Unusual posterior fossa mass caused by Lhermitte-Duclos disease with no symptoms in adults.

We present an asymptomatic case of Lhermitte-Duclos disease (LDD) in a 40-year-old woman and discuss the diagnosis, management and prognosis of this rare disease. Surgical intervention is strongly recommended as an initial therapy strategy even in asymptomatic adult patients. Conservative strategies could be chosen if the mass involves the brainstem or is accidentally found in the elderly.

Development and validation of a prognostic model predicting symptomatic hemorrhagic transformation in acute ischemic stroke at scale in the OHDSI network.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) after cerebral infarction is a complex and multifactorial phenomenon in the acute stage of ischemic stroke, and often results in a poor prognosis. Thus, identifying risk factors and making an early prediction of HT in acute cerebral infarction contributes not only to the selections of therapeutic regimen but also, more importantly, to the improvement of prognosis of acute cerebral infarction. The purpose of this study was to develop and validate a model to predict a patient's risk of HT within 30 days of initial ischemic stroke. METHODS: We utilized a retrospective multicenter observational cohort study design to develop a Lasso Logistic Regression prediction model with a large, US Electronic Health Record dataset which structured to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). To examine clinical transportability, the model was externally validated across 10 additional real-world healthcare datasets include EHR records for patients from America, Europe and Asia. RESULTS: In the database the model was developed, the target population cohort contained 621,178 patients with ischemic stroke, of which 5,624 patients had HT within 30 days following initial ischemic stroke. 612 risk predictors, including the distance a patient travels in an ambulance to get to care for a HT, were identified. An area under the receiver operating characteristic curve (AUC) of 0.75 was achieved in the internal validation of the risk model. External validation was performed across 10 databases totaling 5,515,508 patients with ischemic stroke, of which 86,401 patients had HT within 30 days following initial ischemic stroke. The mean external AUC was 0.71 and ranged between 0.60-0.78. CONCLUSIONS: A HT prognostic predict model was developed with Lasso Logistic Regression based on routinely collected EMR data. This model can identify patients who have a higher risk of HT than the population average with an AUC of 0.78. It shows the OMOP CDM is an appropriate data standard for EMR secondary use in clinical multicenter research for prognostic prediction model development and validation. In the future, combining this model with clinical information systems will assist clinicians to make the right therapy decision for patients with acute ischemic stroke.

MutL homolog 1 contributes to temozolomide-induced autophagy via ataxia-telangiectasia mutated in glioma.

In the present study, mutL homolog 1 (MLH1) small interfering (si)RNA, KU­55933, an ataxia­telangiectasia mutated (ATM) inhibitor, and compound C, an adenosine monophosphate­activated protein kinase (AMPK) inhibitor, were used to investigate the mechanisms underlying temozolomide (TMZ)­induced autophagy and to determine the role of MLH1 and ATM in autophagy. MLH1 siRNA and KU­55933 inhibited the phosphorylation of AMPK and ULK1 and reduced the levels of autophagy. MLH1 siRNA inhibited the phosphorylation of ATM and attenuated TMZ cytotoxicity, whereas the inhibition of ATM­AMPK augmented TMZ cytotoxicity in inherently TMZ­sensitive glioma cells. Therefore, TMZ induced autophagy via the ATM­AMPK pathways and the activation of ATM­AMPK was MLH1­dependent. The inhibition of ATM­AMPK enhanced TMZ cytotoxicity in inherently TMZ­sensitive glioma cells.

Temozolomide induces autophagy via ATM­AMPK­ULK1 pathways in glioma.

Autophagy is a cytoprotective process, which occurs following temozolomide (TMZ) treatment, and contributes to glioma chemoresistance and TMZ treatment failure. However, the molecular mechanisms by which TMZ induces autophagy are largely unknown. In the current study, the ataxia­telangiectasia mutated (ATM) inhibitor KU­55933, adenosine monophosphate­activated protein kinase (AMPK) inhibitor compound C, and U87MG and U251 cell lines were employed to investigate the molecular mechanisms of TMZ­induced autophagy in glioma, and to evaluate the effects of autophagy inhibition on TMZ cytotoxicity. KU­55933 and compound C were observed to inhibit the activation of autophagy­initiating kinase ULK1 and result in a significant decrease of autophagy as indicated by depressed LC3B cleavage and acidic vesicular organelle formation. The activation of AMPK­ULK1 was ATM dependent. Autophagy inhibition via the AMPK inhibitor compound C augmented TMZ cytotoxicity as observed by depressed cell viability, increased γH2AX­marked double­strand breaks (DSBs) and elevated numbers of apoptotic glioma cells. In conclusion, TMZ induced autophagy via ATM­AMPK­ULK1 pathways. TMZ chemoresistance may therefore be overwhelmed by targeting AMPK, particularly for the treatment of O6­methylguanine DNA methyltransferase­negative gliomas.

Gamma-secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function.

The objective of the current study was to investigate the regulation of VEGF signaling and tumor angiogenesis by gamma-secretase inhibitor DAPT in glioblastoma. Effects of DAPT on VEGFR1, VEGFR2, endothelial cell proliferation and vessel function were evaluated using mouse microvascular endothelial H5V cell line and U87MG xenograft mouse models. We found that DAPT efficiently inhibited Notch signaling, increased VEGFR2 expression, but decreased VEGFR1 expression. DAPT treatment enhanced endothelial cell proliferation when used combined with VEGF, but exerted no effect if used alone. In U87MG xenograft mouse models, DAPT treatment increased tumor vessel density but compromised vessel function, as evidenced by poor perfusion and aggravated hypoxia. Therefore, DAPT treatment results in an uncoupling of tumor vessel density from vessel function and suppresses glioblastoma growth; disturbance of angiogenesis with DAPT presents a novel therapeutic approach for glioblastoma.

γ-secretase inhibitor up-regulates vascular endothelial growth factor receptor-2 and endothelial nitric oxide synthase.

Although previous studies have shown that γ-secretase inhibitors significantly suppress tumor growth via anti-angiogenesis, the mechanism involved in the regulation of tumor angiogenesis by γ-secretase inhibitors has not been clearly understood. The objective of this study was to investigate the regulation of vascular endothelial growth factor receptor (VEGFR) and endothelial nitric oxide synthase (eNOS) by a γ-secretase inhibitor in the H5V mouse microvascular endothelial cell line. H5V cells were cultured with different concentrations of the γ-secretase inhibitor DAPT for 48 h and with 100 µmol/l DAPT at different incubation times. Protein and mRNA expression of VEGFR-1, VEGFR-2, VEGFR-3 and eNOS was measured by Western blotting and real-time PCR, respectively. The VEGFR-2 kinase inhibitor was used to assess the role of VEGFR-2 in eNOS regulation. We found that the γ-secretase inhibitor DAPT increased protein and mRNA expression of VEGFR-2 and eNOS, but decreased VEGFR-1 expression and had no significant effect on VEGFR-3. Up-regulation of eNOS was blocked by the VEGFR-2 kinase inhibitor. In conclusion, the γ-secretase inhibitor enhances VEGFR-2 and eNOS expression, and the up-regulation of eNOS is dependent on an increase in VEGFR-2. Thus, we suggest that administration of the γ-secretase inhibitor be combined with disruption of eNOS or interruption of VEGF signaling, which may improve the anti-angiogenic efficacy in tumor treatments.