Search

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Mutations of CUB and sushi multiple domains 3 (CSMD3) gene have been reported in individuals with ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain unexplored. Here, using maleCSMD3knock-out (CSMD3−/−) mice, we found that genetic deletion ofCSMD3produced core autistic-like symptoms (social interaction deficits, restricted interests, and repetitive and stereotyped behaviors) and motor dysfunction in mice, indicating that theCSMD3gene can be considered as a candidate for ASD. Moreover, we discovered that the ablation ofCSMD3in mice led to abnormal cerebellar Purkinje cell (PC) morphology in Crus I/II lobules, including aberrant developmental dendritogenesis and spinogenesis of PCs. Furthermore, combiningin vivofiber photometry calcium imaging andex vivoelectrophysiological recordings, we showed that theCSMD3−/−mice exhibited an increased neuronal activity (calcium fluorescence signals) in PCs of Crus I/II lobules in response to movement activity, as well as an enhanced intrinsic excitability of PCs and an increase of excitatory rather than inhibitory synaptic input to the PCs, and an impaired long-term depression at the parallel fiber–PC synapse. These results suggest that CSMD3 plays an important role in the development of cerebellar PCs. Loss of CSMD3 causes abnormal PC morphology and dysfunction in the cerebellum, which may underlie the pathogenesis of motor deficits and core autistic-like symptoms inCSMD3−/−mice. Our findings provide novel insight into the pathophysiological mechanisms by whichCSMD3mutations cause impairments in cerebellar function that may contribute to ASD.SIGNIFICANCE STATEMENTAutism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD. Recently, a novel giant geneCSMD3encoding a protein with CUB and sushi multiple domains (CSMDs) has been identified as a candidate gene for ASD. However, the underlying mechanisms ofCSMD3for the onset of ASD remain largely unknown. Here, we unravel that loss ofCSMD3results in abnormal morphology, increased intrinsic excitabilities, and impaired synaptic plasticity in cerebellar PCs, subsequently leading to motor deficits and ASD-like behaviors in mice. These results provide novel insight into the pathophysiological mechanisms by whichCSMD3mutations cause impairments in cerebellar function that may contribute to ASD.

Modal parameters are inherent structural characteristics that are valuable for model updating, condition assessment, and early warning of bridges. Operational modal tracking technology has been a popular research topic in bridge structural health monitoring (SHM) because of its output-only advantage; that is, only the vibration responses of the bridge are necessary for modal identification. The real-time objective of bridge SHM requires operational modal tracking to be fully automated. Because the loads acting on long-span high-speed railway bridges are various, the modal identification methods should be changed according to the excitation characteristics; otherwise, the results may be incorrect. However, there is no unified framework for simultaneously tracking the modal evolution of a bridge under different excitations. In this study, modal tracking strategies based on ambient loads, train loads and immediately a train moving past the bridge were developed to identify the operational modal parameters of the bridge. In addition, a unified tracking framework was established to automatically switch among the three-stage modal-tracking strategies, which utilizes the real-time positioning of the axle loads. Furthermore, the computational efficiency of the tracking strategies and the obstacles of operational modal analysis were analyzed to provide a reference for mode-based SHM of bridges, and the essential parameters in the tracking algorithms were suggested. The three-stage modal-tracking methods were validated through long-term monitoring data of a long-span high-speed railway bridge. The results indicated that the best tracking results were generated from free-vibration data, while the modal-tracking under ambient loads had best timeliness.

Backgroud: Transglutaminases (TGs) are multifunctional enzymes with transglutaminase cross-linking, atypical GTPase/ATPase and kinase activity. Here, an integrated comprehensive analysis shows the genomic, transcriptomic and immunological landscapes of the TGs varies among different cancers. Methods Gene expression pattern and immune cell infiltration in pan-cancer were obtained from The Cancer Genome Atlas (TCGA) databases and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence, ELISA, and orthotopic xenograft model were performed to validate our database-derived results. Results The overall expression of TGs (designated as TG score) is significantly upregulated in multiple cancers and related to worse patient survial. The expression of the TG family can be regulated by multiple mechanisms at the genetic, epigenetic and transcriptional levels. Transcriptionfactors crucial for epithelial to mesenchymal transition (EMT) are commonly correlated with TG score in many cancer types. Importantly, TGM2 expression displays a close connection with the chemoresistances of a wide range of chemodrugs. TGM2, F13A1 and overall TG score are positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification reveals that higher TGM2 expression is linked with worse patient survival, increased IC50 value of gemcitabine, and abundant tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, increased C-C motif chemokine ligand 2 (CCL2) release affored by TGM2 contributes to macrophage infiltration with tumor microenvironment. Conclusions These results reveal the relevances and molecular networks of TG genes in human cancers, highlighting the significance of TGM2 in pancreatic cancer which may provide some promising directions for immunotherapy and dealing with chemoresistance.

The “catalytic degradation” of metal oxides limits the wide application of PLA when PLA needs to be modified by adding metal oxides to achieve desired properties. Zinc oxide (ZnO) is a common and widely used agent as it can be used for many properties, such as antioxidant, antibacterial, etc. However, detrimental effects often exist on the properties of polymers after introducing the ZnO, due to the catalytic degradation. In this study, we used polydopamine (PDA) to construct ZnO@PDA core-shell submicron particles via the self-polymerization of dopamine (DA) in alkaline solution, aimed to produce a surface functionalization that would be used to control the rate of degradation of PLA by ZnO during thermal processing, and promote the preservation of mechanical properties. PLA with different contents of ZnO and ZnO@PDA were prepared by a simple melt extrusion method. The degradation behavior, mechanical properties and antibacterial activity of ZnO/PLA and ZnO@PDA/PLA were investigated. It was found that the incorporation of ZnO@PDA in PLA at different contents exhibits a dramatic control over the degradation rate when compared to that of the ZnO/PLA with the same filler content. Notably, the T5% and T50% of 3%-ZnO@PDA/PLA increased by 36.4 oC and 31.9 oC. GPC results showed the molecular weight of 3%-ZnO@PDA/PLA was only reduced by 15.8% after thermal processing. In addition, 3%-ZnO@PDA/PLA can be 3D-printed smoothly. That is to say, the introduction of ZnO@PDA can increase the processing window of PLA/ZnO composites, providing the possibility for materials that need to be included in civil application. Accordingly, ZnO@PDA/PLA samples showed higher tensile strength and elongation at break than that of corresponding ZnO/PLA samples. Regarding the antibacterial behavior, the ZnO@PDA/PLA have more bacterial growth disability effect against Gram(+) bacteria than that of pure PLA. This publication is funded through the project "MAMAP - Materials and models against pandemics" (REACT-EU resources of the Madrid Operational Program 2014-2020, in the action line of R+D+i projects in response to COVID-19). Project funded by the Community of Madrid and by the European Regional Development Fund of the European Union "A way to make Europe". Financed as part of the Union's response to the COVID-19 pandemic, through the agreement signed between the Community of Madrid (Regional Ministry of Education, Universities, Science, and Spokesperson) and the IMDEA Materials Foundation for the direct granting of a grant of 1.937.000.00 euros to fund research activities on SARS-COV 2 and the COVID-19 disease funded with REACT-EU resources from the European Regional Development Fund.

Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.Significance: Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg. Cancer Res; 78(9); 2305–17. ©2018 AACR.

Supplymentary data figure 1-8 and table 1-2

Purpose:Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP–P2RY2 axis could be a potential therapeutic approach for PDAC treatment.Experimental Design:Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression.Results:P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT–mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice.Conclusions:These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

Supplementary figures of expression of SPON2, integrin subunit, LATS1 and YAP, effect of SPON2 on M2-like TAM infiltration, co-location of SPON2 and integrin α4/α5, influence of RhoA T19N/Q63L and Rac1 T17N mutants on active RhoA and Rac1, effect of chemokines on primed THP-1 cell migration

Supplementary materials and methods of isolation of hMC, immunohistochemical and H&E staining, 3D spheroid analysis, PLA, q-PCR, lentivirus production and cell transduction, siRNA, production of rSPON2, ELISA assay and chemokine assay

Endothelial barrier integrity requires recycling of VE-cadherin to adherens junctions. Both p18 and Rab11a play significant roles in VE-cadherin recycling. However, the underlying mechanism and the role of p18 in activating Rab11a have yet to be elucidated. Performing in vitro and in vivo experiments, we showed that p18 protein bound to VE-cadherin before Rab11a through its VE-cadherin-binding domain (aa 1-39). Transendothelial resistance showed that overexpression of p18 promoted the circulation of VE-cadherin to adherens junctions and the recovery of the endothelial barrier. Silencing of p18 caused endothelial barrier dysfunction and prevented Rab11a-positive recycling endosome accumulation in the perinuclear recycling compartments. Furthermore, p18 knockdown in pulmonary microvessels markedly increased vascular leakage in mice challenged with lipopolysaccharide and cecal ligation puncture. This study showed that p18 regulated the pulmonary endothelial barrier function in vitro and in vivo by regulating the binding of Rab11a to VE-cadherin and the activation of Rab11a.

We aimed to identify whether Rho GTPase activating proteins (RhoGAPs) were downregulated in cervical cancers and might be targeted to reduce the growth of cervical cancer using the GEO database and immunohistochemical analysis to identified changes in transcription and protein levels. We analyzed their proliferation, clone formation ability, and their growth as subcutaneous tumors in mice. To detect ARHGAP30 localization in cells, immunofluorescence assays were conducted. Mass spectrometry combined with immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co‐immunoprecipitation assays. Western‐blot and q‐PCR were applied to analyze candidate binding proteins that were associated with ribosome biogenesis. Puromycin incorporation assay was used to detect the global protein synthesis rate. We identified that ARHGAP30 was the only downregulated RhoGAP and was related to the survival of cervical cancer patients. Overexpression of ARHGAP30 in cervical cancer cells inhibited cell proliferation and migration. ARHGAP30 immunoprecipitated proteins were enriched in the ribosome biogenesis process. ARHGAP30 was located in the nucleous and interacted with nucleolin (NCL). Overexpression of ARHGAP30 inhibited rRNA synthesis and global protein synthesis. ARHGAP30 overexpression induced the ubiquitination of NCL and decreased its protein level in Hela cells. The function of ARHGAP30 on cervical cancer cell ribosome biogenesis and proliferation was independent of its RhoGAP activity as assessed with a RhoGAP‐deficient plasmid of ARHGAP30R55A. Overall, the findings revealed that ARHGAP30 was frequently downregulated and associated with shorter survival of cervical cancer patients. ARHGAP30 may suppress growth of cervical cancer by reducing ribosome biogenesis and protein synthesis through promoting ubiquitination of NCL., ARHGAP30 suppressed growth of cervical cancer by reducing ribosome biogenesis and protein synthesis through promoting ubiquitination of nucleolin.

Tropical cyclone is a rapidly rotating storm system with severe excitation such as high wind. This severe excitation may change the performance of structures, such as bridges, wharves and wind turbine structures. It is very necessary to monitor this important change. Modal parameters are the ones to reflect the structural instinct behavior. However, many identification methods assume that the excitation is white noise, which is not the truth during high ocean wind excitation. Therefore, the modal identification method to deal with severe ocean wind excitation should be investigated. This paper proposes an innovative method to eliminate the effect of high ocean wind on modal identification. The formulation to generate an impulse response is described, where the effect of high wind is pointed. Then the elimination method is derived using the wind velocity spectrum and correlation function. After the wind field is simulated, the wind velocities and spectra at all accelerometer positions are obtained. The real impulse response form is obtained. Then, modal identification using the real impulse response is performed. Finally, a practical cable-stayed bridge is employed and modal identification is performed. The results show that the identified modes can reflect structural real behavior.

Comorbid anxiety and depressive symptoms in chronic pain are a common health problem, but the underlying mechanisms remain unclear. Previously, we have demonstrated that sensitization of the CeA neurons via decreased GABAergic inhibition contributes to anxiety-like behaviors in neuropathic pain rats. In this study, by using male Sprague Dawley rats, we reported that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain. Bilateral electrolytic lesions of CeA, but not lateral/basolateral nucleus of the amygdala (LA/BLA), abrogated both pain hypersensitivity and aversive and depressive symptoms of neuropathic rats induced by spinal nerve ligation (SNL). Moreover, SNL rats showed structural and functional neuroplasticity manifested as reduced dendritic spines on the CeA neurons and enhanced LTD at the LA/BLA-CeA synapse. Disruption of GluA2-containing AMPAR trafficking and endocytosis from synapses using synthetic peptides, either pep2-EVKI or Tat-GluA2((3Y)), restored the enhanced LTD at the LA/BLA-CeA synapse, and alleviated the mechanical allodynia and comorbid aversive and depressive symptoms in neuropathic rats, indicating that the endocytosis of GluA2-containing AMPARs from synapses is probably involved in the LTD at the LA/BLA-CeA synapse and the comorbid aversive and depressive symptoms in neuropathic pain in SNL-operated rats. These data provide a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlight that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain. SIGNIFICANCE STATEMENT Several studies have demonstrated the high comorbidity of negative affective disorders in patients with chronic pain. Understanding the affective aspects related to chronic pain may facilitate the development of novel therapies for more effective management. Here, we unravel that the CeA plays a key role in processing both sensory and negative emotional-affective components of neuropathic pain, and LTD at the amygdaloid LA/BLA-CeA synapse mediated by GluA2-containing AMPAR endocytosis underlies the comorbid aversive and depressive symptoms in neuropathic pain. This study provides a novel mechanism for elucidating comorbid aversive and depressive symptoms in neuropathic pain and highlights that structural and functional neuroplasticity in the amygdala may be important as a promising therapeutic target for comorbid negative emotional-affective disorders in chronic pain.

Background Liver fibrosis is a wound-healing response to chronic injury, featuring with excess accumulation of extracellular matrix secreted by the activated hepatic stellate cells (HSC). Disulfiram (DSF), also known as Antabuse, has been used for the treatment of alcohol addiction and substance abuse. Recently, overwhelming studies had revealed anti-cancer effects of DSF in multiple cancers, including liver cancer. But the actual effects of DSF on liver fibrosis and liver function remain unknown. Methods In this study, we evaluated the effects of low-dose DSF in CCl4- and Bile Duct Ligation (BDL)—induced hepatic fibrosis rat models. Cell proliferation was detected by using the Cell-Light™ EdU Apollo®567 Cell Tracking Kit. Cell apoptosis was analyzed using a TdT-mediated dUTP nick end labeling (TUNEL) kit, viability was measured with Cell Counting Kit-8(CCK8). Relative mRNA expression of pro-fibrogenic was assessed using quantitative RT-PCR. The degree of liver fibrosis, activated HSCs, were separately evaluated through Sirius Red-staining, immunohistochemistry and immunofluorescence. Serum alanine aminotransferase (ALT) and asparagine aminotransferase (AST) activities were detected with ALT and AST detecting kits using an automated analyzer. Results Liver fibrosis was distinctly attenuated while liver functions were moderately ameliorated in the DSF-treated group. Activation and proliferation of primary rat HSCs isolated from rat livers were significantly suppressed by low-dose DSF. DSF also inhibited the viability of in vitro cultured rat or human HSC cells dose-dependently but had no repressive role on human immortalized hepatocyte THLE-2 cells. Interestingly, upon DSF treatment, the viability of LX-2 cells co-cultured with THLE-2 was significantly inhibited, while that of THLE-2 co-cultured with LX-2 was increased. Further study indicated that HSCs apoptosis was increased in DSF/CCl4-treated liver samples. These data indicated that DSF has potent anti-fibrosis effects and protective effects toward hepatocytes and could possibly be repurposed as an anti-fibrosis drug in the clinic. Conclusions DSF attenuated ECM remodeling through suppressing the transformation of quiet HSCs into proliferative, fibrogenic myofibroblasts in hepatic fibrosis rat models. DSF provides a novel approach for the treatment of liver fibrosis.

Stroke is an acute cerebrovascular disease and a neurological disorder that occurs due to a cerebral arterial embolism and rupture. Acute stroke is often accompanied by dysphagia, which reduces patients' intake of food and nutrients, decreases their nutritional status, and affects their quality of life.The study intended to identify the demographic and clinical characteristics of stroke patients with dysphagia and to explore the relationship of those characteristics to nutritional status and prognosis.The research team retrospectively collected the clinical data of patients to compare the nutritional status and prognoses of patients with different demographic and clinical characteristics.The study took place in the Department of Neurology at the First People's Hospital of Shenyang in Shenyang, China.Participants were 789 stroke patients with dysphagia who had been admitted to the general ward of the neurology departments of hospitals of Grade 3 or higher in Northeast China between January 2019 and September 2020. Based on the results of the Nutrition Risk Screening (NRS-2002) and Subjective Global Assessment (SGA) scales at baseline, participants were enrolled in this study.The outcomes were the correlations between participants' demographic and clinical characteristics and their nutritional statuses and prognoses. The Modified Rankin Scale (mRS) was used to evaluate the prognosis of the patients at seven days and three months after participants' enrollment in the study. Using the SPSS 26.0, a t test, chi-square test, and F test were performed to analyze and verify the presence of fundamental differences in baseline characteristics between participants with good nutrition and those with poor nutrition. Also, a statistical correlation analysis was performed.The study showed that participants with different nutritional levels had statistically significant differences in the presence or absence of infections and body temperature and scores on the Standardized Swallowing Assessment (SSA) and National Institutes of Health Stroke Scale (NIHSS), with all P.001. At baseline seven days after enrollment, the prognoses of participants were significantly different for different previous histories of stroke (P.001), family history of stroke (P = .005), presence or absence of infections (P.001), body temperature (P.001), and SSA (P.001) and NIHSS (P.001) scale scores. At three months after enrollment, the prognoses of participants were significantly different for previous history of stroke (P = .003), different body temperatures (P.001), presence or absence of infections(P.001), and SSA (P.001) and NIHSS (P.001) scale scores. Age, gender, family history of stroke, smoking, alcohol consumption, previous history of stroke, education level, SSA scale score, NIHSS scale score, body mass index (BMI), body temperature, and infection were adjusted in the model. Nutritional status as classified by NRS-2002 and SGA was significantly correlated with prognosis (P.001). The prognosis of stroke patients with dysphagia was associated with nutritional status by unconditional logistic regression.The prognosis of stroke patients with dysphagia is related to their nutritional status. A better nutritional status indicates the better prognosis, and vice versa. In clinical treatment, attention should be paid to use of a nutritional intervention.

Prolactin binding to the prolactin receptor exerts pleiotropic biological effects in vertebrates. The prolactin receptor (PRLR) has multiple isoforms due to alternative splicing. The biological roles and related signaling of the long isoform (PRLR-LF) have been fully elucidated. However, little is known about the short isoform (PRLR-SF), particularly in cancer development and metabolic reprogramming, a core hallmark of cancer. Here, we reveal the role and underlying mechanism of PRLR-SF in pancreatic ductal adenocarcinoma (PDAC). Methods: A human PDAC tissue array was used to investigate the clinical relevance of PRLR in PDAC. The in vivo implications of PRLR-SF in PDAC were examined in a subcutaneous xenograft model and an orthotopic xenograft model. Immunohistochemistry was performed on tumor tissue obtained from genetically engineered KPC (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) mice with spontaneous tumors. 13C-labeled metabolite measures, LC-MS, EdU incorporation assays and seahorse analyses were used to identify the effects of PRLR-SF on the pentose phosphate pathway and glycolysis. We identified the molecular mechanisms by immunofluorescence, coimmunoprecipitation, proximity ligation assays, chromatin immunoprecipitation and promoter luciferase activity. Public databases (TCGA, GEO and GTEx) were used to analyze the expression and survival correlations of the related genes. Results: We demonstrated that PRLR-SF is predominantly expressed in spontaneously forming pancreatic tumors of genetically engineered KPC mice and human PDAC cell lines. PRLR-SF inhibits the proliferation of PDAC cells (AsPC-1 and BxPC-3) in vitro and tumor growth in vivo. We showed that PRLR-SF reduces the expression of genes in the pentose phosphate pathway (PPP) and nucleotide biosynthesis by activating Hippo signaling. TEAD1, a downstream transcription factor of Hippo signaling, directly regulates the expression of G6PD and TKT, which are PPP rate-limiting enzymes. Moreover, NEK9 directly interacts with PRLR-SF and is the intermediator between PRLR and the Hippo pathway. The PRLR expression level is negatively correlated with overall survival and TNM stage in PDAC patients. Additionally, pregnancy and lactation increase the ratio of PRLR-SF:PRLR-LF in the pancreas of wild-type mice and subcutaneous PDAC xenograft tumors. Conclusion: Our characterization of the relationship between PRLR-SF signaling, the NEK9-Hippo pathway, PPP and nucleotide synthesis explains a mechanism for the correlation between PRLR-SF and metabolic reprogramming in PDAC progression. Strategies to alter this pathway might be developed for the treatment or prevention of pancreatic cancer.

In this work, we apply the Bayesian approach for the acoustic scattering problem to reconstruct the shape of a sound-soft obstacle using the limited-aperture far-field measure data. A novel total variation prior is assigned to the shape parameterization form. This prior is imposed on the Fourier coefficients of the parameterized form of the obstacle. Extensive numerical tests are provided to illustrate the numerical performance.

Serine/threonine protein kinase-3 (STK3) is a critical molecule of the Hippo pathway but little is known about its biological functions in the ovarian cancer development. We demonstrated the roles of STK3 in ovarian cancer. Existing databases were used to study the expression profile of STK3. STK3 was significantly downregulated in OC patients, and the low STK3 expression was correlated with a poor prognosis. In vitro cell proliferation, apoptosis, and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the roles of STK3. The overexpression of STK3 significantly inhibited cell proliferation, apoptosis, and migration of ovarian cancer cells in vitro and tumor growth in vivo. Bisulfite sequencing PCR analysis was performed to validate the methylation of STK3 in ovarian cancer. RNA sequencing and gene set enrichment analysis (GSEA) were used to compare the transcriptome changes in the STK3 overexpression ovarian cancer and control cells. The signaling pathway was analyzed by western blotting. STK3 promoted the migration of CD8+ T-cells by activating nuclear transcription factor κB (NF-κB) signaling. STK3 is a potential predictor of OC. It plays an important role in suppressing tumor growth of ovarian cancer and in chemotaxis of CD8+ T-cells.

Land‐use change is a key factor driving changes in soil organic carbon (SOC) sequestration worldwide. However, the changes in deep (>100 cm depth) SOC stock following land‐use conversion have not been fully elucidated. In this study, to determine the changes in deep SOC stock (to a depth of 400 cm) resulting from conversion of cropland to woodland, shrubland and grassland on the Chinese Loess Plateau, 469 observations from peer‐reviewed publications and original measured data were synthesised. The results were as follows: (a) SOC stock increased significantly at 0–100 and 100–200 cm layers regardless of land‐use conversion types. (b) Carbon loss occurred in the 200–400 cm layers due to land‐use conversion. (c) Changes in SOC stock varied with restoration age, except for conversion of cropland to grassland. Specifically, SOC stock increased with restoration age in the upper 200 cm layers, whereas that in the 200–400 cm layers first increased and then decreased in the middle to later stages under conversion to woodland and shrubland. (d) Initial SOC stock and rainfall zones had significant effects on the changes of deep SOC stock. (e) Furthermore, an accumulation of 1 Mg ha⁻¹ in the upper 100 cm was associated with an approximately 0.45 Mg ha⁻¹ increase in the 100–400 cm soil layers. These results indicate that land‐use conversion, particularly conversion of cropland to woodland, changes deep (>100 cm) SOC stock, and restoration age should be taken into consideration when assessing deep carbon sequestration.

Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

The eyeball distortions caused by eye diseases, such as myopia and strabismus, can lead to the deviations of eye-tracking data. In this paper, a model-based method with geometric solutions is proposed for gaze correction. The deviations of estimated gaze points are geometrically analyzed based on the individual eyeball models with considerations of the distortions caused by myopia and strabismus. A set of integrated geometric solutions is derived from the varied situations including the case of strabismus and the case of myopia and strabismus, and then used for gaze correction in eyetracking. The experimental results demonstrate that this model-based method is effective to reduce deviations in estimated gaze points, and can be used to correct the modeling error in eye-tracking. Moreover, the proposed method has the potential to provide a simple approach to correct the eyetracking data for various populations with eye diseases.

Objective To compare outcomes between intensivist-directed and cardiac surgeon-directed care delivery models. Design This retrospective, historical-control study was performed in a cohort of adult cardiac surgical patients at Zhongshan Hospital (Fudan University, China). During the first phase (March to August 2015), cardiac surgeons were in charge of postoperative care while intensivists were in charge during the second phase (September 2015–June 2016). Both phases were compared regarding successful extubation rate, intensive care unit (ICU) length of stay (LOS), and in-hospital mortality. Setting Tertiary Zhongshan Hospital (Fudan University, China). Patients Consecutive adult patients admitted to the cardiac surgical ICU (CSICU) after heart surgery. Interventions Phase I patients treated by cardiac surgeons, and phase II patients treated by intensivists. Main variables of interest Successful extubation, ICU LOS and in-hospital mortality. Results A total of 1792 (phase I) and 3007 patients (phase II) were enrolled. Most variables did not differ significantly between the two phases. However, patients in phase II had a higher successful extubation rate (99.17% vs. 98.55%; p = 0.043) and a shorter median duration of mechanical ventilation (MV) (18 vs. 19 h; p 48 h, those in phase II had a comparatively higher successful extubation rate (p = 0.033), shorter ICU LOS (p = 0.038) and a significant decrease in in-hospital mortality (p = 0.039). Conclusions The intensivist-directed care model showed improved rates of successful extubation and shorter MV durations after cardiac surgery.

Melanin concentrating hormone (MCH), an orexigenic neuropeptide, is primarily secreted by the hypothalamus and acts on its receptor, the melanin-concentrating hormone receptor 1 (MCHR1), to regulate appetite and energy homeostasis. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues, has been defined as a vital endocrine modulator of five melanocortin receptors (MC1R–MC5R) and several other GPCRs in the regulation of central neuronal activities and peripheral energy balance. Here, we demonstrated the interaction between MRAP2 and MCHR1 by immunoprecipitation and bimolecular fluorescent assay and found that MRAP2 could inhibit MCHR1 signaling in vitro. A series of functional truncations of different regions further identified that the C-terminal domains of MRAP2 protein were required for the pharmacological modulation of intracellular Ca2+ coupled cascades and membrane transport. These findings elucidated the broad regulatory profile of MRAP2 protein in the central nervous system and may provide implications for the modulation of central MCHR1 function in vivo.

In solving Bayesian inverse problems, it is often desirable to use a common density parameterization to characterize the prior and posterior. Typically, we seek an optimal approximation of the true posterior from the same distribution family as the prior. As one of the most important classes of distributions in statistics, the exponential family is considered as the parameterization. The optimal parameter values for representing the approximated posterior are achieved by minimizing the deviation between the parameterized density and a homotopy that deforms the prior density into the posterior density. Instead of the usual moment parameters, we introduce a new parameter system in the process, by which we reduce the dimension of the parameter and therefore the computational cost. The parameters are ruled by a system of explicit first-order differential equations. Solving this system over finite “time” interval yields the desired optimal density parameters. This method is proven to be effective using some numerical examples.

We prepared a series of highly porous Polyrotaxane/sodium alginate, and Polyrotaxane/Chitosan foam alloys according to a sustainable pathway by using water as the only solvent. The foam alloys were further used as supporter materials for poly (ethylene glycol) (PEG) encapsulation, to fabricate shape-stable bio-based phase change materials (PCMs). The pore morphology and the internal interface between PEG and foam alloys were characterized by scanning electron microscope (SEM). Due to the good compatibility between foam alloys and PEG, the PCM performed perfect anti-leakage properties. The introduction of sodium alginate or Chitosan ensures the shape stability of the PCMs during the phase transition. The PCMs performed good cycle stability and showed ultra-high latent heat (171.6 J g−1–189.5 J g−1). Finally, we compared the typical indicators of this work with those reported in the literature, and the comparison highlighted that the present PCMs have the significant advantages: high melting enthalpy, convenient preparation and outstanding sustainability. Notably, the work provided a sustainable idea for the design of anti-leakage and shape-stable PEG-based PCMs. pre-print 1327 KB

With the improvement of people's living level, smart home and comfortable life put forward novel and highly scientific requirements for building materials and home environment. Environmental protection, renewability, processing convenience and use safety (non-toxic/fire safety) are all core indicators that need to be considered in an all-round way in the process of material design. In this work, we used a simple and efficient green process by blending ammonium polyphosphate (APP) and poly (glycerol-itaconic acid) loaded polyethylene glycol (PEG) to prepare fire safe phase change materials (PCMs). The flame retardancy, phase change performance and thermal response behavior (including form stability, thermal conductivity, cycle stability, and latent heat etc.) were systematically characterized. The results showed that limiting oxygen index (LOI) increased significantly with the increase of APP content. Typically, when the filling amount of APP reached 15 wt%, the LOI value increased from 21.6% to 28.7%, vertical testing reached UL-94 V0 rating and the pHRR decreased by 36.15%. The as-prepared PCMs show excellent form stability, and the enthalpy of phase change keeps higher than 70 J g−1, which is at the high level as that of same kinds of PCMs. Notably, due to its high preparation efficiency for PCM fabrication and the profiles of all bio-based supporting matrix, solvent-free pathway, mild curing temperature, and fire safety, it is expected to be effectively applied in building for the thermal regulation. pre-print 1269 KB

Background: Melanin concentrating hormone (MCH), an orexigenic neuropeptide, is primarily secreted by the hypothalamus and acts at its receptor, the melanin-concentrating hormone receptor 1 (MCHR1), to regulate energy homeostasis and body weight. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues, has been defined as a vital endocrine pivot of five melanocortin receptors (MC1R-MC5R) and several other GPCRs in the regulation of central neuronal appetite and peripheral energy homeostasis. However, the regulatory and relationship between MCHR1 and MRAP2 is unknown.Results: In this study, we show that MRAP2 interacts with MCHR1 and suppresses MCHR1 signaling in vitro. We also identified the C-terminal domains of MRAP2 protein required for pharmacological modulation of intracellular Ca2+ cascades and membrane transport. Conclusions: These findings elucidated the broad regulatory profile of MRAP2 protein in the central nervous system and may provide implications for the modulation of central MCHR1 function in vivo.

As a member of the seven-transmembrane rhodopsin-like G protein-coupled receptor superfamily, the melanocortin-3 receptor (MC3R) is vital for the regulation of energy homeostasis and rhythms synchronizing in mammals, and its pharmacological effect could be directly influenced by the presence of melanocortin receptor accessory proteins (MRAPs), MRAP1 and MRAP2. The tetrapod amphibian Xenopus laevis (xl) retains higher duplicated genome than extant teleosts and serves as an ideal model system for embryonic development and physiological studies. However, the melanocortin system of the Xenopus laevis has not yet been thoroughly evaluated. In this work, we performed sequence alignment, phylogenetic tree, and synteny analysis of two xlMC3Rs. Co-immunoprecipitation and immunofluorescence assay further confirmed the co-localization and in vitro interaction of xlMC3Rs with xlMRAPs on the plasma membrane. Our results demonstrated that xlMRAP2.L/S could improve α-MSH-stimulated xlMC3Rs signaling and suppress their surface expression. Moreover, xlMC3R.L showed a similar profile on the ligands and surface expression in the presence of xlMRAP1.L. Overall, the distinct pharmacological modulation of xlMC3R.L and xlMC3R.S by dual MRAP2 proteins elucidated the functional consistency of melanocortin system during genomic duplication of tetrapod vertebrates.

In this work, a series of advanced phase change materials (PCMs) were fabricated by using polyrotaxane (PLR) as supports for encapsulating poly (ethylene glycol) (PEG). Phase-change enthalpy is mainly regulated by the PEG contents, whereas phase change temperature is controlled by PEG molecular weight. All PCMs have good form stabilities due to the good compatibility between PLR and PEG, and supporting ability of PLR. Given that the PLR support itself has phase-transition properties, the resulting composites have high phase change enthalpies (116.1–162.2 J g -1) and very high enthalpy efficiency (>100%). It is a green and efficient preparation method because the whole preparation process did not involve organic solvents, and the material was prepared at room temperature. In addition, the obtained PCMs can be easily extruded and re-molded, which provides technical premise and convenience for the large-scale applications. As a typical application example, the PCMs showed its significant advantages in simulated solid-state disk model temperature regulation, which fully demonstrates the practical and superior application value of the PCMs in the field of thermal management for electronic devices. post-print 9729 KB

Bone cancer pain is a common symptom in cancer patients with bone metastases and its underlying mechanisms remain unknown. Here, we report that Runx1 directly upregulates the transcriptional activity of P2X3 receptor (P2X3R) gene promoter in PC12 cells. Knocking down Runx1 in dorsal root ganglion (DRG) neurons suppresses the functional upregulation of P2X3R, attenuates neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats, whereas overexpressing Runx1 promotes P2X3R gene transcription in DRG neurons, induces neuronal hyperexcitability and pain hypersensitivity in naïve rats. Activation of GDNF-GFRα1-Ret-ERK signaling is required for Runx1-mediated P2X3R gene transcription in DRG neurons, and contributes to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. These findings indicate that the Runx1-mediated P2X3R gene transcription resulted from activation of GDNF-GFRα1-Ret-ERK signaling contributes to the sensitization of DRG neurons and pathogenesis of bone cancer pain. Our findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients.

Objectives. The present study aimed to evaluate prognostic value of inflammatory markers for in-hospital mortality and renal complication in patients undergoing surgery for acute type A aortic diss...

Cancer cells reprogram their energy metabolic system from the mitochondrial oxidative phosphorylation (OXPHOS) pathway to a glucose-dependent aerobic glycolysis pathway. This metabolic reprogramming phenomenon is known as the Warburg effect, a significant hallmark of cancer. However, the detailed mechanisms underlying this event or triggering this reprogramming remain largely unclear. Here, we found that histone H2B monoubiquitination (H2Bub1) negatively regulates the Warburg effect and tumorigenesis in human lung cancer cells (H1299 and A549 cell lines) likely through controlling the expression of multiple mitochondrial respiratory genes, which are essential for OXPHOS. Moreover, our work also suggested that pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, can directly interact with H2B in vivo and in vitro and negatively regulate the level of H2Bub1. The inhibition of cell proliferation and nude mice xenograft of human lung cancer cells induced by PKM2 knockdown can be partially rescued through lowering H2Bub1 levels, which indicates that the oncogenic function of PKM2 is achieved, at least partially, through the control of H2Bub1. Furthermore, PKM2 and H2Bub1 levels are negatively correlated in cancer specimens. Therefore, these findings not only provide a novel mechanism triggering the Warburg effect that is mediated through an epigenetic pathway (H2Bub1) but also reveal a novel metabolic regulator (PKM2) for the epigenetic mark H2Bub1. Thus, the PKM2-H2Bub1 axis may become a promising cancer therapeutic target.

Increasing water content in fixed beds is a prospective way to improve the gas storage density by means of hydrate formation. However, the high water content strongly hinders the hydrate formation. In this study, diesel oil was mixed into highly water-saturated activated carbon beds to establish gas channels so that to improve methane hydrate formation. Hydrate formation experiments in four activated carbons with different particle sizes were conducted at 274.15 K and 6.0 MPa. For wet carbon beds without diesel oil, both of the storage capacity of hydrate (Sw) and the storage density of bed (Sb) increased with an decrease in particle size. When the mass ratio of water to activated carbon was set to 2.0, the highest Sw of 67.98 V/Vw and corresponding Sb of 51.92 V/Vbed among the beds were obtained in the bed with particle size of 100–400 mesh. Sodium dodecyl sulfate (SDS) was found to suppress hydrate formation in fine-particle beds. By adding diesel oil, both the formation kinetics and Sw in highly water-saturated beds especially in small-particle ones were significantly improved. The Sw and Sb in the bed with particle size of 100–400 mesh were increased to 180.41 V/Vw and 111.75 V/Vbed, respectively. Furthermore, by adjusting the proportions of water, oil and activated carbon in the bed, the Sw was further improved. The successive gas storage tests suggested that the oil-contained bed can be simply renewed by manual stirring. Gas recovery experiments showed that the hydrate dissociated faster in the oil-contained bed than that in SDS solution, suggesting more efforts should be made to control the hydrate dissociation to drive this method into practical application.

Acetyl-CoA synthetase 2 (ACSS2) generates acetyl-CoA from acetate is important for histone acetylation and gene expression. ACSS2 fulfills distinct functions depending on its cellular location in tumor cells. The role and cellular localization of ACSS2 in hepatocellular carcinoma (HCC) remains to be studied. Herein, we identified that the alternative transcription start site selection of ACSS2 was significantly different between HCC and corresponding adjacent tissues. Alternative transcription start site selection produced two different ACSS2 transcripts, ACSS2-S1 and ACSS2-S2. The two isoforms of ACSS2 had different subcellular localization and different functions. Overexpression of ACSS2-S2 promoted cell proliferation and invasion, but ACSS2-S1 did not. The ACSS2-S1 was mainly present in cytoplasm, and ACSS2-S2 was distributed in both nucleus and cytoplasm. Finally, we demonstrated that alternative transcription start site selection of ACSS2 correlates ribosome biogenesis in HCC. Our findings reveal an oncogenic role of ACSS2-S2 in HCC progression via increase of ribosome biogenesis, and suggest ACSS2-S2 might be a potential therapeutic target against the HCC.

Background Three-dimensional color flow Doppler (3DCF) is a new convenient technique for cardiac output (CO) measurement. However, to date, no one has evaluated the accuracy of 3DCF echocardiography for CO measurement after cardiac surgery. Therefore, this single-center, prospective study was designed to evaluate the reliability of three-dimensional color flow and two-dimensional pulse wave Doppler (2D-PWD) transthoracic echocardiography for estimating cardiac output after cardiac surgery. Methods Post-cardiac surgical patients with a good acoustic window and a low dose or no dose of vasoactive drugs (norepinephrine

Background and aimsPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.MethodsThe Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.ResultsGABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression.ConclusionsOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

This study investigated the water resource potential for bioenergy production from sweet sorghum (Sorghum bicolor (L.)) in Northern China according to the distribution of water resources, climate conditions and the total water consumption of bioenergy based on sweet sorghum, which consisted of blue water, green water and grey water. At a case study site in Inner Mongolia, simulation with a plant phenological model was used to determine whether sweet sorghum could reach the harvestable stage for sugar juice production. The blue water in the agricultural phase was estimated according to the potential crop evapotranspiration (ETc), the drought sensitivity of sweet sorghum in different stages and the precipitation during the growing season. The results showed that the irrigation water was significantly different among the districts, ranging from 730 to 5500 m3/ha and 2060 to 6680 m3/ha for early-maturing and late-maturing varieties, respectively. To avoid the water pressure level to be exacerbated and the severe reallocation of water resources resulting in negative effects on other sectors, the maximal annual water withdrawal was set to not surpass the upper threshold of water stress level of 40%. That makes the maximum area for the production of sweet sorghum cannot exceed 1.95 × 104 ha, representing only 0.24% of the total marginal land area in Inner Mongolia. However, the economic benefits of bioenergy production from sweet sorghum would be negative due to the high labour input. Therefore, not only the availability of marginal land, the climate conditions and local water resources but also the improvement of mechanisation and agricultural production techniques should be considered to attain the sustainable development of bioenergy production and address global energy and environmental crises.

Background: Endometrial cancer is one of the most common gynecological malignancies and has exhibited an increasing incidence rate in recent years. Cancer stem cells (CSCs), which are responsible for tumor growth and chemoresistance, have been confirmed in endometrial cancer. However, it is still challenging to identify endometrial cancer stem cells to then target for therapy. Methods: Flow cytometry was used to identify the endometrial cancer stem cells. Sphere formation assay, western blotting, qRT-PCR assay, cell viability assay, xenograft assay and immunohistochemistry staining analysis were utilized to evaluate the effect of SPARC-related modular calcium binding 2 (SMOC-2) on the cells proliferation and drug resistance. Cell viability assay, qRT-PCR assay, immunofluorescence staining, Co-IP assay and luciferase reporter gene assay were performed to explore the possible molecular mechanism by which SMOC-2 activates WNT/β-catenin pathway. Findings: We found the expression of SPARC-related modular calcium binding 2 (SMOC-2), a member of SPARC family, was higher in endometrial CSCs than that in non-CSCs. SMOC-2 was also more highly expressed in spheres than in monolayer cultures. The silencing of SMOC-2 suppressed cell sphere ability; reduced the expression of the stemness-associated genes SOX2, OCT4 and NANOG; and enhanced chemosensitivity in endometrial cancer cells. By co-culture IP assay, we demonstrated that SMOC-2 directly interacted with WNT receptors (Fzd6 and LRP6), enhanced ligand-receptor interaction with canonical WNT ligands (Wnt3a and Wnt10b), and finally, activated the WNT/β-catenin pathway in endometrial cancer. SMOC-2 expression was closely correlated with CSC markers CD133 and CD44 expression in endometrial cancer tissue. Interpretation: Taken together, we conclude that SMOC-2 might be a novel endometrial cancer stem cell signature gene and therapeutic target for endometrial cancer. Fund: National Natural Science Foundation of China, Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission, Scientific and Technological Innovation Act Program of Fengxian Science and Technology Commission, Natural Science Foundation of Shanghai. Keywords: SMOC-2, Endometrial carcinoma, Cancer stem cells, Chemoresistance, WNT/β-catenin pathway

Background Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response. Methods Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1−/− mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo. Results Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-β signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC−/− mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA. Interpretation We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-β signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-β signaling and avoid the side effects caused by directly targeting TGF-β. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. Fund This study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Background Endometrial cancer is one of the most common gynecological malignancies and has exhibited an increasing incidence rate in recent years. Cancer stem cells (CSCs), which are responsible for tumor growth and chemoresistance, have been confirmed in endometrial cancer. However, it is still challenging to identify endometrial cancer stem cells to then target for therapy. Methods Flow cytometry was used to identify the endometrial cancer stem cells. Sphere formation assay, western blotting, qRT-PCR assay, cell viability assay, xenograft assay and immunohistochemistry staining analysis were utilized to evaluate the effect of SPARC-related modular calcium binding 2 (SMOC-2) on the cells proliferation and drug resistance. Cell viability assay, qRT-PCR assay, immunofluorescence staining, Co-IP assay and luciferase reporter gene assay were performed to explore the possible molecular mechanism by which SMOC-2 activates WNT/β-catenin pathway. Findings We found the expression of SPARC-related modular calcium binding 2 (SMOC-2), a member of SPARC family, was higher in endometrial CSCs than that in non-CSCs. SMOC-2 was also more highly expressed in spheres than in monolayer cultures. The silencing of SMOC-2 suppressed cell sphere ability; reduced the expression of the stemness-associated genes SOX2, OCT4 and NANOG; and enhanced chemosensitivity in endometrial cancer cells. By co-culture IP assay, we demonstrated that SMOC-2 directly interacted with WNT receptors (Fzd6 and LRP6), enhanced ligand-receptor interaction with canonical WNT ligands (Wnt3a and Wnt10b), and finally, activated the WNT/β-catenin pathway in endometrial cancer. SMOC-2 expression was closely correlated with CSC markers CD133 and CD44 expression in endometrial cancer tissue. Interpretation Taken together, we conclude that SMOC-2 might be a novel endometrial cancer stem cell signature gene and therapeutic target for endometrial cancer. Fund National Natural Science Foundation of China, Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission, Scientific and Technological Innovation Act Program of Fengxian Science and Technology Commission, Natural Science Foundation of Shanghai.

Background Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC. Methods LOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting. Results LOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis. Conclusions Taken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC. Electronic supplementary material The online version of this article (10.1186/s12943-019-0948-8) contains supplementary material, which is available to authorized users.