The effect of carotid sinus neurectomy for carotid restenosis: a study protocol for a double-blinded and randomized controlled trial.

BACKGROUND: Patients undergoing carotid endarterectomy (CEA) have a high restenosis rate, which increases the risk of stroke, and there is still a lack of effective treatment for restenosis. The cause of stenosis is related to local inflammatory reactions. Some basic studies have shown that the inflammatory response causing arterial stenosis is closely related to the nerve axons distributed in its outer membrane, and that removal of the nerve is effective in reducing the inflammatory response to prevent arterial stenosis. Therefore, we propose to design a randomized controlled trial to study whether disconnecting the carotid sinus nerve during a CEA operation can reduce carotid arterial restenosis. METHOD/DESIGN: This study is a randomized, double-blind, single-center study. We will recruit 276 patients, who will be randomly divided into the experimental group and the control group. Based on the standard CEA operation, the operator will search for the carotid sinus nerve on the surface of the internal carotid artery and will entirely transect it in the experimental group. Both groups will be guided with the same postoperative treatment and will be followed up every 3 months for 3 years after the operation. The main indices observed will be the carotid restenosis rate, incidence and nature of carotid plaque, and carotid blood flow velocity. Other indices will be arrhythmia, blood pressure variability, and biomarkers of atherosclerosis, such as blood lipids, hypersensitive C-reactive protein (hs-CRP), homocysteine, and total bilirubin. DISCUSSION: It is expected that carotid sinus nerve transection will significantly reduce the occurrence of restenosis after CEA, decrease the incidence of ischemic stroke, and realize the effective primary prevention of stroke. TRIAL REGISTRATION: ChiCTR2300073652. Registered on July 18, 2023.

Bioinspired Lipoproteins of Furoxans-Gemcitabine Preferentially Targets Glioblastoma and Overcomes Radiotherapy Resistance.

Radiotherapy (RT) resistance is an enormous challenge in glioblastoma multiforme (GBM) treatment, which is largely associated with DNA repair, poor distribution of reactive radicals in tumors, and limited delivery of radiosensitizers to the tumor sites. Inspired by the aberrant upregulation of RAD51 (a critical protein of DNA repair), scavenger receptor B type 1 (SR-B1), and C-C motif chemokine ligand 5 (CCL5) in GBM patients, a reduction-sensitive nitric oxide (NO) donor conjugate of gemcitabine (RAD51 inhibitor) (NG) is synthesized as radio-sensitizer and a CCL5 peptide-modified bioinspired lipoprotein system of NG (C-LNG) is rationally designed, aiming to preferentially target the tumor sites and overcome the RT resistance. C-LNG can preferentially accumulate at the orthotopic GBM tumor sites with considerable intratumor permeation, responsively release the gemcitabine and NO, and then generate abundant peroxynitrite (ONOO- ) upon X-ray radiation, thereby producing a 99.64% inhibition of tumor growth and a 71.44% survival rate at 120 days in GL261-induced orthotopic GBM tumor model. Therefore, the rationally designed bioinspired lipoprotein of NG provides an essential strategy to target GBM and overcome RT resistance.

Exosome-based nanoimmunotherapy targeting TAMs, a promising strategy for glioma.

Exosomes, the cell-derived small extracellular vehicles, play a vital role in intracellular communication by reciprocally transporting DNA, RNA, bioactive protein, chains of glucose, and metabolites. With great potential to be developed as targeted drug carriers, cancer vaccines and noninvasive biomarkers for diagnosis, treatment response evaluation, prognosis prediction, exosomes show extensive advantages of relatively high drug loading capacity, adjustable therapeutic agents release, enhanced permeation and retention effect, striking biodegradability, excellent biocompatibility, low toxicity, etc. With the rapid progression of basic exosome research, exosome-based therapeutics are gaining increasing attention in recent years. Glioma, the standard primary central nervous system (CNS) tumor, is still up against significant challenges as current traditional therapies of surgery resection combined with radiotherapy and chemotherapy and numerous efforts into new drugs showed little clinical curative effect. The emerging immunotherapy strategy presents convincing results in many tumors and is driving researchers to exert its potential in glioma. As the crucial component of the glioma microenvironment, tumor-associated macrophages (TAMs) significantly contribute to the immunosuppressive microenvironment and strongly influence glioma progression via various signaling molecules, simultaneously providing new insight into therapeutic strategies. Exosomes would substantially assist the TAMs-centered treatment as drug delivery vehicles and liquid biopsy biomarkers. Here we review the current potential exosome-mediated immunotherapeutics targeting TAMs in glioma and conclude the recent investigation on the fundamental mechanisms of diversiform molecular signaling events by TAMs that promote glioma progression.

The efficacy of temozolomide combined with levetiracetam for glioblastoma (GBM) after surgery: a study protocol for a double-blinded and randomized controlled trial.

BACKGROUND: Temozolomide is applied as the standard chemotherapy agent in patients with glioblastoma (GBM) after surgery. However, the benefit of this treatment for patients is limited by the invasive growth of gliomas and drug resistance. There are indications from fundamental experimental and retrospective studies that levetiracetam has the potential to improve the survival rate of patients with GBM. However, it has yet to be determined whether the combination of temozolomide and levetiracetam is more effective than standard temozolomide chemotherapy. Therefore, we designed a randomized clinical trial to investigate the therapeutic effect of the new combined regime for treating GBM. METHODS/DESIGN: This is a double-blind and randomized clinical trial conducted in a single center. One hundred forty-two patients will be recruited and screened for the inclusion and exclusion criteria. Then, eligible participants will be randomly assigned to an experimental group or a control group in a 1:1 ratio. Based on the administration of radiation therapy (RT), participants in the experimental group will be prescribed levetiracetam plus temozolomide chemotherapy for 34 weeks while participants in the control group will receive placebo tablets plus temozolomide for the same duration. A 3-year follow-up will be conducted on all patients after intervention. Accordingly, the primary outcome will be progression-free survival (PFS). The secondary endpoints include overall survival (OS), the Karnofsky Performance Status (KPS), the objective response rate (ORR), and adverse event incidence. DISCUSSION: It is expected that the results of this trial will provide high-level evidence regarding the clinical benefits of levetiracetam and temozolomide combined in the treatment of GBM. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100049941 . Registered on 14 August 2021.

Comparison of outcomes between intracapsular resection and pseudocapsule-based extracapsular resection for pituitary adenoma: a systematic review and meta-analysis.

BACKGROUND: Transsphenoidal surgery is the preferred first-line therapy for most pituitary adenoma(PA), and the conventional strategy of treatment is intracapsular resection(IR). The protocol of extracapsular resection(ER), which considers the pseudocapsule as the PA boundary for surgical removal, has also been introduced gradually. In this study, the clinical efficacies and complications were explored and compared between these two procedures. METHODS: A systematic literature review was performed in the PubMed, EMBASE, Web of Science and Cochrane databases. Articles comparing between IR and ER were included. RESULTS: There were 7 studies containing 1768 cases in accordance with the inclusion criteria. Although the meta-analysis showed no significant difference in complete resection, a sensitivity analysis revealed that ER was more conducive to total PA resection than IR. Moreover, we found a significant difference in favor of ER regarding biochemical remission. Furthermore, there was no significant difference in the incidence rate of certain complications, such as hormone deficiency, diabetes insipidus, intraoperative cerebrospinal fluid(CSF) and postoperative CSF leakage. However, a sensitivity analysis suggested that IR decreased the risk of intraoperative CSF leakage. CONCLUSIONS: This meta-analysis unveiled that ER contributed to biochemical remission. To some extent, our results also showed that ER played a positive role in complete resection, but that IR reduced the incidence of intraoperative CSF leakage. However, the available evidence needs to be further authenticated using well-designed prospective, multicenter, randomized controlled clinical trials.

Intracellular and extracellular S100A9 trigger epithelial-mesenchymal transition and promote the invasive phenotype of pituitary adenoma through activation of AKT1.

Pituitary adenoma (PA) is mostly benign intracranial tumor, but it also displays invasive growth characteristics and provokes challenging clinical conditions. S100A9 protein enhances tumor progression. In this study, we firstly demonstrated that both intracellular and extracellular S100A9 promoted the expression of Vimentin and Intercellular cell adhesion molecule-1 (ICAM-1), coupled with reduced E-cadherin in PA. As a result, PA acquired the phenotype of Epithelial-Mesenchymal Transition (EMT), leading to proliferation, cell cycle progression, migration and invasion. In addition, we indicated S100A9-induced EMT was mediated by activation of AKT1. Furthermore, immunohistochemistry showed that S100A9 expression was higher in invasive PA than that in non-invasive PA. These data extended our understanding for the effects of S100A9 on PA invasion and contributed to further development of a promising therapeutic target for invasive PA.

Decompressive Hemicraniectomy Associated With Ultrasound-Guided Minimally Invasive Puncture and Drainage Has Better Feasibility Than the Traditional Hematoma Evacuation for Deteriorating Spontaneous Intracranial Hemorrhage in the Basal Ganglia Region: A Retrospective Observational Cohort Study.

Objectives: Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with higher mortality and disability rates; however, ideal surgical management is still to be determined for critical ICH. The purpose of this study was to prove the feasibility and unique clinical value of a novel combination, decompressive hemicraniectomy associated with ultrasound-guided minimally invasive puncture and drainage (DH + MIPD), for deteriorating ICH in the basal ganglia region. Methods: According to the enrollment criteria, 168 ICH patients were analyzed retrospectively, of which 86 patients received DH + MIPD and 82 patients received DH associated with traditional hematoma evacuation as the control group. The change process of three parameters, including hematoma size, peri-hematoma edema, and intracranial pressure (ICP), in a period of time after operation, as well as the short- and long-term therapeutic effect, was compared. Results: The DH + MIPD method could effectively achieve the evacuation rate of hematoma up to 87% at 5 days post-operation and had the significant advantages of minimal injury to cerebral tissue, less degree of edema, better effect of decreasing ICP, shorter operation time, less blood loss, and lower mortality compared with the control method. The DH + MIPD group had a significantly higher survival rate within 1 year post-operation (P = 0.007) and better functional outcome at 90 and 180 days post-operation (P = 0.004). A subgroup analysis pointed out that the DH + MIPD method had a definite survival advantage for critical ICH patients older than 60 years old and with hematoma located in the left dominant hemisphere. Conclusions: Our results proved the better feasibility of DH + MIPD on hematoma evacuation and implicated its significant advantages of reducing mortality and improving functional recovery. This method provides one more choice for the individualized therapy of ICH in the basal ganglia region.

Combination of 3-methyladenine therapy and Asn-Gly-Arg (NGR)-modified mesoporous silica nanoparticles loaded with temozolomide for glioma therapy in vitro.

Mesoporous silica nanoparticles (MSNPs) of a small diameter were loaded with the anticancer drug temozolomide (TMZ), coated with polydopamine (PDA), and conjugated with Asn-Gly-Arg (NGR) for use in the treatment of glioma. The accumulation of NGR-MSNPs in C6 cells was shown to be higher than that of unmodified MSNPs. Anticancer drugs can cause autophagy in tumor cells, whereas autophagy inhibitors can block this reaction and enhance the therapeutic effect of the drugs. In this study, we demonstrated that MSNP-TMZ-PDA-NGR had stronger autophagy- and apoptosis-inducing effects in C6 cells than TMZ alone, and its anticancer effect was further enhanced when combined with autophagy inhibition. These results demonstrate that the combination of targeting vehicles and autophagy inhibitors may have research value in the treatment of gliomas.

Targeted shRNA-loaded liposome complex combined with focused ultrasound for blood brain barrier disruption and suppressing glioma growth.

Our previous studies have demonstrated that focused ultrasound (FUS) combined with DNA-loaded microbubbles (MBs) can induce noninvasive, reversible, local disruption of the blood brain barrier (BBB) and enable targeted exogenous gene transfer into the central nervous system. However, due to low gene loading or the absence of positive targeting, to date, there has been no therapeutic effect of MBs combined with FUS in tumor treatment. In the current study, we adopted a phospholipid complex that exhibited sufficient gene loading and peptide-mediated targeting to delay glioma growth. First, we bound MBs to shBirc5-lipo-NGR, which performed the dual function of tumor cell targeting and effective gene loading. Next, we demonstrated that FUS-aided MB-shBirc5-lipo-NGR exhibited a higher transfection efficiency compared with the control group. Finally, we evaluated the silencing effect of shBirc5 using an apoptosis assay, real time-polymerase chain reaction (PCR), western blotting (WB) in vitro and a volume measurement survival analysis in vivo. The experimental group exhibited a significant therapeutic effect, while the FUS-only, MB-shBirc5-lipo-NGR-only and FUS-aided MB-shControl-lipo-NGR groups displayed no changes in tumor growth or survival time (P < .01). Consequently, our study indicated that MB-shBirc5-lipo-NGR combined with FUS is a promising new RNA interference technique for the treatment of glioma.

Upregulation of DACT2 suppresses proliferation and enhances apoptosis of glioma cell via inactivation of YAP signaling pathway.

DACT2, one of the Dact gene family members, was shown to function as a tumor suppressor. However, its function in gliomas remains largely unknown. In this study, we investigated the role of DACT2, underlying molecular mechanisms and its clinical significance in glioma patients. Downexpression of DACT2 in gliomas compared with adjacent normal brain tissues was correlated with glioma grade and poor survival. Cox regression analysis revealed that the DACT2 is an independent prognostic indicator for glioma patients. Overexpression of DACT2 in glioma cells inhibited proliferation, cell cycle and enhanced apoptosis, sensitivity to temozolomide in vitro and suppressed tumor growth in vivo. Whereas knockdown of DACT2 induce opposite reaction. Mechanistically, overexpression of DACT2 resulted in upregulation of important signaling molecules such as p-YAP and p-ß-catenin, and prevent YAP translocating into nucleus and sequestering in the cytoplasm to degrade. The study further proved that DACT2 can suppress YAP through Wnt/ß-catenin signaling pathway. Collectively, these data indicate that DACT2 has a tumor suppressor function via inactivation of YAP pathway, providing a promising target for the treatment of gliomas.

PEGylated PLGA-based phase shift nanodroplets combined with focused ultrasound for blood brain barrier opening in rats.

Previous studies have shown that focused ultrasound (FUS) combined with systematic administration of microbubbles (MBs) can open the blood brain barrier (BBB) locally, transiently and reversibly. However, because of the micro size diameters, MBs are restricted in the intravascular space and cannot extravasate into diseased sites through the opened BBB. In this study, we fabricated one kind of nanoscale droplets which consisted of encapsulated liquid perfluoropentane cores and poly (ethyleneglycol) - poly (lactide-co-glycolic acid) shells. The nanodroplets had the capacity to realize liquid to gas phase shift under FUS. Significant extravasation of Evan's blue appeared when acoustic pressure reached 1.0 MPa. Intracerebral hemorrhages and erythrocyte extravasations were observed when the pressure was increased to 1.5 MPa. Prolonged sonication duration could enhance the level of BBB opening and broaden the time window simultaneously. Furthermore, compared with MBs, the distribution of EB extravasation was firmly confined within narrow region in the center of focal zone, suggesting the site of FUS induced BBB opening could be controlled with high precision by this procedure. Our results show the feasibility of serving PEGylated PLGA-based phase shift nanodroplet as an effective alternative mediating agent for FUS induced BBB opening.