SerpinB3 has been recently described as an early marker of liver carcinogenesis, but the potential mechanistic role of this serpin in tumor development is still poorly understood. Overexpression of Myc often correlates with more aggressive tumour forms, supporting its involvement in carcinogenesis. Yes-associated protein (Yap), the main effector of the Hippo pathway, is a central regulator of proliferation and it has been found up-regulated in hepatocellular carcinomas. The study has been designed to investigate and characterize the interplay and functional modulation of Myc by SerpinB3 in liver cancer. Results from this study indicate that Myc was up-regulated by SerpinB3 through calpain and Hippo-dependent molecular mechanisms in transgenic mice and hepatoma cells overexpressing human SerpinB3, and also in human hepatocellular carcinomas. Human recombinant SerpinB3 was capable to inhibit the activity of Calpain in vitro, likely reducing its ability to cleave Myc in its non oncogenic Myc-nick cytoplasmic form. SerpinB3 indirectly increased the transcription of Myc through the induction of Yap pathway. These findings provide for the first time evidence that SerpinB3 can improve the production of Myc through direct and indirect mechanisms that include the inhibition of generation of its cytoplasmic form and the activation of Yap pathway.
Background The Silk Vista Baby (SVB) flow diverter (FDS) is the only FDS deliverable via a 0.017 inch microcatheter and is specifically designed for the distal vasculature. We sought to evaluate the safety and efficacy of the SVB. Materials and Methods We performed a retrospective review to identify SVB cases at 4 tertiary neurosurgical centres within the U.K. Clinical, procedural, angiographic and follow-up data were collected. Results We identified 60 patients (35 female, 58%) of average age 54 ± 10.5 (range 30–72) with 61 aneurysms, 50 (81.9%) located in the anterior circulation. The majority of the aneurysms treated were unruptured (46, 75.4%) and saccular (46, 75.4%). Dome size was 6.2 ± 6.2 mm (range 1–36mm) and parent vessel diameter was 2.3 ± 0.4 mm (range 1.2-3.3 mm). An average number of 1.07 devices were implanted. Coils or other devices were implanted in 14 aneurysms (23.3%). At last angiographic follow-up (n = 55), 7.5 ± 4.2 months post-procedure, 32 aneurysms (57.1%) were graded as RRC I, 7 (12.5%) RRC II, and 17 RRC III (30.4%). Clinical complications, excluding death, were seen in 4 patients (6.8%) including 1 delayed aneurysm rupture and 3 symptomatic ischaemic events. Only one patient had permanent morbidity (mRS 1). 3 patients died during follow-up (5.1%); 2 deaths were related to the aneurysms (3.4%) – one ruptured dissecting MCA aneurysm, and one giant partially thrombosed posterior circulation aneurysm. 93% of patients were mRS ≤ 2 at last follow-up. Conclusion The SVB has high rates of technical success and an acceptable safety profile. Distal aneurysms may occlude slower due to relative oversizing of the devices.
BackgroundThe role of bridging intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) in the treatment of acute ischemic stroke (AIS) remains debatable. Atrial fibrillation (AF) associated strokes may be associated with reduced treatment effect from IVT. This study compares the effect of bridging IVT in AF and non-AF patients.MethodsThis retrospective cohort study comprised anterior circulation large vessel occlusion (LVO) AIS patients receiving EVT alone or bridging IVT plus EVT within 6 hours of symptom onset. Primary outcome was good functional outcome defined as modified Rankin Scale (mRS) 0–2 at 90 days. Secondary outcomes were successful reperfusion defined as expanded Thrombolysis In Cerebral Infarction (eTICI) grading ≥2b flow, symptomatic intracerebral hemorrhage (sICH), and in-hospital mortality.ResultsWe included 705 patients (314 AF and 391 non-AF patients). The mean age was 68.6 years and 53.9% were male. The odds of good functional outcomes with bridging IVT was higher in the non-AF (adjusted odds ratio (aOR) 2.28, 95% CI 1.06 to 4.91, P=0.035) compared with the AF subgroups (aOR 1.89, 95% CI 0.89 to 4.01, P=0.097). However, this did not constitute a significant effect modification by the presence of AF on bridging IVT (interaction aOR 0.12, 95% CI −1.94 to 2.18, P=0.455). The rate of successful reperfusion, sICH, and mortality were similar between bridging IVT and EVT for both AF and non-AF patients.ConclusionThe presence of AF did not modify the treatment effect of bridging IVT. Further individual patient data meta-analysis of randomized trials may shed light on the comparative efficacy of bridging IVT in AF versus non-AF LVO strokes.
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is one of the leading causes of cancer-related death worldwide 1 and generally has a poor prognosis since it is often diagnosed at an advanced stage when treatment is not effective. Great efforts have been made to decipher the molecular mechanisms of HCC and gene expression profiling has been used to identify subgroups of patients according to etiological factors, early pre-neoplastic lesions, stage of the disease, rate of recurrence and survival [2][3][4][5] . Genetic analysis has revealed that Myc oncogene over-expression is present in up to 70% of viral and alcohol-related HCCs. Myc is a potent activator of tumorigenesis and its deregulation has been shown to contribute to a variety of cancers [6][7][8] . Increased Myc levels often correlate with the more advanced and aggressive tumour forms, providing a characteristic signature of cancer progenitor cells and suggesting that its overexpression plays some part in Myc-driven pathogenesis and tumor biology 9,10 . The Myc oncoprotein is a pleiotropic transcription factor belonging to the basic helix-loop-helix-leucine zipper family with a critical role in engaging and coordinating expression of the genes necessary for efficient and ordered proliferation of somatic cells. Myc expression is highly regulated being tightly controlled by a number of mechanisms involving many transcriptional regulatory motifs 11,12 . According to its well established predominant role Myc regulates up to 15% of human genes and is involved in cell growth, proliferation, metabolism, differentiation, and apoptosis 6 . According to data emerging from genome-wide gene expression profiling 13 Myc has been recently suggested to be at the centre of human liver tumor malignant conversion.As expected, given their broad role as transcriptional regulator, Myc family proteins are predominantly localized within nuclear compartment during proliferation, although emerging data indicate
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