Case Report: Whole-Exome Sequencing of Hypothalamic Hamartoma From an Infant With Pallister-Hall Syndrome Revealed Novel de novo Mutation in the GLI3.

Background: GLI-Kruppel family member 3 (GLI3), a zinc finger transcription factor of the sonic hedgehog pathway, is essential for organ development. Mutations in GLI3 cause several congenital conditions, including Pallister-Hall syndrome (PHS), which is characterized by polydactyly and hypothalamic hamartoma. Most patients are diagnosed soon after birth, and surgical removal of hypothalamic hamartoma in the very young is rarely performed because of associated risks. Case presentation: A 7-month-old boy with PHS features, including a suprasellar lesion, bifid epiglottis, tracheal diverticulum, laryngomalacia, left-handed polydactyly and syndactyly, and omental hernia was referred to our service. His suprasellar lesion was partially removed, and whole-exome sequencing was applied to the resected tumor, his peripheral blood, and blood from his parents. Histopathology confirmed the diagnosis of hypothalamic hamartoma, and molecular profiling revealed a likely pathogenic de novo variant, c.2331C>G (p. H777Q), in GLI3. Magnetic resonance imaging follow-up 1 year later showed some residual tumor, and the patient experienced normal development post operation. Conclusions: We presented a case of PHS that carries a novel GLI3 variant. Hypothalamic hamartoma showed a distinct genetic landscape from germline DNA. These data offer insights into the underlying etiology of hypothalamic hamartoma development in patients with PHS.

Identification of a glycolysis-related gene signature associated with clinical outcome for patients with lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC), one of the main types of lung cancer, has caused a huge social burden. There has been no significant progress in its therapy in recent years, Resulting in a poor prognosis. This study aims to develop a glycolysis-related gene signature to predict patients' survival with LUSC and explore new therapeutic targets. METHODS: We obtained the mRNA expression and clinical information of 550 patients with LUSC from the Cancer Genome Atlas (TCGA) database. Glycolysis genes were identified by Gene Set Enrichment Analysis (GSEA). The glycolysis-related gene signature was established using the Cox regression analysis. RESULTS: We developed five glycolysis-related genes signature (HKDC1, AGL, ALDH7A1, SLC16A3, and MIOX) to calculate each patient's risk score. According to the risk score, patients were divided into high- and low-risk groups and exhibited significant differences in overall survival (OS) between the two groups. The ROC curves showed that the AUC was 0.707 for the training cohort and 0.651 for the validation cohort. Additionally, the risk score was confirmed as an independent risk factor for LUSC patients by Cox regression analysis. CONCLUSION: We built a gene signature to clarify the connection between glycolysis and LUSC. This model performs well in evaluating patients' survival with LUSC and provides new biomarkers for targeted therapy.

Simvastatin pretreatment ameliorates t-PA-induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats.

Background: The use of thrombolysis with tissue-plasminogen activator (t-PA) in patients with acute ischemic stroke (AIS) is limited by increased levels of matrix metalloproteinase-9 (MMP-9) and by the increased risk of hemorrhagic transformation (HT). In this study, we investigated the effects of simvastatin pretreatment on t-PA-induced MMP-9/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and HT aggravation in a rat AIS model. Methods: The rat AIS model was established by autologous blood emboli. Two weeks before surgery, rats were pretreated with simvastatin (60 mg/kg/d), and three hours after surgery, t-PA (10 mg/kg) was administered. MMP-9 and TIMP-1 levels in the infarcted zone and plasma were evaluated by Western blot analysis and ELISA; the level of HT was quantified by determining the hemoglobin content. RhoA activation was determined to clarify the potential effect. Results: The results suggested that pretreatment with simvastatin suppressed the increase in t-PA-induced MMP-9 levels and neutralized the elevated MMP-9/TIMP-1 ratio, but had no effect on TIMP-1 levels. Thrombolysis with t-PA after ischemia improved neurological outcome, but increased intracranial hemorrhage. Moreover, t-PA-induced HT aggravation was reduced by simvastatin pretreatment. In addition, we showed that t-PA-induced activation of RhoA was suppressed by simvastatin, and that t-PA-induced MMP-9/TIMP-1 imbalance and hemorrhage was reduced by Rho kinases (ROCK) inhibitor Y-27632. Conclusion: In this study, we showed that simvastatin pretreatment ameliorated t-PA-induced HT and MMP-9/TIMP-1 imbalance, and demonstrated that the RhoA/ROCK pathway was implicated.

Solitaire Stent Permanent Implantation as an Effective Rescue Treatment for Emergency Large Artery Occlusion.

BACKGROUND: In this study, we present our experiences on the feasibility of rescue permanent Solitaire stent placement for failed mechanical thrombectomy (MT) and our protocol to avoid ineffective stent placement. METHODS: We retrospectively evaluated the data for consecutive patients admitted into the Second Affiliated Hospital of Wenzhou Medical University and 2 collaboration hospitals from August 2014 to May 2018 for emergency large artery occlusion. The baseline clinical characteristics and radiologic assessment, interventional data, clinical outcome, and angiographic follow-up data were assessed. Notably, we introduced our protocol for antegrade flow assessment before Solitaire stent detachment to ensure an effective stent implantation. RESULTS: Thirty-nine patients (mean age, 68.1 years, mean preprocedural National Institute of Health Scale Score, 22.1) were included, in which 34 patients had anterior circulation large artery occlusion and 5 patients had posterior circulation large artery occlusion. The MT attempts ranged from 1-5 (3.6 on average). The mean onset-to-puncture time was 4.8 hours (ranging from 2.1-7.8 hours) and the mean procedure time was 87.4 minutes (ranging from 32-124 minutes). Modified thrombolysis in cerebral infarction 2b-3 reperfusions were noted in all cases. The immediate, average postprocedure stenosis rate was 25.3%, and the average stenosis rate at the 3-month angiographic follow-up was 34.7% (data from 15 patients). Three patients died. Nineteen (48.7%) patients had good outcome (modified Rankin Scale, mRS ≤2) at the 3-month follow-up. CONCLUSIONS: Permanent Solitaire stent placement might be a feasible therapy for patients with MT-failed emergency large artery occlusion. For a successful revascularization, careful antegrade flow assessment before stent detachment is critical.

The role of postoperative radiotherapy in pediatric patients with grade II intracranial ependymomas: a population-based, propensity score-matched study.

PURPOSE: The main objectives of this study were to clarify the efficacy of postoperative radiotherapy (PORT) for pediatric intracranial grade II ependymomas (EPNs) and to explore whether various characteristics are associated with different outcomes in patients with and without PORT. PATIENTS AND METHODS: Data from patients younger than 18 years diagnosed with grade II intracranial EPNs and treated by surgery, with or without PORT, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (1973-2013 data set). Propensity score-matched analysis was conducted to balance clinical variables. Patient characteristics were stratified and analyzed. RESULTS: In total, data from 632 patients with grade II EPNs treated by cancer-directed surgery with or without PORT were obtained from the SEER database. Multivariable Cox analysis in the matched cohort suggested that undergoing PORT (overall survival [OS], P=0.020; cancer-specific survival [CSS], P=0.031), undergoing gross total resection (GTR; subtotal resection [STR] vs GTR; OS, P<0.001; CSS, P<0.001), and older age (OS, P<0.001; CSS, P<0.001) were the independent predictors of superior prognosis. Stratified analysis demonstrated that patient characteristics, including infratentorial location, younger age, and STR, were associated with benefit from PORT, while the survival advantage was not detected in patients who underwent GTR. CONCLUSION: Propensity score-matched analysis using SEER data indicates survival advantages of PORT. Given the strong prognostic associations with extent of resection and patient age, we recommend PORT for younger patients treated by STR.

The effects of tumor size and postoperative radiotherapy for patients with adult low-grade (WHO grade II) infiltrative supratentorial astrocytoma/oligodendroglioma: A population-based and propensity score matched study.

BACKGROUND: The update of 2018 NCCN guidelines (central nervous system cancers) recommended the risk classification of postoperative patients diagnosed as adult low-grade (WHO grade II) infiltrative supratentorial astrocytoma/oligodendroglioma (ALISA/O) should take tumor size into consideration. Moreover, the guidelines removed postoperative radiotherapy (PORT) for low risk patients. Our study aimed to explore the specific tumor size to divide postoperative patients into relatively low- or high risk subgroups and the effect of PORT for ALISA/O patients. METHODS: We conducted a retrospective study choosing 1277 postoperative ALISA/O patients from the Surveillance, Epidemiology, and End Results database. The X-tile analysis provided the optimal cutoff point based on tumor size. The differences between surgery alone and surgery +RT groups were balanced by propensity score-matched analysis. The multivariable analysis and the nomogram evaluated multiple prognostic factors based on cancer-specific survival (CSS) and overall survival (OS). RESULTS: X-tile plots defined 59 mm (P < 0.001) as the optimal cutoff tumor size value in terms of CSS, which was verified in multivariate analysis (P < 0.001). The Kaplan-Meier analysis showed that the surgery alone had higher CSS and OS than surgery +RT, while the low risk group had no statistical significance after propensity score match. Multivariable analysis showed that surgery +RT was independently associated with diminished OS and CSS for high risk group, which had no statistical significance for low-risk group. CONCLUSIONS: Our study suggested that tumor size of 59 mm was an optimal cutoff point to divide postoperative patients into relatively low- or high risk subgroups. PORT may not benefit patients, while the effects of PORT for low risk patients need further research.

Optic nerve injury-associated blunt cerebrovascular injury: Three case reports.

RATIONALE: Blunt cerebrovascular injury (BCVI) is a rare complication that may occur after craniocervical trauma. The current literature is limited to extracranial carotid artery injuries; however, no reports have been published on blunt intracranial carotid injury (BICI), especially those associated with optic nerve injury. PATIENT CONCERNS: Here we report on 3 BICI cases that demonstrated optic nerve injuries after craniofacial injuries. All 3 patients showed post-trauma vision loss on the injured side. DIAGNOSES: Optical canal fractures can be found in these patients, and carotid sulcus was compressed by the fragments. Computed tomography angiography (CTA) and digital subtraction angiography (DSA) were performed in all 3 patients. INTERVENTIONS: Case 1 was given no further treatment, except for symptomatic support and rehabilitation therapy. Case 2 was treated with antiplatelet therapy for 3 days, and then a stent was inserted in the injured internal carotid. Case 3 received antiplatelet therapy and a internal carotid compression test was performed simultaneously for 2 weeks, then the injured internal carotid was completely blocked. OUTCOMES: Case 1 developed cerebral infarction that resulted in unilateral hemiplegia. Due to timely treatment, the remaining 2 patients had a better prognosis. LESSONS: CTA should be performed primarily to exclude vascular injury and for CTA-positive patients, a further DSA should be performed to investigate pathological changes and for a definitive diagnosis. At last, the current therapeutic protocols for BCVI are not entirely applicable to intracranial vascular injury, and appropriate protocols for the treatment of BICI should be selected based on the combination of test results and the actual condition of the patient.

Effect of integrated traditional Chinese and Western medicine therapy for acute hypertensive intracerebral hemorrhage: a meta-analysis.

Intracerebral hemorrhage (ICH) is an important public health problem associated with high mortality and morbidity. The aim of this study was to evaluate the clinical efficacy of integrated traditional Chinese (TCM) and Western medicine (WM) therapy for acute hypertensive ICH. Randomized controlled trials were searched in PubMed, Medline, Embase, Wanfang and CNKI database published between January 2000 and June 2016. Our results showed that integrated TCM and WM therapy appeared to be able to improve the clinical effect for patients with acute hypertensive ICH.

Suppression of GLI sensitizes medulloblastoma cells to mitochondria-mediated apoptosis.

PURPOSE: The sonic hedgehog (SHH) signalling pathway plays the important role in medulloblastoma (MB). Altered GLI expression plays a key role in these processes, and the inhibition of GLI may be a good cancer-targeted therapy. This study aimed to investigate whether GANT61, a GLI inhibitor, may inhibit the SHH signalling pathway promoting cell mitochondria-mediated apoptosis and enhance cisplatin apoptosis antineoplastic therapy. METHODS: In our study, we determined the effect of GANT61-mediated inhibition of GLI in Daoy MB cells. Cells were treated with different concentrations of GANT61 alone or in combination with cisplatin. Cell proliferation was assessed with CCK-8 assays, and cell invasion and migration were performed using 8-µm transwell inserts. Cell apoptosis was assessed with flow cytometric analysis and rhodamine 123. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting. RESULTS: The GANT61 significantly inhibited cell proliferation. GANT61 decreased the cell migration and invasion, impairing these crucial steps in tumour progression. Cell apoptosis was significantly increased in Daoy cells. Rhodamine 123 assay showed that GANT61 could decrease the mitochondrial membrane potential promoting cell mitochondria-mediated apoptosis. GANT61 inhibited the expression of GLI and Bcl-2 at both the mRNA and protein levels and might affect the expression of Bax, caspase-3 and caspase-9 to promote cell intrinsic apoptosis. Furthermore, GANT61 could enhance cisplatin-induced apoptosis to decrease the IC50 value of cisplatin. Finally, data suggest that GANT61 could enhance cisplatin-induced apoptosis through promoting the expression of Bax, caspase-3 and caspase-9 protein levels. CONCLUSION: Our data suggest that the SHH signalling pathway plays an important role in MB. GLI is an oncogenic transcription factor in the SHH pathway, and targeting GLI with GANT61 results in favourable antitumour activity and targeted therapy.