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Utilizing transplanted human umbilical cord mesenchymal stem cells (HUMSCs) for cartilage defects yielded advanced tissue regeneration, but the underlying mechanism remain elucidated. Early after HUMSCs delivery to the defects, we observed substantial apoptosis. The released apoptotic vesicles (apoVs) of HUMSCs promoted cartilage regeneration by alleviating the chondro-immune microenvironment. ApoVs triggered M2 polarization in macrophages while simultaneously facilitating the chondrogenic differentiation of endogenous MSCs. Mechanistically, in macrophages, miR-100-5p delivered by apoVs activated the MAPK/ERK signaling pathway to promote M2 polarization. In MSCs, let-7i-5p delivered by apoVs promoted chondrogenic differentiation by targeting the eEF2K/p38 MAPK axis. Consequently, a cell-free cartilage regeneration strategy using apoVs combined with a decellularized cartilage extracellular matrix (DCM) scaffold effectively promoted the regeneration of osteochondral defects. Overall, new mechanisms of cartilage regeneration by transplanted MSCs were unconcealed in this study. Moreover, we provided a novel experimental basis for cell-free tissue engineering-based cartilage regeneration utilizing apoVs.

Abstract Background Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined. Methods The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo. Results We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case. Conclusions Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.

Articular cartilage injury (ACI) remains one of the key challenges in regenerative medicine, as current treatment strategies do not result in ideal regeneration of hyaline-like cartilage. Enhancing endogenous repair via microRNAs (miRNAs) shows promise as a regenerative therapy. miRNA-140 and miRNA-455 are two key and promising candidates for regulating the chondrogenic differentiation of mesenchymal stem cells (MSCs). In this study, we innovatively synthesized a multifunctional tetrahedral framework in which a nucleic acid (tFNA)-based targeting miRNA codelivery system, named A-T-M, was used. With tFNAs as vehicles, miR-140 and miR-455 were connected to and modified on tFNAs, while Apt19S (a DNA aptamer targeting MSCs) was directly integrated into the nanocomplex. The relevant results showed that A-T-M efficiently delivered miR-140 and miR-455 into MSCs and subsequently regulated MSC chondrogenic differentiation through corresponding mechanisms. Interestingly, a synergistic effect between miR-140 and miR-455 was revealed. Furthermore, A-T-M successfully enhanced the endogenous repair capacity of articular cartilage in vivo and effectively inhibited hypertrophic chondrocyte formation. A-T-M provides a new perspective and strategy for the regeneration of articular cartilage, showing strong clinical application value in the future treatment of ACI.

Abstract Due to its unique structure, articular cartilage has limited abilities to undergo self-repair after injury. Additionally, the repair of articular cartilage after injury has always been a difficult problem in the field of sports medicine. Previous studies have shown that the therapeutic use of mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) has great potential for promoting cartilage repair. Recent studies have demonstrated that most transplanted stem cells undergo apoptosis in vivo, and the apoptotic EVs (ApoEVs) that are subsequently generated play crucial roles in tissue repair. Additionally, MSCs are known to exist under low-oxygen conditions in the physiological environment, and these hypoxic conditions can alter the functional and secretory properties of MSCs as well as their secretomes. This study aimed to investigate whether ApoEVs that are isolated from adipose-derived MSCs cultured under hypoxic conditions (hypoxic apoptotic EVs [H-ApoEVs]) exert greater effects on cartilage repair than those that are isolated from cells cultured under normoxic conditions. Through in vitro cell proliferation and migration experiments, we demonstrated that H-ApoEVs exerted enhanced effects on stem cell proliferation, stem cell migration, and bone marrow derived macrophages (BMDMs) M2 polarization compared to ApoEVs. Furthermore, we utilized a modified gelatine matrix/3D-printed extracellular matrix (ECM) scaffold complex as a carrier to deliver H-ApoEVs into the joint cavity, thus establishing a cartilage regeneration system. The 3D-printed ECM scaffold provided mechanical support and created a microenvironment that was conducive to cartilage regeneration, and the H-ApoEVs further enhanced the regenerative capacity of endogenous stem cells and the immunomodulatory microenvironment of the joint cavity; thus, this approach significantly promoted cartilage repair. In conclusion, this study confirmed that a ApoEVs delivery system based on a modified gelatine matrix/3D-printed ECM scaffold together with hypoxic preconditioning enhances the functionality of stem cell-derived ApoEVs and represents a promising approach for promoting cartilage regeneration. Graphical Abstract

The tumor microenvironment (TME) can be regarded as a complex and dynamic microecosystem generated by the interactions of tumor cells, interstitial cells, the extracellular matrix, and their products and plays an important role in the occurrence, progression and metastasis of tumors. In a previous study, we constructed an IEO model (prI-, prE-, and pOst-metastatic niche) according to the chronological sequence of TME development. In this paper, to fill the theoretical gap in spatial heterogeneity in the TME, we defined an MCIB model (Metabolic, Circulatory, Immune, and microBial microenvironment). The MCIB model divides the TME into four subtypes that interact with each other in terms of mechanism, corresponding to the four major links of metabolic reprogramming, vascular remodeling, immune response, and microbial action, providing a new way to assess the TME. The combination of the MCIB model and IEO model comprehensively depicts the spatiotemporal evolution of the TME and can provide a theoretical basis for the combination of clinical targeted therapy, immunotherapy, and other comprehensive treatment modalities for tumors according to the combination and crosstalk of different subtypes in the MCIB model and provide a powerful research paradigm for tumor drug-resistance mechanisms and tumor biological behavior.

Photocatalytic oxygen (O2) reduction has been considered a promising method for hydrogen peroxide (H2O2) production. However, the poor visible light harvesting and low-efficient separation and generation of charge carriers of conventional photocatalysts strongly limited their photocatalytic H2O2 generation performance. Herein, we design a highly efficient photocatalyst in this work by marrying luminescent gold-silver nanoclusters (AuAg NCs) to polyethyleneimine (PEI) modified C3N4 (C3N4-PEI). The key design in this work is the utilization of highly luminescent AuAg NCs as photosensitizers to promote the generation and separation of charge carriers of C3N4-PEI, thereby ultimately producing abundant e− for O2 reduction under visible light illumination (λ ≥ 400 nm). As a result, the as-designed photocatalyst (C3N4-PEI-AuAg NCs) exhibits excellent photocatalytic activity with an H2O2 production capability of 82 μM in pure water, which is 3.5 times higher than pristine C3N4 (23 μM). This interesting design provides a paradigm in developing other high-efficient photocatalysts for visible-light-driven H2O2 production.

Abstract Designing a theranostic probe for noninvasive bone imaging and bone disease therapy is both challenging and desirable. Herein, an ultrasmall Au nanocluster (NC,

Abstract Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster, Dicer-2 (DmDcr-2)-mediated RNAi pathway plays important roles in defending against viral infections and protecting genome integrity. During the maturation of siRNAs, two cofactors can regulate DmDcr-2’s functions: Loqs-PD that is required for dsRNA processing, and R2D2 that is essential for the subsequent loading of siRNAs into effector Ago2 to form RISC complexes. However, due to the lack of structural information, it is still unclear whether R2D2 and Loqs-PD affect the functions of DmDcr-2 simultaneously. Here we present several cryo-EM structures of DmDcr-2/R2D2/Loqs-PD complex bound to dsRNAs with various lengths by the Helicase domain. These structures revealed that R2D2 and Loqs-PD can bind to different regions of DmDcr-2 without interfering with each other. Furthermore, the cryo-EM results demonstrate that these complexes can form large oligomers and assemble into fibers. The formation and depolymerization of these oligomers are associated with ATP hydrolysis. These findings provide insights into the structural mechanism of DmDcr-2 and its cofactors during siRNA processing.

Abstract Designing Pt-based electrocatalysts with high catalytic activity and CO tolerance is challenging but extremely desirable for alkaline hydrogen oxidation reaction. Herein we report the design of a series of single-atom lanthanide (La, Ce, Pr, Nd, and Lu)-embedded ultrasmall Pt nanoclusters for efficient alkaline hydrogen electro-oxidation catalysis based on vapor filling and spatially confined reduction/growth of metal species. Mechanism studies reveal that oxophilic single-atom lanthanide species in Pt nanoclusters can serve as the Lewis acid site for selective OH- adsorption and regulate the binding strength of intermediates on Pt sites, which promotes the kinetics of hydrogen oxidation and CO oxidation by accelerating the combination of OH− and *H/*CO in kinetics and thermodynamics, endowing the electrocatalyst with up to 14.3-times higher mass activity than commercial Pt/C and enhanced CO tolerance. This work may shed light on the design of metal nanocluster-based electrocatalysts for energy conversion.

Hydroxyapatite/polycaprolactone (HA/PCL) composites have been extensively explored in laser powder bed fusion (L-PBF) for bone tissue engineering. However, conventional mechanical mixing methods for preparing composite powders often yield inhomogeneous compositions and suboptimal flowability. In this study, HA/PCL powders were prepared and optimized for L-PBF using the modified emulsion solvent evaporation method. The morphology, flowability and thermal and rheological properties of the powders were systematically investigated, along with the mechanical and biological properties of the fabricated specimens. The HA/PCL powders exhibited spherical morphologies with a homogeneous distribution of HA within the particles. The addition of small amounts of HA (5 wt% and 10 wt%) enhanced the processability and increased the maximum values of the elastic modulus and yield strength of the specimens from 129.8 MPa to 166.2 MPa and 20.2 MPa to 25.1 MPa, respectively, while also improving their biocompatibility. However, excessive addition resulted in compromised sinterability, thereby affecting both mechanical and biological properties.

Abstract Background In recent years, there has been significant research progress on in situ articular cartilage (AC) tissue engineering with endogenous stem cells, which uses biological materials or bioactive factors to improve the regeneration microenvironment and recruit more endogenous stem cells from the joint cavity to the defect area to promote cartilage regeneration. Method In this study, we used ECM alone as a bioink in low-temperature deposition manufacturing (LDM) 3D printing and then successfully fabricated a hierarchical porous ECM scaffold incorporating GDF-5. Results Comparative in vitro experiments showed that the 7% ECM scaffolds had the best biocompatibility. After the addition of GDF-5 protein, the ECM scaffolds significantly improved bone marrow mesenchymal stem cell (BMSC) migration and chondrogenic differentiation. Most importantly, the in vivo results showed that the ECM/GDF-5 scaffold significantly enhanced in situ cartilage repair. Conclusion In conclusion, this study reports the construction of a new scaffold based on the concept of in situ regeneration, and we believe that our findings will provide a new treatment strategy for AC defect repair.

The development of novel strategies for the synthesis of water-soluble alloy nanoclusters (NCs) and investigations of their alloying mechanisms are highly desirable. Herein, we report the design of a metal ion-induced alloying strategy for the synthesis of atomically precise water-soluble alloy NCs. The transformation of Au15(GSH)13 NCs as model seeds (here GSH denotes water-soluble glutathione) into Au18−xAgx(GSH)14 NCs was triggered using Ag(I) ions; subsequently, Au(III) ions were employed to convert the variable-composition Au18−xAgx(GSH)14 NCs into fixed-composition alloy Au26Ag(GSH)17Cl2 NCs. Monitoring of the alloying process showed that the formation of Au18−xAgx(GSH)14 NCs proceeds through the two electron-hopping events (2e− Au15 → 2e− (AuAg)15–17 → 4e− (AuAg)18–19 → 4e− (AuAg)18), whereas the transformation of (AuAg)18 into Au26Ag mainly involved the formation of intermediate species Au26(GSH)17Cln (n = 0–2). Moreover, we determined that the single Ag atom in Au26Ag NCs resides on the NC surface. This study not only provides a novel strategy for the synthesis of water-soluble alloy NCs but also contributes to the fundamental understanding of the alloying mechanism of metal NCs.

IntroductionThoracic endovascular aortic repair (TEVAR) of the arch is challenging given its complex geometry and the involvement of supra-aortic arteries. Different branched endografts have been designed for use in this region, but their haemodynamic performance and the risk for post-intervention complications are not yet clear. This study aims to examine aortic haemodynamics and biomechanical conditions following TVAR treatment of an aortic arch aneurysm with a two-component single-branched endograft.MethodsComputational fluid dynamics and finite element analysis were applied to a patient-specific case at different stages: pre-intervention, post-intervention and follow-up. Physiologically accurate boundary conditions were used based on available clinical information.ResultsComputational results obtained from the post-intervention model confirmed technical success of the procedure in restoring normal flow to the arch. Simulations of the follow-up model, where boundary conditions were modified to reflect change in supra-aortic vessel perfusion observed on the follow-up scan, predicted normal flow patterns but high levels of wall stress (up to 1.3M MPa) and increased displacement forces in regions at risk of compromising device stability. This might have contributed to the suspected endoleaks or device migration identified at the final follow up.DiscussionOur study demonstrated that detailed haemodynamic and biomechanical analysis can help identify possible causes for post-TEVAR complications in a patient-specific setting. Further refinement and validation of the computational workflow will allow personalised assessment to aid in surgical planning and clinical decision making.

Improving the poor microenvironment in the joint cavity has potential for treating cartilage injury, and mesenchymal stem cell (MSC)-derived exosomes (MSC-Exos), which can modulate cellular behavior, are becoming a new cell-free therapy for cartilage repair. Here, we used acellular cartilage extracellular matrix (ACECM) to prepare 3D scaffolds and 2D substrates by low-temperature deposition modeling (LDM) and tape casting. We aimed to investigate whether MSC-Exos cultured on scaffolds of different dimensions could improve the poor joint cavity microenvironment caused by cartilage injury and to explore the related mechanisms. In vitro experiments showed that exosomes derived from MSCs cultured on three-dimensional (3D) scaffolds (3D-Exos) had increased efficiency. In short-term animal experiments, compared with exosomes derived from MSCs cultured in a two-dimensional (2D) environment (2D-Exos), 3D-Exos had a stronger ability to regulate the joint cavity microenvironment. Long-term animal studies confirmed the therapeutic efficacy of 3D-Exos over 2D-Exos. Thus, 3D-Exos were applied in the rat knee osteochondral defect model after adsorption in the micropores of the scaffold and combined with subsequent articular cavity injections, and they showed a stronger cartilage repair ability. These findings provide a new strategy for repairing articular cartilage damage. Furthermore, miRNA sequencing indicated that the function of 3D-Exos may be associated with high expression of miRNAs. Thus, our study provides valuable insights for the design of 3D-Exos to promote cartilage regeneration.

Small cell lung cancer (SCLC) is a highly aggressive and poorly differentiated cancer with high-grade neuroendocrine (NE) features, accounting for approximately 15 % of all lung cancers. For decades, chemotherapy and radiotherapy have predominated the treatment strategy for SCLC, but relapses ensue quickly and result in poor survival of patients. Immunotherapy has brought novel insights, yet the efficacy is still restricted to a limited population with SCLC. Notch signaling is identified to play a key role in the initiation and development of SCLC, and the Notch ligand, Delta-like ligand 3 (DLL3) is found broadly and specifically expressed in SCLC cells. Thus, Notch signaling is under active exploration as a potential therapeutic target in SCLC. Herein, we summarized and updated the functional relevance of Notch signaling in SCLC, discussed Notch signaling-targeted therapy for SCLC and the correspondent preclinical and clinical trials, and investigated the promising synergy effects of Notch signaling targeted therapy and immune checkpoint inhibitors (ICIs) treatment.

While Pt is an active fuel cell catalyst, it’s low abundance and high cost spurs research into boosting performances from lesser Pt amounts. Here, authors design atomically precise triphenylphosphine-stabilized Pt nanoclusters with high activities and durabilities for electrocatalytic H2 oxidation.

Gas pipelines in China have gradually entered the stage of frequent accidents, and gas leakage will increase the safety risk of pipeline operation, even resulting in personnel casualties. By investigating and survey, the progress of researches on the leakage and diffusion of gas pipeline was demonstrated in terms of leakage and diffusion model, numerical simulation, experimental research and soil-atmosphere coupling. Additionally, the current problems of research on leakage and diffusion of gas pipelines were discussed and pointed out. Definitely, most of the present researches focus on the gas leakage of the simple pipe galleries and the overhead pipelines, but little research is on the leakage of buried pipelines. The factors affecting the leakage are not fully considered, with few results on high-pressure pipeline leakage, multi-point leakage superposition influence and leakage sourcing obtained. Most of the soil properties are treated simply in the study of the leakage law of buried pipelines. Moreover, there are few studies on the comparison between numerical simulation and experiment, and the accuracy of simulation results remains to be verified. Conclusively, the research results could make a good preparation for the coming high incidence period of gas pipeline leakage in China in theory and practice.

Since the 1950s, international studies have confirmed the technical advantages of high-voltage direct current (HVDC) transmission projects, such as large capacity, low loss, and high stability. In recent years, due to the reverse distribution of energy demand and resources in China, large-scale long-distance transportation of energy is inevitable. HVDC is especially suitable for large-scale transmission projects such as “west to east power transmission” and “north to south power transmission.” Therefore, a number of HVDC projects have been built in China since the 1980s. However, with the large-scale construction of HVDC transmission projects, the interference effect of HVDC grounding electrode on metal facilities is increasingly prominent, in which the buried pipeline will produce high amplitude of pipe-to-soil potential under HVDC interference. As a result, HVDC interference can cause damage to pipelines, personnel, and related equipment. However, there is no systematic analysis of the causes of high amplitude of pipe-to-soil potential at home and at abroad. Based on the actual engineering parameters, this paper established a calculation model of the high-voltage direct current interference electric field on the buried pipeline and a numerical simulation technology was used to explore the causes of the high amplitude of pipe-to-soil potential under HVDC interference. Moreover, the influence of the distance between the grounding electrode and the pipeline, the type of anti-corrosion coating, the length of the pipeline, and the soil structure on the pipe ground potential under HVDC interference was investigated. Results reveal that the high amplitude of pipe-to-soil potential under HVDC interference is under the joint action of the short distance between the grounding electrode and the pipeline, the high insulation performance of the anti-corrosion layer, the large length of the pipeline, and the soil layered structure with low resistivity at upper and high resistivity at lower.

Immune checkpoint inhibitors (ICI) have improved clinical outcomes of patients with advanced lung cancer, but may lead to fatal cardiac injury. We describe a 66-year-old man with advanced lung adenocarcinoma who presented with chest pain and dyspnea 3 weeks after the first dose of sintilimab. The initial electrocardiogram (ECG) demonstrated ST-elevation in leads V5-V9, and a high-sensitivity troponin level was significantly elevated. However, coronary angiography did not reveal any significant stenosis. The patient was successfully treated with methylprednisolone and immunoglobulin. Cardiac MRI was carried out before discharge and late gadolinium enhancement (LGE) was found to be in the mid layer of the septal segment and the subepicardial layer of the inferolateral wall. Due to the high fatality, ICI-related myocarditis requires close surveillance, prompt management and long-term follow-up.

Background: Tumor cells outcompete T cells for methionine via overexpressing SLC43A2, causing T cells exhaustion. We explored the influence of SLC43A2 on tumor immune microenvironment (TIME), immune-related genes (IRGs) and the prognosis of liver hepatocellular carcinoma (LIHC) patients.Methods: The TCGA-LIHC dataset (n = 374) and the ICGC-LIRI-JP-LIHC (n = 231) datasets were used as training and validation cohort, respectively. IRGs were obtained from ImmPort. Statistical analyses were performed using R (V 4.0.5). Online databases such as GEPIA, GSCALite, the Kaplan–Meier plotter, KEGG, TIMER2, and CMap were used for differential expression, immune infiltration, functional enrichment, survival, and drug-induced gene perturbation analysis.Results: SLC43A2 expression was higher in LIHC, correlated with worse survival, but could not predict prognosis of LIHC separately (AUC = 0.467). SLC43A2 positively correlated with immune exhaustion markers (all p < 0.001) and with increased infiltration of Tregs, macrophages and myeloid-derived suppressor cells (MDSC) (all p < 0.05). SLC43A2 may regulate 120 IRGs. A prognostic risk score model was developed using the TCGA-LIHC cohort and validated by the ICGC-LIRI-JP cohort. Arachidonic acid, SB-202190 and guanethidine were identified as possible immunomodulators pharmacologically targeting SLC43A2 in LIHC.Conclusion: SLC43A2 may create suppressive tumor microenvironment and regulate related IRGs, thus affecting the prognosis of LIHC. Arachidonic acid, SB-202190, and guanethidine may be worthy of further study as immunomodulators on SLC43A2.

A fiber speckle sensor (FSS) based on a tapered multimode fiber (TMMF) has been developed to measure liquid analyte refractive index (RI) in this work. By the lateral and axial offset of input light into TMMF, several high-order modes are excited in TMMF, and the speckle pattern is spatially modulated, which affects an asymmetrical speckle pattern with a random intensity distribution at the output of TMMF. When the TMMF is immersed in the liquid analyte with RI variation, it influences the guided modes, as well as the mode interference, in TMMF. A digital image correlations method with zero-mean normalized cross-correlation coefficient is explored to digitize the speckle image differences, analyzing the RI variation. It is found that the lateral- and axial-offsets-induced speckle sensor can enhance the RI sensitivity from 6.41 to 19.52 RIU−1 compared to the one without offset. The developed TMMF speckle sensor shows an RI resolution of 5.84 × 10−5 over a linear response range of 1.3164 to 1.3588 at 1550 nm. The experimental results indicate the FSS provides a simple, efficient, and economic approach to RI sensing, which exhibits an enormous potential in the image-based ocean-sensing application.

The performance of the filter elements configured at the gas station and the user entrance changes dynamically with the service conditions. If the filter element is not cleaned and replaced in time, the gas passing efficiency will be affected seriously, resulting in the sharp increasing of local resistance and great drop of throughput, and thus endangering the safety of gas supply. Based on the investigation and analysis of the working conditions of gas filters in urban gas engineering, a numerical model of gas filter was established, and the flow field inside the filter was simulated with the CFD software. The results show that the change of inlet speed has a great influence on the filtration effect under the condition that the inlet pressure is remained unchanged, and the blockage of filter element at different locations has different impact on the passing of gas flow. Therefore, regular cleaning, maintenance and replacement of filter elements are very important to keep the filtration efficiency. In the case of limited conditions, it is recommended to give priority to the replacement of the lower filter elements. Generally, the research results could provide reference for further simulation research on the actual working conditions.

BackgroundWith the rapid advance in percutaneous coronary intervention (PCI) technology, patients absorb large volume of iodinated contrast media (ICM). Recent studies suggested that ICM may lead to hyperthyroidism, but the association between ICM volume and thyroid is still unclear. We sought to evaluate the long-term influence of ICM on thyroid dysfunction and disease in patients received PCI.MethodsThis single-center retrospective study included consecutive coronary artery disease (CAD) patients. A covariance (ANCOVA) model was performed to evaluate the change of serum TSH, FT3 and FT4 before and one-year after the PCI procedure. Restricted cubic splines and logistic regression were performed to evaluate the association between ICM volume and thyroid disease.Results2062 patients met inclusion criteria (1381 patients in the low-volume group and 681 patients in the high-volume group). The high-volume group was 0.238 ± 0.092 pmol/L higher than the low-volume group (P = 0.010) in the serum FT4. Restricted cubic splines show that there were linear dose-response relationships for ICM volume and composite endpoint and hyperthyroidism. In all models, there were significant differences in composite endpoint between the two groups. (OR 1.75, 95% CI (1.05, 2.92), P = 0.032, OR 1.73, 95% CI (1.01-2.96), P= 0.032 and OR 1.83, 95% CI (1.09-3.06), P= 0.022, respectively). The positive results were also showed for hyperthyroidism in all models (OR 2.35, 95% CI (1.14-4.84), P = 0.021, OR 10.36, 95% CI (1.20-89.00), P = 0.033 and OR 2.35, 95% CI (1.13-4.87), P = 0.022, respectively).ConclusionThe present analysis gives an overview that ICM volume is associated with an increased risk of thyroid dysfunction and thyroid disease.

Artificial enzymes with reprogrammed and augmented catalytic activity and substrate selectivity have emerged to tackle limitations of noble metals or transition metal oxides. Here, the authors report Au25 clusterzymes which are endowed with high catalytic activity and selectivity in a range of enzyme-mimicking reactions.

Abstract CD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.

Poly-L-lactic acid (PLLA) has gained great popularity with researchers in regenerative medicine owing to its superior biocompatibility and biodegradability, although its inadequate bioactivity inhibits the further use of PLLA in the field of bone regeneration. Zinc oxide (ZnO) has been utilized to improve the biological performance of biopolymers because of its renowned osteogenic activity. However, ZnO nanoparticles tend to agglomerate in the polymer matrix due to high surface energy, which would lead to the burst release of the Zn ion and, thus, cytotoxicity. In this study, to address this problem, carbon–ZnO (C–ZnO) was first synthesized through the carbonization of ZIF-8. Then, C–ZnO was introduced to PLLA powder before it was manufactured as scaffolds (PLLA/C–ZnO) by a selective laser sintering 3D printing technique. The results showed that the PLLA/C–ZnO scaffold was able to continuously release Zn ions in a reasonable range, which can be attributed to the interaction of Zn–N bonding and the shielding action of the PLLA scaffold. The controlled release of Zn ions from the scaffold further facilitated cell adhesion and proliferation and improved the osteogenic differentiation ability at the same time. In addition, C–ZnO endowed the scaffold with favorable photodynamic antibacterial ability, which was manifested by an efficient antibacterial rate of over 95%.

A 64-year-old man was admitted for crushing chest pain. Computed tomography revealed an aortic intramural hematoma, with progression to a penetrating aortic ulcer on day 7 and aortic dissection on day 30. The patient was treated with strict blood pressure control and thoracic endovascular aortic repair. He was discharged 3 days post-operatively. (Level of Difficulty: Beginner.)

Transcatheter aortic valve replacement (TAVI) has become a game changer in the management of severe aortic stenosis shifting the concept from inoperable or high-risk patients to intermediate or low surgical-risk individuals. Among devices available nowadays, there is no clear evidence that one device is better than the other or that one device is suitable for all patients. The selection of the optimal TAVI valve for every patient represents a challenging process for clinicians, given a large number of currently available devices. Consequently, understanding the advantages and disadvantages of each valve and personalising the valve selection based on patient-specific clinical and anatomical characteristics is paramount. This review article aims to both analyse the available devices in the presence of specific clinical and anatomic features and offer guidance to select the most suitable valve for a given patient.

The aorta is the largest artery in the body, delivering oxygenated blood from the left ventricle to all organs. Dissection of the aorta is a lethal condition caused by a tear in the intimal layer of the aorta, followed by blood loss within the aortic wall and separation of the layers to full dissection. The aorta can be affected by a wide range of causes including acute conditions such as trauma and mechanical damage; and genetic conditions such as arterial hypertension, dyslipidaemia, and connective tissue disorders; all increasing the risk of dissection. Both rapid diagnostic recognition and advanced multidisciplinary treatment are critical in managing aortic dissection patients. The treatment depends on the severity and location of the dissection. Open surgical repair is the gold standard of treatment for dissections located to the proximal part of the aorta and the arch, while endovascular interventions are recommended for most distal or type B aortic dissections. In this review article, we examine the epidemiology, pathophysiology, contemporary diagnoses, and management of aortic dissection.

Abstract Although Thoracic Endovascular Aortic Repair is usually applied to patients without connective tissue disorders, our case shows its potential for complicated type B aortic dissection in a Marfan patient as a feasible alternative to open redo surgery with good short‐term outcomes.

Double perovskites (DPs) have been attracting attention in an assortment of optoelectronic applications, for they hold advantages such as high quantum efficiency, long carrier migration distance and strong linear and nonlinear absorptions. As specific kinds of perovskites (PVKs), DPs are gifted with orthorhombic crystal structures which provide rich conversion combinations and broaden the space for research and application. However, few works have been reported about DPs in ultrafast photonics applications. In this article, a DP with chemical formula of Ba2LaTaO6 (BLT) was successfully synthesized by high-temperature solid phase method. The microstructures and morphologies were observed, and the linear and nonlinear absorption were characterized. By first using BLT as a novel saturable absorber in both normal and anomalous dispersion region fiber lasers, dual-wavelength soliton and dissipative soliton were successfully operated at C-band. This study affirms BLT’s nonlinear optical properties, lays the foundation for optical research on BLT, and meanwhile provides a meaningful reference for future development of pulsed lasers based on DPs.

Abstract Endografting for atretic coarctation is technically feasible to avoid the risks of open surgery. It requires a strategic and structured endovascular approach such as the “Railway” technique for safe and successful restructuring of complete aortic atresia and avoiding rupture or bleeding.

This paper examines the damage caused by slickwater fracturing fluid to the microscopic pore structure of tight sandstone in the Chang 7 member in the Ordos Basin. A submicron CT in situ displacement system was used to analyze and graphically represent changes in pores in core samples following fracturing fluid damage. The results show the following: (1) the damage caused by slickwater fracturing fluid to tight sandstone fractures mainly occurs in the early stage of fluid incursion. The damage is characterized by a decrease in the effective pore volume, increase in the number of pores, and insignificant subsequent damage. The main causes of pore damage by slickwater fracturing fluid are retention of slickwater in the liquid phase and hydration swelling of clay minerals in the pores. (2) After the high pressure intrusion of slickwater fluid, the pore size of large-size intergranular pores increases, and there is no obvious damage after water flooding. However, fractures and small dissolution pores in the cores are the main areas of fluid retention after fracturing fluid invasion due to their small flowing radius and complex structure. These are the locations where damage mostly occurs.

The BP/InSe heterojunction has attracted the attention of many fields in successful combined high hole mobility of black phosphorus (BP) and high electron mobility of indium selenide (InSe), and enhanced the environmental stability of BP. Nevertheless, photonics research on the BP/InSe heterostructure was insufficient, while both components are considered promising in the field. In this work, a two-dimensional (2D) BP/InSe heterostructure was fabricated using the liquid-phase exfoliation method. Its linear and non-linear optical (NLO) absorption was characterized by ultraviolet−visible−infrared and Open-aperture Z-scan technology. On account of the revealed superior NLO properties, an SA based on 2D BP/InSe was prepared and embedded into an erbium-doped fiber laser, traditional soliton pulses were observed at 1.5 μm with the pulse duration of 881 fs. Furthermore, harmonic mode locking of bound solitons and dark-bright soliton pairs were also obtained in the same laser cavity due to the cross-coupling effect. The stable mode-locked operation can be maintained for several days, which overcome the low air stability of BP. This contribution further proves the excellent optical properties of 2D BP/InSe heterostructure and provides new probability of developing nano-photonics devices for the applications of double pulses laser source and long-distance information transmission.

This study aims to investigate the ultimate bearing capacity of a novel tubular K-joint used for light-steel structures consisting of thin-walled square hollow section members, a U-shape connector and self-drilling screws, and the effect of three patterns of stamping indentation fabricated on the U-shape connector on the ultimate bearing capacity of the proposed K-joint. Firstly, a total of 12 K-joint specimens were tested to failure under monotonic brace axial compressive loading. Secondly, failure mode and the ultimate bearing capacity of each specimen were investigated and analyzed. Finally, finite element analyses were carried out to study the effect of three key parameters, including chord axial stress ratio, half width-to-thickness ratio of the chord and brace-to-chord wall thickness ratio, on the ultimate bearing capacity of the proposed K-joints using the recommended U-shape connector. It was found that failure mode of the proposed K-joint is governed by both the deformation of the U-shape connector and the chord local plastification. Besides, the K-joint specimen using a U-shape connector with the strip stamping grooves in the horizontal direction generally has a higher bearing capacity and a much smaller connector deformation. Similar to the welded tubular joints, chord axial stresses may also significantly reduce the ultimate bearing capacity of the proposed K-joint.

Synthetic nanochemistry currently lacks the molecular step-by-step routes afforded to organic chemistry by total synthesis. Here, the authors track the seeded growth of atom-precise gold nanoclusters using mass spectrometry, revealing that the clusters evolve through a series of intermediates in two-electron steps.

Abstract Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated. According to the structure of Fc domain, BsAb can be classified into two types: IgG-like format and Fc-free format. Among these formats, bispecific T cell engagers (BiTEs) and triomabs are commonly investigated. BsAb has achieved an exciting breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. In this review, we focus on the preclinical experiments and clinical studies of epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor (HER) family, carcinoembryonic antigen (CEA), and prostate-specific membrane antigen (PSMA) related BsAbs in solid tumors, as well as discuss the challenges and corresponding approaches in clinical application.

Abstract Dachshund homolog 1 (DACH1), a key cell fate determination factor, contributes to tumorigenesis, invasion, metastasis of human breast neoplasm. However, the exact molecular mechanisms for the anti-tumor roles of DACH1 in breast carcinoma are still lack of extensive understanding. Herein, we utilized immunohistochemistry (IHC) staining and public microarray data analysis showing that DACH1 was higher in normal breast, low-grade and luminal-type cancer in comparison with breast carcinoma, high-grade and basal-like tumors respectively. Additionally, both correlation analysis of public databases of human breast carcinoma and IHC analysis of mice xenograft tumors demonstrated that DACH1 inversely related to cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) inducers and basal-enriched molecules, while cluster of differentiation 44 (CD44) behaved in an opposite manner. Furthermore, mice transplanted tumor model indicated that breast cancer cells Met-1 with up-regulation of DACH1 were endowed with remarkably reduced potential of tumorigenesis. Importantly, meta-analysis of 19 Gene Expression Omnibus (GEO) databases of breast cancer implicated that patients with higher DACH1 expression had prolonged time to death, recurrence and metastasis, while CD44 was a promising biomarker predicting worse overall survival (OS) and metastasis-free survival (MFS). Collectively, our study indicated that CD44 might be a novel target of DACH1 in breast carcinoma.

Abstract Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Food and Drug Administration has approved palbociclib and ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, and recent clinical trial data suggest that palbociclib significantly improved clinical outcome when combined with letrozole or fulvestrant. Besides, the favorable effects of abemaciclib on prolonging survival of breast cancer patients have also been observed in clinical trials both for single-agent and combination strategy. In this review, we outline the preclinical and clinical advancement of these three orally bioavailable and highly selective CDK4/6 inhibitors in breast cancer.

Abstract The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy.

Pogostemon cablin (Blanco) Benth. (Patchouli) is not only an important essential oil plant, but also a valuable medicinal plant in China. P. cablin in China can be divided into three cultivars (Shipai, Gaoyao, and Hainan) and two chemotypes (pogostone-type and patchoulol-type). The pogostone-type and patchoulol-type are, respectively, used for medicinals and perfumes. In this study, we sequenced and characterized the plastid genomes for all three Chinese cultivars and aimed to develop a chemotype-specific barcode for future quality control. The plastid genomes of P. cablin cultivars ranged from 152,461 to 152,462 bp in length and comprise 114 genes including 80 protein coding genes, 30 tRNA genes, and four rRNA genes. Phylogenetic analyses suggested that P. cablin cultivars clustered with the other two Pogostemon species with strong support. Although extremely conserved in P. cablin plastid genomes, 58 cpSSRs were filtered out among the three cultivars. One single variable locus, cpSSR, was discovered. The cpSSR genotypes successfully matched the chemotypes of Chinese patchouli, which was further supported by PCR-based Sanger sequences in more Chinese patchouli samples. The barcode developed in this study is thought to be a simple and reliable quality control method for Chinese P. cablin on the market.

Abstract Non-small cell lung cancer (NSCLC) causes considerable mortality in the world. Owing to molecular biological progress, treatments in adenocarcinoma have evolved revolutionarily while those in squamous lung cancer remain unsatisfied. Recent studies revealed high-frequency alteration of Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-like factor 2 (Keap1/Nrf2) pathway within squamous lung cancer, attracting researchers to focus on this particular pathway. In NSCLC patients, deregulated Nrf2 signal is recognized as a common feature at both DNA and protein level. Emerging associations between Nrf2 and other pathways have been elucidated. MicroRNA was also implicated in the regulation of Nrf2. Agents activating or antagonizing Nrf2 showed an effect in preclinical researches, reflecting different effects of Nrf2 during tumor initiation and progression. Prognostic evaluation demonstrated a negative impact of Nrf2 signal on NSCLC patients’ survival. Considering the importance of Nrf2 signal in NSCLC, further studies are required in the future.

The rheology of cement grouts often plays a crucial role in the success of rock grouting. In practice, the rheological parameters should be timely adjusted according to the evolution of grouting pressure, flow rate and injection time. However, obtaining the magnitude of rheological parameters is not easy to achieve under site conditions. More importantly, the ground temperature in deep rock masses is elevated higher than that on the surface or under room conditions, which has been demonstrated to strongly influence the rheological properties of grouts. Reasonable understanding and control of the rheological behavior of cement grouts at true ground temperatures is very important to the quality of grouting. This paper aims to propose a simplified method to approximately estimate the initial yield stress and viscosity of cement grouts for rock grouting under elevated ground temperature that actually exists in deep rock masses, on the basis of the flow spread test. The temperature investigated was controlled between 12 °C and 45 °C to simulate the true ground temperature in rock masses with a maximum depth of 1500 m below the surface. Taking the influences of elevated temperatures into account, a temperature-based model for estimating the initial viscosity of cement grout was successfully developed on the basis of Liu’s model and the results of the flow spread test. However, the yield stress failed to be estimated by the Lapasin model due to the absence of plastic behavior of cement grouts. In contrast, yield stress can be linearly correlated to the measured relative flow area. In this work, it was also found that the dependence of yield stress of cement grouts on relative flow area is a strongly exponential law. The temperature dependence of the viscosity of water was accounted for in both estimations of viscosity and yield stress of grouts. Significantly, it was found that the packing density of cement is dependent on the grout temperature, especially when the temperature is up to 45 °C. The proposed method in this work offers an alternative solution for technicians to reasonably control the rheological properties in the increasing applications of deep rock grouting.

Marfan syndrome is a heritable connective tissue disorder affecting skeletal, ocular and cardiovascular systems. Cardiovascular manifestations comprise aneurysmal dilatation of aortic root, aortic dissection and rupture; peripheral arterial aneurysms have been reported in femoral, iliac and subclavian arteries with surgical reconstruction as the first-line therapeutic option. We report a Marfan patient with a symptomatic aneurysm of left subclavian artery in the intrathoracic retro-clavicular space; instead of open surgical resection, an endovascular solution was successfully applied by use of a flexible self-expanding stent-graft (W.L Gore ® Viabahn ® Endoprosthesis 9 × 100 mm) to exclude the aneurysm. This case exemplifies a modern option to manage vascular pathology even in patients with Marfan syndrome. Follow-up over 1 year proved very reassuring with complete remodelling and resolution of the aneurysm; long-term follow-up is certainly warranted, considering the potential of recurrence or initial reactive hyperplasia.