Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR-RUNX1.

Tumor-derived factors are thought to regulate thrombocytosis and erythrocytopenia in individuals with cancer; however, such factors have not yet been identified. Here we show that tumor cell-released kynurenine (Kyn) biases megakaryocytic-erythroid progenitor cell (MEP) differentiation into megakaryocytes in individuals with cancer by activating the aryl hydrocarbon receptor-Runt-related transcription factor 1 (AhR-RUNX1) axis. During tumor growth, large amounts of Kyn from tumor cells are released into the periphery, where they are taken up by MEPs via the transporter SLC7A8. In the cytosol, Kyn binds to and activates AhR, leading to its translocation into the nucleus where AhR transactivates RUNX1, thus regulating MEP differentiation into megakaryocytes. In addition, activated AhR upregulates SLC7A8 in MEPs to induce positive feedback. Importantly, Kyn-AhR-RUNX1-regulated MEP differentiation was demonstrated in both humanized mice and individuals with cancer, providing potential strategies for the prevention of thrombocytosis and erythrocytopenia.

Clinical Correlation of Function and TCR vß Diversity of MAGE-C2-Specific CD8+ T Cell Response in Esophageal Cancer.

Melanoma-associated Ag (MAGE)-C2, an immunogenic cancer germline (testis) Ag, is highly expressed by various tumor cells, thymic medullary epithelial cells, and germ cells. In this study, we aimed to explore the immunologic properties of MAGE-C2-specific CD8+ T cells and the relationship of its TCR ß-chain V region (TCR vß) subfamily distribution to prognosis of patients with esophageal cancer. PBMCs and tumor-infiltrating lymphocytes expanded by CD3/CD28 Dynabeads and MAGE-C2 peptides in vitro resulted in the induction of lysosome-associated membrane protein-1 (LAMP-1 or CD107a) on the cell surface and the production of IFN-γ by MAGE-C2-specific CD8+ T cells. We found differential TCR vß subfamily distribution among flow-sorted CD107a+IFN-γ+ and CD107a-IFN-γ- CD8+ T cells. The proportion of CD107a+ and/or IFN-γ+ tetramer+ CD8+ T cells was lower in patients with lymph node metastasis, late tumor stage, and poorly differentiated state (p < 0.05). T-box transcription factor was positively correlated with CD107a and IFN-γ. Kaplan-Meier analysis showed that patients whose MAGE-C2-specific CD8+ T cells expressed high CD107a and/or IFN-γ had a longer survival time when compared with patients whose MAGE-C2-specific CD8+ T cells expressed low levels of CD107a and/or IFN-γ. Moreover, analysis of TCR vß subfamily distribution revealed that a higher frequency of TCR vß16 in MAGE-C2-specific CD8+ T cells was positively correlated with a better prognosis. These results suggest that the presence of functional MAGE-C2-specific CD8+ T cells had an independent prognostic impact on the survival of patients with esophageal cancer.

Immuno-oncological role of 20S proteasome alpha-subunit 3 in aggravating the progression of esophageal squamous cell carcinoma.

PSMA3, a member of the proteasome subunit, has been shown to play a major player in protein degradation. Reportedly, PSMA3 functions as a negative regulator in various cancers including colon, pancreatic and gastric cancers. However, the contributions of PSMA3 to the progression of esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remain unclear. Therefore, in this study, we investigated whether PSMA3 is involved in ESCC progression and the potential underlying mechanism. The results revealed that PSMA3 was highly expressed in the ESCC tumor tissues and functioned as a negative indicator according to the data from The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) datasets and clinical patients' samples. Pathway enrichment analysis showed that PSMA3 was closely correlated with ESCC cancer stemness and the inflammatory response; however, this correlation was absent after knockdown of PSMA3 in vitro. We further demonstrated that PSMA3 suppressed CD8+ T-cells infiltration depending on the C-C motif chemokine ligand 3 (CCL3)/C-C motif chemokine receptor 5 (CCR5) axis. Collectively, these results demonstrate the role of PSMA3 in ESCC cancer stemness and the negative regulation of CD8 T-cells infiltration mediated by PSMA3. The results of this study may provide a potential target for the immuno-oncology effect of PSMA3 in ESCC therapy.

Dynamic Hydrogen-Bond Network as a Modulator of Bismuth-Antimony Complex Anodes for Self-Healable and Wider Temperature Adaptive Potassium Ion Batteries.

Antimony (Sb)-based anodes are attractive candidates in potassium-ion batteries (PIBs) due to their superior capacities and rational potassium inserting voltages. However, the sluggish kinetics and poor interface compatibility severely hinder practical application. Herein, Bi0.67 Sb1.33 S3 nanospheres embedded into in situ formed poly(3,4-ethylenedioxythiophene) crosslinked with polythioctic acid (PET@PTA) (Bi0.67 Sb1.33 S3 /PET@PTA) were elaborately conceptualized with hydrogen bonds exchangeable binding (HBEB) sites. Bi0.67 Sb1.33 S3 /PET@PTA exhibits notable self-healing ability and wider temperature adaptability. Bi0.67 Sb1.33 S3 /PET@PTA displays an impressive capacity of 819 mAh g-1 at 0.05 A g-1 , prominent cycle ability with a 73 % capacity conservation after 500 cycles at 2 A g-1 , and high capacity retention of 66 % and 84 % at -40 and 70 °C to that case at room temperature, respectively, for potassium storage. This work provides a new perspective for HBEB sites in maximizing the desirable K+ storage performance.

Long-term clinical efficacy of cytokine-induced killer cell-based immunotherapy in early-stage esophageal squamous cell carcinoma.

BACKGROUND AIMS: In this retrospective clinical study, the authors investigated the impact of cytokine-induced killer (CIK) cell-based immunotherapies on the long-term survival of patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 87 patients with ESCC who received comprehensive treatment were enrolled in the study. Of these patients, 43 were in the control group and 44 were in the CIK treatment group. Flow cytometry analysis was performed to detect the phenotype and anti-tumor function of CIK cells. Clinical characteristics were compared between these two groups, and the survival estimates of ESCC patients were determined using Kaplan-Meier analysis. RESULTS: CIK cells contained a high proportion of the main functional fraction (CD3+CD56+ group) and exhibited a strong killing ability for esophageal cancer cells in vitro. Importantly, overall survival (OS) and progression-free survival (PFS) were significantly higher in the CIK group than in the control group in early-stage ESCC. However, patients with advanced-stage ESCC did not benefit from CIK cell-based therapy in terms of OS and PFS compared with the control group. CONCLUSIONS: These results demonstrate that CIK cells combined with conventional treatments potentially prolong long-term survival of patients and may serve as a combined therapeutic approach for the treatment of early-stage ESCC.

Comprehensive genomic and immunophenotypic analysis of CD4 T cell infiltrating human triple-negative breast cancer.

The aim of this study is to investigate the gene expression module of tumor-infiltrating CD4+T cells and its potential roles in modulating immune cell functions in triple-negative breast cancer. Differentially expressed genes were identified by comparison of the expression profile in CD4+T cells isolated from tumor tissues and peripheral blood of TNBC patients respectively. The differential expression analysis was conducted using R, and then the functional and pathway enrichment of the DEGs were analyzed using GSEA, followed by integrated regulatory network construction and genetic analysis of tumor-infiltrating immune cells based on a scientific deconvolution algorithm. As a result, abundant Treg and exhausted lymphocytes were detected, accompanied by largely decreased of effector/memory and cytotoxic T cells. Immune-related gene correlation analysis showed that the extent of follicular helper T cells gene expression signatures were inversely associated with those of CD4+ naive T cells and CD4+ memory resting T cells, but positively correlated with that of CD4+ memory activated T cells. In addition, we found five core genes including IFNG, CTLA4, FAS, CXCR6, and JUN were significantly over expressed in CD4+ TILs which may contribute to exhaustion of lymphocytes and participate in biological processes associated with regulation of chemotaxis. Study provides a comprehensive understanding of the roles of DEGs associated with the chemotactic and exhausted immunophenotypes of CD4+ TILs that are a valuable resource from which future investigation may be carried out to better understand the mechanisms that promote TNBC progression.

Regulatory T cells promote glioma cell stemness through TGF-ß-NF-κB-IL6-STAT3 signaling.

Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-ß secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-ß acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB-IL6-STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-ß were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.

Organic-Inorganic Hybridization Engineering of Polyperylenediimide Cathodes for Efficient Potassium Storage.

Polyperylenediimide (PDI) is always subject to its modest conductivities, limited reversible active sites and inferior stability for potassium storage. To address these issues, herein, we firstly propose an organic-inorganic hybrid (PDI@Fe-Sn@N-Ti3 C2 Tx ), where Fe/Sn single atoms are bound to the N-doped MXenes (N-Ti3 C2 Tx ) via the unsaturated Fe/Sn-N3 bonds, and functionalized with PDI via d-π hybridization, forming a high conjugated δ skeleton. The resulted hybrid cathode endowed with enhanced electronic/ionic conductivities, lowered dissociation barriers of multiple redox centers and a stable cathode electrolyte interphase layer displays a 14-electron involved high-rate capacities and long cycle life. Moreover, it shows competitive performance in full cells even under different folding states and low operating temperatures.

Interleukin-33-nuclear factor-κB-CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by directing regulatory T cells.

Esophageal cancer is currently one of the most fatal cancers. However, there is no effective treatment. Increasing evidence suggests that interleukin (IL)-33 has a significant role in tumor progression and metastasis. Currently, the underlying cellular and molecular mechanism of IL-33 in promoting esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we investigated whether IL-33 could induce the epithelial-mesenchymal transition (EMT) in ESCC. Interleukin-33 expression was examined in ESCC and corresponding adjacent normal tissues by immunohistochemistry and quantitative real-time PCR experiments. Elevated IL-33 levels were observed in ESCC tissues. Further in vitro experiments were undertaken to elucidate the effect of IL-33 on migration and invasion in KYSE-450 and Eca-109 esophageal cancer cells. Knockdown of IL-33 decreased the metastasis and invasion capacity in esophageal cancer cells, whereas IL-33 overexpression showed the opposite effect. We then screened CCL2 which is a downstream molecule of IL-33, and proved that IL-33 could promote tumor development and metastasis by recruiting regulatory T cells (Tregs) through CCL2, and IL-33 regulated the expression of CCL2 through transforming growth factor-ß in Treg cells. Knockdown of IL-33 decreased the development of human ESCC xenografts in BALB/c nude mice. Collectively, we found that the IL-33/nuclear factor-κB/CCL2 pathway played an essential role in human ESCC progress. Hence, IL-33 should be considered as an effective therapy target for ESCC.

miR-143 Regulates Memory T Cell Differentiation by Reprogramming T Cell Metabolism.

MicroRNAs are an important regulator for T cell immune response. In this study, we aimed to identify microRNAs with the potential to regulate T cell differentiation. The influence of miR-143 on differentiation and function of CD8+ T cells from healthy donors were detected, and it was found that miR-143 overexpression could significantly increase the differentiation of central memory T (Tcm) CD8+ cells, decrease cell apoptosis, and increase proinflammatory cytokine secretion. Furthermore, the specific killing of HER2-CAR T cells against esophageal cancer cell line TE-7 was enhanced by miR-143 overexpression. Glucose transporter 1 (Glut-1) was identified as the critical target gene of miR-143 in the role of T cell regulation. By inhibition Glut-1, miR-143 inhibited glucose uptake and glycolysis in T cell to regulated T cell differentiation. Tcm cell populations were also suppressed in parallel with the downregulation of miR-143 in tumor tissues from 13 patients with esophagus cancer. IDO and its metabolite kynurenine in the tumor microenvironment were screened as an upstream regulator of miR-143. IDO small interfering RNA significantly increased the expression of miR-143 and Tcm cell population. In conclusion, our results show that miR-143 enhanced antitumor effects of T cell by promoting memory T cell differentiation and metabolism reprogramming through Glut-1. Our findings will encourage the development of new strategies targeting miR-143 in both cancer cells and T cells.

A cycle involving HMGB1, IFN-γ and dendritic cells plays a putative role in anti-tumor immunity.

An important subset in regulating antitumor immunity is the maturation and accumulation of intratumor dendritic cells (DCs), inducing potent T cell cytotoxicity. In this study, we explored how the soluble abundant high-mobility group box 1 protein (HMGB1) affected DC activation and retention within lung cancers, and in which way the resultant interferon-γ (IFN-γ) further enhanced DC maturation and accumulation. It was discovered that HMGB1 was correlated with DC markers HLA-DR and CD86 in lung cancers at both mRNA and protein level. Further analyses showed HMGB1 enhanced the maturation of DCs, indicated by upregulated IFN-γ in CD8+ T cells. Additionally, HMGB1 increased the accumulation of DCs by promoting CCR5 and CXCR3 production. Moreover, the resultant IFN-γ elevated the levels of HMGB1 and DC-associated chemokines, CCL5, CXCL10 and CXCL11 in tumor cells. Hence, the HMGB1-IFN-γ cycle may represent an important mechanism underlying DC-mediated anti-tumor immune response.

Dual TGF-ß and PD-1 blockade synergistically enhances MAGE-A3-specific CD8+ T cell response in esophageal squamous cell carcinoma.

PD-1 is highly expressed on tumor-infiltrated antigen-specific T cells and limit the antitumor function. Blocking of PD-1/PD-L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE-A3-specific CD8+ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE-A3-specific CD8+ T cells function in tumor microenvironment (TME) was evaluated. MAGE-A3-specific CD8+ T cells could lyse HLA-A2+ /MAGE-A3+ tumor cells. Tetramer+ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107ahigh expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD-1 was highly expressed on dysfunctional antigen-specific CD8+ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid-derived suppressor cells (MDSCs) derived-TGF-ß mediated PD-1high expression on CD8+ T cells, which led to be resistance to PD-1/PD-L1 blockade in TME. Dual PD-1/PD-L1 and TGF-ß signaling pathway blockades synergistically restored the function and antitumor ability of antigen-specific CD8+ T cells in vitro/vivo assay. The presence of functional MAGE-A3-specific CD8+ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs-derived TGF-ß increased PD-1 expression on T cells and decreased the sensitivity to PD-1/PD-L1 blockade. Combining T cell-based therapy with dual PD-1/PD-L1 and TGF-ß signaling pathway blockade could be considered a promising strategy for cancer treatment.

WASH overexpression enhances cancer stem cell properties and correlates with poor prognosis of esophageal carcinoma.

There is increasing evidence that cytoskeleton remodeling is involved in cancer progression. Wiskott-Aldrich syndrome protein (WASP) family represents a key regulator of actin cytoskeleton remodeling. However, the underlying mechanism of the WASP family in cancer progression remains elusive. Here, we studied the role of WASP and SCAR Homolog (WASH), a recently identified WASP family member, in human esophageal squamous cell carcinoma (ESCC). Using three human ESCC cell lines, we found that WASH expression was significantly elevated in cancer stem-like cells enriched by sphere formation assay. WASH knockdown decreased the sphere-forming capacity of esophageal cancer cells whereas WASH over-expression exhibited the opposite effect. Mechanistically, we identified interleukin-8 (IL-8) as a key downstream target of WASH. IL-8 knockdown completely attenuated tumor sphere formation induced by WASH overexpression. WASH knockdown also delayed the growth of human ESCC xenografts in BALB/c nude mice. Importantly, high WASH levels were associated with poor clinical prognosis in a total of 145 human ESCC tissues. Collectively, our results suggest an essential role of the WASH/IL-8 pathway in human ESCC by maintaining the stemness of cancer cells. Hence, targeting this pathway might represent a promising strategy to control human esophageal carcinoma.

Rab11-FIP2 promotes the metastasis of gastric cancer cells.

Rab11-FIP2 can interact with MYO5B and plays an important role in regulating plasma membrane recycling. Our previous study has shown that MYO5B is epigenetically silenced and associated with c-Met signaling in human gastric cancer. However, little is known of the function of Rab11-FIP2 in gastric cancer. In this study, we investigated Rab11-FIP2 expression by immunohistochemistry in 86 patients with gastric cancer. We found that the expression level of Rab11-FIP2 was significantly increased in gastric cancer tissues and high expression of Rab11-FIP2 was closely correlated with nodal metastasis in gastric cancer patients. Rab11-FIP2 overexpression promoted epithelial-mesenchymal transition (EMT) in a manner associated with gastric cancer metastasis in vitro and in vivo. We also found that hypoxia could enhance the expression of Rab11-FIP2 through HIF-1α. Inactivation of Rab11-FIP2 dramatically decreased hypoxia-induced migration of gastric cancer cells. Suppression of the internalization of EGFR, at least in part, plays an important role in EMT induced by overexpression of Rab11-FIP2 in gastric cancer cells. Finally, we demonstrated that Rab11-FIP2 could regulate actin cytoskeleton dynamics. In conclusion, our findings reveal a novel mechanism underlying the role of Rab11-FIP2 in gastric cancer dissemination, suggesting that Rab11-FIP2 may be a promising candidate target for gastric cancer treatment.

Well-aligned Nd-doped SnO2 nanorod layered arrays: preparation, characterization and enhanced alcohol-gas sensing performance.

Well-oriented neodymium doped SnO2 layered nanorod arrays were synthesized by a substrate-free hydrothermal route using sodium stannate and sodium hydroxide at 210 °C. The morphology and phase structure of the Nd-doped SnO2 nanoarrays were investigated by X-ray powder diffraction spectroscopy, scanning electron microscopy, transmission electron microscopy, Raman scattering spectroscopy, X-ray photoelectron spectroscopy and the BET method. The results demonstrated that the Nd-doped SnO2 layered nanorod arrays showed a unique nanostructure combined together with double layered arrays of nanorods with a diameter of 12 nm and a length of several hundred nanometers. The Nd-doped layered SnO2 nanoarrays kept the crystal structure of the bulk SnO2 and possessed more surface defects caused by the Nd ions doped into the SnO2 lattice. The Nd dopant acts as a crystallite growth inhibitor to prevent the growth of SnO2 nanorods. An investigation into the gas-sensing properties indicated that the optimized doping level of 3.0 at% Nd-doped SnO2 layered nanorod arrays exhibited an excellent sensing response toward alcohol at a lower temperature of 260 °C. The enhanced sensor performance was attributed to the higher specific surface area, multi-defect surface structure and the excellent catalytic properties of Nd dopant that is able to increase the amount of active sites on the surface of semiconducting oxides. The Nd-doped SnO2 nanoarray sensors were considered to be a promising candidate for trace alcohol detections in environmental gas monitoring.

Dynamic surveillance of lymphocyte subsets in patients with non-small cell lung cancer during chemotherapy or combination immunotherapy for early prediction of efficacy.

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Lymphocytes are the primary executors of the immune system and play essential roles in tumorigenesis and development. We investigated the dynamic changes in peripheral blood lymphocyte subsets to predict the efficacy of chemotherapy or combination immunotherapy in NSCLC. Methods: This retrospective study collected data from 81 patients with NSCLC who received treatments at the First Affiliated Hospital of Zhengzhou University from May 2021 to May 2023. Patients were divided into response and non-response groups, chemotherapy and combination immunotherapy groups, and first-line and multiline groups. We analyzed the absolute counts of each lymphocyte subset in the peripheral blood at baseline and after each treatment cycle. Within-group and between-group differences were analyzed using paired Wilcoxon signed-rank and Mann-Whitney U tests, respectively. The ability of lymphocyte subsets to predict treatment efficacy was analyzed using receiver operating characteristic curve and logistic regression. Results: The absolute counts of lymphocyte subsets in the response group significantly increased after the first cycle of chemotherapy or combination immunotherapy, whereas those in the non-response group showed persistent decreases. Ratios of lymphocyte subsets after the first treatment cycle to those at baseline were able to predict treatment efficacy early. Combination immunotherapy could increase lymphocyte counts compared to chemotherapy alone. In addition, patients with NSCLC receiving chemotherapy or combination immunotherapy for the first time mainly presented with elevated lymphocyte levels, whereas multiline patients showed continuous reductions. Conclusion: Dynamic surveillance of lymphocyte subsets could reflect a more actual immune status and predict efficacy early. Combination immunotherapy protected lymphocyte levels from rapid decrease and patients undergoing multiline treatments were more prone to lymphopenia than those receiving first-line treatment. This study provides a reference for the early prediction of the efficacy of clinical tumor treatment for timely combination of immunotherapy or the improvement of immune status.

Experimental Study and Numerical Analysis on the Shear Resistance of Bamboo Fiber Reinforced Steel-Wire-Mesh BFRP Bar Concrete Beams.

Bamboo fiber is a natural and environmentally friendly material made from cheap and widely available resources and is commonly selected as the reinforcement material for steel-wire-mesh BFRPbar concrete beams. In this work, the effects of various fiber lengths and fiber volume rates on the shear properties of bamboo-fiber-reinforced steel-wire-mesh basalt fiber composite reinforcement concrete beams were studied through a combination of shear tests and numerical simulations. The findings demonstrate that the addition of bamboo fiber improves the cracking performance of the beam. The improvement effect of 45 mm bamboo fiber mixed with a 1% volume rate was the most obvious at about 31%. Additionally, the test beam's total stiffness was increased, and the deflection was decreased. However, the use of bamboo fiber was found to decrease the concrete's compressive strength, lowering the final shear capacity for the majority of beams. A method for estimating the shear capacity of the bamboo-fiber-reinforced steel-wire-mesh BFRPbar concrete beams is provided and lays the foundation for engineering practice, in accordance with the impact of bamboo fiber and steel wire mesh on beams that suffer shear breaks.

Construction of Ultrastable Ultrathin Black Phosphorus Nanodisks Hybridized with Fe3 O4 Nanoclusters and Iron (V)-Oxo Complex for Efficient Potassium Storage.

The practical application of metalloid black phosphorus (BP) based anodes for potassium ion batteries is mainly impeded by its instability in air and irreversible/sluggish potassium storage behaviors. Herein, a 2D composite is purposefully conceptualized, where ultrathin BP nanodisks with Fe3 O4 nanoclusters are hybridized with Lewis acid iron (V)-oxo complex (FC) nanosheets (denoted as BP@Fe3 O4 -NCs@FC). The introduced electron coordinate bridge between FC and BP, and hydrophobic surface of FC synergistically assure that BP@Fe3 O4 -NCs@FC is ultrastable in humid air. With the purposeful structural and componential design, the resultant BP@Fe3 O4 -NCs@FC anode is endowed with appealing electrochemical performance in terms of reversible capacity, rate behavior, and long-duration cycling stability in both half and full cells. Furthermore, the underlying formation and potassium-storage mechanisms of BP@Fe3 O4 -NCs@FC are tentatively proposed. The in-depth insights here will provide a crucial understanding in rational exploration of advanced anodes for next-generation PIBs.