Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment.

BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response. CONCLUSIONS: Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.

Bioinformatics analysis of the prognosis and biological significance of N6 methyladenine regulators in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common type of cancer. We performed the present study to explore the function and specific regulatory mechanism of m6A in OSCC and to find a new diagnosis and treatment strategy for OSCC. METHODS: Using bioinformatics, we examined the associations between 20 genes associated with methylation and the epidemiological data about OSCC tumor samples. RESULTS: We created two subgroup curves based on the gene expression levels related to m6A methylation. In total, 14 genes were found to be differentially expressed. Significant differences in terms of survival rates, Grade and gender were found among subgroups with different m6A expression levels. Nine genes had areas under the curves greater than 0.7. Therefore, these genes may be utilized for the clinical diagnosis and prognosis of OSCC. Because of their high individual predictive value, HNRNPC and IGF2BP2 were chosen as the two potential predictors. The two regulatory elements were used to create the prognostic signals for OSCC. The developed prognostic signals made it possible to discern between the samples with good and poor prognoses without potential confounding factors. Four genes (HNRNPC, METTL14, YTHDF2 and ALKBH5) combined well with compounds, which had an anti-cancer effect. CONCLUSIONS: Our findings suggested that OSCC-related genes with m6A methylation could be beneficial treatment targets or prognostic indicators.

Occurrences, Retention and Risk Assessments of PAHs in Beidagang Wetland in Tianjin, China.

Coastal wetlands are the last barriers for pollutants from land to the sea. In this study, a coastal wetland that locates in the lower reach of Haihe River Systems was selected to speculate the removal and retention of polycyclic aromatic hydrocarbons (PAHs) by analyzing their spatial distributions and the changes of composition. The results showed that the overall removal efficiency of PAHs in water phase was 58.1%. There was an accumulation for sedimentary PAHs, reaching 431 ng/g (181 ng/g in the inlet). The compositions of sedimentary PAHs were also changed, high-molecular-weight PAHs were the main component (70-50%), with a steady decreasing trend and the influence of water flow direction. The risk assessment by mean effect range media quotients (M-ERM-Qs) depicted that there was in low ecological risk, due to the degradation of PAHs in the wetlands. Our results clearly demonstrated the coastal wetlands could effectively retain the PAHs, thus we recommend an active protection strategy for the coast wetlands in Tianjin in the future.

TGF-ß1-PML SUMOylation-peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis.

Transforming growth factor-ß (TGF-ß) signaling pathway is involved in fibrosis in most, if not all forms of cardiac diseases. Here, we evaluate a positive feedback signaling the loop of TGF-ß1/promyelocytic leukemia (PML) SUMOylation/Pin1 promoting the cardiac fibrosis. To test this hypothesis, the mice underwent transverse aortic constriction (3 weeks) were developed and the morphological evidence showed obvious interstitial fibrosis with TGF-ß1, Pin1 upregulation, and increase in PML SUMOylation. In neonatal mouse cardiac fibroblasts (NMCFs), we found that exogenous TGF-ß1 induced the upregulation of TGF-ß1 itself in a time- and dose-dependent manner, and also triggered the PML SUMOylation and the formation of PML nuclear bodies (PML-NBs), and consequently recruited Pin1 into nuclear to colocalize with PML. Pharmacological inhibition of TGF-ß signal or Pin1 with LY364947 (3 µM) or Juglone (3 µM), the TGF-ß1-induced PML SUMOylation was reduced significantly with downregulation of the messenger RNA and protein for TGF-ß1 and Pin1. To verify the cellular function of PML by means of gain- or loss-of-function, the positive feedback signaling loop was enhanced or declined, meanwhile, TGF-ß-Smad signaling pathway was activated or weakened, respectively. In summary, we uncovered a novel reciprocal loop of TGF-ß1/PML SUMOylation/Pin1 leading to myocardial fibrosis.

PMLIV overexpression promotes TGF-ß-associated epithelial-mesenchymal transition and migration in MCF-7 cancer cells.

The epithelial-mesenchymal transition (EMT) is a key event associated with metastasis and dissemination in breast tumor pathogenesis. Promyelocytic leukemia (PML) gene produces several isoforms due to alternative splicing; however, the biological function of each specific isoform has yet to be identified. In this study, we report a previously unknown role for PMLIV, the most intensely studied nuclear isoform, in transforming growth factor-ß (TGF-ß) signaling-associated EMT and migration in breast cancer. This study demonstrates that PMLIV overexpression promotes a more aggressive mesenchymal phenotype and increases the migration of MCF-7 cancer cells. This event is associated with activation of the TGF-ß canonical signaling pathway through the induction of Smad2/3 phosphorylation and the translocation of phospho-Smad2/3 to the nucleus. In this study, we report a previously unknown role for PMLIV in TGF-ß signaling-induced regulation of breast cancer-associated EMT and migration. Targeting this pathway may be therapeutically beneficial.

Resilient Output Formation-Tracking of Heterogeneous Multiagent Systems Against General Byzantine Attacks: A Twin-Layer Approach.

This work solves the countermeasure design problems of distributed resilient output time-varying formation-tracking (TVFT) of heterogeneous multiagent systems (MASs) against general Byzantine attacks (GBAs). Inspired by the concept of Digital Twin, a hierarchical protocol equipped with a twin layer (TL) is proposed, which decouples the above problem into the defense against Byzantine edge attacks (BEAs) on the TL and the defense against Byzantine node attacks (BNAs) on the cyber-physical layer (CPL). First, a secure TL with respect to (w.r.t.) the high-order leader dynamics is designed, which achieves resilient estimation against BEAs. A trusted-node strategy against BEAs is proposed, which promotes network resilience by protecting almost the smallest fraction of crucial nodes on the TL. It is proven that strongly (2f+1) -robustness w.r.t. the above trusted nodes is sufficient for the resilient estimation performance of the TL. Second, a decentralized adaptive and chattering-free controller against potentially unbounded BNAs is designed on the CPL. This controller has the merit of uniformly ultimately bounded (UUB) convergence and an assignable exponential decay rate when converging into the above UUB bound. To the best of our knowledge, this article is the first to achieve resilient output TVFT against GBAs, rather than under GBAs. Finally, the practicability and validity of this new hierarchical protocol are illustrated via a simulation example.

Ultra-Wideband and Odometry-Based Cooperative Relative Localization With Application to Multi-UAV Formation Control.

This puts forth an infrastructure-free cooperative relative localization (RL) for unmanned aerial vehicles (UAVs) in global positioning system (GPS)-denied environments. Instead of estimating relative coordinates with vision-based methods, an onboard ultra-wideband (UWB) ranging and communication (RCM) network is adopted to both sense the inter-UAV distance and exchange information for RL estimation in 2-D spaces. Without any external infrastructures prepositioned, each agent cooperatively performs a consensus-based fusion, which fuses the obtained direct and indirect RL estimates, to generate the relative positions to its neighbors in real time despite the fact that some UAVs may not have direct range measurements to their neighbors. The proposed RL estimation is then applied to formation control. Extensive simulations and real-world flight tests corroborate the merits of the developed RL algorithm.

Preview-Based Discrete-Time Dynamic Formation Control Over Directed Networks via Matrix-Valued Laplacian.

This paper studies the dynamic formation control problem for cooperative agents with discrete-time dynamics over directed graphs. Unlike using absolute coordinate, relative coordinate, interagent distance, or interagent bearing to specify the target formation and coordinate agents to achieve the formation, we study a coordination problem where the desired formation varies with time and only its geometric shape is predefined. Matrix-valued Laplacian approach has been adopted to address this problem in the continuous-time setting. However, the discrete-time counterpart is more challenging due to the constraint in information exchange. On the other hand, observe that in many real operations, at a given time instant, the agents will be able to plan their target formation configurations for a period of time ahead. We propose preview-based P-like and PD-like controllers for the formation control. The controllers with proper parameter setting are proved to be effective to address the dynamic formation control problem. Numerical simulations are given to validate the effectiveness of the proposed controllers.

Quantized Consensus of Multi-Agent Networks With Sampled Data and Markovian Interaction Links.

This paper investigates the joint effect of quantization, sampled data, and general Markovian interaction links on consensus networks with a leader under directed graphs. The diversity of edges formed by all the followers and the leader is also considered. Each agent in the network possesses continuous-time general linear dynamics. Each agent's state is measured only at sampling time instants, which is encoded before transmission. Subsequently, the encoded state is transmitted through noiseless digital communication links with Markovian switching rates. For this problem, a sufficient condition is derived to guarantee the convergence of the encoded states, based on which a necessary and sufficient condition is obtained to achieve consensus tracking in the mean-square sense. In addition, two sufficient conditions on coupling gain, one of which is fully distributed, are provided by proposing an optimal linear quadratic regulator-based gain matrix to ensure consensus tracking and then, the analysis of consensus region is presented. Finally, a numerical example is presented for illustrating the effectiveness of the theoretical results.

Risk factors and peripheral blood lymphocyte subset analysis of patients with ventilator-associated pneumonia: a Chinese population-based study.

The aim of this study is to analyze and identify ventilator-associated pneumonia (VAP) risk factors related to pathogens and drug resistance, and explore the theoretical guidance for clinical prevention and treatment strategies of VAP. 478 cases using a ventilator who were hospitalized in July 2014 to November 2016 in our hospital were analyzed in this study. Among them there were 103 patients with VAP. The distribution of pathogenic bacteria and drug resistance in VAP patients was detected and analyzed. 103 patients had VAP (21.5%, 103/478) among 478 cases of patients using a ventilator. Among the 103 patients with VAP, 35 patients died and 43 had simultaneous sepsis. Compared with those of the non-VAP group, the proportion of CD3+ (p = 0.012), CD3+ CD4+ (P = 0.024) and CD8+ CD28+ (P = 0.017) T cells in VAP group increased significantly, which showed a more severe immune response. Multivariate regression model analysis revealed that tracheotomy for mechanical ventilation (P = 0.013), mechanical ventilation time ≥ 7 days (P = 0.02) and aspiration and reflux (P = 0.011) were independent risk factors associated with VAP. Multi-drugs resistance was observed in this study. Modality of mechanical ventilation, mechanical ventilation ≥ 7 days, and aspiration and reflux were independent risk factors associated with VAP. According to the results of bacterial culture and drug sensitivity test, rational selection of antibiotics and monitoring of patients in the ICU can effectively control the incidence of VAP and improve prognosis.

Umbelliferone Alleviates Lipopolysaccharide-Induced Inflammatory Responses in Acute Lung Injury by Down-Regulating TLR4/MyD88/NF-κB Signaling.

This study investigated the protective effect and underlying mechanism of action of umbelliferone (Umb) against lipopolysaccharide (LPS)-induced acute lung injury (ALI). An intragastric Umb injection prior to the administration of LPS dramatically decreased the wet/dry lung weight ratio, attenuated inflammatory cell infiltration in lung tissue, and reduced the LPS-induced production of inflammatory cytokines, including monocyte chemotactic protein-1(MCP-1), interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1ß, in broncheoalveolar lavage fluid (BALF). In addition, Umb resulted in significant anti-oxidative effects as shown by decreased myeloperoxidase (MPO) and malondialdehyde (MDA) activity and increased superoxide dismutase (SOD) activity compared with the LPS group. Finally, the inhibitory effects of Umb on the expression of toll-like receptor 4 (TLR4)/myeloid differentiation protein 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway proteins were also measured. Our results clearly indicated that Umb exerted significant protective effects on LPS-induced ALI by inhibiting the activation of the TLR4/MyD88/NF-κB pathway.

Circulating GRP78 acts as a biomarker in the early diagnosis of lung cancer.

Glucose-regulated protein 78 (GRP78) is a major chaperone in endoplasmic reticulum (ER) and is increased in many types of malignant tumors. The role of GRP78 in early lung cancer diagnosis has not been clearly reported. The aim of this study is to detect the circulating level of GRP78 in the plasma of lung cancer patients and to evaluate the role of GRP78 in the early diagnosis of lung cancer. Plasma was collected from 251 lung cancer patients and 105 healthy controls, and the GRP78 expression in each sample was assayed using a commercially available ELISA kit. A receiver operating characteristic curve (ROC curve) was performed to analyze the role of GRP78 in lung cancer diagnosis. The combination of GRP78 and CEA, Cyfra21-1 was then analyzed using SPSS 17.0. The circulating level of GRP78 was increased dramatically in lung cancer patients (P < 0.0001) compared with the healthy controls. GRP78 provided a more sensitive and specific diagnosis than CEA in all lung cancer, ADC, and SCC patients, as well as in early (stage I) lung cancer patients. The results also indicated that a combination of GRP78, CEA and Cyfra21-1 could increase the accuracy of lung cancer diagnosis. GRP78 could be used as circulating biomarker in early lung cancer diagnosis.

Protective effects of dihydroquercetin on an APAP-induced acute liver injury mouse model.

Dihydroquercetin (DHQ) is a flavonoid in the Chinese traditional herbal medicine Ramulus Euonymi, which has anti-inflammatory, antioxidant and anticancer bioactivity. In the present study, we investigated the protective effects of DHQ on acetaminophen (APAP)-induced liver injury in a mouse model for the first time. The mice received an intraperitoneal dose of APAP for model establishment. After 1 h, they were treated with DHQ at various concentrations. After 48 h of treatment, the mice were sacrificed to determine serum ALT and AST levels and the liver index, examine histopathological changes in the liver through H&E and TUNEL staining, and evaluate TNF-α and IL-6 levels using an ELISA. We also evaluated TNF-α, IL-6, Nrf2 and SOD2 mRNA expression by RT-PCR and Bcl-2, Bax and Pro-caspase-3 expression by Western blot. DHQ treatment significantly attenuated serum ALT and AST levels as well as rescued hepatomegaly. It also down-regulated TNF-α and IL-6, increased Nrf2 and SOD2 mRNA expression, down-regulated Bax, overexpressed Bcl-2 and Pro-caspase-3. Our datas suggest that DHQ treatment can effectively attenuate APAP-induced liver injury by down-regulating inflammatory factors, improving antioxidant capacity and inhibiting hepatocyte apoptosis. DHQ could be a beneficial hepatoprotective agent for the prevention and amelioration of APAP-induced acute liver injury.

Evaluation of prognostic factors for secondary cytoreductive surgery in Chinese patients with recurrent epithelial ovarian carcinoma.

OBJECTIVE: Secondary cytoreductive surgery (SCS) is reported to be beneficial for patients with recurrent epithelial ovarian carcinoma (EOC). The current study is to evaluate risk factors that would affect the surgical optimal resection rate and prognosis of recurrent EOC after SCS in Chinese patients. METHODS: In our study, 44 patients with recurrent EOC treated with SCS at Shandong Cancer Hospital were retrospectively reviewed. Patient characteristics were collected and multivariate logistic regression was used to analyze factors that affect the optimal surgical resection rate. The overall survival rate was calculated by the Kaplan-Meier method. Cox proportional-hazards regression was used to analyze risk factors that affect the overall survival of these patients. RESULTS: 90.9% (40/44) patients achieved optimal cytoreductive surgery. Logistic regression did not find any factor that affects the optimal surgical resection rate. Among 24 cases that received chemotherapy before SCS, 18 cases achieved good response and thus had a better survival rate after SCS. Multivariate Cox proportional hazard regression analysis indicated that differentiation, the extent of surgical resection during the initial surgery, and course and efficacy of chemotherapy prior to SCS, and efficacy of chemotherapy after the first recurrence significantly correlated with survival of patients with recurrent cancer (P < 0.05; OR < 1). CONCLUSION: Selection of patients that are suitable to perform SCS will enhance the optimal surgical resection rate. The prognosis of Chinese patients with recurrent EOC after SCS is affected by histologic grade, the extent of residual disease and the effect of chemotherapy after first relapse.