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The biomedical application of self-healing materials in wet or (under)water environments is quite challenging because the insulation and dissociation effects of water molecules significantly reduce the reconstruction of material–interface interactions. Rapid closure with uniform tension of high-tension wounds is often difficult, leading to further deterioration and scarring. Herein, a new type of thermosetting water-resistant self-healing bioelastomer (WRSHE) was designed by synergistically incorporating a stable polyglycerol sebacate (PGS) covalent crosslinking network and triple hybrid dynamic networks consisting of reversible disulfide metathesis (SS), and dimethylglyoxime urethane (Dou) and hydrogen bonds. And a resveratrol-loaded WRSHE (Res@WRSHE) was developed by a swelling, absorption, and crosslinked network locking strategy. WRSHEs exhibited skin-like mechanical properties in terms of nonlinear modulus behavior, biomimetic softness, high stretchability, and good elasticity, and they also achieved ultrafast and highly efficient self-healing in various liquid environments. For wound-healing applications of high-tension full-thickness skin defects, the convenient surface assembly by self-healing of WRSHEs provides uniform contraction stress to facilitate tight closure. Moreover, Res@WRSHEs gradually release resveratrol, which helps inflammatory response reduction, promotes blood vessel regeneration, and accelerates wound repair.

Abstract Functional segmental trachea reconstruction is a critical concern in thoracic surgery, and tissue‐engineered trachea (TET) holds promise as a potential solution. However, current TET falls short in fully restoring physiological function due to the lack of the intricate multi‐tissue structure found in natural trachea. In this research, a multi‐tissue integrated tissue‐engineered trachea (MI‐TET) is successfully developed by orderly assembling various cells (chondrocytes, fibroblasts and epithelial cells) on 3D‐printed PGS bioelastomer scaffolds. The MI‐TET closely resembles the complex structures of natural trachea and achieves the integrated regeneration of four essential tracheal components: C‐shaped cartilage ring, O‐shaped vascularized fiber ring, axial fiber bundle, and airway epithelium. Overall, the MI‐TET demonstrates highly similar multi‐tissue structures and physiological functions to natural trachea, showing promise for future clinical advancements in functional TETs.

Commonly, articular osteochondral tissue exists significant differences in physiological architecture, mechanical function, and biological microenvironment. However, the development of biomimetic scaffolds incorporating upper cartilage, middle tidemark-like, and lower subchondral bone layers for precise articular osteochondral repair remains elusive. This study proposed here a novel strategy to construct the trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment of both mechanical and biological factors. The cartilage-specific microenvironment was achieved through the grafting of kartogenin (KGN) into gelatin via p-hydroxyphenylpropionic acid (HPA)-based enzyme crosslinking reaction as the upper cartilage layer. The bone-specific microenvironment was achieved through the grafting of atorvastatin (AT) into gelatin via dual-crosslinked network of both HP-based enzyme crosslinking and glycidyl methacrylate (GMA)-based photo-crosslinking reactions as the lower subchondral bone layer. The introduction of tidemark-like middle layer is conducive to the formation of well-defined cartilage-bone integrated architecture. The in vitro experiments demonstrated the significant mechanical difference of three layers, successful grafting of drugs, good cytocompatibility and tissue-specific induced function. The results of in vivo experiments also confirmed the mechanical difference of the trilayered bionic scaffold and the ability of inducing osteogenesis and chondrogenesis. Furthermore, the articular osteochondral defects were successfully repaired using the trilayered biomimetic hydrogel scaffolds by the activation of endogenous recovery, which offers a promising alternative for future clinical treatment.

Abstract Tissue‐engineered bone has emerged as a promising alternative for bone defect repair due to the advantages of regenerative bone healing and physiological functional reconstruction. However, there is very limited breakthrough in achieving favorable bone regeneration due to the harsh osteogenic microenvironment after bone injury, especially the avascular and hypoxic conditions. Inspired by the bone developmental mode of endochondral ossification, a novel strategy is proposed for tolerant and rapid endochondral bone regeneration using framework‐enhanced 3D biomineralized matrix hydrogels. First, it is meticulously designed 3D biomimetic hydrogels with both hypoxic and osteoinductive microenvironment, and then integrated 3D‐printed polycaprolactone framework to improve their mechanical strength and structural fidelity. The inherent hypoxic 3D matrix microenvironment effectively activates bone marrow mesenchymal stem cells self‐regulation for early‐stage chondrogenesis via TGFβ/Smad signaling pathway due to the obstacle of aerobic respiration. Meanwhile, the strong biomineralized microenvironment, created by a hybrid formulation of native‐constitute osteogenic inorganic salts, can synergistically regulate both bone mineralization and osteoclastic differentiation, and thus accelerate the late‐stage bone maturation. Furthermore, both in vivo ectopic osteogenesis and in situ skull defect repair successfully verified the high efficiency and mechanical maintenance of endochondral bone regeneration mode, which offers a promising treatment for craniofacial bone defect repair.

The field of carborane research has witnessed continuous development, leading to the construction and development of a diverse range of crystalline porous materials for various applications. Moreover, innovative synthetic approaches are expanding in this field. Since the first report of carborane-based crystalline porous materials (CCPMs) in 2007, the synthesis of carborane ligands, particularly through innovative methods, has consistently posed a significant challenge in discovering new structures of CCPMs. This paper provides a comprehensive summary of recent advances in various synthetic approaches for CCPMs, along with their applications in different domains. The primary challenges and future opportunities are expected to stimulate further multidisciplinary development in the field of CCPMs.

BackgroundThe benefit of first-line use of sodium-dependent glucose transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) with low risk of cardiovascular diseases are not clear.MethodsPubMed, EMBASE and Cochrane Library databases were searched to identify eligible randomized controlled trials. We used the odds ratio (OR) and mean difference (MD) and the corresponding 95% confidence interval (CI) to assess the dichotomous and continuous variable, respectively.ResultsThirteen studies involving 2,885 T2DM at low risk of cardiovascular diseases were included. Compared to placebo, first line use of SGLT2i significantly reduced glycosylated hemoglobin type A1C (HbA1c) (MD: -0.72), weight (MD: -1.32) and fasting plasma glucose (FPG) (MD: -27.05) levels. Compared with metformin, SGLT2i reduced body weight (MD: -1.50) and FPG (MD: -10.13) more effectively, with similar reduction for HbA1c (MD: -0.05). No significant increased safety adverse was found for SGLT2i, including nasopharyngitis (OR: 1.07), urinary tract infection (OR: 2.31), diarrhea (OR: 1.18) and hypoglycemia (OR: 1.06). GLP-1RAs significantly reduced HbA1c (MD: -1.13), weight (MD: -2.12) and FPG (MD: -31.44) levels as first-line therapy compared to placebo. GLP-1RAs significantly increased occurrence of diarrhea (OR: 2.18), hypoglycemia (OR: 3.10), vomiting (OR: 8.22), and nausea (OR: 4.41).ConclusionFirst line use of SGLT2i and GLP-1RAs is effective in reducing HbA1c, weight, and FPG levels in T2DM patients at low risk for cardiovascular disease. SGLT2i may be superior to metformin in controlling body weight and FPG. GLP-1RAs may increase the occurrence of diarrhea, hypoglycemia, vomiting, and nausea.Systematic review registrationPROSPERO (International Prospective Register of Systematic Reviews. https://www.york.ac.uk/inst/crd, CRD42022347233).

Regenerative cartilage replacements are increasingly required in clinical settings for various defect repairs, including bronchial cartilage deficiency, articular cartilage injury, and microtia reconstruction. Poly (glycerol sebacate) (PGS) is a widely used bioelastomer that has been developed for various regenerative medicine applications because of its excellent elasticity, biodegradability, and biocompatibility. However, because of inadequate active groups, strong hydrophobicity, and limited ink extrusion accuracy, 3D printed PGS scaffolds may cause insufficient bioactivity, inefficient cell inoculation, and inconsistent cellular composition, which seriously hinders its further cartilage regenerative application. Here, we combined 3D printed PGS frameworks with an encapsulated gelatin hydrogel to fabricate a PGS@Gel composite scaffold. PGS@Gel scaffolds have a controllable porous microstructure, with suitable pore sizes and enhanced hydrophilia, which could significantly promote the cells' penetration and adhesion for efficient chondrocyte inoculation. Furthermore, the outstanding elasticity and fatigue durability of the PGS framework enabled the regenerated cartilage built by the PGS@Gel scaffolds to resist the dynamic in vivo environment and maintain its original morphology. Importantly, PGS@Gel scaffolds increased the rate of cartilage regeneration concurrent with scaffold degradation. The scaffold was gradually degraded and integrated to form uniform, dense, and mature regenerated cartilage tissue with little scaffold residue.

Abstract. Background:. Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. Methods:. Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. Results:. A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. Conclusions:. The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

Abstract Molecular mechanisms underlying breast cancer lymph node metastasis remain unclear. Using single-cell sequencing, we investigated the transcriptome profile of 96,796 single cells from 15 paired samples of primary tumors and axillary lymph nodes. We identified nine cancer cell subclusters including CD44 + / ALDH2 + /ALDH6A1 + breast cancer stem cells (BCSCs), which had a copy-number variants profile similar to that of normal breast tissue. Importantly, BCSCs existed only in primary tumors and evolved into metastatic clusters infiltrating into lymph nodes. Furthermore, transcriptome data suggested that NECTIN2-TIGIT-mediated interactions between metastatic breast cancer cells and tumor microenvironment (TME) cells, which promoted immune escape and lymph node metastasis. This study is the first to delineate the transcriptome profile of breast cancer lymph node metastasis using single-cell RNA sequencing. Our findings offer novel insights into the mechanisms underlying breast cancer metastasis and have implications in developing novel therapies to inhibit the initiation of breast cancer metastasis.

With the rapid growth of e-commerce platforms, enterprises face intense competition and must focus on existing customers to explore their value. Customer segmentation aids in formulating marketing strategies by identifying and categorizing customers with similar traits. The widely used RFM model characterizes customer value but solely considers current customer value, neglecting potential value. Hence, this study incorporates behavioral indicators of e-commerce users for segmentation. The unsupervised k-means++ algorithm is employed for clustering, with excellent results indicated by the silhouette coefficient. This analysis identifies a customer segment with high potential value, prompting enterprises to strengthen marketing strategies and convert these customers into loyal customers. [ABSTRACT FROM AUTHOR]