Bioinformatics analysis and validation of genes related to paclitaxel's anti-breast cancer effect through immunogenic cell death.

Research indicated that Paclitaxel (PTX) can induce immunogenic cell death (ICD) through immunogenic modulation. However, the combination of PTX and ICD has not been extensively studied in breast cancer (BRCA). The TCGA-BRCA and GSE20685 datasets were enrolled in this study. Samples from the TCGA-BRCA dataset were consistently clustered based on selected immunogenic cell death-related genes (ICD-RGs). Next, candidate genes were obtained by overlapping differentially expressed genes (DEGs) between BRCA and normal groups, intersecting genes common to DEGs between cluster1 and cluster2 and hub module genes, and target genes of PTX from five databases. The univariate Cox algorithm and the least absolute shrinkage and selection operator (LASSO) were performed to obtain biomarkers and build a risk model. Following observing the immune microenvironment in differential risk subgroups, single-gene gene set enrichment analysis (GSEA) was carried out in all biomarkers. Finally, the expression of biomarkers was analyzed. Enrichment analysis showed that 626 intersecting genes were linked with inflammatory response. Further five biomarkers (CHI3L1, IL18, PAPLN, SH2D2A, and UBE2L6) were identified and a risk model was built. The model's performance was validated using GSE20685 dataset. Furthermore, the biomarkers were enriched with adaptive immune response. Lastly, the experimental results indicated that the alterations in IL18, SH2D2A, and CHI3L1 expression after treatment matched those in the public database. In this study, Five PTX-ICD-related biomarkers (CHI3L1, IL18, PAPLN, SH2D2A, and UBE2L6) were identified to aid in predicting BRCA treatment outcomes.

Secondary Atomization and Micro-Explosion Effect Induced by Surfactant and Nanoparticles on Enhancing the Combustion Performance of Al/JP-10/OA Nanofluid Fuel.

Aluminum/tetrahydrodicyclopentadiene/oleic acid (Al/JP-10/OA) nanofluid fuel is considered a potential fuel for aircraft powered by aviation turbine engines. However, an optimized formula for an Al/JP-10/OA system inducing a secondary atomization and micro-explosion effect and improving the burning performance needs to be developed. With this aim, in this work, the combustion characteristics of pure JP-10, JP-10/OA, JP-10/Al, and Al/JP-10/OA were experimentally tested, and a comparative analysis was conducted. Specifically, the influence of the surfactant and nanoparticle concentrations on the combustion characteristics of Al/JP-10/OA nanofluid fuel, including the flame structure, the flame temperature, the burning rate, the secondary atomization and micro-explosion effect, etc., were evaluated in detail. The results demonstrate that the addition of OA surfactant and Al nanoparticles had a significant effect on the burning rate of fuel droplets. The OA had an inhibition effect, while the Al nanoparticles had a promotion effect. As both OA and Al nanoparticles were added to the JP-10, the synergetic effect had to be considered. At the optimum ratio of OA to Al for the best suspension stability, there is a critical Al concentration of 1.0 wt.% from promotion to inhibition with increases in the Al concentration. The addition of OA and Al nanoparticles induced the secondary atomization and micro-explosion, resulting in an unsteady combustion and chaotic flame structure. The transient flame temperature of hundreds of Kelvins increased, the high-temperature flame zone widened, and thus, the energy release was elevated. Therefore, the combustion performance and energy release of Al/JP-10/OA nanofluid fuel can be improved through the secondary atomization and micro-explosion effect induced by the surfactant and nanoparticles.

Occupational protection behavior and its influencing factors of newly recruited nurses.

AIM: Aim The objective of this study was to understand the occupational protective behaviors of newly recruited nurses and explore the influencing factors. METHODS: A convenience sampling method was used to select newly recruited nurses in our hospital from July 2018 to November 2019. The survey was conducted using the general information questionnaire, work attitude scale (Wa), and occupational protective behavior scale. RESULTS: The total score of occupational protective behaviors of 150 newly enrolled nurses was 18.94 ± 3.59. There was a significant negative correlation between work attitude score and occupational protective behaviors (r = -0.324, p < 0.001). Multiple linear regression analysis showed that gender, previous participation in nursing skill-based competitions, experience of needlestick injuries before recruit, work attitude score, average daily sleep time (p < 0.05) were independent factors influencing occupational protective behaviors. CONCLUSIONS: The overall occupational protective awareness of newly enrolled nurses is relatively weak and needs to be further improved. The group's ability to improve occupational protective behaviors may be positively impacted through increased adaptability, improved sleep, active participation in nursing skill-based competitions, strengthening guidance and education on occupational protection.

Understanding of Contradiction on Concentration Effect on Stability, Physical Properties, Evaporation and Microexplosion Characteristics of Al/JP-10/Oleic Acid Nanofluid Fuel.

An Al/JP-10/oleic acid nanofluid fuel system has demonstrated potential in advanced combustion for aviation turbine engines. To improve the energy density of nanofluid fuel, a higher Al concentration requirement needs to be met. Correspondingly, a higher surfactant oleic acid concentration is required to maintain better dispersion stability. The increment of Al and oleic acid concentrations results in more frequent microexplosions, but a slower evaporation rate. Therefore, this paper proposes to deeply understand the contradiction of the concentration effect on the stability, physical properties, evaporation and microexplosion characteristics and obtain the best Al and oleic acid concentrations to maintain the most suitable comprehensive performance. Experiments on the stability, physical properties, evaporation and microexplosion characteristics were conducted, respectively. The analysis and discussion were then made to reveal the Al and oleic acid concentration effect on the stability, physical properties, evaporation and microexplosion characteristics. The results show that the optimum mass ratio of Al:oleic acid is 1:2 for the nanofluid fuels with Al concentrations of 2.5 wt.% or below, 1:2.5 for 5.0 wt.% or above to obtain the best stability. The physical properties of the nanofluid fuels such as density, surface tension and viscosity are linear, quartic and quadratic functions of Al concentration, respectively, relating to the internal flow and microexplosion of fuel droplets. With increasing oleic acid and Al concentration, the evaporation rates reduced, and the microexplosions became more frequent and intense. At a high ambient temperature of 600 °C, the evaporation rates were kept almost equivalent for JP-10, JP-10/oleic acid, and Al/JP-10/oleic acid fuels. It was found that the increment of ambient temperature can compensate for the reduction of the evaporation rate owing to the addition of oleic acid and Al nanoparticles, improving the evaporation and microexplosion performance.

SNAT7 regulates mTORC1 via macropinocytosis.

Mammalian target of rapamycin complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Some amino acids signal to mTORC1 through the Rag GTPase, whereas glutamine and asparagine activate mTORC1 through a Rag GTPase-independent pathway. Here, we show that the lysosomal glutamine and asparagine transporter SNAT7 activates mTORC1 after extracellular protein, such as albumin, is macropinocytosed. The N terminus of SNAT7 forms nutrient-sensitive interaction with mTORC1 and regulates mTORC1 activation independently of the Rag GTPases. Depletion of SNAT7 inhibits albumin-induced mTORC1 lysosomal localization and subsequent activation. Moreover, SNAT7 is essential to sustain KRAS-driven pancreatic cancer cell growth through mTORC1. Thus, SNAT7 links glutamine and asparagine signaling from extracellular protein to mTORC1 independently of the Rag GTPases and is required for macropinocytosis-mediated mTORC1 activation and pancreatic cancer cell growth.

Effect of Nanoparticle Concentration on Physical and Heat-Transfer Properties and Evaporation Characteristics of Graphite/n-Decane Nanofluid Fuels.

n-Decane-based nanofluid fuels could be one of the most promising alternative fuels as aviation kerosene for aerospace application. However, the physical and heat-transfer properties of n-decane-based nanofuels have been rarely studied, and the influence of the concentration of nanoparticles on the evaporation characteristics of n-decane-based fuels has been sparsely investigated. This paper investigated physical and heat-transfer properties and evaporation characteristics of graphite/n-decane nanofluid fuels and emphasized the concentration effect of adding graphite nanoplatelets (GNPs) on these characteristics. It was found that there are a linear increase of density and thermal conductivity, a binomial increase of viscosity, and a binomial influence on surface tension as GNP concentration increases, while the boiling point almost remains constant, and the latent heat of vaporization largely decays. There exists a critical GNP concentration of 1.75 wt % for the evaporation performance. At 0∼1.75 wt %, the increase of GNP concentration benefits the evaporation. At 1.75∼4.0 wt %, the enhancement of GNP concentration deteriorates the evaporation performance. A detailed discussion of this evaporation behavior was made, which could be attributed to multiple factors, for example, the aggregation of nanoplatelets, the changes of physical and heat-transfer properties owing to the nanoparticle concentration effect, the surfactant concentration, and the ambient temperature. The concentration of surfactants has a binomial effect, and the ambient temperature has a linear effect on the evaporation rate. This study would promote in depth understanding of physical and heat-transfer properties and evaporation characteristics of nanofluid fuels and develop the application in turbine engines and ramjet engines.

ArfGAP1 inhibits mTORC1 lysosomal localization and activation.

The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid-deficient conditions is not completely understood. Here, we identify ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature-sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.

Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy.

Paclitaxel (PTX) has shown pleiotropic immunologic effects on the tumor microenvironment, and nanomicelle has emerged as a promising strategy for PTX delivery. However, the detailed mechanisms remain to be fully elucidated. Meanwhile, immunogenic cell death (ICD) is an effective approach to activate the immune system. This study investigated the ICD effect of PTX and how nanomicelle affected the immune-activation ability of PTX. Methods: The ICD effects of PTX were identified via the expression of ICD markers and cell vaccine experiment. Tumor size and overall survival in multiple animal models with treatment were monitored to evaluate the antitumor effects. The mechanisms of PTX-induced ICD and antitumor immunity were determined by detecting gene expression related to ER stress and analyzing immune cell profile in tumor after treatment. Results: We revealed the immune-regulation mechanism of PTX nanomicelle by inducing ICD, which can promote antigen presentation by dendritic cells (DCs) and activate antitumor immunity. Notably, nanomicelle encapsulation protected the ICD effects and immune activation, which were hampered by immune system impairment caused by chemotherapy. Compared with traditional formulations, a low dose of nanomicelle-encapsulated PTX (nano-PTX) treatment induced immune-dependent tumor control, which increased the infiltration and function of both T cells and DCs within tumors. However, this antitumor immunity was hampered by highly expressed PD-1 on tumor-infiltrating CD8+ T cells and upregulated PD-L1 on both immune cells and tumor cells after nano-PTX treatment. Combination therapy with a low dose of nano-PTX and PD-1 antibodies elicited CD8+ T cell-dependent antitumor immunity and remarkably improved the therapeutic efficacy. Conclusions: Our results provide systemic insights into the immune-regulation ability of PTX to induce ICD, which acts as an inducer of endogenous vaccines through ICD effects, and also provides an experimental basis for clinical combination therapy with nano-PTX and PD-1 antibodies.

Glutamine and asparagine activate mTORC1 independently of Rag GTPases.

Nutrient sensing by cells is crucial, and when this sensing mechanism is disturbed, human disease can occur. mTOR complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway. In contrast, glutamine activates mTORC1 through a Rag GTPase-independent mechanism that requires ADP-ribosylation factor 1 (Arf1). Here, using several biochemical and genetic approaches, we show that eight amino acids filter through the Rag GTPase pathway. Like glutamine, asparagine signals to mTORC1 through Arf1 in the absence of the Rag GTPases. Both the Rag-dependent and Rag-independent pathways required the lysosome and lysosomal function for mTORC1 activation. Our results show that mTORC1 is differentially regulated by amino acids through two distinct pathways.

A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b.

Therapeutic antibodies targeting vascular endothelial growth factor (VEGF) have become a critical regimen for tumor therapy, but the efficacy of monotherapy is usually limited by drug resistance and multiple angiogenic mechanisms. Complement proteins are becoming potential candidates for cancer-targeted therapy based on their role in promoting cancer progression and angiogenesis. However, the antitumor abilities of simultaneous VEGF and complement blockade were unknown. We generated a humanized soluble VEGFR-Fc fusion protein (VID) binding VEGFA/PIGF and a CR1-Fc fusion protein (CID) targeting C3b/C4b. Both VID and CID had good affinities to their ligands and showed effective bioactivities. In vitro, angiogenesis effects induced by VEGF and hemolysis induced by complement were inhibited by VID and CID, respectively. Further, VID and CID confer a synergetic therapeutic effect in a colitis-associated colorectal cancer (CAC) model and an orthotopic 4T1 breast cancer model. Mechanically, combination therapy inhibited tumor angiogenesis, cell proliferation, and MDSC infiltration in the tumor microenvironment and promoted tumor cell apoptosis. Our study offers a novel therapeutic strategy for anti-VEGF-resistant tumors and chronic-inflammation-associated tumors.

Erratum: Author Correction: A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity.

[This corrects the article DOI: 10.1038/sigtrans.2016.25.].

Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy.

Immunotherapy based on the immune checkpoint blockade has emerged as the most promising approach for cancer therapy. However, the proportion of colorectal cancer patients who benefit from immunotherapy is small due to the immunosuppressive tumor microenvironment. Hence, combination immunotherapy is an ideal strategy to overcome this limitation. In this study, we developed a novel combination of CSF-1R (colony-stimulating factor 1 receptor) inhibitor (PLX3397), oncolytic viruses, and anti-PD-1 antibody. Our results demonstrated that the triple treatment synergistically conferred significant tumor control and prolonged the survival of mouse models of colon cancer. Approximately 43% and 82% of mice bearing the CT26 and MC38 tumor, respectively, survived long term following the triple treatment. This combination therapy reprogrammed the immunosuppressive tumor microenvironment toward a CD8+ T cell-biased anti-tumor immunity by increasing T cell infiltration in the tumor and augmenting anti-tumor CD8+ T cell function. Our results provide a robust strategy for clinical combination therapy.

Follistatin-like protein 5 inhibits hepatocellular carcinoma progression by inducing caspase-dependent apoptosis and regulating Bcl-2 family proteins.

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignant tumors in the world, especially in China. Follistatin-like protein 5 (FSTL5) is a member of the FSTL family, which is involved in cell proliferation, migration, differentiation, and embryo development. We aimed to investigate the function and underlying mechanism of FSTL5 in HCC. FSTL5 expression was determined by immunohistochemistry staining in a liver cancer tissue microarray (TMA) and the correlation between FSTL5 and the prognosis of HCC patients was analysed. Further proliferation assay, colony formation assay, flow cytometry, and xenograft tumor model were performed to investigate the bioeffects of FSTL5 in HCC in vitro and in vivo. We found that FSTL5 expression was downregulated in HCC tissues and positively correlated with the prognosis of patients with HCC at tumor node metastasis stage I/II. Overexpression of FSTL5 efficiently impaired HCC growth both in vivo and in vitro with an exogenous manner. Mechanistic investigation demonstrated that FSTL5 promoted HCC cell apoptosis in a caspase-dependent manner and regulated Bcl-2 family proteins. These results indicate that FSTL5 may be a potential novel target for HCC treatment, and a biomarker for tumor prognosis.

Experimental characterization of the radio over fiber aided twin-antenna spatial modulation downlink.

In this paper, we present the design and the experimental demonstration of a radio over fiber (RoF) network relying on state-of-the-art spatial modulation (SM), that activates one out of multiple antennas. We propose a novel RoF-aided SM encoding scheme, where the optical single side-band signal generated by a Mach-Zehnder modulator (MZM) is used for both the antenna selection and for the classic modulated symbol selection. The SM encoding is optically processed in a centralized fashion, aiming for the reduction of power consumption and for enabling cost-effective maintenance and management, which can be employed in the context of a cloud radio access network (C-RAN) and a small-cell front-haul. Furthermore, an experimental demonstration of the proposed system is discussed and analyzed, where a 20 km standard single mode fiber (SSMF) is used for transmission. In this experiment, a 2 Gbps transmission relying on two transmit and two receive antennas is achieved with less than 1 dB SNR degradation compared to those operating without RoF.

DDA1, a novel oncogene, promotes lung cancer progression through regulation of cell cycle.

Lung cancer is globally widespread and associated with high morbidity and mortality. DDA1 (DET1 and DDB1 associated 1) was first discovered and registered in the GenBank database by our colleagues. DDA1, an evolutionarily conserved gene, might have significant functions. Recent reports have demonstrated that DDA1 is linked to the ubiquitin-proteasome pathway and facilitates the degradation of target proteins. However, the function of DDA1 in lung cancer was previously unknown. This study aimed to investigate whether DDA1 contributes to tumorigenesis and progression of lung cancer. We found that the expression of DDA1 in normal lung cells and tissue was significantly lower than that in lung cancer and was associated with poor prognosis. DDA1 overexpression promoted proliferation of lung tumour cells and facilitated cell cycle progression in vitro and subcutaneous xenograft tumour progression in vivo. Mechanistically, this was associated with the regulation of S phase and cyclins including cyclin D1/D3/E1. These results indicate that DDA1 promotes lung cancer progression, potentially through promoting cyclins and cell cycle progression. Therefore, DDA1 may be a potential novel target for lung cancer treatment, and a biomarker for tumour prognosis.

IL-35 Decelerates the Inflammatory Process by Regulating Inflammatory Cytokine Secretion and M1/M2 Macrophage Ratio in Psoriasis.

IL-35 downregulates Th17 cell development and suppresses certain types of autoimmune inflammation such as collagen-induced arthritis and experimental autoimmune uveitis. Psoriasis is thought to be initiated by abnormal interactions between cutaneous keratinocytes and systemic immune cells. However, the role of IL-35 in psoriasis remains unclear. In this study, we assessed IL-35 in three well-known psoriasis models: a human keratinocyte cell line (HaCaT), a keratin 14 (K14)-vascular endothelial growth factor A (VEGF-A)-transgenic (Tg) mouse model, and an imiquimod-induced psoriasis mouse model. First, we found that IL-35 suppressed the expression of IL-6, CXCL8, and S100A7, which are highly upregulated by a mixture of five proinflammatory cytokines in HaCaT. Second, a plasmid coding for the human IL-35 sequence coated with cationic liposomes showed potent immunosuppressive effects on K14-VEGF-A-Tg and imiquimod-induced psoriasis mouse models. In the K14-VEGF-A-Tg model, our results showed that several types of proinflammatory cytokines were significantly reduced, whereas IL-10 was remarkably induced by IL-35. Compared with pcDNA3.1, there was a small number of CD4(+)IL-17(+) T cells and a large number of CD4(+)IL-10(+) and CD4(+)CD25(+)Foxp3(+) T cells in the IL-35 group. Most importantly, we found that IL-35 decreased the total number of macrophages and ratio of M1/M2 macrophages, which has not been reported previously. In addition, compared with dexamethasone, IL-35 showed long-term therapeutic efficacy. In summary, our results strongly indicate that IL-35 plays a potent immunosuppressive role in psoriasis. Thus, IL-35 has potential for development as a new therapeutic strategy for patients with chronic psoriasis and other cutaneous inflammatory diseases.

A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity.

Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T-cell activation. A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as program death-1 (PD-1/PD-L1) pathway in the tumor environment. However, the determinants of response to anti-PD-1 monoclonal antibodies (mAbs) treatment remain incompletely understood. In murine models, PD-1 blockade alone fails to induce effective immune responses to poorly immunogenic tumors, but is successful when combined with additional interventions, such as cancer vaccines. Novel cancer vaccines combined with antibody may offer promising control of cancer development and progression. In this investigation, we generated a novel tumor cell vaccine simultaneously expressing anti-PD-1 mAbs and granulocyte-macrophage colony stimulating factor (GM-CSF) in CT26 colon cancer and B16-F10 melanoma. The antitumor effect of the vaccine was verified by therapeutic and adoptive animal experiments in vivo. The antitumor mechanism was analyzed using Flow cytometry, Elispot and in vivo intervention approaches. The results showed that tumor cell vaccine secreting PD-1 neutralizing antibodies and GM-CSF induced remarkable antitumor immune effects and prolonged the survival of tumor-bearing animals compared with animals treated with either PD-1 mAbs or GM-CSF alone. Antitumor effects and prolonged survival correlated with strong antigen-specific T-cell responses by analyzing CD11c+CD86+ DC, CD11b+F4/80+ MΦ cells, increased ratio of Teff/Treg in the tumor microenvironment, and higher secretion levels of Th1 proinflammatory cytokines in serum. Furthermore, the results of ELISPOT and in vivo blocking strategies further confirmed that the antitumor immune response is acquired by CD4 and CD8 T immune responses, primarily dependent on CD4 Th1 immune response, not NK innate immune response. The combination of PD-1 blockade with GM-CSF secretion potency creates a novel tumor cell vaccine immunotherapy, affording significantly improved antitumor responses by releasing the state of immunosuppressive microenvironment and augmenting the tumor-reactive T-cell responses.

Osteoporosis in the jawbones: a correlative factor of primary trigeminal neuralgia?

Trigeminal neuralgia (TN), a neuropathic disorder of one or both of the trigeminal nerves, occurs most often in people over age 50. Extreme, sporadic, sudden burning or shock-like face pain in common activities greatly lowers quality of life. The precise cause of primary TN remains unknown, but it may be caused by vascular pressing on the trigeminal nerve in its root entry zone (REZ), demyelinization of trigeminal sensory fibers, or jawbone cavity. Accordingly, many treatments carry risks of adverse effects, recurrence, and complications. TN and osteoporosis have similar high-risk populations and a common influential factor - emotional stress - is also closed related to primary TN for calcitonin gene-related peptide and calcitonin. Jawbone cavity, which is a possible pathogenesis of TN, may be another form of jawbone osteoporosis. Therefore, we hypothesized that osteoporosis in jaws could be a correlative factor of primary TN. If this hypothesis is verified, it may suggest specific new ideas for the early preventive treatment of primary TN.