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A guided bone regeneration membrane is a pivotal therapeutic modality used to maintain sufficient space for bone regeneration, which is of great significance in curing alveolar bone defects. Metformin has been found to possess the ability of promoting osteogenic differentiation of bone mesenchymal stem cells. To develop guided bone regeneration membranes with better osteoinductive ability, metformin was incorporated into polycaprolactone/chitosan nanofibrous membranes by electrospinning technique, followed by glutaraldehyde crosslinking to reinforce chitosan stability in aqueous solutions. The fabricated nanofibrous membranes were then characterized by scanning electron microscope, Fourier transform infrared spectroscopy, water contact angle testing, mechanical properties test, and drug release test. Furthermore, rats bone mesenchymal stem cells were seeded on membranes for the evaluation of the effect of metformin-loaded polycaprolactone/chitosan nanofibrous membranes on cell morphology, alkaline phosphate activity, and osteogenic mineralization in vitro. Our results showed that nanofibers were fabricated successfully with smooth surface free from beads formation. The crosslinked-polycaprolactone/chitosan/metformin membranes had a more appropriate water contact angle of 44.25 ± 1.37° and the drug release curve of metformin featured early sudden release and slow release in the later stage over a 23-day period. Besides, in vitro studies suggested that the crosslinked-polycaprolactone/chitosan/metformin membrane was more suitable for cell adhesion, proliferation, and osteogenic differentiation of bone mesenchymal stem cells. Consequently, the metformin-loaded polycaprolactone/chitosan nanofibrous membranes would be promoted for bone regeneration as guided bone regeneration membranes. [ABSTRACT FROM AUTHOR]

Membranes play pivotal role in guided bone regeneration (GBR) technique for reconstruction alveolar bone. GBR membrane that is able to stimulate both osteogenic and angiogenic differentiation of cells may be more effective in clinic practice. Herein, we fabricated the Sr-doped calcium phosphate/polycaprolactone/chitosan (Sr-CaP/PCL/CS) nanohybrid fibrous membrane by incorporating 20 wt% bioactive Sr-CaP nanoparticles into PCL/CS matrix via one-step electrospinning method, in order to endow the membrane with stimulation of osteogenesis and angiogenesis. The physicochemical properties, mechanical properties, Sr2+ release behavior, and the membrane stimulate bone mesenchymal stem cell (BMSCs) differentiation were evaluated in comparison with PCL/CS and CaP/PCL/CS membranes. The SEM images revealed that the nanocomposite membrane mimicked the extracellular matrix structure. The release curve presented a 28-day long continuous release of Sr2+ and concentration which was certified in an optimal range for positive biological effects at each timepoint. The in vitro cell culture experiments certified that the Sr-CaP/PCL/CS membrane enjoyed excellent biocompatibility and remarkably promoted rat bone mesenchymal stem cell (BMSCs) adhesion and proliferation. In terms of osteogenic differentiation, BMSCs seeded on the Sr-CaP/PCL/CS membrane showed a higher ALP activity level and a better matrix mineralization. What's more, the synergism of the Sr2+ and CaP from the Sr-CaP/PCL/CS membrane enhanced BMSCs angiogenic differentiation, herein resulting in the largest VEGF secretion amount. Consequently, the Sr-CaP/PCL/CS nanohybrid electrospun membrane has promising applications in GBR. [ABSTRACT FROM AUTHOR]

Macrophage-targeted therapy offers new options for intractable pancreatic ductal adenocarcinoma (PDAC), which has a low 5-year survival rate. However, the factors regulating the biological function and phenotype of macrophages in PDAC are incompletely understood. Here, we found that CD51 was positively associated with the poor prognosis of PDAC patients and was highly expressed on macrophages but not on pancreatic cancer cells. Subsequently, we found that CD51 was a marker of macrophages, which promoted the stemness of pancreatic cancer cells. Furthermore, knockdown of CD51 in macrophages drove macrophages toward an M1-like phenotype. Mechanistically, macrophage-expressed CD51 contributed to the acquisition of stemness traits of pancreatic cancer cells by regulating the TGF-β1/smad2/3 pathway. Our data demonstrate the central role played by macrophage-expressed CD51 in the acquisition of stemness traits of pancreatic cancer cells through the paracrine induction of TGF-β1. We first show the connection between the CD51/TGF-β1/smad2/3 axis and PDAC cancer stem cell properties and then indicate that CD51-targeted therapy is a new therapeutic modality for PDAC. [ABSTRACT FROM AUTHOR]

We explore the shape effect of microparticles (MPs) on their margination behaviors in blood flow through three-dimensional numerical simulations. Six different shapes of MPs were considered with identical volume, such as sphere, rod, cubic, disk, oblate, and prolate with different aspect ratios. These MPs were immersed in the blood plasma, which consisted of a suspension of red blood cells (RBCs). A simple shear flow was applied with moderate shear rate (200 s−1). The fluid flow and immersed particles (RBCs and MPs) were solved by the lattice Boltzmann method (LBM) and lattice spring model, respectively. The fluid–structure interaction was coupled by the immersed boundary method. Additionally, we adopted a stochastic model to capture the adhesive behavior of MPs near the vessel wall for ligand–receptor binding. Without near-wall adhesion, the spherical particles demonstrated the strongest margination in the blood flow. It can be attributed to the large collision displacement with RBCs and small migration distance in the cross-stream direction under shear flow of spherical particles. Furthermore, under the influence of near-wall adhesion, the margination of differently shaped MPs was examined. Interestingly, the adhesion can either promote or impede the margination behavior depending on the shapes of MPs. When the major axes of MPs are smaller than or comparative to the thickness of the cell-free layer in the flow channel, the adhesion can promote margination of these MPs, while for MPs with large major axes, due to the near-wall adhesion effect, the reduced tumbling frequencies enable them to have enough time to interact with RBCs. In turn, the long interaction with RBCs can drag these MPs to the central stream of blood flow, impeding their margination. However, the prolate particles demonstrated distinct behaviors. Apart from tumbling, the transition to precession of prolate particles near the vessel wall results in the enhancement of margination. Overall, the spherical MPs outperform other nonspherical MPs for their high margination propensity under the influence of near-wall adhesion and moderate shear flow rate. This study might offer theoretical guidance to design MP-based drug carriers in blood flow with high efficacy. [ABSTRACT FROM AUTHOR]

The margination and adhesion of micro-particles (MPs) have been extensively investigated separately, due to their important applications in the biomedical field. However, the cascade process from margination to adhesion should play an important role in the transport of MPs in blood flow. To the best of our knowledge, this has not been explored in the past. Here we numerically study the margination behaviour of elastic MPs to blood vessel walls under the interplay of their deformability and adhesion to the vessel wall. We use the lattice Boltzmann method and molecular dynamics to solve the fluid dynamics and particle dynamics (including red blood cells (RBCs) and elastic MPs) in blood flow, respectively. Additionally, a stochastic ligand–receptor binding model is employed to capture the adhesion behaviours of elastic MPs on the vessel wall. Margination probability is used to quantify the localization of elastic MPs at the wall. Two dimensionless numbers are considered to govern the whole process: the capillary number $Ca$ , denoting the ratio of viscous force of fluid flow to elastic interfacial force of MP, and the adhesion number $Ad$ , representing the ratio of adhesion strength to viscous force of fluid flow. We systematically vary them numerically and a margination probability contour is obtained. We find that there exist two optimal regimes favouring high margination probability on the plane $Ca{-}Ad$. The first regime, namely region I, is that with high adhesion strength and moderate particle stiffness; the other one, region II, has moderate adhesion strength and large particle stiffness. We conclude that the existence of optimal regimes is governed by the interplay of particle deformability and adhesion strength. The corresponding underlying mechanism is also discussed in detail. There are three major factors that contribute to the localization of MPs: (i) near-wall hydrodynamic collision between RBCs and MPs; (ii) deformation-induced migration due to the presence of the wall; and (iii) adhesive interaction between MPs and the wall. Mechanisms (i) and (iii) promote margination, while (ii) hampers margination. These three factors perform different roles and compete against each other when MPs are located in different regions of the flow channel, i.e. near-wall region. In optimal region I, adhesion outperforms deformation-induced migration; and in region II, the deformation-induced migration is small compared to the coupling of near-wall hydrodynamic collision and adhesion. The finding of optimal regimes can help the understanding of localization of elastic MPs at the wall under the adhesion effect in blood flow. More importantly, our results suggest that softer MP or stronger adhesion is not always the best choice for the localization of MPs. [ABSTRACT FROM AUTHOR]

For nanoparticle (NP)-based drug delivery platforms, the elasticity of the NPs has a significant influence on their blood circulation time and cellular uptake efficiency. However, due to the complexity of the endocytosis process and the inconsistency in the definition of elasticity for NPs in experiments, the understanding about the receptor-mediated endocytosis process of elastic NPs is still limited. In this work, we developed a coarse-grained molecular dynamics (CGMD) model for elastic NPs. The energy change of the elastic NPs can be precisely controlled by the bond, area, volume and bending potentials of this CGMD model. To represent liposomes with different elasticities, we systematically varied the bending rigidity of elastic NPs in CGMD simulations. Additionally, we changed the radius of the elastic NPs to explore the potential size effect. Through virtual nano-indentation tests, we found that the effective stiffness of elastic NPs was determined by their bending rigidity and size. Afterwards, we investigated the receptor-mediated endocytosis process of elastic NPs with different sizes and bending rigidities. We found that the membrane wrapping of soft NPs was faster than that of the stiff ones at the early stage, due to the NP deformation induced large contact area between the NPs and the membrane. However, because of the large energy penalties induced by the NP deformation, the membrane wrapping speed of soft NPs slows down during the late stage. Eventually, the soft NPs are wrapped less efficiently than the stiff ones during the membrane wrapping process. Through systematic CGMD simulations, we found a scaling law between the cellular uptake efficiency and the phenomenal bending rigidity of elastic NPs, which agrees reasonably well with experimental observations. Furthermore, we observed that the membrane wrapping efficiencies of soft and stiff NPs with large sizes were close to each other, due to the stronger ligand–receptor binding force and smaller difference in the stiffness of elastic NPs. Our computational model provides an effective tool to investigate the receptor-mediated endocytosis of elastic NPs with well controlled mechanical properties. This study can also be applied to guide the design of NP-based drug carriers with high efficacy, by utilizing their elastic properties. [ABSTRACT FROM AUTHOR]

We develop an efficient numerical method to study adhesion dynamics of a single cell on a substrate under shear flow. This method is based on the coupling of Lattice Boltzmann fluid and coarse-grained cell models through immersed boundary method, and a probabilistic model is adopted to capture dynamics of ligand-receptor binding for adhesion. With such a model at hand, a phase diagram of the adhesion dynamics in terms of adhesion strength $\text{Ad}$ and stiffness of cell $\text{Ca}$ is established. Four types of motion, including free motion, stable rolling, stop-and-go, and firm adhesion, are found through our numerical simulations, depending on the adhesion strength $\text{Ad}$ and stiffness of cell $\text{Ca}$. In addition, demargination behavior of the cell occurs when reducing the adhesion strength $\text{Ad}$ in the regime of soft cells (high $\text{Ca}$). Such a demargination behavior is induced by the deformability of cell, resulting in a wall-induced lift force in the shear flow. Lastly, a scaling relation of a number of ligand-receptor bonds is obtained under the synergistic effect of $\text{Ad}$ and $\text{Ca}$. The present effort provides a robust and efficient way to understand the adhesion dynamics of cells on substrate in shear flow. The obtained results are useful in understanding the biological adhesion process and developing adhesion-based microfluidic technologies. [ABSTRACT FROM AUTHOR]

Background/Aims: Long noncoding RNAs (lncRNAs) are key regulators of cancer initiation and progression. In this study, we investigated the clinical value and functional role of LncRNA DQ786243 (LncDQ) in the pathogenesis of hepatocellular carcinoma (HCC). Methods: To investigate the expression level of LncDQ in HCC, we performed quantitative real-time PCR using total RNA extracted from HCC tumor tissues and their matched non-neoplastic counterparts, as well as from the serum of HCC patients and healthy volunteers. The correlation of LncDQ expression with clinicopathologic features and prognosis was analyzed. The functional role of LncDQ in cell proliferation, migration, and invasion were evaluated by MTT cell viability, wound healing, and transwell assays in vitro and in vivo. RNA immunoprecipitation and chromatin immunoprecipitation assays were performed to analyze the potential mechanism of LncDQ in HCC cells. Results: LncDQ was upregulated in both HCC tissue samples and serum and was correlated with low survival rate and adverse clinical pathological characteristics. Multivariate analysis demonstrated that LncDQ expression was an independent prognostic factor for HCC. The area under the receiver operating characteristic curve was 0.804 with a sensitivity of 0.72 and a specificity of 0.8. Knockdown of LncDQ induced inhibition of cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, LncDQ regulated the epithelial–mesenchymal transition pathway by interacting with EZH2, to epigenetically repress the expression of E-cadherin in HCC cells. Conclusions: Taken together, the results of our study indicate that LncDQ plays a critical role in HCC progression, and may serve as a potential diagnostic and prognostic biomarker for HCC. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-2α ( HIF-2α) plays an important role in increasing cancer progression and distant metastasis in a variety of tumour types. We aimed to investigate its biological function and clinical significance in human pancreatic ductal adenocarcinoma ( PDAC). A total of 283 paired PDAC tissues and adjacent normal tissues were collected from patients who underwent surgery or biopsy at Sun Yat-sen Memorial Hospital between February 2004 and October 2016. In this study, we noted that HIF-2α expression was significantly up-regulated in PDAC, positively associated with disease stage, lymph-node metastasis and patient survival, and identified as an independent prognostic factor of PDAC patients. We demonstrated that HIF-2α silencing could reduce proliferation, migration and invasion of PDAC cells in vitro. The similar effect on growth was demonstrated in vivo. Furthermore, we noted that knock-down of HIF-2α significantly decreased the expression of glutamate oxaloacetate transaminase 1 ( GOT1). Importantly, we confirmed that the PI3K/ mTORC2 pathway promoted GOT1 expression by targeting HIF-2α. Our study validated HIF-2α was an important factor in PDAC progression and poor prognosis and may promote non-canonical glutamine metabolism via activation of PI3K/ mTORC2 pathway. Targeting HIF-2α represents a novel prognostic biomarker and therapeutic target for patients with PDAC. [ABSTRACT FROM AUTHOR]

A core–polyethylene glycol–lipid shell (CPLS) nanoparticle consists of an inorganic core coated with polyethylene glycol (PEG) polymers, surrounded by a lipid bilayer shell. It can be self-assembled from a PEGylated core with surface-tethered PEG chains, where all the distal ends are covalently bonded to lipid molecules. Upon adding free lipids, a complete lipid bilayer shell can be formed on the surface driven by the hydrophobic nature of lipid tails, leading to the formation of a CPLS nanoparticle. The stability of CPLS nanoparticles in shear flow has been systematically studied through large scale dissipative particle dynamics simulations. CPLS nanoparticles demonstrate higher stability and less deformation in shear flow, compared with lipid vesicles. Burst leakage of drug molecules inside lipid vesicles and CPLS NPs can be induced by the large pores at their tips. These pores are initiated by the maximum stress in the waist region. It further grows along with the tank-treading motion of vesicles or CPLS NPs in shear flow. However, due to the constraints applied by PEG polymers, CPLS NPs are less deformed than vesicles with comparable size under the same flow conditions. Thus, the less deformed CPLS NPs express a smaller maximum stress at waists, demonstrating higher stability. Pore formation at waists, evolving into large pores on vesicles, leads to the burst leakage of drug molecules and complete rupture of vesicles. In contrast, although similar drug leakage in CPLS nanoparticles can occur at high shear rates, pores initiated at moderate shear rates tend to be short-lived and close due to the constraints mediated by PEG polymers. This kind of ‘self-healing’ capability can be observed over a wide range of shear rates for CPLS nanoparticles. Our results suggest self-assembled CPLS nanoparticles to exhibit high stability during blood circulation without rapid drug leakage. These features make CPLS nanoparticles candidates for a promising drug delivery platform. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic neuroendocrine tumors (PNETs) exhibit various tumor behaviors and symptoms that are difficult for physicians to stage and predict prognosis. We assess prognostic factors combined with staging classifications to optimal the models and try to improve follow-up strategy to monitor liver metastases after surgery.Methods: Patients with PNETs treated at Sun Yat-sen Memorial Hospital between 2000 and 2015 were recruited. Patients were regrouped on the basis of functional status and mitotic rates. Nomograms to predict the prognostic values of classifications (AJCC, ENETS, and WHO) were constructed; the accuracy of the nomograms were quantified by the C-index and calibration plots.Results: We identified 78 PNETs patients with pathological reports. Correlations with OS in univariate analysis included nonfunctional status (P = 0.002), CgA>200 ng/ml (P < 0.001), Ki-67 (3-20%, P = 0.014; >20%, P < 0.001), and mitotic rate (3-20/10HPF, P = 0.011; >20/10HPF, P < 0.001). By multivariate analysis, nonfunctional status and mitotic rate maintained significance (P = 0.039; 3-20/10HPF, P = 0.015; >20/10HPF, P = 0.007). Evaluating the new proposed system, the difference in OS between low- and high-groups was statistically significant (P = 0.001). The C-index of the regrouped nomograms were higher than that of premise ones (AJCC cohort, 0.605 v 0.576, P < 0.01; ENETS cohort, 0.73 v 0.691, P < 0.01; WHO cohort, 0.678 v 0.603, P < 0.01).Conclusion: An prognostic model based on mitotic rates and functional status correlates strongly with survival. PNETs should return visits every 2 months for the first half years, and every 3 months as followed until 2 years after surgery. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) modification is an important mechanism in miRNA processing and maturation, but the role of its aberrant regulation in human diseases remained unclear. Here, we demonstrate that oncogenic primary microRNA-25 (miR-25) in pancreatic duct epithelial cells can be excessively maturated by cigarette smoke condensate (CSC) via enhanced m6A modification that is mediated by NF-κB associated protein (NKAP). This modification is catalyzed by overexpressed methyltransferase-like 3 (METTL3) due to hypomethylation of the METTL3 promoter also caused by CSC. Mature miR-25, miR-25-3p, suppresses PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), resulting in the activation of oncogenic AKT-p70S6K signaling, which provokes malignant phenotypes of pancreatic cancer cells. High levels of miR-25-3p are detected in smokers and in pancreatic cancers tissues that are correlated with poor prognosis of pancreatic cancer patients. These results collectively indicate that cigarette smoke-induced miR-25-3p excessive maturation via m6A modification promotes the development and progression of pancreatic cancer. Cigarette smoke induces microRNA dysregulation in cancers. Here, the authors show that cigarette smoke promotes the maturation of oncogenic primary miR-25 due to METTL3 hypomethylation, and mature miR-25 suppresses PH domain leucine-rich repeat protein phosphatase 2, resulting in oncogenic AKT activation in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Controlling the iridescent photonic film generated by self‐assembly of colorless cellulose nanocrystal (CNC) from the nanoscale to macroscale is challenging. This study combines experimental and computational approaches to systematically investigate the correlation between electrostatic interactions and chiral nematic structures. The chiral nematic order of the CNC colloidal is preserved in solid films after the evaporation of water. The cross‐sections of the iridescent film show a clear left‐handed helical arrangement of nanocrystals. The helical structure with the aid of acrylic acid exhibits longer organized patterns. This work reveals that compared to CNC prepared by pure sulfuric acid (zeta potential −37.1 mV), the CNC prepared using coupled mineral sulfuric and organic acrylic acid has a higher zeta potential (−67.2 mV), which induces the increase of helical pitch of the cholesteric nematic phase from 312 to 409 nm and a red shift of the iridescent film. Consequently, the tuning of reflected light wavelength lies in the variation of chiral nematic pitch inside the layered structure, which gives rise to different iridescent colors. The bioresourced photonic film is appealing to both academia and industry where optical and photonic components are essential. In this study, sulfuric acid and acrylic acid are coupled to prepare cellulose nanocrystal (CNC) nematic film with larger helical pitch, resulting in redshift of iridescent. Furthermore, theoretical study of the correlation between the CNC repulsion force and pitch length is conducted. This work reveals that the surface charge of CNC is an important parameter to affect the iridescent color. [ABSTRACT FROM AUTHOR]

Background: Understanding the pathogenic mechanism of pancreatic cancer associated diabetes (PCDM) might help yield biomarkers for the early diagnosis of pancreatic cancer (PC) from population with new-onset diabetes. In the current study, we sought to determine the role of macrophage migration inhibitory factor (MIF) in PCDM pathogenesis.Methods: The protein and mRNA levels of MIF in paraffin-embedded human PC samples, chronic pancreatitis specimens, and normal pancreas were measured by immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction. We measured serum levels of MIF in PC patients and controls. The biologic impacts of MIF overexpression on insulin secretion function of mice islets and β cells (HIT-T15) were investigated in vitro.Results: MIF expression was significantly increased in pancreatic cancer tissues compared with chronic pancreatitis or normal pancreas specimens. The insulin secretion function of both islets and HIT-T15 cells was impaired by indirect co-cultured with PC cells or treated with conditioned media from them. Stable MIF knock-down significantly decreased the diabetogenic effect of PC cells, while MIF knock-in HPDE6 cells demonstrated a strong inhibitory effect on insulin secretion function of islets and HIT-T15 cells. MIF impaired βcell function by depressing the Ca⁺ currents, decreasing L-type Ca⁺ channel α1 subunit protein expression level, and enhancing p-Src activity. Mean serum level of MIF was significant higher in new-onset diabetes associated PC patients in comparison with other groups.Conclusions: MIF is up-regulated in patients with pancreatic cancer and causes dysfunction of insulin secretion in β-cells. [ABSTRACT FROM AUTHOR]