Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization

Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury.Strikingly,hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs(HSEVs)exhibit increased therapeutic potency.We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair.SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation.HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation.HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro.Micro RNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that mi R-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1.Reducing mi R-146a-5p expression in HSEVs partially attenuated macrophage polarization.Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting mi R-146a-5p,which alters macrophage polarization.This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Fine-needle aspiration technique under endoscopic ultrasound guidance:A technical approach for RNA profiling of pancreatic neoplasms

BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma(PDAC)has been a longstanding challenge.The prognosis of patients with PDAC depends on the stage at diagnosis.It is necessary to identify biomarkers for the detection and differentiation of pancreatic tumors and optimize PDAC sample preparation procedures for DNA and RNA analysis.Most molecular studies are done using paraffin-embedded blocks;however,the integrity of DNA and RNA is often compromised in this format.Moreover,RNA isolated from human pancreatic tissue samples is generally of low quality,in part,because of the high concentration of endogenous pancreatic RNAse activity present.AIM To assess the potential of endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA)to obtain specimens from pancreatic neoplasms for subsequent RNA molecular profiling,including next-generation sequencing(NGS).METHODS Thirty-four EUS-FNA samples were included in this study:PDAC(n=15),chronic pancreatitis(n=5),pancreatic cysts(n=14),mucinous cysts(mucinous cystic neoplasia/intraductal papillary mucinous neoplasia)n=7,serous cystic neoplasms n=5,and pseudocysts n=2.Cyst material consisted of cyst fluid and cyst wall samples obtained by through-the-needle biopsy(TTNB).Samples were stored at -80℃ until analysis.RNA purity(A260/230,A260/280 ratios),concentration,and integrity(RIN)were assessed.Real-time polymerase chain reaction was conducted on all samples,and small RNA libraries were prepared from solid mass samples.RESULTS RNA was successfully extracted from 29/34(85%)EUS-FNA samples:100% pancreatic adenocarcinoma samples,100% chronic pancreatitis samples,70% pancreatic fluid cyst samples,and 50%TTNB samples.The relative expression of GAPDH and HPRT were obtained for all successfully extracted RNA samples(n=29)including lowquality RNA specimens.Low concentration and nonoptimal RIN values(no less than 3)of RNA extracted from EUS-FNA samples did not prevent NGS library preparation.The suitability of cyst fluid samples for RNA profiling varied.The quality of RNA extracted from mucinous cyst fluid had a median RIN of 7.7(5.0-8.2),which was compatible with that from solid neoplasms[6.2(0-7.8)],whereas the quality of the RNA extracted from all fluids of serous cystic neoplasms and TTNB samples had a RIN of 0.CONCLUSION The results demonstrate the high potential of EUS-FNA material for RNA profiling of various pancreatic lesions,including low-quality RNA specimens.

Repressing iron overload ameliorates central poststroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.

Neutrophil-derived interleukin-17A participates in neuroinflammation induced by traumatic brain injury

After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury(sub-acute phase), genome-wide transcriptomic data showed that interleukin 17 A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17 A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17 A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17 A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17 A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17 A may be a promising therapeutic target for traumatic brain injury.

Sex modulates the outcome of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease

There are many documented sex differences in the clinical course,symptom expression profile,and treatment response of Parkinson’s disease,creating additional challenges for patient management.Although subthalamic nucleus deep brain stimulation is an established therapy for Parkinson’s disease,the effects of sex on treatment outcome are still unclear.The aim of this retrospective observational study,was to examine sex differences in motor symptoms,nonmotor symptoms,and quality of life after subthalamic nucleus deep brain stimulation.Outcome measures were evaluated at 1 and 12 months post-operation in 90 patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation aged 63.00±8.01 years(55 men and 35 women).Outcomes of clinical evaluations were compared between sexes via a Student’s t-test and within sex via a paired-sample t-test,and generalized linear models were established to identify factors associated with treatment efficacy and intensity for each sex.We found that subthalamic nucleus deep brain stimulation could improve motor symptoms in men but not women in the on-medication condition at 1 and 12 months post-operation.Restless legs syndrome was alleviated to a greater extent in men than in women.Women demonstrated poorer quality of life at baseline and achieved less improvement of quality of life than men after subthalamic nucleus deep brain stimulation.Furthermore,Hoehn-Yahr stage was positively correlated with the treatment response in men,while levodopa equivalent dose at 12 months post-operation was negatively correlated with motor improvement in women.In conclusion,women received less benefit from subthalamic nucleus deep brain stimulation than men in terms of motor symptoms,non-motor symptoms,and quality of life.We found sex-specific factors,i.e.,Hoehn-Yahr stage and levodopa equivalent dose,that were related to motor improvements.These findings may help to guide subthalamic nucleus deep brain stimulation patient selection,prognosis,and stimulation programming for optimal therapeutic efficacy in Parkinson’s disease.

Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes

Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.

Tandem Mass Tag-based proteomics analysis reveals the vital role of inflammation in traumatic brain injury in a mouse model

Proteomics is a powerful tool that can be used to elucidate the underlying mechanisms of diseases and identify new biomarkers.Therefore,it may also be helpful for understanding the detailed pathological mechanism of traumatic brain injury(TBI).In this study,we performed Tandem Mass Tag-based quantitative analysis of cortical proteome profiles in a mouse model of TBI.Our results showed that there were 302 differentially expressed proteins in TBI mice compared with normal mice 7 days after injury.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that these differentially expressed proteins were predominantly involved in inflammatory responses,including complement and coagulation cascades,as well as chemokine signaling pathways.Subsequent transcription factor analysis revealed that the inflammation-related transcription factors NF-κB1,RelA,IRF1,STAT1,and Spi1 play pivotal roles in the secondary injury that occurs after TBI,which further corroborates the functional enrichment for inflammatory factors.Our results suggest that inflammation-related proteins and inflammatory responses are promising targets for the treatment of TBI.

Comparison of the Nerve Regeneration Capacity and Characteristics between Sciatic Nerve Crush and Transection Injury Models in Rats

Objective To provide useful information for selecting the most appropriate peripheral nerve injury model for different research purposes in nerve injury and repair studies,and to compare nerve regeneration capacity and characteristics between them.Methods Sixty adult SD rats were randomly divided into two groups and underwent crush injury alone(group A,n=30)or transection injury followed by surgical repair(group B,n=30)of the right hind paw.Each group was subjected to the CatWalk test,gastrocnemius muscle evaluation,pain threshold measurement,electrophysiological examination,retrograde neuronal labeling,and quantification of nerve regeneration before and 7,14,21,and 28 days after injury.Results Gait analysis showed that the recovery speed in group A was significantly faster than that in group B at 14 days.At 21 days,the compound muscle action potential of the gastrocnemius muscle in group A was significantly higher than that in group B,and the number of labeled motor neurons in group B was lower than that in group A.The number of new myelin sheaths and the g-ratio were higher in group A than in group B.There was a 7-day time difference in the regeneration rate between the two injury groups.Conclusion The regeneration of nerve fibers was rapid after crush nerve injury,whereas the transection injury was relatively slow,which provides some ideas for the selection of clinical research models.

Effect of Age and Sex on Stroke Mortality of Young and Middle-aged Adults in China,2002–2019,and Predictions to 2030

Objective This study aimed to examine the trends in stroke mortality among young and middle-aged adults in China.Methods Data were obtained from the China national vital registration system.Significant changes in mortality were assessed by Joinpoint regression.Age-period-cohort analysis was used to explain the reasons for the changes.Future mortality and counts were predicted by the Bayesian age-period-cohort model.Results Between 2002 and 2019,a total of 6,253,951 stroke mortality in young and middle-aged adults were recorded.The age-adjusted mortality rates(AAMRs)of women showed a downward trend.The annual percent changes(APC)were-3.5%(-5.2%,-1.7%)for urban women and-2.8%(-3.7%,-1.9%)for rural women.By contrast,the AAMRs per 100,000 for rural men aged 25–44 years continued to rise from 9.40 to 15.46.The AAMRS for urban men aged 25–44 years and urban and rural men aged 45–64years did not change significantly.Between 2020 and 2030,the projected stroke deaths are 1,423,584 in men and 401,712 in women.Conclusion Significant sex and age disparities in the trends of stroke mortality among young and middle-aged adults were identified in China.Targeted health policy measures are needed to address the burden of stroke in the young generation,especially for rural men,with a focus on the prevention and management of high risk factors.

Erratum to Clinical management and survival outcomes of patients with different molecular subtypes of diffuse gliomas in China(2011-2017):a multicenter retrospective study from CGGA

In the published version of Figure 21,an error appeared in Figure 2C on page 1468.In Figure 2C,the Kaplan-Meier estimation of the overall survival of patients with recurrent DG classified according to molecular subtypes was mistakenly covered by the curves of patients with primary DGs during the figure layout process,while the number statistic under the figure is correct.Figure 2C has been updated to correct this mistake.The error does not affect the conclusions of this article.We apologize for the error and for any confusion that it might have caused.

Evolution-driven crosstalk between glioblastoma and the tumor microenvironment

Glioblastoma(GBM)is a malignant adult brain tumor for which 90%of patients experience recurrence within a year after surgery1.Evolution confers treatment resistance capabilities on tumors2.The diversification of malignant and non-malignant(i.e.,stromal and immune cell)compartments in the tumor microenvironment(TME)during tumor evolution3-7 eventually results in the formation of a complex interaction network that promotes tumor progression.

Induction of Functional Recovery by Co-transplantation of Neural Stem Cells and Schwann Cells in a Rat Spinal Cord Contusion Injury Model

Objective To study the transplantation efficacy of neural stem cells （NSCs） and Schwann cells （SC） in a rat model of spinal cord contusion injury. Methods Multipotent neural stem cells （NSCs） and Schwann cells were harvested from the spinal cords of embryonic rats at 16 days post coitus and sciatic nerves of newborn rats, respectively. The differential characteristics of NSCs in vitro induced by either serum-based culture or co-culture with SC were analyzed by immunofluorescence. NSCs and SCs were co-transplanted into adult rats having undergone spinal cord contusion at T9 level. The animals were weekly monitored using the Basso-Beattie-Bresnahan locomotor rating system to evaluate functional recovery from contusion-induced spinal cord injury. Migration and differentiation of transplanted NSCs were studied in tissue sections using immunohistochemical staining. Results Embryonic spinal cord-derived NSCs differentiated into a large number of oligodendrocytes in serum-based culture upon the withdrawal of mitogens. In cocultures with SCs, NSCs differentiated into neuron more readily. Rats with spinal cord contusion injury which had undergone transplantation of NSCs and SCs into the intraspinal cavity demonstrated a moderate improvement in motor functions. Conclusions SC may contribute to neuronal differentiation of NSCs in vitro and in vivo. Transplantation of NSCs and SCs into the affected area may be a feasible approach to promoting motor recovery in patients after spinal cord injury.

μ-and m-calpain expression and activity changes following diethylstilbestrol injection in the rat anterior pituitary

Little is known about changes in calpain activity in the pituitary gland. In the present study,μ- and m-calpain activity changes were detected in the rat anterior pituitary following intraperitoneal injection of diethylstilbestrol. Double-immunofluorescence labeling confirmed colocalization of μ- and m-calpain in prolactin-secreting cells （lactotrophs）. Western blot analysis revealed significantly increased expression of both calpains, which accompanied upregulated cytosol and membrane zymographic activities at 12 weeks following diethylstilbestrol injection, compared with rats injected with sunflower oil. Moreover, following estrogen injection, pituitary gland pathological damage gradually worsened with increasing time. Results demonstrated that estrogen regulated calpain expression and activity, and both calpains participated in the pathophysiological processes of the pituitary gland. Ubiquitous calpain expression could serve as an effective target for anti-estrogen drugs.

Comparative transcriptomic analysis of rat versus mouse cerebral cortex after traumatic brain injury

The heterogeneity of traumatic brain injury(TBI)-induced secondary injury has greatly hampered the development of effective treatments for TBI patients.Targeting common processes across species may be an innovative strategy to combat debilitating TBI.In the present study, a cross-species transcriptome comparison was performed for the first time to determine the fundamental processes of secondary brain injury in Sprague-Dawley rat and C57/BL6 mouse models of TBI, caused by acute controlled cortical impact.The RNA sequencing data from the mouse model of TBI were downloaded from the Gene Expression Omnibus(ID: GSE79441) at the National Center for Biotechnology Information.For the rat data, peri-injury cerebral cortex samples were collected for transcriptomic analysis 24 hours after TBI.Differentially expressed gene-based functional analysis revealed that common features between the two species were mainly involved in the regulation and activation of the innate immune response, including complement cascades as well as Toll-like and nucleotide oligomerization domain-like receptor pathways.These findings were further corroborated by gene set enrichment analysis.Moreover, transcription factor analysis revealed that the families of signal transducers and activators of transcription(STAT), basic leucine zipper(BZIP), Rel homology domain(RHD), and interferon regulatory factor(IRF) transcription factors play vital regulatory roles in the pathophysiological processes of TBI, and are also largely associated with inflammation.These findings suggest that targeting the common innate immune response might be a promising therapeutic approach for TBI.The animal experimental procedures were approved by the Beijing Neurosurgical Institute Animal Care and Use Committee(approval No.201802001) on June 6, 2018.

Effects of Photodynamic Therapy on the Ultrastructure of Glioma Cells

To study the change in ultrastructure of C6 glioma cells after photodynamic therapy （PDT）, to compare morphological differences in necrosis and apoptosis before and after PDT treatment, and to evaluate the effect of photodynamic therapy on the blood brain tumor barrier （BTB） of C6 glioma. Methods The model was produced by transplanting C6 glioma cells cultured in vitro using Peterson method into the caudate nuclei of Wister rats. The experiment group received PDT for two weeks after the operation. The sub-cellular structure, blood-brain-barrier （BBB） and BTB in both groups were observed under electron microscope. Results Apoptosis in different phases and necrosis could be observed in some C6 glioma cells. Swelling occurred on the ultrastructure of cellular organs such as mitochondria and endoplasmic reticulum in most of the cells. Damage to the BTB, reduction of the number of cellular organs in endothelial cells of the capillary blood vessels, stretch of the tight junction, and enlargement of the gaps between endothelial cells were also seen in the experiment group. Meanwhile, limited impact on the normal sub-ceUular structures and BBB was observed. Conclusion PDT could induce apoptosis and necrosis of C6 glioma cells due to the damage to the ultrastructure of mitochondria and endoplasmic reticulum. The weakened function of C6 glioma BTB initiated by PDT makes it possible to perform a combined therapy of PDT and chemotherapy for glioma.

Prognostic implications of epidermal growth factor receptor variant Ⅲ expression and nuclear translocation in Chinese human gliomas

Objective: To determine the prognostic implications and clinical significance of epidermal growth factor receptor variant Ⅲ(EGFRvⅢ) expression and EGFRvⅢ nuclear translocation in Chinese human gliomas.Methods: We retrospectively examined EGFRvⅢ expression and EGFRvⅢ nuclear translocation using immunohistochemistry in specimens of 240 Chinese patients with glioma, including 84 World Health Organization(WHO) II gliomas, 84 WHO Ⅲ gliomas and 72 glioblastomas(WHO IV). Factors that correlated with EGFRvⅢ and EGFRvⅢ nuclear translocation expression were analyzed by the Chi-square test. Kaplan-Meier methodology and Cox regression were used for the survival analysis.Results: Log-rank tests showed that patient age, Karnofsky performance scale(KPS) score, tumor grade,EGFRvⅢ expression, EGFRvⅢ nuclear translocation, 1 p/19 q codeletion, isocitrate dehydrogenase(IDH)mutation, Ki-67 labeling index and O6-methylguanine-DNA methyltransferase(MGMT) status(P<0.05) were significantly correlated with overall survival(OS) time. Multivariate Cox regression analysis revealed that patient age, tumor grade, EGFRvⅢ nuclear translocation, 1 p/19 q codeletion, and IDH mutation(P<0.05) were significantly correlated with OS. Patients with a high level of EGFRvⅢ nuclear translocation(≥7%) had both significantly shorter OS [hazard ratio(HR): 1.920, 95% confidence interval(95% CI): 1.228-3.003, P=0.004] and progression-free survival(PFS) times(HR: 1.661, 95% CI: 1.116-2.471, P=0.012) than those with a low level of EGFRvⅢ nuclear translocation(<7%).Conclusions: A high level of EGFRvⅢ nuclear translocation in glioma is an independent factor indicating a poor prognosis, but EGFRvⅢ expression is not an independent clinical prognostic factor. The level of EGFRvⅢ nuclear translocation maybe a novel and crucial prognostic biomarker in glioma.

Genome-wide interrogation of transfer RNA-derived small RNAs in a mouse model of traumatic brain injury

Transfer RNA(t RNA)-derived small RNAs(ts RNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that ts RNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether ts RNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated ts RNA and messenger RNA(m RNA) transcriptome sequencing were used. The results revealed that 103 ts RNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 ts RNAs were upregulated and 47 ts RNAs were downregulated. Based on micro RNA-like seed matching and Pearson correlation analysis, 57 differentially expressed ts RNA-m RNA interaction pairs were identified, including 29 ts RNAs and 26 m RNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that ts RNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee(approval No. 20190411) on April 11, 2019.

Clinical management and survival outcomes of patients withdifferent molecular subtypes of diffuse gliomas in China(2011–2017):a multicenter retrospective study from CGGA

Objective:We aimed to summarize the clinicopathological characteristics and prognostic features of various molecular subtypes of diffuse gliomas(DGs)in the Chinese population.Methods:In total,1,418 patients diagnosed with DG between 2011 and 2017 were classified into 5 molecular subtypes according to the 2016 WHO classification of central nervous system tumors.The IDH mutation status was determined by immunohistochemistry and/or DNA sequencing,and 1p/19q codeletion was detected with fluorescence in situ hybridization.The median clinical follow-up time was 1,076 days.T-tests and chi-square tests were used to compare clinicopathological characteristics.Kaplan‒Meier and Cox regression methods were used to evaluate prognostic factors.Results:Our cohort included 15.5%lower-grade gliomas,IDH-mutant and 1p/19q-codeleted(LGG-IDHm-1p/19q);18.1%lowergrade gliomas,IDH-mutant(LGG-IDHm);13.1%lower-grade gliomas,IDH-wildtype(LGG-IDHwt);36.1%glioblastoma,IDHwildtype(GBM-IDHwt);and 17.2%glioblastoma,IDH-mutant(GBM-IDHm).Approximately 63.3%of the enrolled primary gliomas,and the median overall survival times for LGG-IDHm,LGG-IDHwt,GBM-IDHwt,and GBM-IDHm subtypes were 75.97,34.47,11.57,and 15.17 months,respectively.The 5-year survival rate of LGG-IDHm-1p/19q was 76.54%.We observed a significant association between high resection rate and favorable survival outcomes across all subtypes of primary tumors.We also observed a significant role of chemotherapy in prolonging overall survival for GBM-IDHwt and GBM-IDHm,and in prolonging post-relapse survival for the 2 recurrent GBM subtypes.Conclusions:By controlling for molecular subtypes,we found that resection rate and chemotherapy were 2 prognostic factors associated with survival outcomes in a Chinese cohort with DG.

Prediction of radiosensitivity in primary central nervous system germ cell tumors using dynamic contrast-enhanced magnetic resonance imaging

Objective： To evaluate the feasibility of dynamic contrast-enhanced magnetic resonance imaging（DCEMRI） for predicting tumor response to radiotherapy in patients with suspected primary central nervous system（CNS） germ cell tumors（GCTs）.Methods： DCE-MRI parameters of 35 patients with suspected primary CNS GCTs were obtained prior to diagnostic radiation, using the Tofts and Kermode model. Radiosensitivity was determined in tumors diagnosed 2 weeks after radiation by observing changes in tumor size and markers as a response to MRI. Taking radiosensitivity as the gold standard, the cut-off value of DCE-MRI parameters was measured by receiver operating characteristic（ROC） curve. Diagnostic accuracy of DCE-MRI parameters for predicting radiosensitivity was evaluated by ROC curve.Results： A significant elevation in transfer constant（K^trans） and extravascular extracellular space（Ve）（P=0.000）, as well as a significant reduction in rate constant（Kep）（P=0.000） was observed in tumors. K^trans, relative K^trans, and relative Kep of the responsive group were significantly higher than non-responsive groups. No significant difference was found in Kep, Ve, and relative Ve between the two groups. Relative K^trans showed the best diagnostic value in predicting radiosensitivity with a sensitivity of 100%, specificity of 91.7%, positive predictive value（PPV） of 95.8%, and negative predictive value（NPV） of 100%.Conclusions： Relative K^trans appeared promising in predicting tumor response to radiation therapy（RT）. It is implied that DCE-MRI pre-treatment is a requisite step in diagnostic procedures and a novel and reliable approach to guide clinical choice of RT.

Protein profiling identified mitochondrial dysfunction and synaptic abnormalities after dexamethasone intervention in rats with traumatic brain injury

Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability,inhibit free radicals,and reduce cerebrospinal fluid production.According to the latest guidelines for the treatment of traumatic brain injury in the United States,high-dose glucocorticoids cause neurological damage.To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect,rat controlled cortical impact models of traumatic brain injury were established.At 1 hour and 2 days after surgery,rat models were intraperitoneally administered dexamethasone 10 mg/kg.The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment.The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway.Western blot analysis and immunohistochemistry results showed that Ndufv2,Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group.These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits(Ndufs2 and Ndufv2),increase the expression of mitochondrial enzyme Maob,and upregulate synaptic-transmission-related protein Gria3.These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone.The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute(approval No.201802001)on June 6,2018.