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Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2 LMW ) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2 LMW−/− mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS + /CD206 + TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment. Macrophages contribute to tumour progression and response to therapy. Here, the authors show that absence of FGF2 in the tumour microenvironment reduces tumour growth and enhances the anti-tumour immune response by altering macrophage polarization. As a result, disruption of this macrophage programming by anti-FGF2 blocking antibodies enhances the outcome from radiotherapy. 

Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.

Treatment of tumors with ionizing radiation stimulates an antitumor immune response partly dependent on induction of IFNs. These IFNs directly enhance dendritic cell and CD8+ T cell activity. Here we show that resistance to an effective antitumor immune response is also a result of IFN signaling in a different cellular compartment of the tumor, the cancer cells themselves. We abolished type I IFN signaling in cancer cells by genetic elimination of its receptor, IFNAR1. Pronounced immune responses were provoked after ionizing radiation of tumors from 4 mouse cancer cell lines with Ifnar1 knockout. This enhanced response depended on CD8+ T cells and was mediated by enhanced susceptibility to T cell-mediated killing. Induction of Serpinb9 proved to be the mechanism underlying control of susceptibility to T cell killing after radiation. Ifnar1-deficient tumors had an augmented response to anti-PD-L1 immunotherapy with or without radiation. We conclude that type I IFN can protect cancer cells from T cell-mediated cytotoxicity through regulation of Serpinb9. This result helps explain why radiation of tumors can stimulate antitumor immunity yet also result in resistance. It further suggests potential targets for intervention to improve therapy and to predict responses.

Treatment of tumors with ionizing radiation stimulates an antitumor immune response partly dependent on induction of IFNs. These IFNs directly enhance dendritic cell and [CD8.sup.+] T cell activity. Here we show that resistance to an effective antitumor immune response is also a result of IFN signaling in a different cellular compartment of the tumor, the cancer cells themselves. We abolished type I IFN signaling in cancer cells by genetic elimination of its receptor, IFNAR1. Pronounced immune responses were provoked after ionizing radiation of tumors from 4 mouse cancer cell lines with Ifnar1 knockout. This enhanced response depended on [CD8.sup.+] T cells and was mediated by enhanced susceptibility to T cell-mediated killing. Induction of Serpinb9 proved to be the mechanism underlying control of susceptibility to T cell killing after radiation. Ifnar1-deficient tumors had an augmented response to anti-PD-L1 immunotherapy with or without radiation. We conclude that type I IFN can protect cancer cells from T cell-mediated cytotoxicity through regulation of Serpinb9. This result helps explain why radiation of tumors can stimulate antitumor immunity yet also result in resistance. It further suggests potential targets for intervention to improve therapy and to predict responses.

This study aimed to investigate the expression levels of microRNA-195 (miRNA-195) in different types of patients with cholangiocarcinoma (CCA) and its correlation with the prognosis. Serum samples were collected from different types of patients with CCA (I, II, III, IV) and normal cases, followed by detection of expression of miRNA-195 using quantitative polymerase chain reaction (qPCR). The serum samples of 204 patients with CCA, including 75 cases of type I, 68 cases of type II, 35 cases of type III and 26 cases of type IV and 200 healthy subjects were selected. The baseline clinicopathological data of patients with CCA were assessed and recorded, and patients were followed up constantly. The receiver operating characteristic (ROC) curve was established, and the area under the ROC curve (AUC) was calculated to evaluate the difference of miRNA-195 expression levels between patients with CCA and normal controls. Survival curves were set up for groups with high and low expression levels via the Kaplan-Meier method, and the log-rank test was used to evaluate the difference of survival curves between the two groups. The expression of miR-195 in patients with CCA was significantly lower than that in the normal control group, with a sensitivity of 0.78 and a specificity of 0.76, and it was positively correlated with the pathological grade of CCA. Additionally, the expression level of serum miRNA-195 was associated with lymph node metastasis (P=0.009) and tumor-node-metastasis (TNM) classification (P=0.010). The survival analysis revealed that the prognosis in patients with CCA in types III and IV was poorer than that in those with types I and III who had a low expression of miRNA-195 (P=0.0026). The results show that miR-195 is an important marker that reflects the malignant degree of CCA, and it is expected to be a reference marker to determine the prognosis of CCA.

Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Further-more, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.

The formation mechanism of aerosol sulfate during wintertime haze events in China is still largely unknown. As companions, SO 2 and transition metals are mainly emitted from coal combustion. Here, we argue that the transition metal-catalyzed oxidation of SO 2 on aerosol surfaces could be the dominant sulfate formation pathway and investigate this hypothesis by integrating chamber experiments, numerical simulations and in-field observations. Our analysis shows that the contribution of the manganese-catalyzed oxidation of SO 2 on aerosol surfaces is approximately one to two orders of magnitude larger than previously known routes, and contributes 69.2% ± 5.0% of the particulate sulfur production during haze events. This formation pathway could explain the missing source of sulfate and improve the understanding of atmospheric chemistry and climate change. Sulfate aerosols are an important component of wintertime haze events in China, but their production mechanisms are not well known. Here, the authors show that transition metal-catalyzed oxidation of SO 2 on aerosol surfaces could be the dominant sulfate formation pathway in Northern China.

Graphs have provided an expressive mathematical tool to model quantum-mechanical devices and systems. In particular, it has been recently discovered that graph theory can be used to describe and design quantum components, devices, setups and systems, based on the two-dimensional lattice of parametric nonlinear optical crystals and linear optical circuits, different to the standard quantum photonic framework. Realizing such graph-theoretical quantum photonic hardware, however, remains extremely challenging experimentally using conventional technologies. Here we demonstrate a graph-theoretical programmable quantum photonic device in very-large-scale integrated nanophotonic circuits. The device monolithically integrates about 2,500 components, constructing a synthetic lattice of nonlinear photon-pair waveguide sources and linear optical waveguide circuits, and it is fabricated on an eight-inch silicon-on-insulator wafer by complementary metal–oxide–semiconductor processes. We reconfigure the quantum device to realize and process complex-weighted graphs with different topologies and to implement different tasks associated with the perfect matching property of graphs. As two non-trivial examples, we show the generation of genuine multipartite multidimensional quantum entanglement with different entanglement structures, and the measurement of probability distributions proportional to the modulus-squared hafnian (permanent) of the graph’s adjacency matrices. This work realizes a prototype of graph-theoretical quantum photonic devices manufactured by very-large-scale integration technologies, featuring arbitrary programmability, high architectural modularity and massive manufacturing scalability.A graph-theoretical programmable quantum photonic device composed of about 2,500 components is fabricated on a silicon substrate within a 12 mm × 15 mm footprint. It shows the generation, manipulation and certification of genuine multiphoton multidimensional entanglement, as well as the implementations of scattershot and Gaussian boson sampling.

Uric acid (UA), a key end-product of human purine metabolism, serves as an important biomarker linked to multiple disorders. This study developed a novel enzyme-free colorimetric sensing platform based on starch-derived nitrogen-doped biochar (NC) for the highly sensitive and selective detection of UA in human body fluids. The NC material with a high specific surface area and abundant nitrogen active sites was prepared via a two-step strategy involving hydrothermal synthesis followed by high-temperature pyrolysis, using starch and urea as raw materials. Under mild conditions, the NC effectively catalyzes dissolved oxygen to produce reactive oxygen species (·O2− and 1O2), which oxidize 3,3′,5,5′-tetramethylbenzidine (TMB) to a blue-colored oxidation product (TMBox). The presence of UA reduces TMBox to colorless TMB, leading to a measurable decrease in absorbance at 652 nm and enabling quantitative UA detection. Key reaction conditions were systematically optimized. Material characterization and mechanistic investigations confirmed the catalytic performance of the NC. The method demonstrated a wide linear response from 10 to 500 μmol·L−1, with a detection limit of 4.87 μmol·L−1, and demonstrated outstanding selectivity, stability, and reproducibility. Practical application in human serum and urine samples yielded results consistent with clinical reference ranges, and spike-recovery rates ranged from 95.5% to 103.6%, indicating great potential for real-sample analysis.

The uncertainty of target sizes and the complexity of backgrounds are the main reasons for the poor detection performance of small infrared targets. Focusing on this issue, this paper presents a robust and accurate algorithm that combines multiscale kurtosis map fusion and the optical flow method for the detection of small infrared targets in complex natural scenes. The paper has made three main contributions: First, it proposes a structure for infrared small target detection technology based on multiscale kurtosis maps and optical flow fields, which can well represent the shape, size and motion information of the target and is advantageous to the enhancement of the target and the suppression of the background. Second, a strategy of multi-scale kurtosis map fusion is presented to match the shape and the size of the small target, which can effectively enhance small targets with different sizes as well as suppress the highlighted noise points and the residual background edges. During the fusion process, a novel weighting mechanism is proposed to fuse different scale kurtosis maps, by means of which the scale that matches the true target is effectively enhanced. Third, an improved optical flow method is utilized to further suppress the nontarget residual clutter that cannot be completely removed by multiscale kurtosis map fusion. By means of the scale confidence parameter obtained during the multiscale kurtosis map fusion step, the optical flow method can select the optimal neighborhood that matches best to the target size and shape, which can effectively improve the integrity of the detection target and the ability to suppress residual clutter. As a result, the proposed method achieves a superior performance. Experimental results on eleven typical complex infrared natural scenes show that, compared with seven state-of-the-art methods, the presented method outperforms in terms of subjective visual effect, as well as some main objective evaluation indicators such as BSF, SCRG and ROC, etc.