Recent Advance of S100B Proteins in Spontaneous Intracerebral Hemorrhage and Aneurysmal Subarachnoid Hemorrhage.

Human health is seriously endangered by spontaneous intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). Because the majority of ICH and aSAH survivors experience disability, increased risk of stroke recurrence, cognitive decline, and systemic vascular disease, ICH and aSAH assume special importance in neurological disease. Early detection and prediction of neurological function and understanding of etiology and correction are the basis of successful treatment. ICH and aSAH cause complex inflammatory cascades in the brain. In order to establish precise staging and prognosis, as well as provide a basis for treatment selection and monitoring, it is imperative to determine appropriate biological markers according to pathological and physiological mechanisms. In this review, we focus on the research progress of S100B, an endogenous danger signaling molecule, as a potential biomarker for ICH and aSAH, assisting in the development of further basic research and clinical translational studies.

A retrospective study about association of dynamic systemic immune-inflammation index (SII) with 180-day functional outcome after basal ganglia intracerebral hemorrhage.

Objectives: This study aimed to determine whether SII on different days of admission is associated with severity and 180-day functional outcomes after basal ganglia ICH. Methods: In this retrospective study, data on baseline CT imaging characteristics, mRS, hematoma volume, and laboratory variables were included. The SII and NLR, LMR, and PLR were calculated from laboratory data collected on admission day, day 1, and days 5-7. Both univariate and multivariable logistic regression analyses were used to assess the association between the SII and the outcome. The receiver operating characteristic (ROC) analysis and area under the curve (AUC) were also used to evaluate the ability of the SII to predict outcomes. Result: A total of 245 patients were enrolled in the study. On different days, the NLR, PLR, and SII were significantly lower in patients with favorable outcomes than in those with poor outcomes, and the volume of hemorrhage was positively correlated with the SII. These parameters were associated with outcomes in the univariate logistic regression. In the adjusted analyses, the SII and PLR were independent predictors of basal ganglia ICH outcomes. ROC analysis revealed that the SII showed a stronger ability to predict the 6-month outcomes of patients after basal ganglia ICH than the PLR on different days (AUC = 0.642, 0.804, 0.827 vs. 0.592, 0.725, 0.757; all P < 0.001). Conclusion: The SII independently and strongly predicts the outcome of basal ganglia ICH. A high SII was associated with poor 6-month outcomes in patients with basal ganglia ICH.

Neurofilament light chain and S100B serum levels are associated with disease severity and outcome in patients with aneurysmal subarachnoid hemorrhage.

Objectives: Serum neurofilament light chain (NfL) is a biomarker for neuroaxonal damage, and S100B is a blood marker for cerebral damage. In the present study, we investigated the relationship between serum NfL and S100B levels, severity, and outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). Methods: We prospectively recruited aSAH patients and healthy controls between January 2016 and January 2021. Clinical results included mortality and poor outcomes (modified Rankin scale score of 3-6) after 6 months. The ultrasensitive Simoa technique was used to evaluate NfL levels in the blood, and ELISA was used to detect S100B. Results: A total of 91 patients and 25 healthy controls were included in the study, with a death rate of 15.4%. The group of aSAH patients had significantly higher serum levels of NfL and S100B (P < 0.01). Furthermore, the levels of NfL and S100B increased when the Hunt-Hess, World Federation of Neurological Surgeons (WFNS), and Fisher grades increased (P < 0.01). Serum NfL and S100B levels were linked to poor prognoses and low survival rates. The blood levels of NfL and S100B were found to be an independent predictor related to 6-month mortality in multivariable analysis. Additionally, the areas under the curves for NfL and S100B levels in serum were 0.959 and 0.912, respectively; the clinical diagnostic critical thresholds were 14.275 and 26.54 pg/ml, respectively; sensitivities were 0.947 and 0.921, and specificities were 0.849 and 0.811. Conclusions: The NfL and S100B values for aSAH patients within 12 days of admission were considerably associated with Hunt-Hess grade, WFNS, and Fisher grade. The higher the grade, the higher the NfL and S100B value, and the poorer the prognosis. Serum NfL and S100B values could be feasible biomarkers to predict the clinical prognosis of patients with aSAH.

Impact of operation details on hydrocephalus after decompressive craniectomy.

OBJECTIVE: To evaluate the correlation between the distance of craniectomy from the midline and hydrocephalus after DC. METHODS: The following electronic databases were searched from their inception to June 2015: Cochrane Library, MEDLINE, Science Direct, EMBASE, Scopus, Google Scholar, the Chinese Biomedical Database (CBM), and the Chinese National Knowledge Infrastructure (CNKI). All randomized clinical trials, prospective cohort, retrospective observational cohort, and case-control studies investigating the relationship between distance of craniectomy from the midline and hydrocephalus after DC were enrolled. The Cochrane Collaborations software RevMan 5.3 was used for meta-analysis. RESULTS: Six retrospective cohort studies involving 462 participants were included. Pooled analysis of 4 studies suggested that craniectomy close to the midline (<25 mm) was associated with a significantly increased risk of postoperative hydrocephalus (odds ratio [OR] = 3.61, 95% confidence interval [CI]: 1.3 - 9.97, p=0.01). However, meta analysis of 4 studies did not find statistical differences when comparing the distance of craniectomy from the midline in the hydrocephalus group and that in the non-hydrocephalus group (OR= - 0.14, 95% CI: -0.44 - 0.15, p=0.34). CONCLUSION: Available evidence was insufficient to support the theory that craniectomy close to the midline increases the risk of developing hydrocephalus after DC. Well conducted randomized clinical trials are required to verify this issue.

Hydrocephalus after decompressive craniectomy for malignant hemispheric cerebral infarction.

PURPOSE: Several studies have investigated the incidence and risk factors of hydrocephalus after decompressive craniectomy (DC) for malignant hemispheric cerebral infarction. However, the results are controversial. Therefore, the following is a retrospective cohort study to determine the incidence and risk factors of hydrocephalus after DC for malignant hemispheric cerebral infarction. MATERIALS AND METHODS: From January 2004 to June 2014, patients at two medical centres in south-west China, who underwent DC for malignant hemispheric cerebral infarction, were included. The patients' clinical and radiologic findings were retrospectively reviewed. A chi-square test, Mann-Whitney U-test and logistic regression model were used to identify the risk factors. RESULTS: A total of 128 patients were included in the study. The incidence of ventriculomegaly and shunt-dependent hydrocephalus were 42.2% (54/128) and 14.8% (19/128), respectively. Lower preoperative Glasgow Coma Scale (GCS) score and presence of subarachnoid haemorrhage (SAH) were factors significantly associated with the development of post-operative hydrocephalus after DC. CONCLUSIONS: Cerebral infarction patients receiving DC have a moderate tendency to suffer from post-operative hydrocephalus. A poor GCS score and the presence of SAH were significantly associated with the development of hydrocephalus after DC.

The clinical value of serum hepatocyte growth factor levels in patients undergoing primary radiotherapy for glioma: effect on progression-free survival.

Hepatocyte growth factor (HGF) has been shown to be overexpressed in gliomas, and high-grade gliomas (glioblastoma multiforme) express more HGF than lower-grade astrocytoma, and HGF enhances their resistance to radiotherapy. To examine the effect of serum HGF levels on the likelihood of response to radiotherapy and the disease-free survival in patients with glioma, the blood samples of the patients were collected before commencing treatment and serum HGF was measured by quantitative ELISA in 48 patients with glioma grade I-IV, and all patients underwent primary conventionally fractionated radiotherapy. For statistical analysis, SPSS Version 13.0 software was used. Thirty-eight of the 48 patients had a response to treatment, and ten patients had persistent disease at 3 months. Overall, the median serum HGF level was 1,219.5 pg/ml (range 650.4-2,264.7 pg/ml). Eight patients with local failure had HGF levels >1,219.5 pg/ml, and 28 patients with response had serum HGF level of ≤ 1,219.5 pg/ml (P = 0.01). The median time to progression was 6 months in patients with HGF level of >1,219.5 pg/ml compared with 17 months in patients with HGF level of ≤ 1,219.5 pg/ml (log-rank, P = 0.041). In multivariate analysis, serum HGF, the KPS, tumour size and pathological grade, but not the patient's age, gender and oligodendroglial component influenced the progression-free survival. Elevated pre-therapeutic serum HGF levels are associated with poor response and a shorter time to progression in patients with glioma undergoing primary radiotherapy.

Inhibition of human glioma U251 cells growth in vitro and in vivo by hydroxyapatite nanoparticle-assisted delivery of short hairpin RNAs against SATB1.

Special AT-rich sequence-binding protein-1 (SATB1) has been reported to be over-expressed in many human tumors and knockdown of SATB1 can inhibit tumor growth. The present study was designed to determine the role of SATB1 in the growth of human glioma U251 cells using the plasmid-based SATB1 short hairpin RNA (shRNA) delivered by hydroxyapatite nanoparticles in vitro and in vivo. The in vitro growth, invasion and angiogenesis assays of human glioma U251 cells were done. U251 cells tumor blocks were transplanted into the nude mice. CaCl2-modified hydroxyapatite nanoparticles carrying shRNA-SATB1 plasmids were injected into the tumors. The apoptosis of the tumor U251 cells was examined with TUNEL assay and flow cytometer (FCM). The tumor growth and immunohistochemistry were measured. The expression level of SATB1 mRNA was investigated by RT-PCR. The expression levels of SATB1, Cyclin D1, MMP-2, VEGF, Bax and Caspase-9 protein were determined by western blot analysis. The results showed that hydroxyapatite nanoparticles-delivered shRNA-SATB1 could significantly inhibit the growth, invasion and angiogenesis of U251 cells in vitro and the growth of U251 cells in vivo. FCM results showed that Nano HAP-shRNA-SATB1-induced apoptosis (up to 67.8 %). SATB1 expression was strongly down-regulated in the tumor U251 cells. Cyclin D1, MMP-2 and VEGF were also down-regulated in the tumor tissues that also displayed significant increased in Bax expression and Caspase-9 activity. These results show that Nano HAP-shRNA-SATB1 can inhibit the growth of human glioma U251 cells in vitro and in vivo, and hydroxyapatite nanoparticles can be used for the in vitro and in vivo delivery of plasmid-based shRNAs into U251 cells.

MicroRNAs might be promising biomarkers of human gliomas.

Recently, altered expression levels of several microRNAs have been observed in gliomas, the most frequent primary brain tumor in adults. To review whether microRNAs might be promising biomarkers of human gliomas, we comprehensively searched the Cochrane Library, Medline and EMbase from 1966 to 2010 with the language limitation of English. We found that further understanding of the functions of miRNAs in specific cellular events is needed; the continuous technological advances in accurate and cost-effective miRNAs detection provide the prospect of a very promising role for miRNAs as novel diagnostic biomarkers of gliomas.

CXCR4 and SDF-1 production are stimulated by hepatocyte growth factor and promote glioma cell invasion.

BACKGROUND: Hepatocyte growth factor (HGF) and its receptor play an important role in the formation and progression of glioma and can promote tumor proliferation. In this study, we investigated the ability of HGF to promote the proliferation and invasion of U251n cells; we also tested the effects of HGF on stromal cell-derived factor 1 (SDF1) and CXCR4 mRNA expression. METHODS: We measured the effect of HGF on the proliferation of U251n cells using enzyme-linked immunosorbent assays (ELISAs) to detect incorporated bromodeoxyuridine (BrdU) as a marker of DNA synthesis. The effects of HGF and SDF-1 on U251n cell invasion and proliferation were measured using the inhibitors K252a to c-Met and AMD3100 to CXCR4. SDF-1 and CXCR4 mRNA and protein expression were measured using quantitative polymerase chain reaction (PCR) and fluorescence-activated cell sorter (FACS) analysis. Small interfering (si)RNAs were also used to down-regulate HGF and c-Met expression in U251n cells. RESULTS: HGF significantly increased U251n cell proliferation and invasion in a dose-dependent manner; K252a blocked this. AMD3100 blocked invasion but not proliferation. CXCR4 and SDF-1 mRNAs were up-regulated when cells were treated with HGF. CXCR4 and SDF-1 mRNA levels and HGF and c-Met protein levels were down-regulated after cells were transfected with siRNAs. CONCLUSIONS: HGF has a direct effect on glioma cell proliferation and invasion. HGF up-regulates SDF-1 and CXCR4 mRNA expression and contributes to cell invasion.

RNA interference targeting EphA2 inhibits proliferation, induces apoptosis, and cooperates with cytotoxic drugs in human glioma cells.

BACKGROUND: Overexpression of EphA2 was detected in low- and high-grade glioma. To examine the role of EphA2 in human glioma cells, we studied its effects on proliferation and apoptosis using gene silencing through RNA interference. METHODS: One siRNA targeting EphA2 gene was synthesized in vitro and was transfected into the glioma U251n cells. Expression of EphA2 proteins was detected by Western blots and immunofluorescence. Cell apoptosis and mitochondrial membrane potential were analyzed by flow cytometry and annexin-V/fluorescein isothiocyanate/propidium iodide, respectively. Caspase-3 activity was measured by a spectrofluorometer. MTT assay was used to examine changes in cell proliferation. RESULTS: After treatment with sequence-specific siRNA targeting EphA2, the protein level of the transfected group decreased significantly. As compared to non-siRNA transfected cells, the transfected group showed lower proliferation, higher apoptosis, and loss of mitochondrial membrane potential. Caspase-3 activity increased in cells treated with siRNA and downregulated when treated with caspase-3 inhibitor. And the effects were clearly additive when siRNA transfected cells treated with the anticancer agents. CONCLUSIONS: The results suggest that EphA2-siRNA inhibit U251n cell proliferation and induce their apoptosis. It is possible that EphA2 via mitochondrial and caspase-3 inhibits U251n cell apoptosis. And EphA2-siRNA transfection enhances U251n cells' sensitivity to chemotherapy. EphA2 may be an effective therapeutic target in patients with glioma. Silencing the receptor EphA2 gene is a novel approach for the containment of growth and migration of tumor in patients with malignant glioma.

[Effect of cryotherapy and 5-fluorouracil on apoptosis of G422 glioma cells].

BACKGROUND & OBJECTIVE: It was unknown whether the combination of cryotherapy and 5-fluorouracil (5-FU) could produce a synergistic effect, though both of them could induce apoptosis of glioma cells. The aim of this study was to observe the effect of cryotherapy and 5-fluorouracil on apoptosis of G422 glioma cells and to investigate the potential mechanism. METHODS: (1)Experimental mice models with G422 glioma were established. Cryotherapy (-180 degrees C,90s),chemotherapy (5-FU, 18 mg/kg), and cryochemotherapy were performed on them,respectively.(2)TUNEL was used to determine the apoptosis of glioma cells in each group at different time points.(3)The expression of the p53 and the HSP90alpha gene of the frozen glioma were analyzed by immunohistochemical staining. RESULTS: Cryotherapy or 5-FU induced apoptosis of G422 glioma cells, while the combination of cryotherapy and 5-FU remarkably increased the apoptosis rate. The numbers of apoptotic cells of combination group were 30.6+/-11.7, 86.4+/-21.5, 128.1+/-4.1, 237.0+/-30.1, 72.8+/-23.0 at 6h, 12h, 24h, 48h, 72h after cryochemotherapy, respectively, which were significantly higher than those of other groups. There was no expression of HSP90alpha and p53 in the center of freezing area. The p53 and the HSP90alpha proteins increased obviously in the periphery area especially at 48h after freezing compared with control group [(73.1+/-9.3)% vs (60.6+/-9.9)%, (35.6+/-6.6)% vs (13.7+/-6.5)%](P< 0.01). The expression of p53 was positively correlated with expression of HSP90alpha in frozen glioma (r=0.3610, P< 0.01). CONCLUSION: Combination of cryotherapy with 5-FU could enhance the apoptosis of G422 glioma cells presumably through modulating the HSP90alpha and p53 expression pattern. Cryochemotherapy showed better effect than that of cryotherapy or chemotherapy alone.