Hypoxia-induced DTL promotes the proliferation, metastasis, and sorafenib resistance of hepatocellular carcinoma through ubiquitin-mediated degradation of SLTM and subsequent Notch pathway activation.

Denticleless E3 ubiquitin protein ligase homolog (DTL), the substrate receptor of the CRL4A complex, plays a central role in genome stability. Even though the oncogenic function of DTL has been investigated in several cancers, its specific role in hepatocellular carcinoma (HCC) still needs further elucidation. Data from a clinical cohort (n = 209), RNA-sequencing, and public database (TCGA and GEO) were analyzed, indicating that DTL is closely related to patient prognosis and could serve as a promising prognostic indicator in HCC. Functionally, DTL promoted the proliferation, metastasis, and sorafenib resistance of HCC in vitro. In the orthotopic tumor transplantation and tail vein injection model, DTL promoted the growth and metastasis of HCC in vivo. Mechanically, we revealed for the first time that DTL was transcriptionally activated by hypoxia-inducible factor 1α (HIF-1α) under hypoxia and functioned as a downstream effector molecule of HIF-1α. DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.

Acute inferior wall myocardial infarction induced by aortic dissection in a young adult with Marfan syndrome: A case report.

BACKGROUND: Aortic dissection (AD) is an emergent and life-threatening disorder, and its in-hospital mortality was reported to be as high as 24.4%-27.4%. AD can mimic other more common disorders, especially acute myocardial infarction (AMI), in terms of both symptoms and electrocardiogram changes. Reperfusion for patients with AD may result in catastrophic outcomes. Increased awareness of AD can be helpful for early diagnosis, especially among younger patients. CASE SUMMARY: We report a 28-year-old man with acute left side chest pain without cardiovascular risk factors. He was diagnosed with acute inferior ST-segment elevation myocardial infarction (STEMI), which, based on illness history, physical examination, and intraoperative findings, was eventually determined to be type A AD caused by Marfan syndrome. Emergent coronary angiography revealed the anomalous origin of the right coronary artery as well as eccentric stenosis of the proximal segment. Subsequently, computed tomography angiography (CTA) showed intramural thrombosis of the ascending aorta. Finally, the patient was transferred to the cardiovascular surgery department for a Bentall operation. He was discharged 13 d after the operation, and aortic CTA proved a full recovery at the 2-year follow-up. CONCLUSION: It is essential and challenging to differentiate AD from AMI. Type A AD should be the primary consideration in younger STEMI patients without cardiovascular risk factors but with outstanding features of Marfan syndrome.

Whole-course management of interventional treatment in liver cancer patients with portal hypertension.

Primary liver cancer often occurs in patients with hepatitis and cirrhosis. Some patients have portal hypertension due to cirrhosis, and present with varying degrees of collateral circulation, splenomegaly and hypersplenism, ascites, and liver dysfunction. It often interferes with the treatment of tumors and affects the disease prognosis. There are internationally recognized guidelines for interventional treatment of liver cancer and portal hypertension which will not be repeated in this paper. This paper focuses on how to treat portal hypertension and intervene with tumors in the treatment of liver cancer to optimize the management of patients with liver cancer and portal hypertension. We propose that the Interventional Management Mode of Liver Cancer with Portal Hypertension can improve the treatment of liver cancer patients with portal hypertension.

Primary Glioblastoma of Cerebellopontine Angle in Adult Mimicking Acoustic Neuroma.

BACKGROUND: Gliomas are usually located in the supratentorial region and are extremely rare at the cerebellopontine angle (CPA). Consequently, gliomas in the CPA are easy to misdiagnose preoperatively. CASE DESCRIPTION: This paper presents a 55-year-old man with an extraaxial CPA glioblastoma arising from the proximal portion of cranial nerve (CN) VIII. Preoperative imaging findings suggested an acoustic neuroma. The tumor was removed subtotally, and it was completely separated from the brainstem and cerebellum. The histopathologic examination showed a glioblastoma. CONCLUSIONS: To our knowledge, this case is the second report of a true primary extraaxial CPA glioblastoma. Therefore glioma should be considered in the differential diagnosis of CPA masses with atypical imaging features, although they are extremely rare.

Effects of AQP5 gene silencing on proliferation, migration and apoptosis of human glioma cells through regulating EGFR/ERK/ p38 MAPK signaling pathway.

We investigated the effects of aquaporin 5 (AQP5) gene silencing on the proliferation, migration and apoptosis of human glioma cells through regulating the EGFR/ERK/p38MAPK signaling pathway. qRT-PCR was applied to examine the mRNA expressions of AQP5 in five human glioma cell lines. U87-MG, U251 and LN229 cells were selected and assigned into blank, vector, AQP5 siRNA and FlagAQP5 groups. MTT assay was used to measure cell proliferation. Flow cytometry (FCM) with AnnexinV-FITC/PI double staining and PI staining were employed to analyze cell apoptosis and cell cycle respectively. Scratch test was used to detect cell migration. Western blotting was performed to determine the EGFR/ERK/p38 MAPK signaling pathway-related proteins. Results showed that the positive expression of AQP5 in primary glioblastoma was associated with the tumor size and whether complete excision was performed. The mRNA expressions of AQP5 in cell lines of U87-MG, U251 and LN229 were significantly higher than in U373 and T98G. The proliferation rates of U87-MG, U251 and LN229 cells in the AQP5 siRNA group were lower than in the vector and blank groups. The apoptosis rate increased in the AQP5 siRNA group compared with the vector group. Scratch test demonstrated that AQP5 gene silencing could suppress cell migration. Compared with the vector and blank groups, the AQP5 siRNA group showed decreased expressions of the ERK1/2, p38 MAPK, p-ERK1/2 and p-p38 MAPK proteins. AQP5 gene silencing could inhibit the cell proliferation, reduce cell migration and promote the cell apoptosis of U87-MG, U251 and LN229 by suppressing EGFR/ERK/p38 MAPK signaling pathway.

IDH1R¹³²H decreases the proliferation of U87 glioma cells through upregulation of microRNA-128a.

Mutations in isocitrate dehydrogenase 1 (IDH1) are found in >70% of secondary glioblastomas and lower-grade gliomas (grades II-III). Among the numerous phenotypic differences between IDH1 mutant and wild-type glioma patients, the most salient is an improved survival rate for patients with a mutation. MicroRNAs (miRNAs) are a class of small, non­coding, single­stranded RNAs that can negatively regulate gene expression at the post­transcriptional level, predominantly by binding to the 3'­untranslated region of their target mRNAs. The dysregulated expression of several miRNAs has been reported to modulate glioma progression; however, it is unclear whether mutations in IDH1 regulate glioma cell proliferation through miRNA dysregulation. In the present study, stable overexpression of IDH1WT or IDH1R132H was established in the U87 glioma cell line. It was found that IDH1R132H decreased cell proliferation of U87 glioma cells by inducing the expression of the miRNA miR­128a. This process was dependent on the transcription factor hypoxia inducible factor­1α (HIF­1α), which binds to a hypoxia response element in the promoter of miR­128a. Furthermore, miR­128a negatively regulated the expression of B­cell­specific Moloney murine leukemia virus integration site 1 protein (Bmi­1), which is involved in suppressing cell proliferation. These findings suggest that the IDH1R132H­HIF­1α­miR­128a­Bmi­1 pathway is involved in glioma cell proliferation.

Factors influencing the functional significance in intermediate coronary stenosis.

OBJECTIVE: To analyze the influencing factors of the functional significance determined by fractional flow reserve (FFR) in intermediate coronary artery stenosis. METHODS: The study enrolled 143 patients with 203 intermediate coronary lesions. Pressure-derived FFR of these lesions was gained at maximal hyperemia induced by intravenous adenosine infusion. An FFR < 0.80 was considered as abnormal functional significance. Anatomic parameters at the lesion sites were obtained by off-line quantitative coronary angiography analysis (QCA). The predictive value of the demographic characteristics and anatomic parameters for FFR in these intermediate lesions was assessed using multiple linear and binary logistic regression analysis. RESULTS: Overall, FFR < 0.8 was found in 70 (34%) of the total 203 intermediate coronary lesions. FFR values were positively correlated with QCA-measured minimum lumen diameters (MLD, r = 0.372, P = 0.000) and the reference vessel diameters (RVD, r = 0.217, P = 0.002) were negatively correlated with percent area stenosis (AS, r = -0.251, P = 0.000) and percent diameter stenosis (DS, r = -0.210, P = 0.000). Age, MLD and the lesion location in different coronary arteries were the independent determinants of FFR < 0.8. CONCLUSIONS: MLD can predict the functional significance of intermediate coronary stenosis, while age and the lesion location in different coronary arteries should be taken into account as important influencing factors of FFR values.

Usefulness of lumen area parameters determined by intravascular ultrasound to predict functional significance of intermediate coronary artery stenosis.

BACKGROUND: Coronary artery disease is the leading cause of death in China. Percutaneous coronary intervention is a recent milestone technology for treatment coronary artery disease. However, clinical decision making for patients with intermediate coronary stenosis is still controversial. We designed this study to assess the optimal intravascular ultrasound (IVUS) criteria for predicting functional significance of intermediate coronary lesions. METHODS: We enrolled 141 patients with 165 intermediate coronary lesions located in vessels with a diameter ≥ 2.50 mm. IVUS of intermediate coronary lesions were performed before intervention. Pressure-derived fractional flow reserve (FFR) was measured at maximal hyperemia induced by adenosine infusion. An FFR < 0.80 was considered as abnormal functional significance. RESULTS: For the overall 165 lesions, the mean FFR value was 0.84 ± 0.09. The diameter of the stenosis by visual estimation on angiogram was (59.63 ± 11.29)%. Minimum lumen diameter (MLD), minimum lumen area (MLA) and plaque burden (PB) were (2.00 ± 0.36) mm, (3.88 ± 1.34) mm(2), (67.28 ± 9.89)% respectively by IVUS measurements. An FFR < 0.80 was seen in 43 lesions (30.5%). There was a moderate correlation between IVUS parameters and FFR, including MLD (r = 0.372, P < 0.001), MLA (r = 0.442, P < 0.001) and PB (r = -0.172, P < 0.05). MLA was a predictor for FFR as a continuous variable independent of possible confounding variables (P < 0.05), and MLA and PB, were predictors for FFR < 0.80 as binary variables (P < 0.05). The best cutoff value of MLA to predict FFR < 0.80 was < 3.15 mm(2), with a 73.6% diagnostic accuracy; sensitivity 71.4%, specificity 67.0%, AUC = 0.709, and P < 0.001. The cutoff value of the PB to predict FFR < 0.80 was 65.45%; sensitivity 82.6%, specificity 41.2%, AUC = 0.644, and P < 0.01. If both MLA and PB were taken into account, the negative predictive value and the positive predictive value were 88.7% and 64.8% respectively. CONCLUSIONS: Anatomic measurements of intermediate coronary lesions obtained by IVUS showed a moderate correlation to FFR values. IVUS-derived MLA ≥ 3.15 mm(2) may be useful to exclude FFR < 0.80, but poor specificity limits its applicability for physiological assessment of lesions < 3.15 mm(2). MLA was one of many factors affecting coronary flow hemodynamics. Both MLA and PB should be taken into account when determining functional ischemia.

Predictors of outcome in the surgical treatment for epilepsy.

BACKGROUND: Knowledge about factors influencing the prognosis of resective epilepsy surgery can be used to identify which patients are most suitable for surgical treatment. The aim of this study was to identify preoperative prognostic factors associated with the chance of achieving long-term seizure freedom. METHODS: We retrospectively reviewed seizure outcomes and clinical, electroencephalography (EEG), magnetic resonance imaging (MRI), histopathology, and surgical variables from 99 epilepsy surgery patients with at least one year of postoperative follow-up. Seizure outcomes were categorized based on the modified classification by the International League Against Epilepsy. RESULTS: We found that the seizure-free rate was 27.9% after one year, and that it stabilized at about 20.0% between two and six years after surgery. Univariate analysis showed that medial temporal lobe epilepsy with hippocampal sclerosis, MRI with visible focal lesions concordant with EEG, and regional ictal EEG and electrocorticography patterns were associated with a favorable surgical outcome. On the other hand, seizure recurrence within six months, incomplete focus resection, and surgical complications were associated with a poor outcome. Multivariate analysis showed that medial temporal lobe epilepsy with hippocampal sclerosis and MRI with visible focal lesions were independent presurgical predictors of a favorable outcome (P < 0.01). Seizure recurrence within six months was the only significant independent predictor associated with a poor outcome (P < 0.01). CONCLUSION: Hippocampal sclerosis and abnormal MRI findings are strongly associated with a favorable surgical outcome, whereas seizure recurrence within six months is associated with a poor outcome.

Overexpression of Mitofusin 2 inhibited oxidized low-density lipoprotein induced vascular smooth muscle cell proliferation and reduced atherosclerotic lesion formation in rabbit.

Our previous studies have implies that Mitofusin 2 (Mfn2), which was progressively reduced in arteries from ApoE(-/-) mice during the development of atherosclerosis, may take part in pathogenesis of atherosclerosis. In this study, we found that overexpression of Mfn2 inhibited oxidized low-density lipoprotein or serum induced vascular smooth muscle cell proliferation by down-regulation of Akt and ERK phosphorylation. Then we investigated the in vivo role of Mfn2 on the development of atherosclerosis in rabbits using adenovirus expressing Mitofusin 2 gene (AdMfn2). By morphometric analysis we found overexpression of Mfn2 inhibited atherosclerotic lesion formation and intima/media ratio by 66.7% and 74.6%, respectively, compared with control group. These results suggest that local Mfn2 treatment suppresses the development of atherosclerosis in vivo in part by attenuating the smooth muscle cell proliferation induced by lipid deposition and vascular injury.

[The in vivo and in vitro effects on neovascularization of VEGF gene transfer with a new pseudotyped rAAV1 vector].

OBJECTIVE: To investigate the effects of vascular endothelial growth factor (VEGF) gene transfer with a new pseudotyped recombinant adeno-associated virus (rAAV) vector with AAV serotype 1 capsid protein (rAAV1) vector on neovascularization. METHODS: PBS, rAAV1-GFP and rAAV1-VEGF vectors were added in C2C12 derived myotubes [10(5) vg (vector genomes) per cell]. Transfer efficiency was determined by fluorescent microscope and VEGF protein concentration in the culture media measured by ELISA. Ten days following ischemia in a hindlimb ischemic mouse model, PBS, 3 x 10(11)vg rAAV1-LacZ vectors and rAAV1-VEGF165 vectors were injected in ischemic thigh muscles. VEGF protein at ischemic thigh muscle was measured by ELISA at 1 month after vector infection. Capillaries and arterioles were observed by immunohistochemical analysis at 6 weeks after vector infection. RESULTS: GFP expression was found in 60% - 80% myotubes at 120 hours after rAAV1-GFP infection. VEGF protein peaked at the 3rd day post rAAV1-VEGF infection with an average concentration of (567.7 +/- 16.8) pg/ml. Transfer efficacy in ischemic thigh muscle was 100% one month post rAAV1-LacZ infection. The average concentration of VEGF protein in ischemic skeletal muscles is (205.4 +/- 36.1) pg/mg total protein in rAAV1-VEGF165 treated mice. Extensive angiogenesis [(147.0 +/- 13.3)/mm(2)] and arteriogenesis [(17.0 +/- 1.2)/mm(2)] were observed in ischemic skeletal muscles at 6 weeks post rAAV1-VEGF165 injection. CONCLUSION: Gene transfer with the new pseudotyped rAAV1-VEGF165 vector might be an effective therapeutic approach for ischemic cardiovascular diseases.