Mechanisms and Translational Applications of Regeneration in Limbs: From Renewable Animals to Humans.

BACKGROUND: The regenerative capacity of organisms declines throughout evolution, and mammals lack the ability to regenerate limbs after injury. Past approaches to achieving successful restoration through pharmacological intervention, tissue engineering, and cell therapies have faced significant challenges. OBJECTIVES: This review aims to provide an overview of the current understanding of the mechanisms behind animal limb regeneration and the successful translation of these mechanisms for human tissue regeneration. RESULTS: Particular attention was paid to the Mexican axolotl (Ambystoma mexicanum), the only adult tetrapod capable of limb regeneration. We will explore fundamental questions surrounding limb regeneration, such as how amputation initiates regeneration, how the limb knows when to stop and which parts to regenerate, and how these findings can apply to mammalian systems. CONCLUSIONS: Given the urgent need for regenerative therapies to treat conditions like diabetic foot ulcers and trauma survivors, this review provides valuable insights and ideas for researchers, clinicians, and biomedical engineers seeking to facilitate the regeneration process or elicit full regeneration from partial regeneration events.

Automatic Lenke classification of adolescent idiopathic scoliosis with deep learning.

Purpose: The Lenke classification system is widely utilized as the preoperative evaluation protocol for adolescent idiopathic scoliosis (AIS). However, manual measurement is susceptible to observer-induced variability, which consequently impacts the evaluation of progression. The goal of this investigation was to develop an automated Lenke classification system utilizing innovative deep learning algorithms. Methods: Using the database from the First Affiliated Hospital of Sun Yat-sen University, the whole spinal x-rays images were retrospectively collected. Specifically, images collection was divided into AIS and control group. The control group consisted of individuals who underwent routine health checks and did not have scoliosis. Afterwards, relative features of all images were annotated. Deep learning was implemented through the utilization of the key-point based detection method to realize the vertebral detection, and Cobb angle measurement and scoliosis classification were performed based on relevant standards. Besides, the segmentation method was employed to achieve the recognition of lumbar vertebral pedicle to determine the type of lumbar spine modifier. Finally, the model performance was further quantitatively analyzed. Results: In the study, a total of 2082 spinal x-ray images were collected from 407 AIS patients and 227 individuals in the control group. The model for vertebral detection achieved an F1-score of 0.809 for curve type evaluation and an F1-score of 0.901 for thoracic sagittal profile. The intraclass correlation efficient (ICC) of the Cobb angle measurement was 0.925. In the analysis of performance for vertebra pedicle segmentation model, the F1-score of lumbar modification profile was 0.942, the intersection over union (IOU) of the target pixels was 0.827, and the Hausdorff distance (HD) was 6.565 ± 2.583 mm. Specifically, the F1-score for ultimate Lenke type classifier was 0.885. Conclusions: This study has constructed an automated Lenke classification system by employing the deep learning networks to achieve the recognition pattern and feature extraction. Our models require further validation in additional cases in the future.

TAK1 in Vascular Signaling: "Friend or Foe"?

The maintenance of normal vascular function and homeostasis is largely dependent on the signaling mechanisms that occur within and between cells of the vasculature. TGF-ß-activated kinase 1 (TAK1), a multifaceted signaling molecule, has been shown to play critical roles in various tissue types. Although the precise function of TAK1 in the vasculature remains largely unknown, emerging evidence suggests its potential involvement in both physiological and pathological processes. A comprehensive search strategy was employed to identify relevant studies, PubMed, Web of Science, and other relevant databases were systematically searched using keywords related to TAK1, TABs and MAP3K7.In this review, we discussed the role of TAK1 in vascular signaling, with a focus on its function, activation, and related signaling pathways. Specifically, we highlight the TA1-TABs complex is a key factor, regulating vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) involved in the processes of inflammation, vascular proliferation and angiogenesis. This mini review aims to elucidate the evidence supporting TAK1 signaling in the vasculature, in order to better comprehend its beneficial and potential harmful effects upon TAK1 activation in vascular tissue.

A review of lactate-lactylation in malignancy: its potential in immunotherapy.

Lactic acid was formerly regarded as a byproduct of metabolism. However, extensive investigations into the intricacies of cancer development have revealed its significant contributions to tumor growth, migration, and invasion. Post-translational modifications involving lactate have been widely observed in histone and non-histone proteins, and these modifications play a crucial role in regulating gene expression by covalently attaching lactoyl groups to lysine residues in proteins. This discovery has greatly enhanced our comprehension of lactic acid's involvement in disease pathogenesis. In this article, we provide a comprehensive review of the intricate relationship between lactate and tumor immunity, the occurrence of lactylation in malignant tumors, and the exploitation of targeted lactate-lactylation in tumor immunotherapy. Additionally, we discuss future research directions, aiming to offer novel insights that could inform the investigation, diagnosis, and treatment of related diseases.

Deep learning for virtual orthodontic bracket removal: tool establishment and application.

OBJECTIVE: We aimed to develop a tool for virtual orthodontic bracket removal based on deep learning algorithms for feature extraction from bonded teeth and to demonstrate its application in a bracket position assessment scenario. MATERIALS AND METHODS: Our segmentation network for virtual bracket removal was trained using dataset A, containing 978 bonded teeth, 20 original teeth, and 20 brackets generated by scanners. The accuracy and segmentation time of the network were tested by dataset B, which included an additional 118 bonded teeth without knowing the original tooth morphology. This tool was then applied for bracket position assessment. The clinical crown center, bracket center, and orientations of separated teeth and brackets were extracted for analyzing the linear distribution and angular deviation of bonded brackets. RESULTS: This tool performed virtual bracket removal in 2.9 ms per tooth with accuracies of 98.93% and 97.42% (P < 0.01) in datasets A and B, respectively. The tooth surface and bracket characteristics were extracted and used to evaluate the results of manually bonded brackets by 49 orthodontists. Personal preferences for bracket angulation and bracket distribution were displayed graphically and tabularly. CONCLUSIONS: The tool's efficiency and precision are satisfactory, and it can be operated without original tooth data. It can be used to display the bonding deviation in the bracket position assessment scenario. CLINICAL SIGNIFICANCE: With the aid of this tool, unnecessary bracket removal can be avoided when evaluating bracket positions and modifying treatment plans. It has the potential to produce retainers and orthodontic devices prior to tooth debonding.

Superconductivity in the High-Entropy Ceramics Ti0.2 Zr0.2 Nb0.2 Mo0.2 Ta0.2 Cx with Possible Nontrivial Band Topology.

Topological superconductors have drawn significant interest from the scientific community due to the accompanying Majorana fermions. Here, the discovery of electronic structure and superconductivity (SC) in high-entropy ceramics Ti0.2 Zr0.2 Nb0.2 Mo0.2 Ta0.2 Cx (x = 1 and 0.8) combined with experiments and first-principles calculations is reported. The Ti0.2 Zr0.2 Nb0.2 Mo0.2 Ta0.2 Cx high-entropy ceramics show bulk type-II SC with Tc ≈ 4.00 K (x = 1) and 2.65 K (x = 0.8), respectively. The specific heat jump (∆C/γTc ) is equal to 1.45 (x = 1) and 1.52 (x = 0.8), close to the expected value of 1.43 for the BCS superconductor in the weak coupling limit. The high-pressure resistance measurements show a robust SC against high physical pressure in Ti0.2 Zr0.2 Nb0.2 Mo0.2 Ta0.2 C, with a slight Tc variation of 0.3 K within 82.5 GPa. Furthermore, the first-principles calculations indicate that the Dirac-like point exists in the electronic band structures of Ti0.2 Zr0.2 Nb0.2 Mo0.2 Ta0.2 C, which is potentially a topological superconductor. The Dirac-like point is mainly contributed by the d orbitals of transition metals M and the p orbitals of C. The high-entropy ceramics provide an excellent platform for the fabrication of novel quantum devices, and the study may spark significant future physics investigations in this intriguing material.

Manganese Enhances the Osteogenic Effect of Silicon-Hydroxyapatite Nanowires by Targeting T Lymphocyte Polarization.

Biomaterials encounter considerable challenges in extensive bone defect regeneration. The amelioration of outcomes may be attainable through the orchestrated modulation of both innate and adaptive immunity. Silicon-hydroxyapatite, for instance, which solely focuses on regulating innate immunity, is inadequate for long-term bone regeneration. Herein, extra manganese (Mn)-doping is utilized for enhancing the osteogenic ability by mediating adaptive immunity. Intriguingly, Mn-doping engenders heightened recruitment of CD4+ T cells to the bone defect site, concurrently manifesting escalated T helper (Th) 2 polarization and an abatement in Th1 cell polarization. This consequential immune milieu yields a collaborative elevation of interleukin 4, secreted by Th2 cells, coupled with attenuated interferon gamma, secreted by Th1 cells. This orchestrated interplay distinctly fosters the osteogenesis of bone marrow stromal cells and effectuates consequential regeneration of the mandibular bone defect. The modulatory mechanism of Th1/Th2 balance lies primarily in the indispensable role of manganese superoxide dismutase (MnSOD) and the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). In conclusion, this study highlights the transformative potential of Mn-doping in amplifying the osteogenic efficacy of silicon-hydroxyapatite nanowires by regulating T cell-mediated adaptive immunity via the MnSOD/AMPK pathway, thereby creating an anti-inflammatory milieu favorable for bone regeneration.

Senolytic Treatment Improve Small Intestine Regeneration in Aging.

Aging induces a series of alterations, specifically a decline in the stature and number of villi and crypts in the small intestine, thus compromising the absorbent capability of the villi. This investigation employed a senolytic combination of dasatinib and quercetin (D+Q) to examine its impact on the intestinal tract of elderly mice. Our findings demonstrate that D+Q treatment leads to a decrease in the expression of p21, p16, and Ki67, while concurrently triggering removal of apoptotic cells within the villi. Additionally, D+Q treatment exhibits the ability to promote growth in both the height and quantity of villi and crypts, along with stimulating nitric oxide (NO) production in aged mice. The study presented a model to assess strategies to alleviate age-related senescence in the intestinal tract of elderly mice. Importantly, D+Q showcases promising potential in enhancing intestinal functionality within the aging.

Senolytics prevent caveolar CaV 3.2-RyR axis malfunction in old vascular smooth muscle.

Aging is a major risk factor for cardiovascular diseases. Our previous studies demonstrate that aging impairs the caveolar T-type CaV 3.2-RyR axis for extracellular Ca2+ influx to trigger Ca2+ sparks in vascular smooth muscle cells (VSMCs). We hypothesize that the administration of senolytics, which can selectively clear senescent cells, could preserve the caveolar CaV 3.2-RyR axis in aging VSMCs. In this study, 10-month-old mice were administered the senolytics cocktail consisting of dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Using VSMCs from mouse mesenteric arteries, we found that Ca2+ sparks were diminished after caveolae disruption by methyl-ß-cyclodextrin (10 mM) in cells from D + Q treated but not vehicle-treated 14-month-old mice. D + Q treatment promoted the expression of CaV 3.2 in 14-month-old mesenteric arteries. Structural analysis using electron tomography and immunofluorescence staining revealed the remodeling of caveolae and co-localization of CaV 3.2-Cav-1 in D + Q treatment aged mesenteric arteries. In keeping with theoretical observations, Cav 3.2 channel inhibition by Ni2+ (50 µM) suppressed Ca2+ in VSMCs from the D + Q group, with no effect observed in vehicle-treated arteries. Our study provides evidence that age-related caveolar CaV 3.2-RyR axis malfunction can be alleviated by pharmaceutical intervention targeting cellular senescence. Our findings support the potential of senolytics for ameliorating age-associated cardiovascular disease.

Identification and validation of a novel overall survival prediction model for immune-related genes in bone metastases of prostate cancer.

Immunotherapy has become a revolutionary treatment for cancer and brought new vitality to tumor immunity. Bone metastases are the most prevalent metastatic site for advanced prostate cancer (PCa). Therefore, finding new immunotherapy targets in PCa patients with bone metastasis is urgently needed. We conducted an elaborative bioinformatics study of immune-related genes (IRGs) and tumor-infiltrating immune cells (TIICs) in PCa bone metastases. Databases were integrated to obtain RNA-sequencing data and clinical prognostic information. Univariate and multivariate Cox regression analyses were conducted to construct an overall survival (OS) prediction model. GSE32269 was analyzed to acquire differentially expressed IRGs. The OS prediction model was established by employing six IRGs (MAVS, HSP90AA1, FCGR3A, CTSB, FCER1G, and CD4). The CIBERSORT algorithm was adopted to assess the proportion of TIICs in each group. Furthermore, Transwell, MTT, and wound healing assays were employed to determine the effect of MAVS on PCa cells. High-risk patients had worse OS compared to the low-risk patients in the training and validation cohorts. Meanwhile, clinically practical nomograms were generated using these identified IRGs to predict the 3- and 5-year survival rates of patients. The infiltration percentages of some TIICs were closely linked to the risk score of the OS prediction model. Some tumor-infiltrating immune cells were related to the OS. FCGR3A was closely correlated with some TIICs. In vitro experiments verified that up-regulation of MAVS suppressed the proliferation and metastatic abilities of PCa cells. Our work presented a thorough interpretation of TIICs and IRGs for illustrating and discovering new potential immune checkpoints in bone metastases of PCa.

Risk factors for cardiovascular adverse events from immune checkpoint inhibitors.

Immune-related adverse events (irAEs), including skin injury, liver and kidney injury, colitis, as well as cardiovascular adverse events, are a series of complications arising during the treatment of immune checkpoint inhibitors (ICIs). Cardiovascular events are the most urgent and the most critical, as they can end life in a short period of time. With the widespread use of ICIs, the number of immune-related cardiovascular adverse events (irACEs) induced by ICIs has increased. More attention has been paid to irACEs, especially regarding cardiotoxicity, the pathogenic mechanism, diagnosis and treatment. This review aims to assess the risk factors for irACEs, to raise awareness and help with the risk assessment of irACEs at an early stage.

Single-Cell and Transcriptome-Based Immune Cell-Related Prognostic Model in Clear Cell Renal Cell Carcinoma.

Traditional studies mostly focus on the role of single gene in regulating clear cell renal cell carcinoma (ccRCC), while it ignores the impact of tumour heterogeneity on disease progression. The purpose of this study is to construct a prognostic risk model for ccRCC by analysing the differential marker genes related to immune cells in the single-cell database to provide help in clinical diagnosis and targeted therapy. Single-cell data and ligand-receptor relationship pair data were downloaded from related publications, and ccRCC phenotype and expression profile data were downloaded from TCGA and CPTAC. Based on the DEGs of each cluster acquired from single-cell data, immune cell marker genes, and ligand-receptor gene data, we constructed a multilayer network. Then, the genes in the network and the genes in TCGA were used to construct the WGCNA network, which screened out prognosis-associated genes for subsequent analysis. Finally, a prognostic risk scoring model was obtained, and CPTAC data showed that the effectiveness of this model was good. A nomogram based on the predictive model for predicting the overall survival was established, and internal validation was performed well. Our findings suggest that the predictive model built and based on the immune cell scRNA-seq will enable us to judge the prognosis of patients with ccRCC and provide more accurate directions for basic relevant research and clinical practice.

Neuroprotective Roles of Apelin-13 in Neurological Diseases.

Apelin is a natural ligand for the G protein-coupled receptor APJ, and the apelin/APJ system is widely distributed in vivo. Among the apelin family, apelin-13 is the major apelin isoform in the central nervous system and cardiovascular system, and is involved in the regulation of various physiopathological mechanisms such as apoptosis, neuroinflammation, angiogenesis, and oxidative stress. Apelin is currently being extensively studied in the nervous system, and apelin-13 has been shown to be associated with the onset and progression of a variety of neurological disorders, including stroke, neurodegenerative diseases, epilepsy, spinal cord injury (SCI), and psychiatric diseases. This study summarizes the pathophysiological roles of apelin-13 in the development and progression of neurological related diseases.

Sarcopenia as a risk factor of progression-free survival in patients with metastases: a systematic review and meta-analysis.

BACKGROUND: Metastasis of cancer causes more than 90% of cancer deaths and is severely damaging to human health. In recent years, several studies have linked sarcopenia to shorter survival in patients with metastatic cancer. Several predictive models exist to predict mortality in patients with metastatic cancer, but have reported limited accuracy. METHODS: We systematically searched Medline, EMBASE, and the Cochrane Library for articles published on or before October 14, 2022. Pooled Hazard Ratio (HR) estimates with 95% confidence intervals (CIs) were calculated using a random effects model. The primary outcome was an increased risk of death or tumor progression in patients with metastatic cancer, which is expressed as progression-free survival (PFS). In addition, we performed subgroup analyses and leave-one-out sensitivity analyses to explore the main sources of heterogeneity and the stability of the results. RESULTS: Sixteen retrospective cohort studies with 1,675 patients were included in the 888 papers screened. The results showed that sarcopenia was associated with lower progression-free survival (HR = 1.56, 95% CI = 1.19-2.03, I2 = 76.3%, P < 0.001). This result was further confirmed by trim-and-fill procedures and leave-one-out sensitivity analysis. CONCLUSIONS: This study suggests that sarcopenia may be a risk factor for reduced progression-free survival in patients with metastatic cancer. Further studies are still needed to explain the reason for this high heterogeneity in outcome. TRIAL REGISTRATION: CRD42022325910.

Dynamic network biomarker identifies cdkn1a-mediated bone mineralization in the triggering phase of osteoporosis.

The identification of predictive markers to determine the triggering phase prior to the onset of osteoporosis is essential to mitigate further irrevocable deterioration. To determine the early warning signs before osteoporosis, we used the dynamic network biomarker (DNB) approach to analyze time-series gene expression data in a zebrafish osteoporosis model, which revealed that cyclin-dependent kinase inhibitor 1 A (cdkn1a) is a core DNB. We found that cdkn1a negatively regulates osteogenesis, as evidenced by loss-of-function and gain-of-function studies. Specifically, CRISPR/Cas9-mediated cdkn1a knockout in zebrafish significantly altered skeletal development and increased bone mineralization, whereas inducible cdkn1a expression significantly contributed to osteoclast differentiation. We also found several mechanistic clues that cdkn1a participates in osteoclast differentiation by regulating its upstream signaling cascades. To summarize, in this study, we provided new insights into the dynamic nature of osteoporosis and identified cdkn1a as an early-warning signal of osteoporosis onset.

[Study on promoting bone formation in osteoporotic zebrafish by lithium-doped hydroxyapatite nanowires].

PURPOSE: To observe the regulatory effect of lithium-doped hydroxyapatite nanowires on bone metabolism in osteoporotic zebrafish induced by dexamethasone. METHODS: Pure hydroxyapatite nanowires(nHA) and hydroxyapatite nanowires doped with 10% lithium ions (Li-nHA) were prepared by using hydrothermal method, and then material characterization was performed. The juvenile zebrafish cultured for 3 days(3dpf) were selected and co-cultured with nHA and Li-nHA extracts up to 7dpf. A negative(0.1% DMSO) control group was set up and transgenic zebrafish Tg(ola.sp7:nlsGFP) was used to select the best concentration for promoting bone formation. The osteoporotic zebrafish were induced by dexamethasone and incubated with nHA and Li-nHA extracts. The wild-type zebrafish was stained with alizarin red and the osteogenic differentiation was observed in transgenic zebrafish. Real-time quantitative PCR was adopted to detect osteogenic maker genes, such as zinc finger transcription factor (SP7), alkaline phosphatase (ALP), osteoprotegerin (OPG), Runt related transcription factor 2(Runx2) and osteocalcin (OCN). Statistical analysis was performed with GraphPad Prism 9.3 software. RESULTS: nHA and Li-nHA promoted bone formation and up-regulated expression levels of ALP, OCN, Runx2, SP7 and OPG of osteoporotic zebrafish. Compared with nHA, Li-nHA significantly increased the mineralization specific staining area and cumulative optical density of zebrafish bone, and the expression of osteogenic maker genes was also significantly increased. CONCLUSIONS: Doping lithium ions in nano hydroxyapatite can enhance its osteoinductive properties, and Li-nHA can effectively improve bone formation of osteoporotic zebrafish.

Case report of old anterior dislocation of the shoulder joint and review of the literature.

Background: Dislocation of the shoulder joint is the most common type of joint dislocation. It is rare to be in a persistent dislocation that has not been reset. Successful arthroscopic treatment of the obsolete shoulder is relatively uncommon. Case report: We report a rare case of persistent anterior dislocation of the old shoulder joint in a 30-year-old female patient. The patient underwent an emergency shoulder dislocation at a local hospital after a traumatic injury and re-dislocated persistently after surgery. 26 days later, she was admitted to our department for treatment, mainly because of joint deformity and limitation of motion. We adopted arthroscopic release and repositioning surgery. The patient was followed up for 1 year after surgery. Functional recovery was satisfactory. Conclusion: The state of obsolete shoulder dislocation rarely occurs after shoulder dislocation and the prognosis of the patient is good after complete arthroscopic release and repositioning. It provides a reference for clinical arthroscopic treatment of old shoulder dislocations.

Anterior cruciate ligament deficiency versus intactness for outcomes in patients after unicompartmental knee arthroplasty: a systematic review and meta-analysis.

Objective: The unicondylar knee arthroplasty (UKA) procedure is primarily indicated for osteoarthritis of the knee. Anterior cruciate ligament (ACL) defects have long been considered a contraindication to UKA. However, recent clinical studies have found that ACL defects do not affect postoperative outcomes in UKA. To elucidate whether ACL defects affect postoperative outcomes in UKA, we performed a systematic review and Meta-analysis of observational cohort studies comparing the effects of ACL defects and intactness on surgical outcomes in UKA. Methods: In this study, we used "Anterior Cruciate Ligament", "Anterior Cruciate Ligament Injuries" and "Arthroplasty, Replacement, Knee" as the subject terms according to PICOS principles. These subject terms and the corresponding free texts were used to conduct a systematic search in the three major databases PubMed, Embase and Cochrane on December 9, 2021. The main study variables included age, gender, region, definition of ACL defect and diagnosed diseases. The study used a random effect model to pool the effect of 95% CIs. To explore the sources of heterogeneity and to test the stability of the results, a sensitivity analysis was performed. Results: The systematic review found no significant differences in postoperative clinical outcomes in the elderly population when unicondylar replacement was performed in the setting of multiple factors such as injury, defects, longitudinal tear, and synovial bursa injury defined as ACL deficiency. The primary clinical outcomes included postoperative revision, Tegner activity score, and Oxford Knee Score (OKS). After statistical meta-analysis, postoperative outcomes such as postoperative revision (OR, 1.174; 95% CIs, 0.758-1.817) and Tegner activity score (OR, -0.084; 95% CIs, -0.320-0.151) were not statistically different. Conclusion: There was no difference in postoperative revision rates and functional outcomes such as Tegner activity score between the ACL-deficient group compared with the ACL-intact group. For the present results, it is not advisable to consider ACL deficiency as a contraindication of UKA.

Microglia Pyroptosis: A Candidate Target for Neurological Diseases Treatment.

In addition to its profound implications in the fight against cancer, pyroptosis have important role in the regulation of neuronal injury. Microglia are not only central members of the immune regulation of the central nervous system (CNS), but are also involved in the development and homeostatic maintenance of the nervous system. Under various pathological overstimulation, microglia pyroptosis contributes to the massive release of intracellular inflammatory mediators leading to neuroinflammation and ultimately to neuronal damages. In addition, microglia pyroptosis lead to further neurological damage by decreasing the ability to cleanse harmful substances. The pathogenic roles of microglia in a variety of CNS diseases such as neurodegenerative diseases, stroke, multiple sclerosis and depression, and many other neurological disorders have been gradually unveiled. In the context of different neurological disorders, inhibition of microglia pyroptosis by targeting NOD-like receptor family pyrin domain containing (NLRP) 3, caspase-1 and gasdermins (GSDMs) by various chemical agents as well as natural products significantly improve the symptoms or outcome in animal models. This study will provide new ideas for immunomodulatory treatment of CNS diseases.