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Abstract Background Cancer-associated fibroblasts (CAFs) are a pivotal component of the tumor microenvironment (TME), playing key roles in tumor initiation, metastasis, and chemoresistance. While glycosylation is known to regulate various cellular processes, its impact on CAFs activation remains insufficiently explored. Methods We assessed the correlation between bisecting GlcNAc levels and CAFs markers (α-SMA, PDGFRA, PDGFRB) in breast cancer tissues. The effects of small extracellular vesicles (sEVs) derived from MDA-MB-231/OEvec and MDA-MB-231/OEMGAT3 cells on CAFs activation were examined using western blotting, transwell, and collagen contraction assays. Proteomic analysis was performed to identify dysregulated proteins in sEVs from different cell lines. The role of GAS6 in CAFs activation was validated through in vitro and in vivo experiments. The impact of bisecting GlcNAc modification on GAS6 expression and function was analyzed through protein degradation and N-glycosylation site mutation. The effect of activated CAFs on breast cancer metastasis was evaluated using western blotting and transwell assays. Results We found that low bisecting GlcNAc levels were associated with CAFs activation within the TME of breast cancer. Breast cancer-derived sEVs stimulated the conversion of normal fibroblasts to CAFs, with GAS6 in sEVs playing a key role by interacting with AXL receptors on fibroblasts. Introducing GAS6 into normal fibroblasts induced their conversion into CAFs, which enhanced breast cancer cell metastasis. Notably, GAS6 was decorated with bisecting GlcNAc, which promoted its degradation in donor cells, leading to reduced GAS6 levels in sEVs and attenuating GAS6-mediated CAFs activation. Conclusion Taken together, our findings provide new insights into the functional role of bisecting GlcNAc on GAS6-mediated CAFs activation in breast cancer.

In the era of intelligent media, human users and chatbots have established a deep dependency relationship through communication, making media dependence a behavioral foundation that widely permeates human social practice. This article investigates how media dependence affects human social interaction during emotional interactions between human users and chatbots. Based on the theory of media dependence, the existing mature scales of media dependence and interpersonal communication were adapted, and 496 Replika user questionnaires were collected. After screening the validity of the questionnaires, 428 valid questionnaires were obtained. Descriptive statistical analysis, correlation analysis, multiple linear regression analysis, and mediation effect testing were used to analyze the impact of media dependence on human–computer emotional interaction. Results indicate a significant positive correlation between human–chatbot emotional interaction and human user social interaction. Media dependence significantly positively regulates emotional interactions between humans and chatbots. In addition, the social interactions of human users are partially influenced by factors such as user nature, age, education, and income.

Abstract This study aimed to evaluate the association between polymyxin B (PMB) exposure and acute kidney injury (AKI) and analyze the risk factors for PMB‐induced AKI in critically ill patients. Plasma concentrations of PMB were determined using an ultraperformance liquid chromatography–tandem mass spectrometer in intensive care unit patients who were administered PMB. Univariate and multivariate analyses were conducted to identify risk factors. A receiver operating characteristic curve was constructed to assess the discriminant power of the factors and to identify the cutoff value for AKI. The white blood cell count and estimated area under the concentration–time curve (AUC) of patients administered PMB were independent risk factors for PMB‐induced AKI, where AUC were calculated using a first‐order pharmacokinetic equation based on the mid‐dosing interval concentration (C1/2t) and peak concentration. The area under the receiver operating characteristic curve of the final model was 0.805 (95% confidence interval, 0.690–0.921). The cutoff value for the combined predictor was 0.57. Alternatively, when using C1/2t, which was strongly correlated with AUC, as the only independent risk factor, the analysis showed that the 3.47 μg/ml threshold provides favorable differentiation between the AKI and non‐AKI groups. These results provide insightful information for therapeutic drug monitoring–guiding PMB dosing in clinical practice.

Purposes Error calibration between equipment manufacturing has become a practical challenge for various inspection methods. Methods In this paper, a portable magnetoelastic (ME) biodetection device is proposed for calibration-free detection of classical swine fever virus E2 antibody (anti-CSFV E2), on the basis of magnetostrictive effect, by monitoring the resonance frequency shift caused by anti-CSFV E2 to react to the concentration of analytes. The device consists of two parts, namely the magnetoelastic test strip and the intelligent magnetoelastic resonance frequency detector. The test strip is very small, and the external dimension is about 1/20 of the size of the ELISA kit. By using the ELISA kit as a control, the accuracy of the portable ME device is verified by detecting the same concentration of pig serum samples. Findings The results show that the detection results of the calibration-free portable ME device and the ELISA kit have good consistency, and the accuracy rate is 98%. The experimental results show that the sensitivity is 7.20 Hz/(μg/mL) and the linear range is 0.1~100 μg/mL, and the device can quickly and accurately detect anti-CSFV E2 without calibration, with good specificity and stability. Conclusions The calibration-free portable ME unit provides an effective method for the diagnosis of swine fever and the monitoring of the effectiveness of anti-swine fever vaccination.

The thermal-controlled fracture method has been increasingly focused upon in the high-quality cutting of advanced ceramic materials due to its excellent characteristics. The successful application of this method in cutting ceramics mainly depends on the volumetric heating effect. However, most ceramics are treated using the surface heating mode. For the surface heating mode, the processing quality, including fracture trajectory and fracture quality, is far lower than the industrial application standards. This work was conducted to reveal the mechanism of this processing quality. Experiments involving cutting ceramics in single-surface heating mode indicate that the fracture trajectories of the upper and lower surfaces display a significant inconsistency, and the fracture quality is worse than that using the dual-surface heating mode. A cutting model was established to calculate the thermal stress distribution and to simulate the crack-propagation behaviors. The simulation results show good agreement with the experiment and provide the stress distribution, and are used to understand the reason for the processing quality problem. The mechanism of the trajectory deviation and uneven distribution of the fracture quality is revealed based on the simulation and calculation results. This study helps provide a deep understanding of the processing problems arising from this method and thus helps to innovate high-quality processing methods in this field.

ObjectivesThis study seeks to explore the dynamic response characteristics of a marine steam power system under the condition of rapid and large power disturbance. MethodsA complete set of onshore experimental devices for a steam power system is established, and the dynamic response characteristics are studied by applying power disturbance by simulated load. ResultsThe experimental results show that under the condition of a single period disturbance, the fluctuation range of the drum pressure is within ± 1.5% and that of the propeller speed is within ± 2.5%; under the condition of continuous periodic disturbance, the fluctuation range of the drum pressure is within ± 2.5% and that of the propeller speed is within ± 3.5%; during the experiment, the steam power system generally runs in a stable manner. ConclusionThe results of this study can provide technical support for the actual operation and use of steam power systems.

Canine mammary tumors (CMTs) are the most common type of tumor in female dogs. In this study, we obtained a metastatic key protein, Fascin-1, by comparing the proteomics data of in situ tumor and metastatic cell lines from the same individual. However, the role of Fascin-1 in the CMT cell line is still unclear. Firstly, proteomics was used to analyze the differential expression of Fascin-1 between the CMT cell lines CHMm and CHMp. Then, the overexpression (CHMm-OE and CHMp-OE) and knockdown (CHMm-KD and CHMp-KD) cell lines were established by lentivirus transduction. Finally, the differentially expressed proteins (DEPs) in CHMm and CHMm-OE cells were identified through proteomics. The results showed that the CHMm cells isolated from CMT abdominal metastases exhibited minimal expression of Fascin-1. The migration, adhesion, and invasion ability of CHMm-OE and CHMp-OE cells increased, while the migration, adhesion, and invasion ability of CHMm-KD and CHMp-KD cells decreased. The overexpression of Fascin-1 can upregulate the Tetraspanin 4 (TSPAN4) protein in CHMm cells and increase the number of migrations. In conclusion, re-expressed Fascin-1 could promote cell EMT and increase lamellipodia formation, resulting in the enhancement of CHMm cell migration, adhesion, and invasion in vitro. This may be beneficial to improve female dogs’ prognosis of CMT.

ObjectivesTumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder characterized by hypophosphatemia resulting from tumor-secreted fibroblast growth factor-23 (FGF23). Surgical resection of the culprit TIO is the first choice of treatment. However, TIO is difficult to detect with conventional diagnostic tools due to its small size and variable location in the body. Somatostatin receptor scintigraphy (SSR) has recently emerged as a functional molecular imaging choice for TIO detection and localization. This research was undertaken to evaluate the efficacy of 99mTc-labeled hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) SPECT/CT in detecting TIO.Methods99mTc-HYNIC-TOC SPECT/CT and the available clinical data of 25 patients with suspected TIO were analyzed retrospectively. The 99mTc-HYNIC-TOC SPECT/CT findings were compared with the post-surgical pathology diagnosis and clinical follow-up results.ResultsUsing 99mTc-HYNIC-TOC SPECT/CT, suspicious tumors were found in 18 of the 25 patients, and 15 of them underwent surgical resection. The post-operative pathology confirmed a TIO in those 13 patients whose symptoms and biochemical anomalies gradually resolved after the surgery. The remaining five patients were finally considered false positives. Moreover, the 99mTc-HYNIC-TOC SPECT/CT results were negative in seven patients, with six patients being true negative (4 patients were diagnosed with acquired Fanconi syndrome and 2 patients responded well to conservative therapy) and one being false negative. Therefore, the sensitivity and specificity values of 99mTc-HYNIC-TOC SPECT/CT in the evaluation of TIO were 92.9% (13/14) and 54.5% (6/11), respectively. The overall accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting TIO was 76.0% (19/25).ConclusionsThe 99mTc-HYNIC-TOC SPECT/CT is an accurate imaging modality for locating culprit tumors in TIO.

Blended learning has increasingly grown in importance as a method of classroom instruction in Chinese higher education classrooms in the context of fast-evolving network information technology, higher standards of educational informatization, and growing attention to the reform of teaching modes in higher education. The efficiency of blended learning can be increased by better understanding the students’ learning satisfaction and its key influencing factors. Based on the theories of constructivism and phenomenology, the study constructs an index system of student satisfaction with blended learning in higher education, and conducts a questionnaire survey on 650 students with blended learning experience in 6 universities in Sichuan Province, China, obtaining 598 valid questionnaires after reviewing the collected questionnaires for missing values. This study uses descriptive statistical analysis (DSA), one-way ANOVA, Pearson correlation analysis, and multiple linear regression (MLR) to analyze the effects of each factor in the index system on satisfaction. Results indicate that the overall level of student satisfaction with blended learning in universities is moderately high, with students’ self-satisfaction being the lowest, and that substantial disparities exist in the evaluation of satisfaction with blended learning on various online resources, online teaching forms, and offline teaching methods. This study applies multiple linear regression (MLR) to conclude that students’ learning attitudes, curriculum design, and teachers’ teaching methods are the most important factors influencing satisfaction with blended learning in universities. Results indicate that a blended learning system be built from the three dimensions of students, teachers, and curriculum, offering a theoretical foundation and point of reference for the ongoing reform of blended learning in higher education. The study is of great significance in optimizing teaching quality and deepening the reform of blended learning.

As an application of the Legendrian singularity theory, we classify the bifurcations of a holonomic first-order differential equation with a complete integral. The equations satisfy that the one-parameter integral diagrams are R+-simple and stable. Using this result, the parametric differential equation models in electrical power systems and engineering can be studied.

ObjectivesIn order to ensure safe and stable operation of the marine steam power systems, it is necessary to study the dynamic response characteristics of the system under the rapid power generation disturbance of a turbo-generator set. MethodsAn overall simulation model of a marine steam power system is established, and the simulation analysis of the dynamic characteristics of the system is carried out according to the operating conditions of single and continuous rapid disturbance of power generation. ResultsThe simulation results show that the steam intake pressure of the main engine fluctuates by no more than 5% under single rapid disturbance, and by no more than 7% under continuous rapid disturbance, and the fluctuation of the propeller's revolution speed under the two disturbance conditions is not more than 2%, which can meet the stable steam supply demand of the system. ConclusionsThe results of this study can provide references for the safety design of marine steam power systems.

Objectives99mTc-HYNIC-PSMA is a novel technetium-99m-labeled small-molecule inhibitor of prostate-specific membrane antigen (PSMA) for detection of prostate cancer. The present study investigated the diagnostic yield of 99mTc-HYNIC-PSMA Single photon emission computed tomography (SPECT)/CT in 147 patients with biochemically recurrent prostate cancer after radical prostatectomy.Methods147 patients with biochemical relapse after radical prostatectomy were finally eligible for this retrospective analysis. The median prostate-specific antigen (PSA) level was 8.26 ng/mL (range, 0.22-187.40 ng/mL). Of the 147 patients, 72 patients received androgen deprivation therapy (ADT) at least 6 months before the 99mTc-HYNIC-PSMA SPECT/CT. All patients underwent planar whole-body scans and subsequent SPECT/CT of the thoracic and abdominal regions after intravenous injection of 705 ± 70 MBq of 99mTc-HYNIC-PSMA. Images were evaluated for the presence and location of PSMA-positive lesions, in which SUVmax were also measured. Detection rates were stratified according to PSA levels, ADT and Gleason scores. The relationships between SUVmax and clinical characteristics were analyzed using univariate and multivariable linear regression models for patients with positive findings.ResultsOf the 147 patients, 99mTc-HYNIC-PSMA SPECT/CT revealed at least one positive lesion in 118 patients with a high detection rate (80.3%). The detection rates were 48.6% (17/35), 85.1% (40/47), 92.1% (35/38), and 96.3% (26/27) at PSA levels of greater than 0.2 to 2, greater than 2 to 5, greater than 5 to 10, and greater than 10 ng/mL, respectively. PSMA SPECT/CT indicated local recurrence, lymph node metastases, bone metastases, and visceral metastases in 14 (9.5%), 73 (49.7%), 48 (32.7%) and 3 (2.0%) patients. The detection rates of local recurrence and metastasis increased with increasing PSA levels. The detection rate was higher in patients treated with ADT than those without (90.3% vs. 70.7%; P =0.0029). In patients with Gleason scores ≥8, detection rate was slightly higher than those with ≤7 (81.7% vs. 78.5%), but not statistically significant (P = 0.6265). Multivariable linear regression analysis showed a significant correlation of PSA levels and ADT with SUVmax (P=0.0005 and P=0.0397).Conclusions99mTc-HYNIC-PSMA SPECT/CT offers high detection rates for biochemically recurrent prostate cancer after radical prostatectomy. The detection rate and SUVmax were positively correlated with PSA levels and ADT.

Background: To develop a population pharmacokinetic (PPK) model for caspofungin, identify parameters influencing caspofungin pharmacokinetics, and assess the required probability of target attainment (PTA) and cumulative fraction of response (CFR) for various dosing regimens of caspofungin in all patients and intensive care unit (ICU)-subgroup patients.Method: The general PPK model was developed based on data sets from all patients (299 patients). A ICU-subgroup PPK model based on data sets from 136 patients was then analyzed. The effects of demographics, clinical data, laboratory data, and concomitant medications were tested. Monte-Carlo simulations (MCS) were used to evaluate the effectiveness of different caspofungin dosage regimens.Results: One-compartment model best described the data of all patients and ICU patients. Clearances (CL) were 0.32 L/h and 0.40 L/h and volumes of distribution (V) were 13.31 L and 10.20 L for the general and ICU-subgroup PPK models, respectively. In the general model, CL and V were significantly associated with albumin (ALB) concentration and body weight (WT). In the ICU-subgroup model, CL was associated with WT. The simulated exposure in ICU patients was lower than that in all patients (p < 0.05). MCS indicated that higher caspofungin maintenance doses of 70–150 mg may achieve target CFR of >90% for patients with higher WT (>70 kg) or with C. albicans or C. parapsilosis infections, and especially for ICU patients with hypoalbuminaemia.Conclusion: The PPK model and MCS presented in the study demonstrated that the recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure.

Hypoxia-inducible factor (HIF), which plays a crucial role in oxygen homeostasis, contributes to immunosuppression, tumor angiogenesis, multidrug resistance, photodynamic therapy resistance, and metastasis. HIF as a therapeutic target has attracted scientists’ strong academic research interests. Short interfering RNA (siRNA) and antisense oligonucleotide (ASO) are the more promising and broadly utilized methods for oligonucleotide-based therapy. Their physicochemical characteristics such as hydrophilicity, negative charge, and high molecular weight make them impossible to cross the cell membrane. Moreover, siRNA and ASO are subjected to a rapid deterioration in circulation and cannot translocate into nuclear. Delivery of siRNA and ASO to specific gene targets should be realized without off-target gene silencing and affecting the healthy cells. Nanoparticles as vectors for delivery of siRNA and ASO possess great advantages and flourish in academic research. In this review, we summarized and analyzed regulation mechanisms of HIF under hypoxia, the significant role of HIF in promoting tumor progression, and recent academic research on nanoparticle-based delivery of HIF siRNA and ASO for cancer immunotherapy, antiangiogenesis, reversal of multidrug resistance and radioresistance, potentiating photodynamic therapy, inhibiting tumor metastasis and proliferation, and enhancing apoptosis are reviewed in this thesis. Furthermore, we hope to provide some rewarding suggestions and enlightenments for targeting HIF gene therapy.

In multirobot task planning, the goal is to meet the multi-objective requirements of the optimal and balanced energy consumption of robots. Thus, this paper introduces the energy penalty strategy into the GA (genetic algorithm) to achieve the optimization of the task planning of multiple robots in different operation scenarios. First, the algorithm model is established, after which the objective function is constructed by taking the energy excess of the relative average energy consumption of each robot as the penalty energy, along with the total energy consumption of multiple robots. In the genetic operation, two-segment chromosome coding is used to realize the iterative optimization of the number and task sequences of robots through diversified cross and mutation operators. Then, in the task scenario with obstacles, the A* (A-Star) algorithm and GA are used to plan the optimal obstacle avoidance path and to realize the secondary optimization of the robot task sequence without changing the number of tasks. During optimization, the energy penalty strategy imposes punishment on the objective function through the size of the penalty energy, enabling the robot energy consumption to reach an equilibrium state by maintaining the total energy consumption at the minimum. Finally, the MATLAB platform is used to conduct the simulation experiments to compare with basic genetic algorithms and penalty function algorithms, after which the optimal allocation scheme and energy consumption iteration of the algorithm are analyzed under different robot numbers, task numbers, and task scenarios, and the simulation results include robot task sequences, total energy consumption, average energy consumption, and standard deviation of energy consumption.

Abstract Background Invasion of the superior vena cava (SVC) by thoracic tumors and occurrence of SVC syndrome are often encountered in clinical practice; but the prognosis in these cases is poor. Replacement of the SVC with autologous pericardial tissue is rarely performed. In this study, we sought to investigate the postoperative outcomes of this rare procedure. Methods We performed a retrospective analysis of six patients who underwent SVC replacement using autologous pericardial tissue between October 2010 and November 2016. We collected data on the patients’ pathological features, operative characteristics, postoperative outcomes, and survival. Results All six patients were male with an average age of 52 years (range, 18–62 years). Three of the patients had lung cancer, one had stage III thymoma, and two had germinoma. Four of the six patients had mild or moderate superior vena cava compression and no corresponding clinical symptoms. The other two patients had severe compression and obvious symptoms of SVC syndrome, with the typical swelling of the face, eyelids, and upper extremities. All six patients underwent complete tumor resection, with two of the lung cancer patients undergoing right lobectomy and one undergoing right pneumonectomy. With respect to the postoperative outcomes, one patient died, whereas the others did not develop any major complications. At the end of the follow-up period, five of the patients were alive and none of the patients had developed thrombosis in the grafts. Conclusions Our findings indicated that SVC replacement with autologous pericardium is technically feasible and safe, with few postoperative complications and favorable long-term effects. Although it has some limitations, this method appears to be useful in achieving SVC reconstruction of moderate size. SVC replacement with autologous pericardium appears to have the potential for widespread clinical use.

Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir (TFV) that has been approved for the treatment of chronic hepatitis B virus (HBV) infection. It has greater plasma stability and more favorable renal safety than tenofovir disoproxil fumarate (TDF), the first approved oral prodrug of TFV. However, the distribution of TFV in the breast milk of mothers treated with TAF is still unclear. In this study, sixteen participants with chronic HBV infection were enrolled and received antiretroviral therapy with 25 mg of TAF or 300 mg of TDF daily from 24 to 28 weeks of gestation until the 4th week postpartum. For the first time, the distribution of TFV in the breast milk of mothers with chronic HBV infection treated with TAF and its difference from TDF were evaluated by using a sensitive UPLC–MS/MS method. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C18 column (1.7 µm 2.1 × 100 mm). Mass spectrometry analysis was performed in positive electrospray ionization mode and multiple reaction monitoring (MRM) conditions of transitions m/z 288.1→176.2 for TFV. This method was linear from 0.5 to 500 ng/ml. Surprisingly, on the third postpartum day, the median Cmax of TFV in the breast milk was much higher in the mothers treated with TAF (101.2 ng/ml) than TDF (21.6 ng/ml) at a similar Tmax of 4 h. Accordingly, the median AUC0-8 value was 755.6 ng h/mL in the mothers taking TAF, which was at a 5-fold higher level than TDF. The concentration of TFV in the breast milk of mothers in both groups decreased with increasing lactation time. These data indicated that there was a relatively higher exposure of TFV in the breast milk of mothers taking TAF, despite the lower dosage compared to TDF. This study provides support for further evaluating the safety of breastfeeding after the administration of TAF and TDF.

The thermal-controlled fracture method has been increasingly focused upon in the high-quality splitting of advanced brittle materials due to its excellent characteristics related to the fact that it does not remove material. For opaque, brittle materials, their poor fracture quality and low machining capacity resulting from their single-sided heat mode is a bottleneck problem at present. This work proposed the use of dual-sided thermal stress induced by microwave to split opaque, brittle materials. The experimental results indicate that the machining capacity of this method is more than twice that of the single-sided heat mode, and the fracture quality in splitting opaque, brittle materials was significantly improved by dual-sided thermal stress. A microwave cutting experiment was carried out to investigate the distribution characteristic of fracture quality by using different workpiece thicknesses and processing parameters. A dual-sided thermal stress cutting model was established to calculate the temperature field and thermal stress field and was used to simulate the crack propagation behaviors. The accuracy of the simulation model was verified using temperature measurement experiments. The improvement mechanism of the machining capacity and fracture quality of this method was revealed using the fracture mechanics theory based on calculation results from a simulation. This study provides an innovative and feasible method for cutting opaque, brittle materials with promising fracture quality and machining capacity for industrial application.

Over the years, the manipulation and clinical application of drug-delivery nanosystems for cancer diseases have attracted a rapid growth of academic research interests, and some nanodrugs have been approved for clinic application. Although encouraging achievements have been made, the potency of nanomedicines in cancer treatment is far from satisfaction, and one significant reason is the inefficient penetration of nanoparticles into solid tumors. Particle size is one of the most significant features that influence diffusion ability of the drug-delivery system in tumors. Size-shrinkable drug-delivery nanosystems possess a size-switchable property that can achieve passive targeting via the enhanced permeability and retention (EPR) effect and transform into ultrasmall particles in tumors for deep penetration into tumors. The tumor microenvironment is characterized by acidic pH, hypoxia, upregulated levels of enzymes, and a redox environment. In this review, we summarize and analyze the current research progresses and challenges in tumor microenvironment responsive size-shrinkable drug-delivery nanosystems. We further expect to present some meaningful proposals and enlightenments on promoting deep penetration into tumors of nanoparticles.

Summary: TGF-β has been demonstrated to promote tumor metastasis, and the regulatory mechanisms are poorly understood. Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. The phosphorylation of USP2a and SMAD2 is positively correlated in human tumor biopsies, and USP2a is hyper-phosphorylated in lung adenocarcinomas with lymph node invasion. Depletion or pharmacologic inhibition of USP2a dampens TGF-β-triggered signaling and metastasis. Our findings have characterized an essential role of USP2a as a potential target for treatment of metastatic cancers. : Zhao et al. find that USP2a deconjugates K33-linked ubiquitination of TGFBR1 at Lys502 and is phosphorylated at Ser207/Ser225 by TGFBR2 after TGF-β stimulation. This allows R-SMAD recruitment to and subsequent disassociation from the TGFBR1/2 receptor complex. Keywords: USP2a, TGF-β, epithelial-to-mesenchymal transition, metastasis, ubiquitination, phosphorylation, SMAD2/3, TGFBR1/2, signaling transduction

Objective Ceramides are associated with coronary plaque vulnerability. We aim to investigate the potential diagnostic value of ceramides for acute coronary syndrome (ACS) in Chinese patients with chest pain.Design Prospective observational survey.Setting Shanghai, China, 2016–2017.Participants A total of 2773 patients with chest pain from four hospitals in Shanghai, China, between August 2016 and October 2017.Main outcome measures Performance of metabolites model in detection of ACS cases including ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina.Results Plasma levels of 12 ceramide molecules and corresponding ratios were compared between patients diagnosed with ACS and those without. Cer(d18:1/24:1(15Z))/Cer(d18:1/24:0) ratio, Cer(d18:1/14:0) and Cer(d18:1/22:0) were independent predictors of ACS after adjustment of traditional risk factors and high-sensitivecardiac troponin T. Receiver operating characteristic curve analysis showed a significant improvement in detecting ACS in the multivariable model with ceramides compared with that without (0.865 (0.840 to 0.889) vs 0.808 (0.776 to 0.841), p

Granulocyte-macrophage colony-stimulating factor has been widely used as an adjuvant therapy for cancer patients exhibiting myelosuppression induced by chemotherapy or radiotherapy. However, the effects of granulocyte-macrophage colony-stimulating factor on tumor growth, as well as its precise mechanism, are still controversial due to inconsistent evidence. This study investigated the effect of exogenous granulocyte-macrophage colony-stimulating factor on the growth of B16 melanoma, S180 sarcoma, and U14 cervical carcinoma in mice. The angiogenesis and recruitment of bone-marrow-derived cells were analyzed in tumor tissues. Interactions among granulocyte-macrophage colony-stimulating factor, bone-marrow-derived cells, and B16 tumor cells were investigated in vitro. Proangiogenic types of bone-marrow-derived cells in blood were assessed both in vivo and in vitro. The results showed that granulocyte-macrophage colony-stimulating factor markedly facilitated the growth of B16 and S180 tumors, but not U14 tumors. Granulocyte-macrophage colony-stimulating factor increased the densities of blood vessels and the number of bone-marrow-derived cells in B16 tumor tissues. The granulocyte-macrophage colony-stimulating factor–induced enhancement of tumor cell proliferation was mediated by bone-marrow-derived cells in vitro. Meanwhile, a distinct synergistic effect on endothelial cell function between granulocyte-macrophage colony-stimulating factor and bone-marrow-derived cells was observed. After separating two types of bone-marrow-derived cells, granulocyte-macrophage colony-stimulating factor–induced enhancement of tumor growth and angiogenesis in vivo was mediated by proangiogenic cells in granulocytes, but not monocytes, with CD11b + , vascular endothelial growth factor receptor 2, and C-X-C chemokine receptor 4 granulocytes possibly involved. These data suggest that granulocyte-macrophage colony-stimulating factor contributes to the growth and angiogenesis of certain types of tumor, and these mechanisms are probably mediated by proangiogenic cells in granulocytes. Applying granulocyte-macrophage colony-stimulating factor may attenuate the antitumor effects of chemotherapy and radiotherapy in certain types of tumor.