Cediranib enhances the transcription of MHC-I by upregulating IRF-1.

Diminished or lost Major Histocompatibility Complex class I (MHC-I) expression is frequently observed in tumors, which obstructs the immune recognition of tumor cells by cytotoxic T cells. Restoring MHC-I expression by promoting its transcription and improving protein stability have been promising strategies for reestablishing anti-tumor immune responses. Here, through cell-based screening models, we found that cediranib significantly upregulated MHC-I expression in tumor cells. This finding was confirmed in various non-small cell lung cancer (NSCLC) cell lines and primary patient-derived lung cancer cells. Furthermore, we discovered cediranib achieved MHC-I upregulation through transcriptional regulation. interferon regulatory factor 1 (IRF-1) was required for cediranib induced MHC-I transcription and the absence of IRF-1 eliminated this effect. Continuing our research, we found cediranib triggered STAT1 phosphorylation and promoted IRF-1 transcription subsequently, thus enhancing downstream MHC-I transcription. In vivo study, we further confirmed that cediranib increased MHC-I expression, enhanced CD8+ T cell infiltration, and improved the efficacy of anti-PD-L1 therapy. Collectively, our study demonstrated that cediranib could elevate MHC-I expression and enhance responsiveness to immune therapy, thereby providing a theoretical foundation for its potential clinical trials in combination with immunotherapy.

Shewanella oneidensis MR-1 dissimilatory reduction of ferrihydrite to highly enhance mineral transformation and reactive oxygen species production in redox-fluctuating environments.

Diverse paths generated by reactive oxygen species (ROS) can mediate contaminant transformation and fate in the soil/aquatic environments. However, the pathways for ROS production upon the oxygenation of redox-active ferrous iron minerals are underappreciated. Ferrihydrite (Fh) can be reduced to produce Fe(II) by Shewanella oneidensis MR-1, a representative strain of dissimilatory iron-reducing bacteria (DIRB). The microbial reaction formed a spent Fh product named mr-Fh that contained Fe(II). Material properties of mr-Fh were characterized with X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). Magnetite could be observed in all mr-Fh samples produced over 1-day incubation, which might greatly favor the Fe(II) oxygenation process to produce hydroxyl radical (•OH). The maximum amount of dissolved Fe(II) can reach 1.1 mM derived from added 1 g/L Fh together with glucose as a carbon source, much higher than the 0.5 mM generated in the case of the Luria-Bertani carbon source. This may confirm that MR-1 can effectively reduce Fh and produce biogenetic Fe(II). Furthermore, the oxygenation of Fe(II) on the mr-Fh surface can produce abundant ROS, wherein the maximum cumulative •OH content is raised to about 120 µM within 48 h at pH 5, but it is decreased to about 100 µM at pH 7 for the case of MR-1/Fh system after a 7-day incubation. Thus, MR-1-mediated Fh reduction is a critical link to enhance ROS production, and the •OH species is among them the predominant form. XPS analysis proves that a conservable amount of Fe(II) species is subject to adsorption onto mr-Fh. Here, MR-1-mediated ROS production is highly dependent on the redox activity of the form Fe(II), which should be the counterpart presented as the adsorbed Fe(II) on surfaces. Hence, our study provides new insights into understanding the mechanisms that can significantly govern ROS generation in the redox-oscillation environment.

Insights into the role of derailed endocytic trafficking pathway in cancer: From the perspective of cancer hallmarks.

The endocytic trafficking pathway is a highly organized cellular program responsible for the regulation of membrane components and uptake of extracellular substances. Molecules internalized into the cell through endocytosis will be sorted for degradation or recycled back to membrane, which is determined by a series of sorting events. Many receptors, enzymes, and transporters on the membrane are strictly regulated by endocytic trafficking process, and thus the endocytic pathway has a profound effect on cellular homeostasis. However, the endocytic trafficking process is typically dysregulated in cancers, which leads to the aberrant retention of receptor tyrosine kinases and immunosuppressive molecules on cell membrane, the loss of adhesion protein, as well as excessive uptake of nutrients. Therefore, hijacking endocytic trafficking pathway is an important approach for tumor cells to obtain advantages of proliferation and invasion, and to evade immune attack. Here, we summarize how dysregulated endocytic trafficking process triggers tumorigenesis and progression from the perspective of several typical cancer hallmarks. The impact of endocytic trafficking pathway to cancer therapy efficacy is also discussed.

A Comprehensive Review of Digital Twin from the Perspective of Total Process: Data, Models, Networks and Applications.

With the rapid development of industrial digitalization and intelligence, there is an urgent need to accurately depict the physical world in digital space, and, in turn, regulate and optimize the behavior of physical entities based on massive data collection and analysis. As a technology that combines virtual space and physical space, digital twin can satisfy all of the above needs, and has attracted widespread attention. Due to the promising application prospects of digital twins, both academia and industry have launched research in this field, and related studies have been conducted from different perspectives. Accordingly, some articles summarizing the existing work have also been published, but they are all from a single perspective, lacking a systematic introduction and summary. Based on this, this paper conducts a comprehensive review of the existing work on digital twins from four perspectives: data, model, network and application, and strives to gain a better understanding of the development of the field from the physical to the virtual and back to the physical. Meanwhile, current research challenges and future directions for the development of digital twins are all discussed.

Erratum: Author correction to 'Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA' [Acta Pharmaceutica Sinica B 13 (2023) 2585-2600].

[This corrects the article DOI: 10.1016/j.apsb.2023.04.002.].

Physiologically-based pharmacokinetic modeling for optimal dosage prediction of olaparib when co-administered with CYP3A4 modulators and in patients with hepatic/renal impairment.

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict the maximum plasma concentration (Cmax) and trough concentration (Ctrough) at steady-state of olaparib (OLA) in Caucasian, Japanese and Chinese. Furthermore, the PBPK model was combined with mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered to patients with hepatic/renal impairment. The dosing regimens were determined based on safety and efficacy PK threshold Cmax (< 12,500 ng/mL) and Ctrough (772-2500 ng/mL). The population PBPK model for OLA was successfully developed and validated, demonstrating good consistency with clinically observed data. The ratios of predicted to observed values for Cmax and Ctrough fell within the range of 0.5 to 2.0. When OLA was co-administered with a strong or moderate CYP3A4 inhibitor, the recommended dosing regimens should be reduced to 100 mg BID and 150 mg BID, respectively. Additionally, the PBPK model also suggested that OLA could be not recommended with a strong or moderate CYP3A4 inducer. For patients with moderate hepatic and renal impairment, the dosing regimens of OLA were recommended to be reduced to 200 mg BID and 150 mg BID, respectively. In cases of severe hepatic and renal impairment, the PBPK model suggested a dosing regimen of 100 mg BID for OLA. Overall, this present PBPK model can determine the optimal dosing regimens for various clinical scenarios involving OLA.

KLF12 transcriptionally regulates PD-L1 expression in non-small cell lung cancer.

Recent studies have pointed to the role of Krüpple-like factor 12 (KLF12) in cancer-associated processes, including cancer proliferation, apoptosis, and metastasis. However, the role of KLF12 in tumor immunity remains obscure. Here, we found that KLF12 expression was significantly higher in non-small cell lung cancer (NSCLC) cells with higher programmed death-ligand 1 (PD-L1) expression. Additionally, a positive correlation between KLF12 and PD-L1 was observed in clinical patient tumor tissues. By chromatin immunoprecipitation (ChIP) analysis, KLF12 was identified to bind to the CACCC motif of the PD-L1 promoter. Overexpression of KLF12 promoted PD-L1 transcription, whereas silencing of KLF12 inhibited PD-L1 transcription. Furthermore, signal transducer and activator of transcription 1 (STAT1)- and STAT3-triggered PD-L1 transcription was abolished in the absence of KLF12, and KLF12 knockdown weakened the binding of STAT1 and STAT3 to the PD-L1 promoter. Mechanistically, KLF12 physically interacted with P300, a histone acetyltransferase. In addition, KLF12 silencing reduced P300 binding to the PD-L1 promoter, which subsequently caused decreased acetylation of histone H3. PD-L1 transcription driven by KLF12 overexpression was eliminated by EP300 silencing. In immunocompetent mice, KLF12 knockout inhibited tumor growth and promoted infiltration of CD8+ T cells. However, this phenomenon was not observed in immunodeficient mice. Overall, this study reveals KLF12-mediated transcriptional regulation of PD-L1 in NSCLC; targeting KLF12 may be a potential therapeutic strategy for NSCLC.

Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA.

Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

Hybrid Cooperative Cache Based on Temporal Convolutional Networks in Vehicular Edge Network.

With the continuous development of intelligent vehicles, people's demand for services has also rapidly increased, leading to a sharp increase in wireless network traffic. Edge caching, due to its location advantage, can provide more efficient transmission services and become an effective method to solve the above problems. However, the current mainstream caching solutions only consider content popularity to formulate caching strategies, which can easily lead to cache redundancy between edge nodes and lead to low caching efficiency. To solve these problems, we propose a hybrid content value collaborative caching strategy based on temporal convolutional network (called THCS), which achieves mutual collaboration between different edge nodes under limited cache resources, thereby optimizing cache content and reducing content delivery latency. Specifically, the strategy first obtains accurate content popularity through temporal convolutional network (TCN), then comprehensively considers various factors to measure the hybrid content value (HCV) of cached content, and finally uses a dynamic programming algorithm to maximize the overall HCV and make optimal cache decisions. We have obtained the following conclusion through simulation experiments: compared with the benchmark scheme, THCS has improved the cache hit rate by 12.3% and reduced the content transmission delay by 16.7%.

Superior photo-Fenton degradation of acetamiprid by α- Fe2O3-pillared bentonite/L-cysteine complex: Synergy of L-cysteine and visible light.

Acetamiprid is a potential threat to human health, aquatic life, soil microorganisms and beneficial insects as a recalcitrant pollutant in wastewater treatment plant effluents. In this work, the synthesized α-Fe2O3-pillared bentonite (FPB) was used to degrade acetamiprid in the photo-Fenton process with the assistance of L-cysteine (L-cys) existing in natural aquatic environment. The kinetic constant k of acetamiprid degradation by FPB/L-cys in the photo-Fenton process was far more than that in the Fenton process of FPB/L-cys lacking light and the photo-Fenton process of FPB without L-cys. The positive linear correlation between k and ≡Fe(II) content indicated the synergy of L-cys and visible light accelerated the cycle of Fe(III) to Fe(II) in FPB/L-cys during the degradation of acetamiprid by elevating the visible light response of FPB, and promoting the interfacial electron transfer from the active sites of FPB to hydrogen peroxide and photo-generated electron transfer from conduction band of α-Fe2O3 to the active sites of FPB. The boosting •OH and 1O2 were predominantly responsible for acetamiprid degradation. Acetamiprid could be efficiently degraded into less toxic small molecules in the photo-Fenton process via C-N bond breaking, hydroxylation, demethylation, ketonization, dechlorination, and ring cleavage.

Strategies to synergize PD-1/PD-L1 targeted cancer immunotherapies to enhance antitumor responses in ovarian cancer.

Anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) antibodies have developed rapidly but exhibited modest activity in ovarian cancer (OC), achieving a clinical response rate ranging from 5.9% to 19%. Current evidence indicate that the establishment of an integrated cancer-immunity cycle is a prerequisite for anti-PD-1/PD-L1 antibodies. Any impairment in this cycle, including lack of cancer antigens release, impaired antigen-presenting, decreased T cell priming and activation, less T cells that are trafficked or infiltrated in tumor microenvironment (TME), and low tumor recognition and killings, will lead to decreased infiltrated cytotoxic T cells to tumor bed and treatment failure. Therefore, combinatorial strategies aiming to modify cancer-immunity cycle and reprogram tumor immune microenvironment are of great interest. By far, various strategies have been studied to enhance responsiveness to PD-1/PD-L1 inhibitors in OC. Platinum-based chemotherapy increases neoantigens release; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) improve the function of antigen-presenting cells and promote the trafficking of T cells into tumors; epigenetic drugs help to complete the immune cycle by affecting multiple steps; immunotherapies like anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies reactivate T cells, and other treatment strategies like radiotherapy helps to increase the expression of tumor antigens. In this review, we will summarize the preclinical studies by analyzing their contribution in modifying the cancer immunity cycle and remodeling tumor environment, and we will also summarize recent progress in clinical trials and discuss some perspectives to improve these treatment strategies.

Strategies involving STING pathway activation for cancer immunotherapy: Mechanism and agonists.

Recent studies have expanded the known functions of cGAS-STING in inflammation to a role in cancer due to its participation in activating immune surveillance. In cancer cells, the cGAS-STING pathway can be activated by cytosolic dsDNA derived from genomic, mitochondrial and exogenous origins. The resulting immune-stimulatory factors from this cascade can either attenuate tumor growth or recruit immune cells for tumor clearance. Furthermore, STING-IRF3-induced type I interferon signaling can enforce tumor antigen presentation on dendritic cells and macrophages and thus cross-prime CD8+ T cells for antitumor immunity. Given the functions of the STING pathway in antitumor immunity, multiple strategies are being developed and tested with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells to elicit immunostimulatory effects, either alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. Based on the canonical molecular mechanism of STING activation, numerous strategies for inducing mitochondrial and nuclear dsDNA release have been used to activate the cGAS-STING signaling pathway. Other noncanonical strategies that activate cGAS-STING signaling, including the use of direct STING agonists and STING trafficking facilitation, also show promise in type I interferon release and antitumor immunity priming. Here, we review the key roles of the STING pathway in different steps of the cancer-immunity cycle and characterize the canonical and noncanonical mechanisms of cGAS-STING pathway activation to understand the potential of cGAS-STING agonists for cancer immunotherapy.

Intrusion Detection Method for Internet of Vehicles Based on Parallel Analysis of Spatio-Temporal Features.

The problems with network security that the Internet of Vehicles (IoV) faces are becoming more noticeable as it continues to evolve. Deep learning-based intrusion detection techniques can assist the IoV in preventing network threats. However, previous methods usually employ a single deep learning model to extract temporal or spatial features, or extract spatial features first and then temporal features in a serial manner. These methods usually have the problem of insufficient extraction of spatio-temporal features of the IoV, which affects the performance of intrusion detection and leads to a high false-positive rate. To solve the above problems, this paper proposes an intrusion detection method for IoV based on parallel analysis of spatio-temporal features (PA-STF). First, we built an optimal subset of features based on feature correlations of IoV traffic. Then, we used the temporal convolutional network (TCN) and long short-term memory (LSTM) to extract spatio-temporal features in the IoV traffic in a parallel manner. Finally, we fused the spatio-temporal features extracted in parallel based on the self-attention mechanism and used a multilayer perceptron to detect attacks in the Internet of Vehicles. The experimental results show that the PA-STF method reduces the false-positive rate by 1.95% and 1.57% on the NSL-KDD and UNSW-NB15 datasets, respectively, with the accuracy and F1 score also being superior.

The impact of lipids on the cancer-immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy.

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer-immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.

Highly stable and efficient Cr(VI) immobilization from water by adsorption with the La-substituted ferrihydrite as a naturally-occurring geosorbent in soils.

Ferrihydrite (Fh) is a vital geosorbent in the natural environment. Here, Fh materials with lanthanum (La) substituted in varied La/La + Fe ratios were synthesized, and these La-Fh materials were investigated in-depth via adsorption kinetic and isothermal experiments to explore their adsorption performance for chromate [Cr(VI)] in soils. Material properties of La-Fh were further characterized with X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectrometer (FTIR), and X-ray photoelectron spectroscopy (XPS). The results clearly indicate that La3+ can be integrated into the Fh lattice, but the increase in La amount substituted into Fh is slowed down when the La/La + Fe ratio reaches to a larger value. Those La3+ cations that fail to become integrated may either get adsorbed or form a phase of La(OH)3 on La-Fh surfaces. We also find that La substitution reduces the specific surface area (SSA) of La-Fh samples but raises their pHpzc, which hampers La-Fh conversion to hematite and thus increases the chemical stability. These changes are related to the La-Fh structure and surface aspects, but they do not negatively affect the Cr(VI) adsorption efficacy, which can be promoted over a wide pH range to an alkaline pH. For instance, the maximum adsorption amount of Cr(VI) by 20%La-Fh is 30.2 mg/g at a near-neutral pH. However, the entire chromate adsorption processes are affected by H2PO4- and humic acid due to their strong affinities for Cr(VI), but almost not influenced by NO3- and Cl-. All the Cr(VI)-Fh reactions are well described by the fitted adsorption Freundlich model and conform to the pseudo-second-order reaction kinetic equation. The mechanisms which enhance La-Fh's adsorption ability for Cr(VI) are governed by chemical interactions, because La substitution can increase the hydroxyl density on Fh surfaces and thus improve the reactivity of La-Fh towards Cr(VI), leading to an evidently enhanced Cr(VI) immobilization onto La-Fh.

Prediction for Plasma Trough Concentration and Optimal Dosing of Imatinib under Multiple Clinical Situations Using Physiologically Based Pharmacokinetic Modeling.

(1) Purpose: This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the trough concentration (C trough) of imatinib (IMA) at steady state in patients and to explore the role of free concentration (f up), α1-acid glycoprotein (AGP) level, and organic cation transporter 1 (OCT1) activity/expression in clinical efficacy. (2) Methods: The population PBPK model was built using physicochemical and biochemical properties, metabolizing and transporting kinetics, tissue distribution, and human physiological parameters. (3) Results: The PBPK model successfully predicted the C trough of IMA administered alone in chronic phase (CP) and accelerated phase (AP) patients, the C trough of IMA co-administered with six modulators, and C trough in CP patients with hepatic impairment. Most of the ratios between predicted and observed data are within 0.70-1.30. Additionally, the recommendations for dosing adjustments for IMA have been given under multiple clinical uses. The sensitivity analysis showed that exploring the f up and AGP level had a significant influence on the plasma C trough of IMA. Meanwhile, the simulations also revealed that OCT1 activity and expression had a significant impact on the intracellular C trough of IMA. (4) Conclusion: The current PBPK model can accurately predict the IMA C trough and provide appropriate dosing adjustment recommendations in a variety of clinical situations.

Direct Atomic-Scale Insight into the Precipitation Formation at the Lanthanum Hydroxide Nanoparticle/Solution Interface.

Understanding precipitation formation at lanthanum hydroxide (La(OH)3) nanoparticle-solution interfaces plays a crucial role in catalysis, adsorption, and electrochemical energy storage applications. Liquid-phase transmission electron microscopy enables powerful visualization with high resolution. However, direct atomic-scale imaging of the interfacial metal (hydro)oxide nanostructure in solutions has been a major challenge due to their beam-driven dissolution. Combining focused ion beam and aberration-corrected high-angle annular dark-field scanning transmission electron microscopy, we present an atomic-scale study of precipitation formation at La(OH)3 nanoparticle interfaces after reaction with phosphate. The structure transformation is observed to occur at high- and low-crystalline La(OH)3 nanoparticle surfaces. Low-crystalline La(OH)3 mostly transformed and high-crystalline ones partly converted to LaPO4 precipitations on the outer surface. The long-term structure evolution shows the low transformation of high-crystalline La(OH)3 nanoparticles to LaPO4 precipitation. Because precipitation at solid-solution interfaces is common in nature and industry, these results could provide valuable references for their atomic-scale observation.

A Semantic-Enhancement-Based Social Network User-Alignment Algorithm.

User alignment can associate multiple social network accounts of the same user. It has important research implications. However, the same user has various behaviors and friends across different social networks. This will affect the accuracy of user alignment. In this paper, we aim to improve the accuracy of user alignment by reducing the semantic gap between the same user in different social networks. Therefore, we propose a semantically enhanced social network user alignment algorithm (SENUA). The algorithm performs user alignment based on user attributes, user-generated contents (UGCs), and user check-ins. The interference of local semantic noise can be reduced by mining the user's semantic features for these three factors. In addition, we improve the algorithm's adaptability to noise by multi-view graph-data augmentation. Too much similarity of non-aligned users can have a large negative impact on the user-alignment effect. Therefore, we optimize the embedding vectors based on multi-headed graph attention networks and multi-view contrastive learning. This can enhance the similar semantic features of the aligned users. Experimental results show that SENUA has an average improvement of 6.27% over the baseline method at hit-precision30. This shows that semantic enhancement can effectively improve user alignment.

Evaluation of the coracoid bone tunnel placement on Dog Bone™ button fixation for acromioclavicular joint dislocation: a cadaver study combined with finite element analysis.

BACKGROUND: Dog Bone™ button fixation is frequently used to treat acromioclavicular joint (ACJ) dislocation. However, various studies have reported complications after fixation. OBJECTIVE: To investigate the effect of the coracoid bone tunnel location on the treatment of ACJ dislocation through single-tunnel coracoclavicular (CC) ligament fixation with the Dog Bone™ button. METHODS: Six cadaveric shoulders were used. Each specimen was subjected to five testing conditions in the following order: (1) normal ACJ (Gn); (2) acromioclavicular and CC ligaments were removed (G0); (3) CC ligament reconstruction was performed using the Dog Bone™ technique, and the coracoid bone tunnel was at the center of the coracoid base (G1); (4) reconstruction was performed at 5 mm distal from the G1 site, along the axis of the coracoid (G2); (5) reconstruction was performed at 10 mm distal from the G1 site, along the axis of the coracoid (G3). The angles of pronation and supination of the clavicle under the same load (30 N) were measured. Next, a finite element (FE) model was created using computed tomography (CT) images of the normal shoulder. Model 1 (M1), model 2 (M2), and model 3 (M3) correspond to G1, G2, and G3, respectively. A force of 70 N was applied as a vertical upward load to the distal clavicle. Subsequently, the von Mises stress, the strain LE along the FiberWire, and the displacement nephogram of the three models were obtained. RESULTS: After single-tunnel CC ligament fixation using the Dog Bone™ technique, the clavicle in the G2 group (20.50 (19.50, 21.25) °, 20.00 (18.75, 21.25) °) had the best rotational stability. The peak von Mises stress, the strain LE along the FiberWire, and the maximum displacement were smaller in M2 than in M1 and M3. CONCLUSIONS: When the coracoid bone tunnel was located 5 mm anterior to the center of the coracoid base (along the axis of the coracoid), the clavicle showed greater rotational stability.

Differentiation of umbilical cord mesenchymal stem cells into hepatocytes with CYP450 metabolic enzyme activity induced by a liver injury microenvironment.

The aim of this study was to observe the effect of a simulated liver tissue injury microenvironment on the directed differentiation of umbilical cord mesenchymal stem cells into hepatocytes with CYP450 metabolic activity in vitro, and to explore the mechanisms underlying this directed differentiation. Normal and damaged liver tissue homogenate supernatants (LHS and CCl4-LHS, respectively) were used as induction fluids. After induction for different durations, Western blot and RT-PCR were used to measure the protein and gene expression of the hepatocellular proteins AFP, CK18, ALB, and the CYP450 family. Simultaneously, the metabolic activity of CYP450 in hepatocytes was determined. Compared with the LHS and CCl4-LHS controls, the LHS and CCl4-LHS induction groups showed a significantly elevated protein and gene expression of AFP, CK18, ALB, CYP1A1/2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 (P < 0.05). The metabolic activity of CYP450 in hepatocytes was increased (P < 0.05). In addition, compared with the LHS group, the CCl4-LHS group induced cell differentiation more rapidly and with a higher efficiency. The results suggested that a liver injury microenvironment is conducive for the directed differentiation of umbilical cord mesenchymal stem cells into hepatocytes with metabolic enzyme activity.