A novel molecular classification method for osteosarcoma based on tumor cell differentiation trajectories

Subclassification of tumors based on molecular features may facilitate therapeutic choice and increase the response rate of cancer patients.However,the highly complex cell origin involved in osteosarcoma(OS)limits the utility of traditional bulk RNA sequencing for OS subclassification.Single-cell RNA sequencing(sc RNA-seq)holds great promise for identifying cell heterogeneity.However,this technique has rarely been used in the study of tumor subclassification.By analyzing sc RNA-seq data for six conventional OS and nine cancellous bone(CB)samples,we identified 29 clusters in OS and CB samples and discovered three differentiation trajectories from the cancer stem cell(CSC)-like subset,which allowed us to classify OS samples into three groups.The classification model was further examined using the TARGET dataset.Each subgroup of OS had different prognoses and possible drug sensitivities,and OS cells in the three differentiation branches showed distinct interactions with other clusters in the OS microenvironment.In addition,we verified the classification model through IHC staining in 138 OS samples,revealing a worse prognosis for Group B patients.Furthermore,we describe the novel transcriptional program of CSCs and highlight the activation of EZH2 in CSCs of OS.These findings provide a novel subclassification method based on sc RNA-seq and shed new light on the molecular features of CSCs in OS and may serve as valuable references for precision treatment for and therapeutic development in OS.

EVs-mediated delivery of CB2 receptor agonist for Alzheimer’s disease therapy

Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.

Spinal cord injury:molecular mechanisms and therapeutic interventions

Spinal cord injury(SCI)remains a severe condition with an extremely high disability rate.The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system.In the past few decades,researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling.

Temporal and spatial cellular and molecular pathological alterations with single-cell resolution in the adult spinal cord after injury

Spinal cord injury(SCI)involves diverse injury responses in different cell types in a temporally and spatially specific manner.Here,using single-cell transcriptomic analyses combined with classic anatomical,behavioral,electrophysiological analyses,we report,with single-cell resolution,temporal molecular and cellular changes in crush-injured adult mouse spinal cord.Data revealed pathological changes of 12 different major cell types,three of which infiltrated into the spinal cord at distinct times post-injury.We discovered novel microglia and astrocyte subtypes in the uninjured spinal cord,and their dynamic conversions into additional stage-specific subtypes/states.Most dynamic changes occur at 3-days post-injury and by day-14 the second wave of microglial activation emerged,accompanied with changes in various cell types including neurons,indicative of the second round of attacks.By day-38,major cell types are still substantially deviated from uninjured states,demonstrating prolonged alterations.This study provides a comprehensive mapping of cellular/molecular pathological changes along the temporal axis after SCI,which may facilitate the development of novel therapeutic strategies,including those targeting microglia.

Efficacy and safety of external tissue expansion technique in the treatment of soft tissue defects:a systematic review and meta-analysis of outcomes and complication rates

Background:Currently,various external tissue expansion devices are becoming widely used.Considering the scarcity of relevant application standards,this systematic review was performed to explore the effectiveness and safety of external tissue expansion techniques for the reconstruction of soft tissue defects.Method:A systematic review and meta-analysis on the efficacy and safety of external tissue expansion technique was conducted.A comprehensive search was performed in the following electronic databases:PubMed/Medline,Embase,Cochrane Library(Wiley Online Library),andWeb of Science.Studies reporting patients with soft tissue defects under the treatment of external tissue expansion technique were included.Results:A total of 66 studies with 22 different types of external tissue expansion devices met the inclusion criteria.We performed a descriptive analysis of different kinds of devices.A single-arm meta-analysis was performed to evaluate the efficacy and safety of the external tissue expansion technique for different aetiologies.The pooled mean wound healing time among patients with defects after fasciotomy was 10.548 days[95%confidence interval(CI)=5.796-15.299].The pooled median wound healing times of patients with defects after excisional surgery,trauma,chronic ulcers and abdominal defects were 11.218 days(95%CI=6.183-16.253),11.561 days(95%CI=7.062-16.060),15.956 days(95%CI=11.916-19.996)and 12.853 days(95%CI=9.444-16.227),respectively.The pooled wound healing rates of patients with defects after fasciotomy,excisional surgery,trauma,chronic ulcers and abdominal defects were 93.8%(95%CI=87.1-98.2%),97.2%(95%CI=92.2-99.7%),97.0%(95%CI=91.2-99.8%),99.5%(95%CI=97.6-100%),and 96.8%(95%CI=79.2-100%),respectively.We performed a subgroup analysis in patients with diabetic ulcers and open abdominal wounds.The pooled median wound healing time of patients with diabetic ulcers was 11.730 days(95%CI=10.334-13.125).The pooled median wound healing time of patients with open abdomen defects was 48.810 days(95%CI=35.557-62.063)and the pooled successful healing rate was 68.8%(95%CI=45.9-88.1%).A total of 1686 patients were included,265(15.7%)of whom experienced complications.The most common complication was dehiscence(n=53,3.14%).Conclusions:Our systematic review is the first to demonstrate the efficacy and safety of external tissue expansion in the management of soft tissue defects.However,we must interpret the meta-analysis results with caution considering the limitations of this review.Large-scale randomized controlled trials and long-term follow-up studies are still needed to confirm the effectiveness and evaluate the quality of healing.