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Trophoblasts are important parts of the placenta and exert vital roles in the maternal‐foetal crosstalk, and sufficient trophoblasts migration and invasion is critical for embryo implantation and normal pregnancy. Macrophages, as the major components of decidual microenvironment at maternal‐foetal interface, can interact with trophoblasts to participate in the regulation of normal pregnancy. Previously, our group have demonstrated that trophoblasts could induce macrophages polarization to M2 subtype by secreting interleukin‐6 (IL‐6); however, the understanding of macrophages regulating the migration and invasion of trophoblasts is limited. In the present study, we used the co‐cultured model to further investigate the effects of macrophages on trophoblasts migration and invasion. Our results showed that co‐culture with macrophages promoted epithelial‐to‐mesenchymal transition (EMT) of trophoblasts, thereby enhancing their migrative and invasive abilities. Further experiments revealed that M2 macrophage‐derived G‐CSF was a key factor, which promoted the EMT, migration and invasion of trophoblasts via activating PI3K/Akt/Erk1/2 signalling pathway. Clinically, G‐CSF was highly expressed in placental villous tissues of normal pregnancy patients compared to patients with recurrent spontaneous abortion, and its expression level was significantly correlation with EMT markers. Taken together, these findings indicate the important role of M2 macrophages in regulating trophoblasts EMT, migration and invasion, contributing to a new insight in concerning the crosstalk between macrophages and trophoblasts in the establishment and maintenance of normal pregnancy.

The tumor immune microenvironment plays a key role in the regulation of cancer progression. Recent studies have suggested a relation between diverse tumor genotypes and tumor immune microenvironment phenotypes for cholangiocarcinoma (CCA). However, the contribution of tumor‐infiltrating immune cells to CCA progression has remained unclear, underscoring the need for genetically defined CCA models in immunocompetent mice. We here aimed to generate genetically engineered and transplantable CCA organoids from C57BL/6 mice and to investigate the role of tumor‐infiltrating immune cells in CCA progression with this model. CCA organoids were generated ex vivo with the use of the CRISPR/Cas9 system. Orthotopic transplantation of CCA organoids harboring mutations in Smad4, Trp53, and Kras into wild‐type C57BL/6 mice resulted in tumor formation accompanied by distant metastasis. Selective depletion of immune cell types in the tumor‐bearing mice revealed an antitumor action of tumor‐infiltrating neutrophils (TINs) that was mediated by direct killing of cancer cells through the production of reactive oxygen species. Furthermore, administration of recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) increased the number and cytotoxicity of TINs, suppressed tumor growth, and prolonged the survival of tumor‐bearing mice. Finally, combination treatment with rhG‐CSF and standard chemotherapy resulted in a synergistic attenuation of tumor growth. Our study therefore provides a syngeneic and genetically defined mouse model of CCA and highlights the therapeutic potential of targeting TINs with rhG‐CSF. This study developed a genetically engineered and transplantable cholangiocarcinoma (CCA) organoid model in immunocompetent mice to investigate the role of tumor‐infiltrating immune cells in CCA progression. The findings revealed that tumor‐infiltrating neutrophils (TINs) exhibit antitumor activity by directly killing cancer cells through reactive oxygen species, and their effects were enhanced by recombinant human granulocyte colony‐stimulating factor (rhG‐CSF), which suppressed tumor growth and improved survival. Additionally, combining rhG‐CSF with standard chemotherapy showed synergistic tumor suppression, highlighting the therapeutic potential of targeting TINs in CCA.

Cancer cells can be released from a cancerous lesion and migrate into the circulatory system, from whereon they may form metastases at distant sites. Today, it is possible to infer cancer progression and treatment efficacy by determining the number of circulating tumor cells (CTCs) in the patient's blood at multiple time points; further valuable information about CTC phenotypes remains inaccessible. In this article, a microfluidic method for integrated capture, isolation, and analysis of membrane markers as well as quantification of proteins secreted by single CTCs and CTC clusters is introduced. CTCs are isolated from whole blood with extraordinary efficiencies above 95% using dedicated trapping structures that allow co‐capture of functionalized magnetic beads to assess protein secretion. The patform is tested with multiple breast cancer cell lines spiked into human blood and mouse‐model‐derived CTCs. In addition to immunostaining, the secretion level of granulocyte growth stimulating factor (G‐CSF), which is shown to be involved in neutrophil recruitment, is quantified The bead‐based assay provides a limit of detection of 1.5 ng mL−1 or less than 3700 molecules per cell. Employing barcoded magnetic beads, this platform can be adapted for multiplexed analysis and can enable comprehensive functional CTC profiling in the future. Circulating tumor cells (CTCs) isolated from liquid biopsies carry valuable functional information about the tumor phenotype. Here, a uniquely integrated microfluidic device for efficient isolation of CTCs from whole blood and subsequent determination of the protein expression as well as secretion of G‐CSF, a key factor involved in the recruitment of myeloid cells, is presented.

Objectives Bone marrow edema is a universal manifestation of rheumatoid arthritis (RA), and its pathological essence is a bone marrow lesion (BML) formed by various bone marrow (BM) immune cells. Neutrophils play an important role in inflammatory arthritis, but the role and mechanism of neutrophils in BML are not clear. Materials and methods Granulocyte colony‐stimulating factor (G‐CSF) −/− mice and wild type (WT) C57BL/6 mice were immunized for collagen‐induced arthritis (CIA). Histological scores of arthritis were evaluated. Immunohistochemistry staining with anti‐Ly6G was conducted. Neutrophil extracellular traps (NETs) in joint sections were determined by immunofluorescence staining. BM neutrophils were isolated for flow cytometry and NETosis induction in vitro. Results Histological study showed significant neutrophil infiltrations in BML of CIA mice. Inhibition of BM neutrophil production by G‐CSF knock out can obstruct the induction of BML and CIA. In addition to abundant infiltrated NETs intra‐articular, remarkable NETosis primed BM neutrophils were infiltrated in BML of CIA mice, which was positively related to bone erosion. Neutrophils derived from G‐CSF−/− mice have diminished ability of NETs formation in vitro, while G‐CSF induction can enhance its capacity of NETs formation. Conclusions We propose for the first time that the overproduced BM neutrophils in CIA mice are primed for NETosis in a G‐CSF dependent manner, and these pathogenic cells may have an important role in inflammatory arthritis. Blocking this pathological process could be a potential strategy for the treatment of RA.

Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infection in children for which no specific treatment option is available. The RSV virion contains two surface glycoproteins (F and G) that are vital for the initial phases of infection, making them critical targets for RSV therapeutics. Recent studies have identified the broad-spectrum antiviral properties of silver nanoparticles (AgNPs) against respiratory pathogens, such as adenovirus, parainfluenza, and influenza. AgNPs achieve this by attaching to viral glycoproteins, blocking entry into the host cell. The objective of this study was to evaluate the antiviral and immunomodulatory effects of AgNPs in RSV infection. Herein we demonstrate AgNP-mediated reduction in RSV replication, both in epithelial cell lines and in experimentally infected BALB/c mice. Marked reduction in pro-inflammatory cytokines (i.e., IL-1α, IL-6, TNF-α) and pro-inflammatory chemokines (i.e., CCL2, CCL3, CCL5) was also observed. Conversely, CXCL1, G-CSF, and GM-CSF were increased in RSV-infected mice treated with AgNPs, consistent with an increase of neutrophil recruitment and activation in the lung tissue. Following experimental antibody-dependent depletion of neutrophils, the antiviral effect of AgNPs in mice treated was ablated. To our knowledge, this is the first in vivo report demonstrating antiviral activity of AgNPs during RSV infection.

Cytokines are known to shape the tumor microenvironment and although progress has been made in understanding their role in carcinogenesis, much remains to learn regarding their role in tumor growth and progression. We have identified granulocyte colony-stimulating factor (G-CSF) as one such cytokine, showing that G-CSF is linked with metastasis in human gastrointestinal tumors and neutralizing G-CSF in a mouse model of colitis-associated cancer is protective. Here, we set out to identify the role of G-CSF and its receptor, G-CSFR, in CD4 and CD8 T cell responses in the tumor microenvironment. MC38 colon cancer cells were injected into WT, G-CSFR mice, or Rag2 mice. Flow cytometry, Real Time PCR and Multiplex cytokine array analysis were used for T cell phenotype analysis. Adoptive transfer of WT or G-CSFR CD4 of CD8 T cells were performed. Mouse tumor size, cytokine expression, T cell phenotype, and cytotoxic activity were analyzed. We established that in G-CSFR mice, tumor growth of MC38 colon cancer cells is significantly decreased. T cell phenotype and cytokine production were also altered, as both and approaches revealed that the G-CSF/G-CSFR stimulate IL-10-producing, FoxP3-expressing CD4 and CD8 T cells, whereas G-CSFR T cells exhibit increased IFNγ and IL-17A production, leading to increased cytotoxic activity in the tumor microenvironment. Furthermore, peritumoral injection of recombinant IFNγ or IL-17A inhibited colon and pancreas tumor growth compared to controls. Taken together, our data reveal an unknown mechanism by which G-CSF, through its receptor G-CSFR, promotes an inhibitory Treg phenotype that limits tumor immune responses and furthermore suggest that targeting this cytokine/receptor axis could represent a novel therapeutic approach for gastrointestinal, and likely other tumors with high expression of these factors.

Background PEGylated granulocyte colony-stimulating factor (G-CSF) is a safe alternative to G-CSF to improve chemotherapy-induced neutropenia (CIN). This superiority has resulted in its increased use by physicians; however, the superiority of PEGylated G-CSF for CIN in breast cancer has not been conclusively determined. Objectives To assess the superiority of PEGylated G-CSF for CIN in breast cancer in terms of effectiveness and safety via a systematic review and meta-analysis. Methods A literature search in PubMed, Embase, Cochrane Library, and Web of Science was performed for eligible studies published from database inception to December 2019. All studies comparing PEGylated G-CSF and G-CSF for CIN of breast cancer were reviewed. After literature selection, data extraction and quality assessment were performed by two reviewers independently. Meta-analysis was conducted using Revman, version 5.2. Results Nine randomized controlled trials were finally identified. The publication bias of these studies was acceptable. For the endpoint of effectiveness, analysis of the incidence/duration of grade ≥ 3 neutropenia, the duration of grade 4 neutropenia, the incidence of febrile neutropenia (FN), and the time to absolute neutrophil count recovery showed no advantage of PEGylated G-CSF over G-CSF for CIN of breast cancer ( P  > 0.05), with the premise of a sufficient dose of G-CSF according to the guidelines. No significant differences in grade 4 adverse events were observed between the groups ( P  = 0.29), and PEGylated G-CSF did not increase the incidence of skeletal and/or muscle pain compared with G-CSF ( P  = 0.32). Conclusion PEGylated G-CSF was as effective and safe as G-CSF to reduce CIN in breast cancer but did not show an obvious superiority. However, in clinical practice, PEGylated G-CSF has an obvious advantage in terms of convenience, which could improve patient’s quality of life.

BackgroudGranulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days.MethodsThis current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes.ResultsThrough the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/μL), quality of life, and pain, were not apparent.ConclusionsA single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

Radiation therapy (RT), a major modality for treating localized tumors, can induce tumor regression outside the radiation field through an abscopal effect that is thought to involve the immune system. Our studies were designed to understand the early immunological effects of RT in the tumor microenvironment using several syngeneic mouse tumor models. We observed that RT induced sterile inflammation with a rapid and transient infiltration of CD11b⁺Gr-1high+ neutrophils into the tumors. RT-recruited tumor-associated neutrophils (RT-Ns) exhibited an increased production of reactive oxygen species and induced apoptosis of tumor cells. Tumor infiltration of RT-Ns resulted in sterile inflammation and, eventually, the activation of tumor-specific cytotoxic T cells, their recruitment into the tumor site, and tumor regression. Finally, the concurrent administration of granulocyte colony-stimulating factor (G-CSF) enhanced RT-mediated antitumor activity by activating RT-Ns. Our results suggest that the combination of RT and G-CSF should be further evaluated in preclinical and clinical settings.

To determine the influence of graft composition in haplo-HSCT, we summarized the long-term consequences of 251 consecutive transplantations from haploidentical donors. For donor-recipient HLA3/6-matched setting, 125 cases used G-CSF-mobilized BM and PBSCs mixtures, while 126 cases only used G-CSF-mobilized PBSCs in HLA4/6-matched transplantation. On the one hand, we wanted to explore the effect of harvests (CD34+ cells and TNCs dosages) on transplantation outcome in the context of haplo-HSCT no matter HLA4/6 or HLA3/6-matched setting. On the other hand, for patients using G-CSF-mobilized BM and PBSCs combination in HLA3/6-matched setting, we attempted to analyze whether TNCs or CD34+ cells from G-CSF-mobilized BM or G-CSF-mobilized PBSCs play the most paramount role on transplantation prognosis. Collectively, patients with hematologic malignancies receiving G-CSF-primed BM and PBSCs harvests had comparable consequences with patients only receiving G-CSF-mobilized PBSCs. Moreover, when divided all patients averagely according to the total amount of transfused nucleated cells, 3-year TRM of the intermediate group (13.06-18.05×10 8 /kg) was only 4.9%, which was remarkably reduced when compared to lower and higher groups with corresponding values 18.3%, 19.6% ( P =0.026). The 3-year probabilities of OS and DFS of this intermediate group were 72.6% and 66.5%, which were slightly improved than the lower and higher groups. Most importantly, these data suggest that the transfused nucleated cells from G-CSF-primed BM above than 5.20×10 8 /kg could achieve remarkably lower TRM in haplo-HSCT receiving G-CSF-mobilized BM and PBSCs harvests. These encouraging results suggested that we could improve the efficacy of haplo-HSCT by adjusting the component and relative ratio of transfused graft cells. Nevertheless, the above findings should be confirmed in a randomized prospective comparative research with adequate follow-up.