Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells (ECs), to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Lineage-tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, evidence of trans-differentiation of GBM cells into vascular cells was barely detected. Intriguingly, GBM cells could promiscuously express markers for mural cells during gliomagenesis. Furthermore, single-cell RNA sequencing showed that patterns of copy number variations (CNVs) of mural cells and ECs were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Importantly, single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages. Rather than expansion owing to trans-differentiation, vascular cell expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.
Mice ; Animals ; Humans ; Glioblastoma/pathology* ; Endothelial Cells/pathology* ; DNA Copy Number Variations ; Brain/metabolism* ; Brain Neoplasms/pathology*

Long non-coding RNAs (lncRNAs) regulate transcription to control development and homeostasis in a variety of tissues and organs. However, their roles in the development of the cerebral cortex have not been well elucidated. Here, a bioinformatics pipeline was applied to delineate the dynamic expression and potential cis-regulating effects of mouse lncRNAs using transcriptome data from 8 embryonic time points and sub-regions of the developing cerebral cortex. We further characterized a sense lncRNA, SenZfp536, which is transcribed downstream of and partially overlaps with the protein-coding gene Zfp536. Both SenZfp536 and Zfp536 were predominantly expressed in the proliferative zone of the developing cortex. Zfp536 was cis-regulated by SenZfp536, which facilitates looping between the promoter of Zfp536 and the genomic region that transcribes SenZfp536. Surprisingly, knocking down or activating the expression of SenZfp536 increased or compromised the proliferation of cortical neural progenitor cells (NPCs), respectively. Finally, overexpressing Zfp536 in cortical NPCs reversed the enhanced proliferation of cortical NPCs caused by SenZfp536 knockdown. The study deepens our understanding of how lncRNAs regulate the propagation of cortical NPCs through cis-regulatory mechanisms.

Objective:To explore the significance of plasma homocysteine (Hcy) as a new biomarker for the differential diagnosis of postural tachycardia syndrome (POTS) and suspected myocarditis in children.Methods:A total of 24 children diagnosed with POTS and 21 children diagnosed with suspected myocarditis treated in the Pediatrics Department of the Peking University First Hospital from July to December 2016 were included in the study.Plasma Hcy levels were measured in each subject and compared between children with POTS and suspected myocarditis.The receiver operating characteristic (ROC) curves were depicted for assessing the diagnostic potential of Hcy in distinguishing POTS from suspected myocarditis.Results:Plasma Hcy level in the POTS group was significantly higher than that in the suspected myocarditis group [(14.25±8.09) μmol/L vs.(8.99±3.19) μmol/L], which was also significantly higher than that of the mean levels in Beijing children [(8.82±5.58) μmol/L] (all P<0.05). When the cut-off was 9.36 μmol/L, the area under the ROC curve was 0.76, and the sensitivity and specificity for distinguishing POTS from suspected myocarditis were 71% and 68%, respectively. Conclusions:Plasma Hcy levels are helpful in the differential diagnosis of POTS and suspected myocarditis in children.

Objective To explore the effect of different concentrations of endothelin-1 (ET-1)on the en-dogenous nitric oxide (NO)and hydrogen sulfide (H2S)pathways of vascular smooth muscle cells (A7r5 cell lines)in rats.Methods A7r5 cell lines were divided into the control group and the experimental group.ET-1 at a concentra-tion of 10 -8-10 -6 mol/L was added into the experimental group,and as for the control group,the same volume of sterile phosphate buffered saline (PBS)buffer solution was added.The content of NO and H2S in A7r5 cell lines was detected by fluorescent NO probe and H2S probe after ET-1 stimulation for 48 h,respectively.The content of NO in the supernatant was measured by NO assay kit at 48 h of the incubation.The content of H2S in the supernatant was measured by polarographic H2S sensor at 48 h of the incubation. The expressions of inducible nitric oxide synthase (NOS2),endothelial nitric oxide synthase (NOS3),cystathionine -γ -lyase (CSE),cystathionine -β -synthase (CBS)and proliferating cell nuclear antigen (PCNA)were detected by the Western blot method.Results The rela-tive fluorescence intensity of the content of NO in the A7r5 cell lines of ET-1 10 -8,10 -7 and 10 -6mol/L groups (0. 078 ± 0. 080,0.075 ± 0.002,0.056 ± 0.009)was markedly lower than that in the control group(0.094 ± 0. 061), and the differences were statistically significant(F＝15.248,P＜0.05);Compared with the control group[(2. 131 ± 0. 484)μmol/L],the content of NO in the supernatant of the experimental groups [(1.391 ± 0.134 )μmol/L, (1.219 ± 0. 280)μmol/L,(1.116 ± 0.181)μmol/L]was significantly decreased,and the differences were statistically significant(F＝20.833,P＜0.01);NOS2 protein expression(0.457 ± 0.097,0.462 ± 0.116,0.438 ± 0.180)was decreased markedly compared with that of the control group(0.721 ± 0.222),and the differences were statistically sig-nificant(F＝6.196,P＜0.01),but the expression of NOS3 showed no significant differences(F＝2.669,P＞0.05). The relative fluorescence intensity of the content of H2S in the A7r5 cell lines of ET-1 10 -8,10 -7 and 10 -6mol/L groups (0.063 ± 0.002,0.056 ± 0.008,0.042 ± 0.009)was markedly lower than that in the control group (0.082 ± 0. 006),and the differences were statistically significant(F ＝16.297,P＜0.01);Compared with the control group [(29.439 ±4.236)μmol/L],the content of H2S in the supernatant of the experimental groups [(17.516 ±5.144) μmol/L,(14.481 ± 4.885)μmol/L]was significantly decreased,and the differences were statistically significant (F＝12.518,P ＜0.01).CBS protein expression(0.359 ± 0.096,0.270 ± 0.038,0.174 ± 0.051)was decreased markedly compared with that of the control group(0.707 ± 0.107),and the differences were statistically significant (F＝20.833,P＜0.01),and the expression of CSE showed no significant differences(F＝0.708,P＞0.05).The data showed that PCNA protein expression in the 10 -7mol/L ET-1 group(0.686 ± 0.180)significantly increased com-pared with that of the control group(0.437 ± 0.191),and the difference was statistically significant (t＝ -2.840,P＜0.01).Conclusion ET-1 stimulation can lead to the proliferation of vascular smooth muscle cells and down-regu-late its endogenous NO and H2S pathways.

Hypertensive crisis is defined as significantly elevated blood pressure accompanied by heart,kidney and central nervous system and other target organ damage. Hypertensive crisis is rare but often occult in children. It acts as a serious threatening to children′s health. At different ages,there are different eti-ologies of composition. So the hypertensive children need to be monitored closely,and given targeted individ-ualized treatment. Venous anti-hypertensive drugs are recommended to be used under monitoring as initial treatment to control the blood pressure decline speed precisely,and then gradually changed to oral anti-hyper-tensive drugs,to maximize the protection of target organs and avoid permanent damage caused by fluctuation of the blood pressure.

Objective To investigate the opioidergic mechanism of the central nucleus of the amygdala (CeA) for regulating sodium appetite in rats.Methods Using the elaborate invasive cerebral cannulation and brain microinjection method,we observed the effects of bilateral intra-CeA injections of DAMGO (a selective μ-opioid receptor agonist) and CTAP (a highly selective μ-opioid receptor antagonist),either alone or in combination,on NaCl solution (0.3 mol/L) and water intake by rats in different models of Na+ ingestion.Results In the two-bottle tests,bilateral injections of DAMGO at 1,2,and 4 nmol into the CeA induced a dose-related increase of NaCl and water intake in rats treated with water deprivation with partial rehydration (WD-PR),and pretreatment with 0.5,1,and 2 nmol CTAP injected into the CeA significantly suppressed DAMGO-induced NaCl and water intake in a dose-dependent manner:in the one-bottle tests,bilateral injections of DAMGO (2 noml) into the CeA had no effect on water intake of the rats.In rats with subcutaneous injection of furosemide (FURO) combined with captopril (CAP) (FURO+CAP),bilateral intra-CeA injections of DAMGO (2 nmol) caused increased NaCl and water intake in the two-bottle tests,but such effects were suppressed by pretreatment with CTAP injection into the CeA;in the one-bottle tests,bilateral intra-CeA injections of DAMGO had no effect on water intake of the rats.Conclusion μ-opioid receptors in the CeA are involved in the excitatory regulation of sodium appetite to mediate sodium intake.μ-opioid receptor antagonists are expected to be targets for developing inhibitors of sodium appetite.

Objective To investigate the opioidergic mechanism of the central nucleus of the amygdala (CeA) for regulating sodium appetite in rats.Methods Using the elaborate invasive cerebral cannulation and brain microinjection method,we observed the effects of bilateral intra-CeA injections of DAMGO (a selective μ-opioid receptor agonist) and CTAP (a highly selective μ-opioid receptor antagonist),either alone or in combination,on NaCl solution (0.3 mol/L) and water intake by rats in different models of Na+ ingestion.Results In the two-bottle tests,bilateral injections of DAMGO at 1,2,and 4 nmol into the CeA induced a dose-related increase of NaCl and water intake in rats treated with water deprivation with partial rehydration (WD-PR),and pretreatment with 0.5,1,and 2 nmol CTAP injected into the CeA significantly suppressed DAMGO-induced NaCl and water intake in a dose-dependent manner:in the one-bottle tests,bilateral injections of DAMGO (2 noml) into the CeA had no effect on water intake of the rats.In rats with subcutaneous injection of furosemide (FURO) combined with captopril (CAP) (FURO+CAP),bilateral intra-CeA injections of DAMGO (2 nmol) caused increased NaCl and water intake in the two-bottle tests,but such effects were suppressed by pretreatment with CTAP injection into the CeA;in the one-bottle tests,bilateral intra-CeA injections of DAMGO had no effect on water intake of the rats.Conclusion μ-opioid receptors in the CeA are involved in the excitatory regulation of sodium appetite to mediate sodium intake.μ-opioid receptor antagonists are expected to be targets for developing inhibitors of sodium appetite.

Humans ; Mucocutaneous Lymph Node Syndrome ; drug therapy ; Tumor Necrosis Factor-alpha ; antagonists & inhibitors ; Tumor Necrosis Factors

Objective To investigate the clinical efficacy of drug phonophoresis therapy in the treatment of acute iridocyclitis.Methods According to randomized block design,104 patients with acute iridocyclitis were divided into the control group of 52 cases (72 eyes)with 1％ atropine mydriasis,oral prednisone tablets and subconjunctival injection of dexamethasone treatment,76 eyes of 52 cases in the treatment group with 1％ atropine mydriasis,oral prednisone tablets and dexamethasone phonophoresis intraocular treatment.Results Compared with the control group,the cure rates of treatment group and control group were 84.2％ and 58.5％ respectively,there was significantly significant difference between the two groups(x2 =12.598,P =0.000),oral hormone time from the beginning to the first reduction[treatment group and control group were (5.12 ± 1.00) d and (7.32 ± 0.97) d respectively (t =-13.495,P =0.000)] and oral hormone total time [treatment group and control group were (27.82 ± 4.84) d and (35.49 ± 4.74) d respectively (t =-9.720,P =0.000)] were significantly shortened,complications decreased significantly[conjunctival edema rate (x2 =9.657,P =0.002),subconjunctival hemorrhage rate (x2 =6.601,P =0.010),conjunctival scarring rate (x2 =4.340,P =0.037),pain rate (x2 =63.419,P =0.000) and oculocardiac reflectivity rate (x2 =33.293,P =0.000)] and patient satisfaction improved significantly (treatment group and control group were 94.7％ and 69.4％ respectively) (x2 =16.333;P =0.000).Conclusion Dexamethasone phonophoresis therapy has better clinical efficacy and higher cure rate,and it is non-invasive,safe and reliable,less complications and high satisfaction in the treatment of acute iridocyclitis.

Objective To investigate the prevalence of metabolic syndrome in patients with maintenance hemodialysis, and to analyze the potential risk factors. Methods The clinical data of 472 patients with maintenance hemodialysis from 7 blood purification centers were collected. Patients were divided into the MS group and the non-MS group. The demographic data , anthropometric examinations , dialysis prescription and results of laboratory were compared between these two groups. Multivariate Logistic regression analysis was performed to analyze the risk factors of MS. Results The morbidity of MS was 34.75%. There were significant differences in weight , waist circumference , waist-hip ratio , frequency of dialysis , time of hemodialysis perweek , urea reduction ratio, urea clearance index (Kt/v), iron, intact parathyroid hormone (iPTH), leukocytes, high sensitivity C-reactive protein (hs-CRP) between these two groups (P < 0.05, resectively). Multivariate Logistic regression analysis revealed that iron (OR = 1.084, P = 0.042), iPTH (OR = 1.754, P = 0.035), waist-hip 1ratio (OR = 2.013,P = 0.021), hs-CRP (OR = 4.245,P = 0.000)were correlated with MS. Conclusion The morbidity of MS in patients with maintenance hemodialysis is higher. Iron, iPTH, waist-hip ratio, hs-CRP are potential risk fctors of MS for the patients with maintenance hemodialysis.