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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]

We develop a multiscale and multiphysics computational method to investigate the transport of magnetic particles as drug carriers in blood flow under influence of hydrodynamic interaction and external magnetic field. A hybrid coupling method is proposed to handle red blood cell (RBC)-fluid interface (CFI) and magnetic particle-fluid interface (PFI), respectively. Immersed boundary method (IBM)-based velocity coupling is used to account for CFI, which is validated by tank-treading and tumbling behaviors of a single RBC in simple shear flow. While PFI is captured by IBM-based force coupling, which is verified through movement of a single magnetic particle under non-uniform external magnetic field and breakup of a magnetic chain in rotating magnetic field. These two components are seamlessly integrated within the LAMMPS framework, which is a highly parallelized molecular dynamics solver. In addition, we also implement a parallelized lattice Boltzmann simulator within LAMMPS to handle the fluid flow simulation. Based on the proposed method, we explore the margination behaviors of magnetic particles and magnetic chains within blood flow. We find that the external magnetic field can be used to guide the motion of these magnetic materials and promote their margination to the vascular wall region. Moreover, the scaling performance and speedup test further confirm the high efficiency and robustness of proposed computational method. Therefore, it provides an efficient way to simulate the transport of nanoparticle-based drug carriers within blood flow in a large scale. The simulation results can be applied in the design of efficient drug delivery vehicles that optimally accumulate within diseased tissue, thus providing better imaging sensitivity, therapeutic efficacy and lower toxicity. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by perineural invasion (PNI), which is associated with excruciating neuropathic pain and malignant progression. However, the relationship between PNI and tumour stromal cells has not been clarified. Methods: The dorsal root ganglia or sciatic nerves nerve model was used to observe the paracrine interaction and the activation effect among Schwann cells, tumour-associated macrophages (TAMs), and pancreatic cancer cells in vitro. Next generation sequencing, enzyme-linked immunosorbent assay and chromatin immunoprecipitation were used to explore the specific paracrine signalling between TAMs and Schwann cells. Results: We demonstrated that more macrophages were expressed around nerves that have been infiltrated by pancreatic cancer cells compared with normal nerves in murine and human PNI specimens. In addition, high expression of CD68 or GFAP is associated with an increased incidence of PNI and indicates a poor 5-year survival rate in patients with PDAC. Mechanistically, tumour-associated macrophages (TAMs) activate Schwann cells via the bFGF/PI3K/Akt/c-myc/GFAP pathway. Schwann cells secrete IL-33 to recruit macrophages into the perineural milieu and facilitate the M2 pro-tumourigenic polarisation of macrophages. Conclusions: Our study demonstrates that the bFGF/IL-33 positive feedback loop between Schwann cells and TAMs is essential in the process of PNI of PDAC. The bFGF/PI3K/Akt/c-myc/GFAP pathway would open potential avenues for targeted therapy of PDAC. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of immune checkpoint inhibitors in treating gallbladder cancer (GBC) remains unsatisfactory. Recently, several new immune checkpoints have been identified. However, investigations exploring these immune checkpoints in GBC are limited. In this study, we aim to investigate the expression patterns and clinical implications of various immune checkpoints, and further characterize the spatial and quantitative heterogeneity of immune components in GBC. Methods: We employed single and multiplex immunohistochemistry to evaluate the expression of five immune checkpoint markers and four immune cell markers in the primary tumor core, hepatic invasion margin, and liver metastasis. Subsequently, we analyzed their interrelationships and their prognostic significance. Results: We observed a robust positive correlation between PD1/TIM3 expression in GBC (R = 0.614, P < 0.001). The co-expression of PD1/TIM3 exhibited a synergistic effect in predicting poor prognosis among postoperative GBC patients. Further analysis revealed that the prognostic significance of PD1/TIM3 was prominent in the subgroup with high infiltration of CD8 + T cells (P < 0.001). Multiplex immunohistochemistry reveals that PD1 + TIM3 + FOXP3 + cells constitute a significant proportion of FOXP3 + TILs in GBC tissue. Moreover, the co-high expression of PD1 and TIM3 is positively correlated with the accumulation of CD8 + TILs at the hepatic invasion margin. Lastly, our findings indicated reduced expression levels of immune checkpoints and diminished immune cell infiltration in liver metastases compared to primary tumors. Conclusions: Increased co-expression of PD1/TIM3 is associated with poor prognosis in GBC patients and is related to the heterogeneity of immune microenvironment between GBC primary tumor and its hepatic invasion margin or liver metastases, which may be a potential target for future immunotherapy of GBC. [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]

Single-cell mechanics have gained much attention due to its importance in a broad range of biological applications. Different experimental approaches have been used for measuring the mechanical properties of individual cells. However, the technical demands and time-consuming nature of these procedures have limited the throughput of single-cell measurement, necessitating the development of alternative computational approaches. Recently, single-cell deformability can be predicted using a convolutional neural network (CNN) model, shedding a light on using machine learning (ML) algorithms for high-throughput characterizations of single-cell mechanical properties. In this work, we developed a novel ML-based computational framework that can reproduce a physical microfluidic system to investigate the individual cell's deformability. The datasets for the training and testing of our model were generated using high-fidelity fluid-structure interaction (FSI) simulations. Our FSI-based ML approach of adopting CNN algorithms demonstrated a highly accurate prediction for the membrane stiffness of a microcapsule (maximum R2 = 0.98) based on its deformed shape. In this paper, we show that by applying physical constraints including the microcapsule's total surface area and total volume, we were able to build a physics-constrained ML model that possesses better convergence and higher stability during both training and validation. Finally, we found that ML models that used the three-dimensional geometry of the capsule as input could outperform the typical CNN models that relied solely on the two-dimensional images. We expect that this physics-constrained computational framework will serve as a basis for developing future tools for real-time biological applications through the integration of high-fidelity simulations with ML algorithms. • Integration of machine learning (ML) algorithms and fluid dynamics simulations to study individual cell's deformability. • This computational framework predicts accurately microcapsule's membrane stiffness based on its deformed shape. • Applying physical constraints on the ML models achieves better convergences during both training and validation. • CNN models using three-dimensional geometry as input outperform typical CNN models that solely use two-dimensional images. [ABSTRACT FROM AUTHOR]

6K: overlap was found between the Transwell invasion assay Vector group and PLACT1+JSH-23 group; the correct image is now used (column 1, row 2) Graph The corrected figures are provided here. Correction: lncRNA-PLACT1 sustains activation of NF- B pathway through a positive feedback loop with I B /E2F1 axis in pancreatic cancer 2K: overlap was found between the Transwell migration assay and invasion assay in si-PLACT1#1 group of AsPC-1 cells; the representative image of the invasion assay in si-PLACT1#1 group of AsPC-1 cells has been replaced with the correct image Graph Fig. [Extracted from the article]

Background: The activation of NF-κB signaling pathway is regarded as the dominant process that correlates with tumorigenesis. Recently, increasing evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-κB signaling pathway. However, the underlying mechanisms have not yet been elucidated. Methods: The expression and clinical features of PLACT1 were analyzed in a 166-case cohort of PDAC by qRT-PCR and in situ hybridization. The functional role of PLACT1 was evaluated by both in vitro and in vivo experiments. Chromatin isolation by RNA purification assays were utilized to examine the interaction of PLACT1 with IκBα promoter. Results: We identified a novel lncRNA-PLACT1, which was significantly upregulated in tumor tissues and correlated with progression and poor survival in PDAC patients. Moreover, PLACT1 promoted the proliferation and invasion of PDAC cells in vitro. Consistently, PLACT1 overexpression fostered the progression of PDAC both in orthotopic and lung metastasis mice models. Mechanistically, PLACT1 suppressed IκBα expression by recruiting hnRNPA1 to IκBα promoter, which led to increased H3K27me3 that decreased the transcriptional level of IκBα. Furthermore, E2F1-mediated overexpression of PLACT1 modulated the progression of PDAC by sustained activation of NF-κB signaling pathway through forming a positive feedback loop with IκBα. Importantly, administration of the NF-κB signaling pathway inhibitor significantly suppressed PLACT1-induced sustained activation of NF-κB signaling pathway, leading to reduced tumorigenesis in vivo. Conclusions: Our findings suggest that PLACT1 provides a novel epigenetic mechanism involved in constitutive activation of NF-κB signaling pathway and may represent a new therapeutic target of PDAC. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Increased co-expression of PD1 and TIM3 is associated with poor prognosis and immune microenvironment heterogeneity in gallbladder cancer" published in the Journal of Translational Medicine. The correction states that the original article was published without including the sentence about the authors' contribution. The corrected version now includes the statement that Xing He, Yaorong Peng, and Gui He contributed equally to the work. The publisher, Springer Nature, maintains a neutral stance on jurisdictional claims and institutional affiliations. The authors of the article are Xing He, Yaorong Peng, Gui He, Huilin Ye, Liqiang Liu, Qixian Zhou, Juanyi Shi, Sha Fu, Jie Wang, Zhenyu Zhou, and Wenbin Li. [Extracted from the article]

Our previous study demonstrated that long non-coding RNA (lncRNA) HOTTIP was maximally expressed in PDAC, and promoted cancer cell progression and epithelial to mesenchymal transition (EMT). Numerous studies indicated that lncRNAs or EMT supported cancer stem cells. However, the role of HOTTIP in pancreatic cancer stem cells (PCSCs) remains unclear. Here, we evaluated the role and mechanism of HOTTIP in PCSCs. First, we analyzed the relationship between HOTTIP expression and overall or disease-free survival in 90 patients with PDAC after radical resection. Patients with higher HOTTIP expression had shorter disease-free survival and overall survival than those with lower expression. Expression of HOTTIP and other lncRNAs was detected in PCSCs and non-PCSCs by laser capture microdissection (LCM). HOTTIP was highly expressed in PCSCs. In addition, in vitro assays showed that HOTTIP alterations affected stemness, including sphericity, tumorigenesis, and stem factors (LIN28, NANOG, OCT4, and SOX2) and markers (ALDH1, CD44, and CD133). Mechanistically, HOTTIP mediated HOXA9 to enhance the Wnt/β-catenin pathway by binding to WDR5 in PCSCs. In vivo results showed that HOTTIP or HOXA9 alterations influenced stemness. Our results indicate that the HOTTIP/WDR5/HOXA9/Wnt axis contributes to PCSC stemness and is a potential therapeutic target for PDAC. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we found that a novel lncRNA, LOC389641, was upregulated in PDAC tissues and cell lines. The expression of LOC389641 was significantly correlated with staging, lymph node metastasis and overall survival. Knockdown of LOC389641 impaired cell proliferation and invasion and induced cell apoptosis in vitro, whereas overexpression of LOC389641 had the opposite effect. The growth promoting effect of LOC389641 was also demonstrated in vivo. Further, a significant negative correlation was observed between E-cadherin levels and LOC389641 levels in vivo. Knockdown of LOC389641 upregulated E-cadherin expression, but knockdown of E-cadherin had a limited influence on LOC389641. Importantly, after E-cadherin was inhibited, the enhancement of LOC389641 on cell invasion was hindered. Moreover, the expression of LOC389641 was closely associated with its genomic neighboring gene TNFRSF10A. Lastly, knockdown experiments showed that TNFRSF10A might be a connection between LOC389641and E-cadherin. We conclude that LOC389641 promotes PDAC progression and increases cell invasion by regulating E-cadherin with the possible involvement of TNFRSF10A. [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]