Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations.

Many human spinal cord injuries are anatomically incomplete but exhibit complete paralysis. It is unknown why spared axons fail to mediate functional recovery in these cases. To investigate this, we undertook a small-molecule screen in mice with staggered bilateral hemisections in which the lumbar spinal cord is deprived of all direct brain-derived innervation, but dormant relay circuits remain. We discovered that a KCC2 agonist restored stepping ability, which could be mimicked by selective expression of KCC2, or hyperpolarizing DREADDs, in the inhibitory interneurons between and around the staggered spinal lesions. Mechanistically, these treatments transformed this injury-induced dysfunctional spinal circuit to a functional state, facilitating the relay of brain-derived commands toward the lumbar spinal cord. Thus, our results identify spinal inhibitory interneurons as a roadblock limiting the integration of descending inputs into relay circuits after injury and suggest KCC2 agonists as promising treatments for promoting functional recovery after spinal cord injury.

Microglia-organized scar-free spinal cord repair in neonatal mice.

Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons1-4. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.

Reprogramming to recover youthful epigenetic information and restore vision.

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1-3. Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity5-7. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.

RSK1 promotes mammalian axon regeneration by inducing the synthesis of regeneration-related proteins.

In contrast to the adult mammalian central nervous system (CNS), the neurons in the peripheral nervous system (PNS) can regenerate their axons. However, the underlying mechanism dictating the regeneration program after PNS injuries remains poorly understood. Combining chemical inhibitor screening with gain- and loss-of-function analyses, we identified p90 ribosomal S6 kinase 1 (RSK1) as a crucial regulator of axon regeneration in dorsal root ganglion (DRG) neurons after sciatic nerve injury (SNI). Mechanistically, RSK1 was found to preferentially regulate the synthesis of regeneration-related proteins using ribosomal profiling. Interestingly, RSK1 expression was up-regulated in injured DRG neurons, but not retinal ganglion cells (RGCs). Additionally, RSK1 overexpression enhanced phosphatase and tensin homolog (PTEN) deletion-induced axon regeneration in RGCs in the adult CNS. Our findings reveal a critical mechanism in inducing protein synthesis that promotes axon regeneration and further suggest RSK1 as a possible therapeutic target for neuronal injury repair.

MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury.

Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.

Enhancing Zn2+ Storage Performance by Constructing the Interfaces Between VO2 and Co-N-C Layers.

Vanadium oxides have aroused attention as cathode materials in aqueous zinc-ion batteries (AZIBs) due to their low cost and high safety. However, low ion diffusion and vanadium dissolution often lead to capacity decay and deteriorating stability during cycling. Herein, vanadium dioxides (VO2) nanobelts are coated with a single-atom cobalt dispersed N-doped carbon (Co-N-C) layer via a facile calcination strategy to form Co-N-C layer coated VO2 nanobelts (VO2@Co-N-C NBs) for cathodes in AZIBs. Various in-/ex situ characterizations demonstrate the interfaces between VO2 layers and Co-N-C layers can protect the VO2 NBs from collapsing, increase ion diffusion, and enhance the Zn2+ storage performance. Additional density functional theory (DFT) simulations demonstrate that Co─O─V bonds between VO2 and Co-N-C layers can enhance interfacial Zn2+ storage. Moreover, the VO2@Co-N-C NBs provided an ultrahigh capacity (418.7 mAh g-1 at 1 A g-1), outstanding long-term stability (over 8000 cycles at 20 A g-1), and superior rate performance.

Resveratrol modulates the inflammatory response in hPDLSCs via the NRF2/HO-1 and NF-κB pathways and promotes osteogenic differentiation.

OBJECTIVE: The purpose of this study was to investigate resveratrol's specific role as an anti-inflammatory and osteogenic differentiation of hPDLSCs in periodontitis and to reveal the mechanisms involved. BACKGROUND: Numerous studies have shown that inhibiting the inflammatory response of periodontal tissues and promoting the regeneration of alveolar bone are crucial treatments for periodontitis. Resveratrol has been found to have certain anti-inflammatory property. However, the anti-inflammatory mechanism and osteogenic effect of resveratrol in periodontitis are poorly understood. MATERIALS AND METHODS: We constructed an in vitro periodontitis model by LPS stimulation of hPDLSCs and performed WB, RT-qPCR, and immunofluorescence to analyze inflammatory factors and related pathways. In addition, we explored the osteogenic ability of resveratrol in in vitro models. RESULTS: In vitro, resveratrol ameliorated the inflammatory response associated with activation of the NF-κB pathway through activation of the NRF2/HO-1 pathway, characterized by inhibition of p65/p50 nuclear translocation and the proinflammatory cytokines interleukin-1ß levels. Resveratrol also has a positive effect on osteogenic differentiation. CONCLUSIONS: Observations suggest that resveratrol modulates the inflammatory response in hPDLSCs via the NRF2/HO-1 and NF-κB pathways and promotes osteogenic differentiation.

Network pharmacology, molecular docking, and molecular dynamics simulation analysis reveal the molecular mechanism of halociline against gastric cancer.

Halociline, a derivative of alkaloids, was isolated from the marine fungus Penicillium griseofulvum by our group. This remarkable compound exhibits promising antineoplastic activity, yet the precise molecular mechanisms underlying its anticancer properties remain enigmatic. To unravel these mechanisms, we employed an integrated approach of network pharmacology analysis, molecular docking simulations, and molecular dynamics simulations to explore halociline therapeutic targets for gastric cancer. The data from network pharmacology indicate that halociline targets MAPK1, MMP-9, and PIK3CA in gastric cancer cells, potentially mediated by diverse pathways including cancer, lipid metabolism, atherosclerosis, and EGFR tyrosine kinase inhibitor resistance. Notably, molecular docking and dynamics simulations revealed a high affinity between halociline and these targets, with free binding energies (ΔEtotal) of - 20.28, - 27.94, and - 25.97 kcal/mol for MAPK1, MMP-9, and PIK3CA, respectively. This study offers valuable insights into the potential molecular mechanism of halociline's inhibition of gastric cancer cells and serves as a valuable reference for future basic research efforts.

Epigenetic activation of METTL14 promotes docetaxel resistance in prostate cancer by promoting pri-microRNA-129 maturation.

The development of resistance to Docetaxel (DTX) compromises its therapeutic efficacy and worsens the prognosis of prostate cancer (PCa), while the underlying regulatory mechanism remains poorly understood. In this study, METTL14 was found to be upregulated in DTX-resistant PCa cells and PCa tissues exhibiting progressive disease during DTX therapy. Furthermore, overexpression of METTL14 promoted the development of resistance to DTX in both in vitro and in vivo. Interestingly, it was observed that the hypermethylation of the E2F1 targeting site within DTX-resistant PCa cells hindered the binding ability of E2F1 to the promoter region of METTL14, thereby augmenting its transcriptional activity. Consequently, this elevated expression level of METTL14 facilitated m6A-dependent processing of pri-miR-129 and subsequently led to an increase in miR-129-5p expression. Our study highlights the crucial role of the E2F1-METTL14-miR-129-5p axis in modulating DTX resistance in PCa, underscoring METTL14 as a promising therapeutic target for DTX-resistant PCa patients.

Pyrrolidine, Piperazine, and Diazinane Alkaloids from the Marine Bacterium Strain Vibrio ruber ZXR-93.

Four new alkaloids, vibripyrrolidine A (1), vibripiperazine A (2), and vibridiazinane A, B (3, 4), comprising one pyrrolidine, one piperazine, and two diazinane alkaloids, along with two known analogs (5, 6), were isolated from the marine bacterium Vibrio ruber ZXR-93 cultured in ISP2 medium. Their chemical structures were elucidated by analysis of their 1D and 2D NMR, mass spectra, and electronic circular dichroism (ECD) calculations. Compounds 1 and 3-6 showed vigorous antibacterial activity against Staphylococcus aureus, with MIC values ranging from 0.96 to 7.81 µg/mL. Moreover, compound 1 exhibited robust anti-inflammatory activity in vitro using the LPS-induced RAW264.7 macrophage model. All compounds also showed moderate antineoplastic activity against cervical cancer cells (HeLa) and gastric cancer cells (SGC-7901).

The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration.

BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS: By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS: Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION: Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.

Transcriptome sequencing promotes insights on the molecular mechanism of SKP-SC-EVs mitigating denervation-induced muscle atrophy.

BACKGROUND: Complex pathophysiological changes accompany denervation-induced skeletal muscle atrophy, but no effective treatment strategies exist. Our previous study indicated that extracellular vesicles derived from skin-derived precursors-derived Schwann cells (SKP-SC-EVs) can effectively mitigate denervation-induced muscle atrophy. However, the specific molecular mechanism remains unclear. METHODS AND RESULTS: In this study, we used bioinformatics methods to scrutinize the impact of SKP-SC-EVs on gene expression in denervation-induced skeletal muscle atrophy. We found that SKP-SC-EVs altered the expression of 358 genes in denervated skeletal muscles. The differentially expressed genes were predominantly participated in biological processes, including cell cycle, inflammation, immunity, and adhesion, and signaling pathways, such as FoxO and PI3K.Using the Molecular Complex Detection (MCODE) plugin, we identified the two clusters with the highest score: cluster 1 comprised 37 genes, and Cluster 2 consisted of 24 genes. Then, fifty hub genes were identified using CytoHubba. The intersection of Hub genes and genes obtained by MCODE showed that all 23 genes related to the cell cycle in Cluster 1 were hub genes, and 5 genes in Cluster 2 were hub genes and associated with inflammation. CONCLUSIONS: Overall, the differentially expressed genes in denervated skeletal muscle following SKP-SC-EVs treatment are primarily linked to the cell cycle and inflammation. Consequently, promoting proliferation and inhibiting inflammation may be the critical process in which SKP-SC-EVs delay denervation-induced muscle atrophy. Our findings contribute to a better understanding of the molecular mechanism of SKP-SC-EVs delaying denervation-induced muscle atrophy, offering a promising new avenue for muscle atrophy treatment.

Silencing LINC00491 inhibits prostate cancer development through the miR-384/TRIM44 axis.

Accumulating evidence has demonstrated the key role of long noncoding (lnc)RNAs in tumorigenesis. Prostate cancer (PCa) is a cancer with high mortality that requires further exploration of the underlying molecular mechanisms. In the present study, we aimed to discover novel potential biomarkers for diagnosing PCa and targeting treatment. Overexpression of the lncRNA, LINC00491, was verified in PCa tumor tissues and cell lines using the real-time polymerase chain reaction. Cell proliferation and invasion were then analyzed via the Cell Counting Kit-8, colony formation, and transwell assays in vitro, and tumor growth in vivo. The interaction of miR-384 with LINC00491, as well as TRIM44, was investigated via bioinformatics analyses, subcellular fractionation, luciferase reporter gene assays, radioimmunoprecipitation, pull-down, and western blot analyses. LINC00491 was overexpressed in PCa tissues and cell lines. LINC00491 knockdown resulted in impaired cell proliferation and invasion in vitro and decreased tumor growth in vivo. Moreover, LINC00491 acted as a sponge for miR-384 and its downstream target, TRIM44. Additionally, miR-384 expression was downregulated in PCa tissues and cell lines, and its expression was negatively correlated with LINC00491. A miR-384 inhibitor restored the inhibitory effects of LINC00491 silencing on PCa cell proliferation and invasion. LINC00491 is a tumor promoter in PCa via enhancing TRIM44 expression by sponging miR-384 to facilitate the development of PCa. LINC00491 plays a significant role in PCa and could serve as both a biomarker for early diagnosis and a novel treatment target.

The acetylome of adult mouse sciatic nerve.

Lysine acetylation is a reversible post-translational modification (PTM) involved in multiple physiological functions. Recent studies have demonstrated the involvement of protein acetylation in modulating the biology of Schwann cells (SCs) and regeneration of the peripheral nervous system (PNS). However, the mechanisms underlying these processes remain partially understood. Here, we characterized the acetylome of the mouse sciatic nerve (SN) and investigated the cellular distribution of acetylated proteins. We identified 483 acetylated proteins containing 1442 acetylation modification sites in the SN of adult C57BL/6 mice. Bioinformatics suggested that these acetylated SN proteins were mainly located in the myelin sheath, mitochondrial inner membrane, and cytoskeleton, and highlighted the significant differences between the mouse SN and brain acetylome. Manual annotation further indicated that most acetylated proteins (> 45%) were associated with mitochondria, energy metabolism, and cytoskeleton and cell adhesion. We verified three newly discovered acetylation-modified proteins, including neurofilament light polypeptide (NEFL), neurofilament medium/high polypeptide (NFM/H), and periaxin (PRX). Immunofluorescence illustrated that the acetylated proteins, including acetylated alpha-tubulin, were mainly co-localized with S100-positive SCs. Herein, we provided a comprehensive acetylome for the mouse SN and demonstrated that acetylated proteins in the SN were predominantly located in SCs. These results will extend our understanding and promote further study of the role and mechanism of protein acetylation in SC development and PNS regeneration.

Ethanol Extract of Eryngium Foetidum Leaves Induces Mitochondrial Associated Apoptosis via ROS Generation in Human Gastric Cancer Cells.

Background: Eryngium foetidum has long been used as a food ingredient and folk medicine in tropical regions. The anticancer activity of EF extract and the mechanisms remains unclear. Herein, we prepared four solvent extracts of EF leaves, detected the cytotoxic effects, and explored the potential mechanism by which these extracts induce cell death. Methods: The anticancer activity of the EF extracts was measured by MTT, CCK-8 and BrdU assays. The cell cycle was evaluated by flow cytometry and western blot. Apoptotic events were investigated with Hoechst, Annexin V/PI assays and western blot. The mitochondrial membrane potential was monitored using JC-1 staining, and ROS production was assessed with immunofluorescence. Results: The ethanol extract of EF leaves exhibited the strongest cytotoxic effect against SGC-7901 cells. The EFE extract significantly inhibited the SGC-7901 cells viability, arrested the cell cycle, increased the numbers of apoptotic cells, caused the loss of MMP, increased the Bax/Bcl-2 ratio, and led to cytochrome c release, and triggered ROS production. Conclusion: Our findings demonstrated for the first time that EFE extract induces mitochondrial associated apoptosis via ROS generation in SGC-7901 cells. Thus, EFE extract could be identified as a potential edible phytotherapy for the treatment of human gastric cancer.

Genistein attenuates LPS-induced inflammatory injury of rat dorsal root ganglion neuron via down-regulating HDAC6. / é‡‘é›€å¼‚é»„ç´ é€šè¿‡ä¸‹è°ƒHDAC6减轻LPSè¯±å¯¼çš„å¤§é¼ èƒŒæ ¹ç¥žç»èŠ‚ç¥žç»å ƒç‚Žæ€§æŸä¼¤.

OBJECTIVES: Neuropathic pain (NP) is a chronic pain caused by somatosensory neuropathy or disease, and genistein (Gen) might be a potential drug for the treatment of NP. Therefore, this study aims to investigate the effect of Gen on lipopolysaccharide (LPS)-induced inflammatory injury of dorsal root ganglion neuron (DRGn) in rats and the possible molecular mechanism. METHODS: The DRGn of 1-day-old juvenile rats were taken for isolation and culture. The DRGn in logarithmic growth phase were divided into a control group, a LPS group, a tubastatin hydrochloride (TSA)+LPS group, a Gen1+LPS group, a Gen2+LPS group, a Gen2+LPS+TSA group, a Gen2+pcDNA-histone deacetylase 6 (HDAC6)+LPS group, and a Gen2+pcDNA3.1+LPS group. The LPS group was treated with 1 µg/mL LPS for 24 h; the TSA+LPS group, the Gen1+LPS group, the Gen2+LPS group were treated with 5 µmol/L TSA, 5 µmol/L Gen, 10 µmol/L Gen respectively for 0.5 h, and then added 1 µg/mL LPS for 24 h; the Gen2+TSA+LPS group was treated with 10 µmol/L Gen and 5 µmol/L TSA for 0.5 h and then added 1 µg/mL LPS for 24 h; the Gen2+pcDNA-HDAC6+LPS group and the Gen2+pcDNA3.1+LPS group received 100 nmol/L pcDNA-HDAC6 and pcDNA3.1 plasmids respectively, and 24 h after transfection, 10 µmol/L Gen was pretreated for 0.5 h, and then added 1 µg/mL LPS for 24 h. Real-time RT-PCR was used to detect the HDAC6 mRNA expression in DRGn; CCK-8 method was used to detect cell viability of DRGn; flow cytometry was used to detect cell apoptosis of DRGn; ELISA was used to detect the levels of IL-1ß, IL-6, and TNF-α in DRGn culture supernatant; Western blotting was used to detect the protein expression of HDAC6, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and NF-κB p65 in DRGn. RESULTS: Compared with the control group, the expression levels of HDAC6 mRNA and protein, the expression levels of TLR4 and MyD88 protein in DRGn of LPS group rats were significantly up-regulated, the ratio of p-NF-κB p65/NF-κB p65 was significantly increased, and the activity of DRGn was significantly decreased, the apoptosis rate was significantly increased, and the levels of IL-1ß, IL-6 and TNF-α in the DRGn culture supernatant were significantly increased (all P<0.05). Compared with the LPS group, the expression levels of HDAC6 mRNA and protein, TLR4 and MyD88 protein expression levels in DRGn of the TSA+LPS group, the Gen1+LPS group, the Gen2+LPS group and the Gen2+TSA+LPS group were significantly down-regulated, the ratio of p-NF-κB p65/NF-κB p65 was significantly decreased, the activity of DRGn was significantly increased, the apoptosis rate was significantly decreased, and the levels of IL-1ß, IL-6 and TNF-α in the DRGn culture supernatant were significantly decreased (all P<0.05), and the above changes were most obvious in the Gen2+TSA+LPS group. Compared with the Gen2+LPS group, the expression levels of HDAC6 mRNA and protein, TLR4 and MyD88 protein expression levels in DRGn of the Gen2+pcDNA-HDAC6+LPS group were significantly up-regulated, the ratio of p-NF-κB p65/NF-κB p65 was significantly increased, the activity of DRGn was significantly decreased, and the apoptosis rate was significantly increased, and the levels of IL-1ß, IL-6 and TNF-α in the DRGn culture supernatant were significantly increased (all P<0.05). CONCLUSIONS: Gen can alleviate LPS-induced DRGn inflammatory injury in rats, which might be related to down-regulating the expression of HDAC6 and further inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway.

Lunar Surface Fault-Tolerant Soft-Landing Performance and Experiment for a Six-Legged Movable Repetitive Lander.

The cascading launch and cooperative work of lander and rover are the pivotal methods to achieve lunar zero-distance exploration. The separated design results in a heavy system mass that requires more launching costs and a limited exploration area that is restricted to the vicinity of the immovable lander. To solve this problem, we have designed a six-legged movable repetitive lander, called "HexaMRL", which congenitally integrates the function of both the lander and rover. However, achieving a buffered landing after a failure of the integrated drive units (IDUs) in the harsh lunar environment is a great challenge. In this paper, we systematically analyze the fault-tolerant capacity of all possible landing configurations in which the number of remaining normal legs is more than two and design the landing algorithm to finish a fault-tolerant soft-landing for the stable configuration. A quasi-incentre stability optimization method is further proposed to increase the stability margin during supporting operations after landing. To verify the fault-tolerant landing performance on the moon, a series of experiments, including five-legged, four-legged and three-legged soft-landings with a vertical landing velocity of -1.9 m/s and a payload of 140 kg, are successfully carried out on a 5-DoF lunar gravity ground-testing platform. The HexaMRL with fault-tolerant landing capacity will greatly promote the development of a next-generation lunar prober.

Nomograms for predicting overall survival and cancer-specific survival of chondroblastic osteosarcoma patients.

BACKGROUND: The establishment of precise and personalized prediction systems for chondroblastic osteosarcoma patients is important for guiding the treatment. METHODS: The univariate logrank test and multivariate Cox regression analysis were performed to identify independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Nomograms were constructed to estimate the OS and CSS based on these factors. Internal and external validation was performed. The predictive power of the nomograms was determined by C-index and calibration plots. RESULTS: A total of 401 chondroblastic osteosarcoma cases were identified. Univariate and multivariate analysis revealed that age at diagnosis, histological grade, tumor size, Surveillance, Epidemiology, and End Results stage, and surgical resection were independent prognostic factors for OS and CSS. The five factors were incorporated to construct the nomograms for estimating the 3- and 5-year OS and CSS. The C-index values for the internal validation of the OS and CSS nomogram were 0.732 and 0.746, respectively, and for the external validation were 0.780 and 0.808, respectively. The calibration curves revealed that the predicted OS and CSS could well match the actual survival rate. CONCLUSIONS: The nomograms for predicting 3- and 5-year OS and CSS were constructed and were proved to be accurate and reliable by the internal and external validation.

Prognostic Factors and Treatment Options for Patients with High-Grade Chondrosarcoma.

BACKGROUND The goal of this study was to determine the prognostic factors exclusive for high-grade chondrosarcoma and whether adjuvant radiotherapy could achieve better overall survival (OS) or cancer-specific survival (CSS) for patients with high-grade chondrosarcoma. MATERIAL AND METHODS Surveillance, Epidemiology, and End Results (SEER) cancer registry database was utilized to extract the chondrosarcoma cases diagnosed between 1973 and 2014. Among these cases, the histological grades of poorly differentiated (grade 3) and undifferentiated (grade 4) were categorized as high-grade and included in this study. Chondrosarcoma OS and CSS were the primary outcomes in the present study. The log-rank test was performed for univariate analysis, and the Cox regression model was conducted for multivariate analysis. RESULTS A total of 743 patients with high-grade chondrosarcoma were identified in this study (430 cases were poorly differentiated tumors, and 313 cases were undifferentiated tumors). Age at diagnosis, pathological grade, histo-type, SEER stage, tumor size and surgical resection were identified as independent predictors in both OS and CSS analysis of high-grade chondrosarcoma. When stratified by histological grade, surgical resection remained the effective treatment. Strikingly, radiotherapy was determined as an independent protective factor in both OS and CSS analysis of undifferentiated (grade 4) dedifferentiated chondrosarcoma, and adjuvant radiotherapy combined surgical resection could improve both the OS and CSS of patients with undifferentiated myxoid and dedifferentiated chondrosarcoma compared with other treatment regimens. CONCLUSIONS Our study first demonstrated that adjuvant radiotherapy combined surgery could improve the survival of patients with undifferentiated myxoid and dedifferentiated chondrosarcoma. These results encourage the application of adjuvant radiotherapy for patients with high-grade chondrosarcoma and maximize the patients' outcome.