Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer.

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8+ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8+ T cells and facilitates the generation of progenitor exhausted CD8+ T cells (Tpex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.

Mechanisms underlying neutrophils adhesion to triple-negative breast cancer cells via CD11b-ICAM1 in promoting breast cancer progression.

BACKGROUND: Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood. METHODS: Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC. RESULTS: TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin. CONCLUSIONS: Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC.

Three-Dimensional PdPtCu Nanoalloys with a Controllable Composition and Spiny Surface for the Enhancement of Ethanol Electrocatalytic Properties.

Pt-based nanomaterials have been proven to be effective catalysts for direct alcohol fuel cells (DAFCs). Specifically, the ternary nanoalloys (NAs) composed of Pt with other noble metals and transition metals can not only reduce the component of Pt but also enhance the electrocatalytic property and durability for alcohol oxidation. Herein, ternary PdPtCu NAs were synthesized through the solvothermal method using ethylene glycol as the solvent and reducing agent. The morphology and composition of PdPtCu NAs can be effectively controlled via selecting suitable surfactants and adjusting the proportion of precursors. The three-dimensional (3D) PdPtCu NAs with spiny rambutan-like morphology were obtained using the triblock copolymer Pluronic F-127 (PF-127) as the surfactant and adding three precursors with an equal molar ratio. The unique structure of PdPtCu NAs and the synergistic effect between the components significantly improved the electrocatalytic activity toward ethanol oxidation. Compared with different atomic ratio binary or ternary nanomaterials, 3D PdPtCu NAs manifested the best electrocatalytic performance.

Ultrasmall black phosphorus quantum dots: synthesis, characterization, and application in cancer treatment.

Black phosphorus quantum dots (BPQDs) are gaining popularity for applications in various fields because of their unique advantages. For biomedical applications, good biosafety is a prerequisite for the use of BPQDs in vivo. However, currently, little information is available about their basic properties and biocompatibility, which are of great importance for potential biomedical applications. In this work, we prepared BPQDs by an improved solvothermal method and evaluated their fluorescence, biocompatibility, and photothermal therapy (PTT) effectiveness. First, the structures and functions of the BPQDs were investigated at the cellular and molecular levels. It was found that the fluorescence of the BPQDs is wavelength-dependent and that they absorb in the UV-vis range; also, their quantum yield reached 10.2%. In particular, we considered the morphology and lysis of human red blood cells, in vivo blood coagulation, and plasma recalcification profiles. We found that the BPQDs have excellent biocompatibility and hemocompatibility with blood components. Overall, concentrations of the BPQDs ≤0.5 mg mL-1 had few adverse effects on blood components. The resulting BPQDs can efficiently convert near-infrared (NIR) light into heat; thus, they are suitable as a novel nanotheranostic agent for PTT of cancer. Meanwhile, the results of serum biochemistry tests revealed that the indicators were at similar levels for mice exposed to BPQDs and for control mice. Furthermore, from biodistribution analysis of the BPQDs, no apparent pathological damage was observed in any organs, especially in the spleen and kidneys, during the 30 day period. Our research indicates that the BPQDs have bio-imaging capability and biocompatibility and highlights their great potential in the therapy of cancer.

Synthesis and properties study of the uniform nonspherical styrene/methacrylic acid copolymer latex particles.

A facile method to prepare the nonspherical amphiphilic random copolymer of poly(styrene-co-methacrylic acid) (poly(St-co-PMAA)) latex particles with well-defined shapes and high yields by one-step batch emulsifier-free polymerization was demonstrated. In our strategy, only varying the molar ratio of styrene (St) to methacrylic acid (MAA), no seed-particles, no cross-linker, and no multistep control procedures were needed. Due to the presence of carboxyl groups on the surface of (poly(St-co-PMAA) latex particles, these latex particles can be used as templates for fabricating core-shell nonspherical functional materials, such as poly(St-co-PMAA)@SiO2 and poly(St-co-PMAA)@polypyrrole). The corresponding nonspherical hollow structures (SiO2 and polypyrrole) could be obtained after removal of the templates. In addition, poly(St-co-PMAA) latex particles exhibit interesting morphologies in ethanol.

Using a Macroporous Silver Shell to Coat Sulfonic Acid Group-Functionalized Silica Spheres and Their Applications in Catalysis and Surface-Enhanced Raman Scattering.

In this paper, novel organic sulfonic acid group-functionalized silica spheres (SiO2-SO3H) were chosen as a template for fabricating core-shell SiO2-SO3H@Ag composite spheres by the seed-mediated growth method. The SiO2-SO3H spheres could be obtained easily by oxidation of the thiol group-terminated silica spheres (SiO2-SH) with H2O2. Due to the presence of sulfonic acid groups, the [Ag(NH3)2](+) ions were captured on the surface of the silica spheres, followed by in-site reduction to silver nanoseeds for further growth of the silver shell. By this strategy, the complete silver shell could be obtained, and the surface morphologies and structures of the silver shell could be controlled by adjusting the number of sulfonic acid groups on the silica spheres. A large number of sulfonic acid groups on the SiO2-SO3H spheres favored the formation of the macroporous silver shell, which was unique and exhibited good catalytic performance and a high surface-enhanced Raman scattering (SERS) enhancement ability.

Chronic stress induces pulmonary epithelial cells to produce acetylcholine that remodels lung pre-metastatic niche of breast cancer by enhancing NETosis.

BACKGROUND: Chronic stress promotes most hallmarks of cancer through impacting the malignant tissues, their microenvironment, immunity, lymphatic flow, etc. Existing studies mainly focused on the roles of stress-induced activation of systemic sympathetic nervous system and other stress-induced hormones, the organ specificity of chronic stress in shaping the pre-metastatic niche remains largely unknown. This study investigated the role of chronic stress in remodeling lung pre-metastatic niche of breast cancer. METHODS: Breast cancer mouse models with chronic stress were constructed by restraint or unpredictable stress. Expressions of tyrosine hydroxylase, vesicular acetylcholine transporter (VAChT), EpCAM and NETosis were examined by immunofluorescence and confocal microscopy. mRNA and protein levels of choline acetyltransferase (ChAT), VAChT, and peptidylarginine deiminase 4 were detected by qRT-PCR and Western blotting, respectively. Immune cell subsets were analyzed by flow cytometry. Acetylcholine (ACh) and chemokines were detected by ELISA and multi chemokine array, respectively. ChAT in lung tissues from patients was examined by immunohistochemistry. RESULTS: Breast cancer-bearing mice suffered chronic stress metastasized earlier and showed more severe lung metastasis than did mice in control group. VAChT, ChAT and ChAT+ epithelial cells were increased significantly in lung of model mice undergone chronic stress. ACh and chemokines especially CXCL2 in lung culture supernatants from model mice with chronic stress were profoundly increased. Chronic stress remodeled lung immune cell subsets with striking increase of neutrophils, enhanced NETosis in lung and promoted NETotic neutrophils to capture cancer cells. ACh treatment resulted in enhanced NETosis of neutrophils. The expression of ChAT in lung tissues from breast cancer patients with lung metastasis was significantly higher than that in patients with non-tumor pulmonary diseases. CONCLUSIONS: Chronic stress promotes production of CXCL2 that recruits neutrophils into lung, and induces pulmonary epithelial cells to produce ACh that enhances NETosis of neutrophils. Our findings demonstrate for the first time that chronic stress induced epithelial cell derived ACh plays a key role in remodeling lung pre-metastatic niche of breast cancer.

Synthesis of rGO supported Cu@FeCo catalyst and catalytic hydrolysis of ammonia borane.

Highly dispersed Cu@FeCo/rGO catalysts have been prepared by two-step reduction method and used for hydrogen production from ammonia borane (NH3BH3, AB) hydrolysis at 298 K. The activity and reusability of synthesized composite catalyst were much more higher than Cu@FeCo for AB hydrolysis dehydrogenation at 298 K. Kinetic study manifested that AB hydrolysis dehydrogenation with Cu@FeCo/rGO catalysts was approaching to the first order at different catalyst concentrations. The hydrolysis reaction completed within four minutes, and its maximum hydrogen production rate reached to 7863.0 ml min-1 g-1 at 298 K.

Multi-Omics Profiling Suggesting Intratumoral Mast Cells as Predictive Index of Breast Cancer Lung Metastasis.

Breast cancer lung metastasis has a high mortality rate and lacks effective treatments, for the factors that determine breast cancer lung metastasis are not yet well understood. In this study, data from 1067 primary tumors in four public datasets revealed the distinct microenvironments and immune composition among patients with or without lung metastasis. We used multi-omics data of the TCGA cohort to emphasize the following characteristics that may lead to lung metastasis: more aggressive tumor malignant behaviors, severer genomic instability, higher immunogenicity but showed generalized inhibition of effector functions of immune cells. Furthermore, we found that mast cell fraction can be used as an index for individual lung metastasis status prediction and verified in the 20 human breast cancer samples. The lower mast cell infiltrations correlated with tumors that were more malignant and prone to have lung metastasis. This study is the first comprehensive analysis of the molecular and cellular characteristics and mutation profiles of breast cancer lung metastasis, which may be applicable for prognostic prediction and aid in choosing appropriate medical examinations and therapeutic regimens.

Facile Synthesis Of Composition-Controllable PtPdAuTe Nanowires As Superior Electrocatalysts For Direct Methanol Fuel Cells.

Multicomponent Pt-based nanowires (NWs) have attracted widespread attention as eletrocatalysts toward direct alcohol fuel cells because of their unique one-dimensional structure and high reaction dynamics. Quaternary PtPdAuTe NWs are designed via a facile template method, and NWs with a different composition are obtained by adjusting the feed ratio of metal precursors. The direct displacement reaction of metal precursors with Te NWs and the partial oxidation of Te lead to the formation of quaternary NWs. The rough surface and abundant reactive sites deriving from the rearrangement of metal atoms on the Te NWs surface endow the PtPdAuTe NWs with a superior electrocatalytic property and durability for methanol oxidation. The Pt20 Pd20 Au10 Te50 NWs display the largest mass activity and best stability among all catalysts. The preparation of PtPdAuTe NWs could provide a viable strategy for the preparation of other multicomponent NWs.

Ag@Fe3O4@C nanoparticles for multi-modal imaging-guided chemo-photothermal synergistic targeting for cancer therapy.

Novel multifunctional core-shell nanoparticles (NPs) have attracted widespread attention due to their easy-to-modify surface properties and abundant functional groups. This study introduces a facile approach to synthesize Ag@ iron oxide (Fe3O4) @C NPs, and modify with amino-poly (ethylene glycol) (PEG)-carboxyl and folate (FA) on the exposed carbon surface to produce high contrast for excellent stability, good biocompatibility, cancer cell targeting, and synergistic treatment. The multi-armed PEG at the edge of Ag@Fe3O4@C NPs provides the materials an excellent capacity for doxorubicin (DOX) loading. The carbon layer could be used as a photothermal reagent due to its excellent near-infrared (NIR) absorbance capacity, and Fe3O4 was used as a reagent for magnetic resonance (MR) imaging. In vivo combination therapy with this agent was administered in a mouse tumor model, and a remarkable synergistic antitumor effect that is superior to that obtained by monotherapy was achieved. Concerning these features together, these unique multifunctional Ag@Fe3O4@C-PEG-FA/DOX NPs could be regarded as an attractive nanoplatforms for chemo-photothermal synergistic tumor therapy with dual-modal fluorescence and MR imaging-guided targeting.

Facile Synthesis of PdCu Echinus-Like Nanocrystals as Robust Electrocatalysts for Methanol Oxidation Reaction.

Exploiting high-performance and inexpensive electrocatalysts for methanol electro-oxidation is conductive to promoting the commercial application of direct methanol fuel cells. Here, we present a facile synthesis of echinus-like PdCu nanocrystals (NCs) via a one-step and template-free method. The echinus-like PdCu NCs possess numerous straight and long branches which can provide abundant catalytic active sites. Owing to the novel nanoarchitecture and electronic effect of the PdCu alloy, the echinus-like PdCu NCs display high electrocatalytic performance toward methanol oxidation reaction in an alkaline medium. The mass activity of echinus-like PdCu NCs is 1202.1 mA mgPd -1 , which is 3.7 times that of Pd/C catalysts. In addition, the echinus-like structure, as a kind of three-dimensional self-supported nanoarchitecture, endows PdCu NCs with significantly enhanced stability and durability. Hence, the echinus-like PdCu NCs hold prospect of being employed as electrocatalysts for direct alcohol fuel cells.

Bioinspired carbon quantum dots for sensitive fluorescent detection of vitamin B12 in cell system.

Zwitterion-modification, as a bioinspired strategy, provides greatly promising platforms for biological detection and sensor applications. A green, low-cost and straight-forward method for synthesis of highly fluorescent biomimetic carbon quantum dots (BCQDs) has been developed via pyrolysis of cytidine diphosphate choline (CDPC) and ethylenediamine. The BCQDs with a strong emission at wavelength of 450 nm shows ultrasensitive sensing capability for vitamin B12 with high selectivity. Using the fluorometric assay, the detection limit (DL) for vitamin B12 was found to be as low as 81 nM. Meanwhile, the results of 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), hemolysis measuring and morphological characterization of Red blood cells (RBCs) confirms the excellent biocompatibility of BCQDs. The imaging experiments of human cervical cancer cells (HeLa) certify that BCQDs could be served as an effective fluorescent sensing probe for label-free sensitive and selective detection of vitamin B12 in biological samples on account of their low toxicity and good biocompatibility. The BCQDs, further, were successfully applied to probe vitamin B12 in living cells, which broaden its potential application in vivo system.