Prognosis of colorectal cancer, prognostic index of immunogenic cell death associated genes in response to immunotherapy, and potential therapeutic effects of ferroptosis inducers.

Introduction: This study leverages bioinformatics and medical big data to integrate datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), providing a comprehensive overview of immunogenic cell death (ICD)-related gene expression in colorectal cancer (CRC). The research aims to elucidate the molecular pathways and gene networks associated with ICD in CRC, with a focus on the therapeutic potential of cell death inducers, including ferroptosis agents, and their implications for precision medicine. Methods: We conducted differential expression analysis and utilized advanced bioinformatic techniques to analyze ICD-related gene expression in CRC tissues. Unsupervised consensus clustering was applied to categorize CRC patients into distinct ICD-associated subtypes, followed by an in-depth immune microenvironment analysis and single-cell RNA sequencing to investigate immune responses and cell infiltration patterns. Experimental validation was performed to assess the impact of cell death inducers on ICD gene expression and their interaction with ferroptosis inducers in combination with other clinical drugs. Results: Distinct ICD gene expression profiles were identified in CRC tissues, revealing molecular pathways and intricate gene networks. Unsupervised consensus clustering refined the CRC cohort into unique ICD-associated subtypes, each characterized by distinct clinical and immunological features. Immune microenvironment analysis and single-cell RNA sequencing revealed significant variations in immune responses and cell infiltration patterns across these subtypes. Experimental validation confirmed that cell death inducers directly affect ICD gene expression, highlighting their therapeutic potential. Additionally, combinatorial therapies with ferroptosis inducers and clinical drugs were shown to influence drug sensitivity and resistance in CRC. Discussion: Our findings underscore the importance of ICD-related genes in CRC prognosis and therapeutic targeting. The study provides actionable insights into the efficacy of cell death-inducing therapies, particularly ferroptosis inducers, and their regulatory mechanisms in CRC. These discoveries support the development of precision medicine strategies targeting ICD genes and offer valuable guidance for translating these therapies into clinical practice, with the potential to enhance CRC treatment outcomes and patient survival.

MXene film electrodes with high mechanical strength, graded ion channels and high pseudocapacitive activity enabled by lignin-containing cellulose fibers.

Cellulose nanofiber (CNF) has been widely used in MXene film electrodes to improve its mechanical properties and rate capability for supercapacitors. However, all the above enhancements are obtained with inevitably sacrificing the capacitance, because of the non-electrochemically-active characteristic of CNF. Herein, to address this issue, lignin-containing cellulose fibers (LCNF) is innovatively used to substitute CNF. Specifically, LCNF play a role as a bridge to significantly reinforce mechanical strength of LCNF/MXene film electrode (LM) by binding the adjacent MXene nanosheets, reaching a tensile strength of 34.2 MPa. Lignin in LCNF contributes to pseudocapacitance through the reversible conversion of its quinone/hydro-quinone (Q/QH2), thus yielding an excellent capacitance of 364.4 F g-1 at 1 A g-1. Meanwhile, LCNF has different diameters in which microfibers form a loose structure for LM, nanofibers enlarge d-spacing between adjacent MXene nanosheets, and fibers self-crosslinking creates abundant pores, thus constructing graded channels to achieve an outstanding rate capability of 87 % at 15 A g-1. The fabricated supercapacitor demonstrates a large energy density of 1.8 Wh g-1 at 71.3 W g-1. This work provides a promising approach to decouple the trade-off between electrochemical performance and mechanical properties of MXene film electrodes caused by using CNF, thus obtaining high-performance supercapacitors.

Brain functional connectivity alterations in patients with anterior cruciate ligament injury.

Recent advancements in neuroimaging have illustrated that anterior cruciate ligament (ACL) injuries could impact the central nervous system (CNS), causing neuroplastic changes in the brain beyond the traditionally understood biomechanical consequences. While most of previous functional magnetic resonance imaging (fMRI) studies have focused on localized cortical activity changes post-injury, emerging research has suggested disruptions in functional connectivity across the brain. However, these prior investigations, albeit pioneering, have been constrained by two limitations: a reliance on small-sample participant cohorts, often limited to two to three patients, potentially limiting the generalizability of findings, and an adherence to region of interest based analysis, which may overlook broader network interactions. To address these limitations, our study employed resting-state fMRI to assess whole-brain functional connectivity in 15 ACL-injured patients, comparing them to matched controls using two distinct network analysis methods. Using Network-Based Statistics, we identified widespread reductions in connectivity that spanned across multiple brain regions. Further modular connectivity analysis showed significant decreases in inter-modular connectivity between the sensorimotor and cerebellar modules, and intra-modular connectivity within the default-mode network in ACL-injured patients. Our results thus highlight a shift from localized disruptions to network-wide dysfunctions, suggesting that ACL injuries induce widespread CNS changes. This enhanced understanding has the potential to stimulate the development of strategies aiming to restore functional connectivity and improve recovery outcomes.

Bioinformatics analysis of MMP14+ myeloid cells affecting endothelial-mesenchymal transformation and immune microenvironment in glioma.

Background: Gliomas, known for their complex and aggressive characteristics, are deeply influenced by the tumor microenvironment. Matrix metalloproteinases (MMPs) play a vital role in shaping this environment, presenting an opportunity for novel treatment strategies. Methods: We collected six bulk RNA datasets, one single-cell RNA sequencing (scRNA-seq) dataset, and gene sets related to Matrix Metalloproteinases (MMPs), Endothelial-Mesenchymal Transformation (EndMT), and sprouting angiogenesis. We computed enrichment scores using Gene Set Variation Analysis (GSVA) and Single-sample Gene Set Enrichment Analysis (ssGSEA). To analyze immune infiltration, we employed the CIBERSORT method. Data analysis techniques included the log-rank test, Cox regression, Kruskal-Wallis test, and Pearson correlation. For single-cell data, we utilized tools such as Seurat and CellChat for dimensionality reduction, clustering, and cell communication analysis. Results: 1. MMP14 was identified as an independent prognostic marker, highly expressed in myeloid cells in recurrent glioblastoma, highlighting these cells as functionally significant. 2. C-C Motif Chemokine Ligand (CCL) signaling from MMP14+ myeloid cells was identified as a critical immune regulatory pathway, with high C-C Motif Chemokine Receptor 1 (CCR1) expression correlating with increased M2 macrophage infiltration and PD-L1 expression. 3. Patients with high MMP14 expression showed better responses to bevacizumab combined chemotherapy. 4. Signaling pathways involving Visfatin, VEGF, and TGFb, emanating from myeloid cells, significantly impact endothelial cells. These pathways facilitate EndMT and angiogenesis in gliomas. 5. Nicotinamide Phosphoribosyltransferase (NAMPT) showed a strong link with angiogenesis and EndMT, and its association with chemotherapy resistance and differential sensitivity to bevacizumab was evident. Conclusions: MMP14+ myeloid cells are critical in promoting tumor angiogenesis via EndMT and in mediating immunosuppression through CCL signaling in glioblastoma. MMP14 and NAMPT serve as vital clinical indicators for selecting treatment regimens in recurrent glioma. The study suggests that a combined blockade of CCR1 and CD274 could be a promising therapeutic strategy.

Phase II study of SOXIRI (S-1/oxaliplatin/irinotecan) chemotherapy in patients with unresectable pancreatic ductal adenocarcinoma.

BACKGROUND: To provide data on the safety and efficacy of a combination chemotherapy regimen consisting of S-1, oxaliplatin, and irinotecan (SOXIRI) as a first-line therapy in unresectable pancreatic ductal adenocarcinoma (UPDA) patients. METHODS: Patients with UPDA and no prior treatment chemotherapy in the UPDA setting were enrolled. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. Patients received 80 mg/m2 S-1 twice a day for 2 weeks in an alternate-day administration cycle, 85 mg/m2 oxaliplatin on Day 1, and 150 mg/m2 irinotecan on Day 1 of a 2-week cycle. RESULTS: In these 62 enrolled patients, the ORR was 27.4 %, median OS was 12.1 months, and median PFS was 6.5 months. Major grade 3 or 4 toxicity included neutropenia (22.3 %), leucopenia (16.1 %), nausea (9.7 %), vomiting (9.7 %), thrombocytopenia (6.5 %), anorexia (8.5 %), anemia (4.8 %), and diarrhea (1.6 %). No treatment-related deaths occurred. In addition, the analysis of 32 patients suffering pain revealed that the rate of pain relief was 34.4 %. CONCLUSION: SOXIRI might be a standard regimen with an acceptable toxicity profile and favorable efficacy for use as chemotherapy in patients with UPDA.

Colorectal cancer and gut viruses: a visualized analysis based on CiteSpace knowledge graph.

Background: Gut microbiome is a complex community of microbes present in the human gut and plays an important role in the occurrence and progression of colorectal cancer (CRC). However, the relationship between virus and CRC has not been fully understood. Objective: To explore the hot spots and research trends in the field of CRC and virus. Methods: By using the bibliometric analysis tool CiteSpace and based on the articles of the Web of Science Core Collection (WoSCC) database, the country, institution, highly cited literature, keywords and so on were visually analyzed. Results: A total of 356 research articles on CRC from 2001 to 2023 were thoroughly analyzed. The USA and China have made the largest contribution in the field of virus and CRC. The Helmholtz Association published the most papers. There were relatively few cooperations among institutions from different countries. The results of keyword cluster analysis proved that the literature on the relationship between human cytomegalovirus (CMV) and CRC was the most widely studied aspect in this field. "Gut microbiota," "inflammatory bowel disease," "hepatitis b virus," and "human papillomavirus infection" are the current research hotspots; "oncolytic virus," "apoptosis," and "gut microbiome" are the recent research frontiers and should be paid closer attention. Conclusion: By using CiteSpace bibliometric software, the visual analysis reflected the research trends and hot topics of virus and CRC. In addition, the prevalence and mechanism of specific virus on CRC were also reviewed, which provides valuable references for future CRC research.

Cholesterol induction in CD8+ T cell exhaustion in colorectal cancer via the regulation of endoplasmic reticulum-mitochondria contact sites.

BACKGROUND: Hypercholesterolemia is one of the risk factors for colorectal cancer (CRC). Cholesterol can participate in the regulation of human T cell function and affect the occurrence and development of CRC. OBJECTIVE: To elucidate the pathogenesis of CRC immune escape mediated by CD8+ T cell exhaustion induced by cholesterol. METHODS: CRC samples (n = 217) and healthy individuals (n = 98) were recruited to analyze the relationship between peripheral blood cholesterol levels and the clinical features of CRC. An animal model of CRC with hypercholesterolemia was established. Intraperitoneal intervention with endoplasmic reticulum stress (ERS) inhibitors in hypercholesterolemic CRC mice was performed. CD69, PD1, TIM-3, and CTLA-4 on CD8+ T cells of spleens from C57BL/6 J mice were detected by flow cytometry. CD8+ T cells were cocultured with MC38 cells (mouse colon cancer cell line). The proliferation, apoptosis, migration and invasive ability of MC38 cells were detected by CCK-8 assay, Annexin-V APC/7-AAD double staining, scratch assay and transwell assay, respectively. Transmission electron microscopy was used to observe the ER structure of CD8+ T cells. Western blotting was used to detect the expression of ERS and mitophagy-related proteins. Mitochondrial function and energy metabolism were measured. Immunoprecipitation was used to detect the interaction of endoplasmic reticulum-mitochondria contact site (ERMC) proteins. Immunofluorescence colocalization was used to detect the expression and intracellular localization of ERMC-related molecules. RESULTS: Peripheral blood cholesterol-related indices, including Tc, low density lipoproteins (LDL) and Apo(a), were all increased, and high density lipoprotein (HDL) was decreased in CRCs. The proliferation, migration and invasion abilities of MC38 cells were enhanced, and the proportion of tumor cell apoptosis was decreased in the high cholesterol group. The expression of IL-2 and TNF-α was decreased, while IFN-γ was increased in the high cholesterol group. It indicated high cholesterol could induce exhaustion of CD8+ T cells, leading to CRC immune escape. Hypercholesterolemia damaged the ER structure of CD8+ T cells and increased the expression of ER stress molecules (CHOP and GRP78), lead to CD8+ T cell exhaustion. The expression of mitophagy-related proteins (BNIP3, PINK and Parkin) in exhausted CD8+ T cells increased at high cholesterol levels, causing mitochondrial energy disturbance. High cholesterol enhanced the colocalization of Fis1/Bap31, MFN2/cox4/HSP90B1, VAPB/PTPIP51, VDAC1/IPR3/GRP75 in ERMCs, indicated that high cholesterol promoted the intermolecular interaction between ER and mitochondrial membranes in CD8+ T cells. CONCLUSION: High cholesterol regulated the ERS-ERMC-mitophagy axis to induce the exhaustion of CD8+ T cells in CRC.

Shape and Stiffness Switchable Hydroplastic Wood with Programmability and Reproducibility.

Stiffness switchable materials (e.g., supramolecular polymers, metals) that alter their shape and mechanical properties in response to specific stimuli are potentially utilized in the structural engineering field but still limited due to the use of petroleum-based synthetic monomers and large energy consumption. Herein, a sustainable and facile solvent casting strategy is proposed to fabricate the "hydroplastic wood" with shape and stiffness switchable properties via cell wall wetting, cell wall softening and subsequent moisture evaporation. Therein, a wetting agent with low surface tension and low viscosity is utilized for covering the rough surface of solid wood to form a liquid lubricating layer, thereby increasing the interfacial wettability and achieving uniform softening of the cell walls. This interface wetting treatment can easily break through the hydro-plasticization process for thick wood (Balsa wood, Ochroma lagopus Swartz, density: 0.25 g/cm3; Pinewood, Pinus armandii, density: 0.38 g/cm3). Additionally, the capillary force arising from moisture evaporation induces the self-densification of oriented cellulose nanofibrils and achieves moisture-mediated shape design capabilities through periodic saturation-dehydration. This work makes hydroplastic wood a promising candidate for engineering materials because of its combined advantages of strong durability, formability, and load-carrying capacity.

Modelling and analysis of periodic impulsive releases of the Nilaparvata lugens infected with wStri-Wolbachia.

In this paper, we formulate a population suppression model and a population replacement model with periodic impulsive releases of Nilaparvata lugens infected with wStri. The conditions for the stability of wild-N.lugens-eradication periodic solution of two systems are obtained by applying the Floquet theorem and comparison theorem. And the sufficient conditions for the persistence in the mean of wild N.lugens are also given. In addition, the sufficient conditions for the extinction and persistence of the wild N.lugens in the subsystem without wLug are also obtained. Finally, we give numerical analysis which shows that increasing the release amount or decreasing the release period are beneficial for controlling the wild N.lugens, and the efficiency of population replacement strategy in controlling wild populations is higher than that of population suppression strategy under the same release conditions.

Low-temperature strain-sensitive sensor based on cellulose-based ionic conductive hydrogels with moldable and self-healing properties.

Bioelectronics based on high-performance conductive ionic hydrogels, which can create novel technological interfaces with the human body, have attracted significant interest from both academia and industry. However, it is still a challenge to fabricate hydrogel sensor with integration of good mechanical properties, fast self-healing ability and flexible strain sensitivity below 0 °C. In this paper, we present a moldable, self-healing and adhesive cellulose-based ionic conductive hydrogel with strain-sensitivity, which was prepared by forming dual-crosslinked networks using poly(vinyl alcohol) (PVA) with borax, calcium chloride (CaCl2), zinc chloride (ZnCl2) and 2,2,6,6-tetramethylpiperidine-1-oxyl oxidized cellulose nanofibril (TCNF). The hydrogel exhibited fast self-healing within 10 s, moderate modulus of 5.13 kPa, high elongation rate of 1500 % and excellent adhesion behavior on various substrates. Due to multiple hydrogen bonding and the presence of CaCl2 and ZnCl2, the hydrogel presented a reduced freezing point as low as -41.1 °C, which enabled its application as a low-temperature strain sensor. The proposed hydrogel provides a simple and facile method for fabricating multi-functional hydrogels that can be used as suitable strain sensors for applications such as wearable electronic sensor, soft robotics and electronic skins in a wide temperature range.

Inversely engineered biomimetic flexible network scaffolds for soft tissue regeneration.

Graft-host mechanical mismatch has been a longstanding issue in clinical applications of synthetic scaffolds for soft tissue regeneration. Although numerous efforts have been devoted to resolve this grand challenge, the regenerative performance of existing synthetic scaffolds remains limited by slow tissue growth (comparing to autograft) and mechanical failures. We demonstrate a class of rationally designed flexible network scaffolds that can precisely replicate nonlinear mechanical responses of soft tissues and enhance tissue regeneration via reduced graft-host mechanical mismatch. Such flexible network scaffold includes a tubular network frame containing inversely engineered curved microstructures to produce desired mechanical properties, with an electrospun ultrathin film wrapped around the network to offer a proper microenvironment for cell growth. Using rat models with sciatic nerve defects or Achilles tendon injuries, our network scaffolds show regenerative performances evidently superior to that of clinically approved electrospun conduit scaffolds and achieve similar outcomes to autologous nerve transplantation in prevention of target organ atrophy and recovery of static sciatic index.

Characteristics and classification of first primary cancer patients with second primary cancer: a population-based cohort study.

Cancer survivors have an increased risk of developing subsequent primary tumors. However, the characteristics of first primary cancers (FPCs) with various types of second primary cancers (SPCs) are poorly understood, which hinders screening strategies. We analyzed data from 1,893,258 patients from the Surveillance, Epidemiology, and End Results (SEER) database to characterize and classify of FPC patients with subsequent SPCs at the pan-cancer level. In total, 3% of patients had SPC, with varied incidence rates observed depending on the types of FPC. Their onset patterns of SPC and diversity of SPC varied. Based on the diversity of the high-incidence sites of SPC, we classified FPCs into two categories: FPCs that require whole-body screening and those that need screening of particular body parts. Moreover, according to the different timing of high incidence of SPCs, our system classifies FPCs into two subtypes: FPCs that require long-term monitoring for the occurrence of SPCs and those that require screening at specific time points for SPCs. Furthermore, we identified 11 anatomical sites where over half of FPC types are prone to SPC occurrence at these locations. The risk factors for SPC occurrence in different FPC types and prognostic factors were also elucidated. Overall, we characterize and classify of FPC patients with subsequent SPCs at the pan-cancer level, which can guide the development of distinct screening strategies for each FPC type.

Survival analysis of a stochastic impulsive single-species population model with migration driven by environmental toxicant.

Considering the influence of environmental toxicant on population migration between patches, we propose and study a stochastic impulsive single-species population model with migration driven by environmental toxicant in this paper. We first discuss the existence and uniqueness of global positive solutions of the model by constructing the Lyapunov function. Then, we obtain sufficient conditions for extinction, stochastic persistence and persistence in the mean of the single-species population. Finally, we present some numerical simulations to illustrate our results. These results provide insights for the conservation and management of species in polluted environments.

Clinical Outcomes After Arthroscopic Microfracture Treatment of Coexisting Talar and Tibial Osteochondral Lesions.

Background: Despite increased recognition of coexisting tibial and talar osteochondral lesions (OCLs), the risk factors influencing clinical outcomes remain unclear. Purpose: To report clinical follow-up results after arthroscopic microfracture surgery in patients with OCLs of the distal tibial plafond and talus and assess possible factors affecting these clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: A total of 40 patients with coexisting talar and tibial OCLs who underwent arthroscopic microfracture surgery were included. For analysis, the study used the American Orthopaedic Foot & Ankle Society (AOFAS) scale, Karlsson-Peterson scale, and visual analog scale (VAS) for pain for clinical evaluations on the day before surgery, 12 months after surgery, and at the last follow-up. A stepwise regression model and Spearman rank correlation were used to assess possible factors affecting these clinical outcomes. Results: The median follow-up time was 34.5 months (interquartile range [IQR], 26.5-54 months). At the final follow-up, the cohort included 40 patients (26 men and 14 women) with a mean age of 38.8 years (range, 19-60 years). The median AOFAS score increased from 57.5 (IQR, 47-65) before surgery to 88 (IQR, 83-92.5) at the final follow-up, the median Karlsson-Peterson score increased from 48 (IQR, 38.5-67) to 82 (IQR, 76-92), and the median VAS score improved from 5 (IQR, 4-6) to 1 (IQR, 0-2). All scale scores showed significant differences between the preoperative and final follow-up evaluations (P < .001). In the stepwise regression model and Spearman rank correlation analysis, the grade of tibial OCL had a significant independent effect on the final postoperative AOFAS scores of the patients (ß = -0.502, P = .001; r = -0.456, P = .003). The size of the tibial lesion also had a significant independent effect on the final postoperative Karlsson-Peterson scores of the patients (ß = -0.444, P = .004; r = -0.357, P = .024). Conclusion: Arthroscopic microfracture treatment for coexisting talar and tibial OCLs can achieve good short- to midterm clinical outcomes. The grade and size of tibial OCLs are the main risk factors affecting the prognostic functional scores of such patients.

New Research Progress of Modified Bone Cement Applied to Vertebroplasty.

Percutaneous vertebroplasty and percutaneous kyphoplasty are effective methods to treat acute osteoporotic vertebral compression fractures that can quickly provide patients with pain relief, prevent further height loss of the vertebral body, and help correct kyphosis. Many clinical studies have investigated the characteristics of bone cement. Bone cement is a biomaterial injected into the vertebral body that must have good biocompatibility and biosafety. The optimization of the characteristics of bone cement has become of great interest. Bone cement can be mainly divided into 3 types: polymethyl methacrylate, calcium phosphate cement, and calcium sulfate cement. Each type of cement has its own advantages and disadvantages. In the past 10 years, the performance of bone cement has been greatly improved via different methods. The aim of our review is to provide an overview of the current progress in the types of modified bone cement and summarize the key clinical findings.

Efficacy of Aidi injection combined with chemotherapy, radiotherapy or chemoradiotherapy for unresectable esophageal cancer treatment: A meta-analysis and systematic review of 29 randomized controlled trials based on Asian populations (China).

OBJECTIVES: This study aimed to assess the efficacy of Aidi combined with standard treatment, including radiotherapy (R), chemotherapy (C), or chemoradiotherapy (CR), for unresectable esophageal cancer (EC). METHODS: Eight online databases were queried to collect randomized controlled trials (RCTs) published from database construction to August 2022. Patients in the control group underwent standard treatment with R, C, or CR, whereas those in the experimental group underwent Aidi combined with standard treatment. RESULTS: In this meta-analysis, 29 reports with 2079 patients were included. The results showed that the Aidi-based combination therapy groups had higher objective response rates (ORRs), disease control rates (DCRs), one-year overall survival (OS) and improvement and stability of Karnofsky performance status (KPS) than the control group (risk ratio (RR) = 1.24 (95% CI = 1.17-1.33), 1.09 (95% CI = 1.05-1.14), 1.50 (95% CI = 1.31-1.72), and 1.28 (95% CI = 1.16-1.41)). The Aidi-based combination therapy groups also had lower total incidence rates of bone marrow suppression (BMS), chemotherapy-induced nausea and vomiting (CINV) and radiation esophagitis (RE) than the control group (RR = 0.48 (95% CI = 0.41-0.56), 0.46 (95% CI = 0.36-0.58), and 0.49 (95% CI = 0.38-0.62)). In addition, subgroup analysis suggested that the optimal dose and cycle of Aidi injection combined therapy was 80-100 ml/time and 30 days/2 cycles. The efficacy of Aidi combined with DP (docetaxel + cisplatin) was better than the Aidi combined with PF (cisplatin plus fluorouracil). CONCLUSION: Aidi-based combination therapy showed high efficacy for unresectable EC treatment and reduced the incidence rates of adverse events. However, further studies including higher-quality RCTs are needed to validate these findings. TRIAL REGISTRATION NUMBER: INPLASY 202290020.

Tail nerve electrical stimulation promoted the efficiency of transplanted spinal cord-like tissue as a neuronal relay to repair the motor function of rats with transected spinal cord injury.

Following transected spinal cord injury (SCI), there is a critical need to restore nerve conduction at the injury site and activate the silent neural circuits caudal to the injury to promote the recovery of voluntary movement. In this study, we generated a rat model of SCI, constructed neural stem cell (NSC)-derived spinal cord-like tissue (SCLT), and evaluated its ability to replace injured spinal cord and repair nerve conduction in the spinal cord as a neuronal relay. The lumbosacral spinal cord was further activated with tail nerve electrical stimulation (TNES) as a synergistic electrical stimulation to better receive the neural information transmitted by the SCLT. Next, we investigated the neuromodulatory mechanism underlying the action of TNES and its synergism with SCLT in SCI repair. TNES promoted the regeneration and remyelination of axons and increased the proportion of glutamatergic neurons in SCLT to transmit brain-derived neural information more efficiently to the caudal spinal cord. TNES also increased the innervation of motor neurons to hindlimb muscle and improved the microenvironment of muscle tissue, resulting in effective prevention of hindlimb muscle atrophy and enhanced muscle mitochondrial energy metabolism. Tracing of the neural circuits of the sciatic nerve and tail nerve identified the mechanisms responsible for the synergistic effects of SCLT transplantation and TNES in activating central pattern generator (CPG) neural circuits and promoting voluntary motor function recovery in rats. The combination of SCLT and TNES is expected to provide a new breakthrough for patients with SCI to restore voluntary movement and control their muscles.

Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2.

Activation of endothelial YAP/TAZ signaling is crucial for physiological and pathological angiogenesis. The mechanisms of endothelial YAP/TAZ regulation are, however, incompletely understood. Here we report that the protocadherin FAT1 acts as a critical upstream regulator of endothelial YAP/TAZ which limits the activity of these transcriptional cofactors during developmental and tumor angiogenesis by promoting their degradation. We show that loss of endothelial FAT1 results in increased endothelial cell proliferation in vitro and in various angiogenesis models in vivo. This effect is due to perturbed YAP/TAZ protein degradation, leading to increased YAP/TAZ protein levels and expression of canonical YAP/TAZ target genes. We identify the E3 ubiquitin ligase Mind Bomb-2 (MIB2) as a FAT1-interacting protein mediating FAT1-induced YAP/TAZ ubiquitination and degradation. Loss of MIB2 expression in endothelial cells in vitro and in vivo recapitulates the effects of FAT1 depletion and causes decreased YAP/TAZ degradation and increased YAP/TAZ signaling. Our data identify a pivotal mechanism of YAP/TAZ regulation involving FAT1 and its associated E3 ligase MIB2, which is essential for YAP/TAZ-dependent angiogenesis.

New Staging System and Prognostic Model for Malignant Phyllodes Tumor Patients without Distant Metastasis: A Development and Validation Study.

PURPOSE: To build a new staging system and new prognostic models for MPTB. METHODS: We performed a comprehensive analysis of the data from the SEER database. RESULTS: We discussed the characteristics of MPTB by comparing 1085 MPTB cases with 382,718 invasive ductal carcinoma cases. We established a new stage- and age-stratification system for MPTB patients. Furthermore, we built two prognostic models for MPTB patients. The validity of these models was confirmed through multifaceted and multidata verification. CONCLUSIONS: Our study provided a staging system and prognostic models for MPTB patients, which can not only help to predict patient outcomes, but also enhance the understanding of the prognostic factors associated with MPTB.

Wnt3a-Modified Nanofiber Scaffolds Facilitate Tendon Healing by Driving Macrophage Polarization during Repair.

Inflammation is part of the natural healing response, but persistent inflammatory events tend to contribute to pathology changes of tendon or ligament. Phenotypic switching of macrophages within the inflammatory niche is crucial for tendon healing. One viable strategy to improve the functional and biomechanical properties of ruptured tendons is to modulate the transition from inflammatory to regenerative signals during tendon regeneration at the site of injury. Here, we developed a tendon repair scaffold made of biodegradable polycaprolactone by electrospinning, which was modified to deliver Wnt3a protein and served as an implant to improve tendon healing in a rat model of Achilles tendon defect. During the in vitro study, Wnt3a protein promoted the polarization of M2 macrophages. In the in vivo experiment, Wnt3a scaffold promoted the early recruitment and counting curve of macrophages and increased the proportion of M2 macrophages. Achilles function index and mechanical properties showed that the implantation effect of the Wnt3a group was better than that of the control group. We believe that this type of scaffold can be used to repair tendon defects. This work highlights the beneficial role of local delivery of biological factors in directing inflammatory responses toward regenerative strategies in tendon healing.