Regulation of pathological blood-brain barrier for intracranial enhanced drug delivery and anti-glioblastoma therapeutics

The blood-brain barrier(BBB)is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system(CNS).During the occurrence and development of glioblastoma(GBM),BBB is pathologically destroyed with a marked increase in permeability.Due to the obstruction of the BBB,current strategies for GBM therapeutics still obtain a meager success rate and may lead to systemic toxicity.Moreover,chemotherapy could promote pathological BBB functional restoration,which results in significantly reduced intracerebral transport of therapeutic agents during multiple administrations of GBM and the eventual failure of GBM chemotherapy.The effective delivery of intracerebral drugs still faces severe challenges.However,strategies that regulate the pathological BBB to enhance the transport of therapeutic agents across the barrier may provide new opportunities for the effective and safe treatment of GBM.This article reviews the structure and function of BBB in physiological states,the mechanisms underlying BBB pathological fenestration during the development of GBM,and the therapeutic strategies of GBM based on BBB intervention and medicinal drugs transporting across the BBB.

The potential function of transhiatal esophagectomy in the treatment of esophageal carcinoma

Objective: To analyze the results and introduce the experiences of transhiatal esophagectomy in combined with different synthetic therapy. Methods: Seventy-one patients with esophageal carcinoma, median age was 62, 40 of stage I, 26 of IIa, 4 of stage IIb, 1 of stage IV, were treated with transhiatal esophagectomy. 9 and 17 patients were treated with preopera- tive radiotherapy (4000 cGy) and postoperative adjuvant radiotherapy (6000 cGy) respectively; 5 patients were treated with preoperative chemotherapy. Results: The postoperative 1, 3 and 5 years survival rates were 100%, 91.43%, and 86.21% for stage I; 92%, 83.33%, and 57.14% for stage IIa; 75%, 50%, and 50% for stage IIb; 100%, 0, and 0 for stag IV and 95.71%, 86.89%, and 71.70% as a whole, respectively. The incidence of complications was 12.68%. Conclusion: Transhiatal esopha- gectomy combined with chemotherapy or radiotherapy may be beneficial to patients with esophageal carcinoma at stage IIa or earlier who can’t tolerate or need not be treated by transthoracic esophagectomy.

Experimental demonstration of transverse mode instability enhancement by a counter-pumped scheme in a 2 kW all-fiberized laser

Transverse mode instability(TMI)has become the major limitation for power scaling of fiber lasers with nearly diffraction-limited beam quality.Compared with a co-pumped fiber laser,a counter-pumped fiber laser reveals TMI threshold enhancement through a semi-analytical model calculation.We demonstrated a 2 kW high-power counter-pumped all-fiberized laser without observation of TMI.Compared with the co-pumped scheme,the TMI threshold is enhanced at least 50%in counter-pumped scheme,moreover,stimulated Raman scattering and four-wave mixing are suppressed simultaneously.

Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics

Glioblastoma(GBM)is one of the malignant brain tumors with high mortality and no curative treatments.Abnormally elevated vascular endothelial growth factor(VEGF)in GBM seriously disrupts the blood brain barrier(BBB)with an increased permeability,resulting in poor outcome and prognosis.RNAi interference has shown strong potential to inhibit VEGF expression,thus it is necessary to development an effective and safe gene delivery system possessing the ability to cross the BBB and target GBM cells.This study aims to explore the anti-GBM effect of angiopep-2(Ap)peptide modified reactive oxygen species(ROS)cleavable thioketal(TK)linked glycolipid-like nanocarrier(CSTKSA)delivering anti-VEGF siRNA(R),termed as Ap-CSTKSA/R complexes.Ap functionalized modification produced an enhanced cellular uptake and a stronger bio-distribution of Ap-CSTKSA/R complexes in U87 MG cells and brain tumor tissues,respectively.Ap-CSTKSA/R complexes exhibited great superiority in GBM growth inhibition and finally translated into the longest survival period mainly via receptor-mediated targeting delivery,VEGF gene silencing accompanied with remarkable angiogenesis inhibition,and suppressed expression of caveolin-1 which is involved in BBB functional regulation in the occurrence and treatment of GBM.The study indicated that Ap functionalization on ROS-responsive glycolipid-like copolymer exhibits a promising and effective gene delivery platform for GBM targeted treatment.

A novel single-trial event-related potential estimation method based on compressed sensing

Cognitive functions are often studied using eventrelated potentials（ERPs）that are usually estimated by an averaging algorithm.Clearly,estimation of single-trial ERPs can provide researchers with many more details of cognitive activity than the averaging algorithm.A novel method to estimate single-trial ERPs is proposed in this paper.This method includes two key ideas.First,singular value decomposition was used to construct a matrix,which mapped singletrial electroencephalographic recordings（EEG）into a low-dimensional vector that contained little information from the spontaneous EEG.Second,we used the theory of compressed sensing to build a procedure to restore single-trial ERPs from this low-dimensional vector.ERPs are sparse or approximately sparse in the frequency domain.This fact allowed us to use the theory of compressed sensing.We verified this method in simulated and real data.Our method and dVCA（differentially variable component analysis）,another method of single-trial ERPs estimation,were both used to estimate single-trial ERPs from the same simulated data.Results demonstrated that our method significantly outperforms dVCA under various conditions of signal-to-noise ratio.Moreover,the single-trial ERPs estimated from the real data by our method are statistically consistent with the theories of cognitive science.

AD-16 Protects Against Hypoxic-Ischemic Brain Injury by Inhibiting Neuroinflammation

Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.