expression of p-PI3K, p-AKT and Bcl-xl proteins in cells and the effects were the strongest in the combination group. Both anlotinib and PD-L1 inhibitor inhibited the growth of transplanted tumors in mice, and the combined group demonstrated the strongest growth suppression. Conclusions: Anlotinib and PD-L1 inhibitor can inhibit cell proliferation, migration, and invasion of TNBC and promote cell apoptosis, and the two drugs show combined anti-tumor effects in vivo and in vitro. The combination of anlotinib and PD-L1 inhibitor may promote apoptosis of TNBC cells through PI3K/AKT/Bcl-xl signaling pathways, which might offer potential clinical treatment roles for these.

Exosomal PD-L1 confers chemoresistance and promotes tumorigenic properties in esophageal cancer cells via upregulating STAT3/miR-21.

Chemotherapy resistance remains a major obstacle in the treatment of esophageal cancer. Previous researches have shown that an increase in exosomal PD-L1 expression was positively associated with a more advanced clinical stage, a poorer prognosis as well as drug resistance in patients with esophageal squamous cell carcinoma (ESCC). To explore the role of exosomal PD-L1 in ESCC, we performed bioinformatics analysis as well as several in vitro/in vivo functional experiments in a parental sensitive cell line EC-9706 and its derivative, a paclitaxel-resistant subline EC-9706R, and found that the exosomal PD-L1 from EC-9706R was higher than that from EC-9706. Moreover, exosomes from EC-9706R significantly increased invasion, migration and chemoresistance of EC-9706. Anti-PD-L1 treatment in combination with chemotherapy also led to reduced tumor burden in vivo. Inhibition of the release of exosomes by GW4869 or inhibition of STAT3 phosphorylation by stattic could effectively reverse the resistance to paclitaxel mediated by exosomal PD-L1. Furthermore, we found that PD-L1, miR-21, and multidrug resistance (MDR1) gene are involved in the process of exosomal transfer. Moreover, PD-L1 could enhance miR-21 expression by increasing the enrichment of STAT3 on miR-21 promoter. Our results suggested that exosomal PD-L1 may contribute to drug resistance to paclitaxel by regulating the STAT3/miR-21/PTEN/Akt axis and promote tumorigenic phenotype. This study provides a novel potential therapeutic approach to reverse chemoresistance and tumor progression through exosomal PD-L1 in ESCC patients.

Evaluating the predictive significance of systemic immune-inflammatory index and tumor markers in lung cancer patients with bone metastases.

Objective: This study aims to develop a predictive model for identifying lung cancer patients at elevated risk for bone metastases, utilizing the Unified Immunoinflammatory Index and various tumor markers. This model is expected to facilitate timely and effective therapeutic interventions, especially in the context of the growing significance of immunotherapy for lung cancer treatment. Methods: A retrospective analysis was conducted on 324 lung cancer patients treated between January 2019 and January 2021. After meeting the inclusion criteria, 241 patients were selected, with 56 exhibiting bone metastases. The cohort was divided into a training group (169 patients) and a validation group (72 patients) at a 7:3 ratio. Lasso regression was employed to identify critical variables, followed by logistic regression to construct a Nomogram model for predicting bone metastases. The model's validity was ascertained through internal and external evaluations using the Concordance Index (C-index) and Receiver Operating Characteristic (ROC) curve. Results: The study identified several factors influencing bone metastasis in lung cancer, such as the Systemic Immune-Inflammatory Index (SII), Carcinoembryonic Antigen (CEA), Neuron Specific Enolase (NSE), Cyfra21-1, and Neutrophil-to-Lymphocyte Ratio (NLR). These factors were incorporated into the Nomogram model, demonstrating high validation accuracy with C-index scores of 0.936 for internal and 0.924 for external validation. Conclusion: The research successfully developed an intuitive and accurate Nomogram prediction model utilizing clinical indicators to predict the risk of bone metastases in lung cancer patients. This tool can be instrumental in aiding clinicians in developing personalized treatment plans, thereby optimizing patient outcomes in lung cancer care.

Inflammation-based prognostic scoring system for predicting the prognosis of advanced small cell lung cancer patients receiving anlotinib monotherapy.

BACKGROUND: According to the randomized multicenter phase II trial (ALTER1202), anlotinib has been approved as a third-line therapy for advanced small-cell lung cancer (SCLC). Some studies showed the predictive function of inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in the different cancers treated with anti-vascular targeting drugs. However, none of the studies showed the roles of NLR, PLR, and LMR in SCLC patients receiving anlotinib. Thus, our objective was to establish a scoring system based on inflammation to individuate patient stratification and selection based on NLR, PLR, and LMR. METHODS: NLR, PLR, and LMR and their variations were calculated in 53 advanced SCLC patients receiving anlotinib as a third- or further-line treatment at Ningbo Medical Center Lihuili Hospital between January 2019 and December 2021. Kaplan-Meier curves were plotted. Both univariate and multivariate Cox regressions were used to identify predictors of survival. RESULTS: Disease control rate was related to pre-NLR, pre-PLR, pre-LMR, post-NLR elevation, post-PLR elevation, and post-LMR elevation. The multivariate analysis determined post-NLR elevation, pre-PLR > 240.56, and pre-LMR ≤1.61 to be independently associated with progression-free survival, not overall survival. The inflammation-based prognostic scoring system demonstrated favorable predictive ability from the receiver operating characteristic curve (AUC: 0.791, 95% CI: 0.645-0.938). CONCLUSIONS: Post-NLR variation, pre-PLR, and pre-LMR were independent prognostic factors for PFS in advanced SCLC receiving anlotinib monotherapy. The inflammation-based prognostic scoring system can accurately predict effectiveness and survival.