Colorectal cancer (CRC) is one of the most common human malignancies in the digestive tract with high mortality. Alantolactone (ATL), as a plant-derived sesquiterpene lactone, has shown a variety of ...pharmacological activities, such as antibacterial, anti-inflammatory, anti-virus and so on. However, the exact molecular mechanism of ATL in colorectal cancer remains largely unknown. Here, we performed a study to explore the effect and mechanism of ATL on colorectal cancer. The CCK-8 assay, colony formation assay, Wound-healing and Transwell assays were performed to evaluate the cytotoxic effect, antiproliferative effect, anti-migratory and anti-invasive properties of ATL respectively. The xenograft tumor model was established in Balb/c mice to evaluate the anti-tumor effect. The expression levels of proteins involved the MAPK-JNK/c-Jun signaling pathway were measured by Western blot and RT-qPCR both in cells and tumor tissues. The results showed that ATL could inhibit the cells activities of various colon cancer cell lines. Moreover, ATL could induce HCT-116 cells nuclear pyknosis, mitochondrial membrane potential loss, G0/G1 phase arrest, as well as enhance the proportion of apoptosis cells and inhibit colony formation. The migration distance and invasion rate of cells were significantly reduced after treated with ATL. Additionally, in the xenograft model, ATL (50 mg/kg) significantly decreased the tumor tumor volume and weight (
p
< 0.001). For the anti-colon cancer mechanism, the ATL showed the anti-proliferative and pro-apoptosis effect by activating MAPK-JNK/c-Jun signaling pathway. In conclusion, ATL exhibits anti-proliferation and apoptosis-promoting potential in colon cancer via the activation of MAPK-JNK/c-Jun signaling pathway.
•Macro-to-micro FEM with dual-scale modelling approach for holed structures.•Accurate crack initiation life prediction abilities within ±2.0 error band.•Simulated crack initiation sites in ...consistency with microstructure observations.•Potential values for the dual-scale approach in scientific and engineering aspects.
In this paper, a dual-scale modelling approach is developed to investigate creep-fatigue behavior and predict crack initiation life for holed structures under multi-axial stress state. The macro-scale simulation supplies local deformation histories to the dual-scale simulation as boundary conditions. In the dual-scale simulation process, the micro-mechanical behavior and damage evolution are described by using crystal plasticity. In order to validate the dual-scale simulation procedures, a series of creep-fatigue tests as well as the post-test characterizations were carried out for nickel-based Inconel 718 at 650 ℃. The detailed results of macro- and micro-scale simulations are presented in terms of stress–strain behavior, damage evolution and life prediction. Regarding the macro-scale simulations as the benchmark, it may provide an assistant support and precognition for the micro-scale damage calculation at higher cycles. The predicted cycle numbers to crack initiation are in agreement with the experimental ones. More advantages are manifested in the potential scientific and engineering significance for the dual-scale modelling approach.
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•Tumor tissue with acidic environment and overexpressed enzyme compared to normal tissue.•Many over-expressed enzymes and acid-sensitive groups are summarized.•Classification of ...enzymes and chemical groups based on drug release characteristics.
It is necessary to design a reasonable drug delivery system(DDS) for targeted release to overcome the potential toxicity and poor selectivity of anti-tumor drug. How a drug is released from a DDS is a critical issue that determines whether the DDS is designed successfully. We all know that the microenvironment of tumors is quite different from normal tissues, such as its acidic environment, different expression levels of some enzymes, etc. These features are widely used in the design of DDSs and play an important role in the drug release process in vivo. Numerous DDSs have been designed and synthesized. This article attention to how drugs are released from DDSs. We summarizes and classify the characteristic enzymes and chemical bonds used in the drug release process by browsing a large number of papers, and describes how they are applied in DDSs with specific examples. By understanding these acid-sensitive chemical bonds and over-expressed enzymes in tumors, different DDSs can be designed for different drug structures to solve specific problems of anti-tumor drugs.
Surgical residual tumor lesions (R1 resection of surgical procedures (e.g., liver cancer infiltrating the diaphragm, surgical residual breast cancer, postoperative residual ovarian cancer) or ...boundary residual after ablation) and lymph node metastasis that cannot be surgically resected (retroperitoneal lymph nodes) significantly affect postoperative survival of tumor patients. This clinical conundrum poses three challenges for local drug delivery systems: stable and continuous delivery, good biocompatibility, and the ability to package new targeted drugs that can synergize with other treatments. Here, a drug‐laden hydrogel generated from pure DNA strands and highly programmable in adjusting its mesh size is reported. Meanwhile, the DNA hydrogel can assist the microcrystallization of novel radiosensitizing drugs, ataxia telangiectasia and rad3‐related protein (ATR) inhibitor (Elimusertib), further facilitating its long‐term release. When applied to the tumor site, the hydrogel system demonstrates significant antitumor activity, minimized systemic toxicity, and has a modulatory effect on the tumor‐immune cell interface. This drug‐loaded DNA‐hydrogel platform represents a novel modality for adjuvant therapy in patients with surgical residual tumor lesions and lymph node metastasis.
Surgical residual tumor lesions and lymph node metastasis significantly affect postoperative survival of tumor patients. Here, a drug‐laden hydrogel platform which assists the microcrystallization of novel radiosensitizing drugs, ATR inhibitor (Elimusertib), further facilitating its long‐term release is developed. The hydrogel system demonstrates significant antitumor activity, minimized systemic toxicity, and has a modulatory effect on the tumor‐immune cell interface.
The difference in the strengthening effect of different thickness reinforcement plates on an LY12 aluminum alloy central defect plate and the load distribution between the reinforcement plate and ...central defect plate in the reinforcement plate structure were studied. Through a method of equivalent transverse load in a small interval a + Δa, the equivalent cyclic load of the central defect plate in the reinforced plate structure under different crack lengths was calculated, and then the distribution of the internal load of the reinforced plate structure with a different thickness with the crack propagation was solved. The secondary development program of the finite element software Abaqus was written in Python language, so that Abaqus software can solve the problem of high cycle fatigue. The finite element simulation of the different thickness-reinforced plate structure is carried out by this program. Through the output data, the equivalent cyclic load of the central defect plate in the reinforced plate structure under different crack lengths is calculated. Through three different fitting methods, the mathematical relationship between the equivalent cyclic load Δσ and the crack length a at both ends of the central defect plate in the reinforced plate structure is described. Based on the mathematical relationship and the finite element output data, the fatigue crack propagation life of the reinforced plate structures with different thicknesses is calculated. It is found that, under the same crack conditions, with the increase in the thickness of the reinforced plate, the bearing load of the cracked plate decreases and the life of the cracked plate increases. With the expansion of the crack, the bearing load ratio of the reinforced plate increases. The simulation method is compared with the experimental results to verify its effectiveness.
•Numerical procedure is developed for the prediction of creep-fatigue life improvement.•Creep-fatigue life improvement by SMA-WJP process is reduced with increasing hold time.•Surface strengthening ...effect and grain boundary cavity are considered to dual-scale modeling.
The elucidation of creep-fatigue damage mechanisms is still controversial for high-temperature structures after surface strengthening treatments, which serves as a critical foundation for the development of an accurate life prediction method. In this work, a numerical procedure is constructed for the prediction of creep-fatigue life improvement, where a dual-scale modeling approach is proposed to integrate important strengthening factors and microstructure features. The macro-scale finite element (FE) simulation aims to investigate the cyclic deformation behavior in a notched structure by using a viscoplastic constitutive model. The initial stress field is predetermined based on the experimental residual stress. The micro-scale FE analysis is employed to investigate the local damage evolution occurring at the notched root by combining size-dependent crystal plasticity with grain boundary cavity model. The cycle-by-cycle deformation histories are extracted from the macro-scale FE model and subsequently are utilized as boundary conditions in the micro-scale FE one. From the experimental perspective, the submerged micro-abrasive waterjet peening (SMA-WJP) process is carried out for creep-fatigue life improvement of the notched structure. Results shows that the notched structure treated by the SMA-WJP process forms an obvious plastic layer with the depth of 20 μm and residual stress with the maximum value of -926 MPa. The predicted numbers of cycles to crack initiation agree with the creep-fatigue experimental ones before and after SMA-WJP. In detail, the surface residual stress and plastic layer are unable to suppress the cavity nucleation on the grain boundaries of internal material. As a consequence, the creep-fatigue life improvement is diminished as the hold time increases, which can be accurately predicted by the developed numerical procedure.
Programmed cell death 1 (PD-1) blockade is considered contraindicated in liver transplant (LT) recipients due to potentially lethal consequences of graft rejection and loss. Though post-transplant ...PD-1 blockade had already been reported, pre-transplant use of PD-1 blockade has not been thoroughly investigated. This study explores the safety and efficacy of neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC) after registration on the waiting list. Seven transplant recipients who underwent neoadjuvant PD-1 blockade combined with lenvatinib and subsequent LT were evaluated. The objective response rate (ORR) and disease control rate (DCR) was 71% and 85% according to the mRECIST criteria. Additionally, a literature review contained 29 patients were conducted to summarize the PD-1 blockade in LT for HCC. Twenty-two LT recipients used PD-1 inhibitors for recurrent HCC. 9.1% (2/22) and 4.5% (1/22) recipients achieved complete remission (CR) and partial remission (PR), respectively; 40.9% (9/22) recipients had progressive disease (PD). Allograft rejection occurred in 45% of patients. In total, seven patients from our center and three from the literature used pretransplant anti-PD-1 antibodies, eight patients (80%) had a PR, and the disease control rate was 100%. Biopsy-proven acute rejection (BPAR) incidence was 30% (3 in 10 patients), two patients died because of BPAR. This indicated that neoadjuvant PD-1-targeted immunotherapy plus tyrosine kinase inhibitors (TKI) exhibited promising efficacy with tolerable mortality in transplant recipients under close clinical monitoring.
Based on previous studies about microflora regulation and immunity enhancement activities of polysaccharides from
Nannf. var.
(Nannf.) L. T. Shen (CPP), there is little study on intestinal mucosal ...immunity, which is a possible medium for contacting microflora and immunity. In the present study, the BALB/c mice were divided into five groups (eight mice in each group), including a normal group (Con), a model control group (Model), and model groups that were administered CPP (50, 100, 200 mg/kg/d) orally each day for seven days after intraperitoneal injection of 60 mg/kg BW/d cyclophosphamide (CP) for three days. CPP recovered the spleen index and restored the levels of IFN-γ, IL-2, IL-10, as well as serum IgG. In addition, it elevated ileum secretory immunoglobulin A (sIgA), the number of
and acetic acid content in cecum. These results indicated that CPP plays an important role in the protection against immunosuppression, especially mucosa immune damage, and the inhibition of pathogenic bacteria colonization, which could be considered a potential natural source of immunoregulator.
Highly crosslinked ultrahigh molecular weight polyethylene (UHMWPE) stabilized by vitamin E (VE) is widely applied in artificial joints as the bearings. Despite the approval, there is a discord that ...VE lowers the crosslinking efficiency, limiting its use at high concentration. In this work, we aim to obtain highly crosslinked and oxidation resistant UHMWPE through the conjunction of tea polyphenol and chemical crosslinking. We hypothesized that highly incorporated tea polyphenol with multiple reactive sites can ameliorate crosslinking efficiency of chemical crosslinked UHMWPE in comparison to VE. Epigallocatechin gallate (EGCG) as representative tea polyphenol was incorporated into UHMWPE at high concentration (2–8 wt%), followed by chemical crosslinking with 2 wt% organic peroxide. Unlike VE/UHMWPE blends as the control, chemical crosslinking achieved an increasing trend in crosslink density of EGCG/UHMWPE blends with increasing antioxidant concentration. High concentration of EGCG also enhanced the oxidation stability of UHMWPE. Intriguingly, EGCG endowed UHMWPE with an excellent antimicrobial property, which was inefficient in VE/UHMWPE. Cell viability was hardly affected by the high loaded antioxidant and peroxide. The chemically crosslinked UHMWPE blended with EGCG is proved to be a reasonable, cost effective and realistic alternative for use in artificial joints.
Peroxide crosslinking of EGCG‐blended UHMWPE offers a feasible alternative to fabricate functional UHMWPE total joint implants with a prolonged lifespan. Compared to Vitamin E, addition of EGCG in the presence of peroxide led to a highly crosslinked and antioxidative UHMWPE material with good antimicrobial property and biocompatibility.
•Filling the gaps of fatigue tests under non-proportional multiaxial random loading.•Elucidating the cyclic behaviors under different non-proportion factors.•Revealing the deformation mechanisms ...under various random loadings.•Proposing an effective life evaluation method for random loading conditions.
Fatigue tests on AISI304 stainless steel under non-proportional multiaxial random loading conditions were conducted with uniform hollow specimens at room temperature. The results revealed initial hardening and subsequent cyclic softening under uniaxial loadings and additional hardening under non-proportional multiaxial loadings. This shift from softening to additional hardening significantly reduced the failure life. Fractographic analysis and Electron Backscatter Diffraction (EBSD) observations identified planar slip as the dominant deformation mechanism under uniaxial loading. Multiple slip system activations, strong slip interactions, and martensitic transformation were key factors influencing changes in cyclic deformation behavior under non-proportional loadings. A novel life evaluation method based on the Itoh–Sakane (IS) method was established, demonstrating accurate evaluations for both uniaxial and non-proportional multiaxial fatigue life under random loading conditions.
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