The oncogenic roles of Notch1 in astrocytic gliomas in vitro and in vivo

Notch receptors play an essential role in cellular processes during embryonic and postnatal development, including maintenance of stem cell self-renewal, proliferation, and determination of cell fate and apoptosis. Deregulation of Notch signaling has been implicated in some genetic diseases and tumorigenesis. The function of Notch signaling in a variety of tumors can be either oncogenic or tumor-suppressive, depending on the cellular context. In this study, Notch1 overexpression was observed in the majority of 45 astrocytic gliomas with different grades and in U251MG glioma cells. Transfection of siRNA targeting Notch1 into U251 cells in vitro downregulated Notch1 expression, associated with inhibition of cell growth, arrest of cell cycle, reduction of cell invasiveness, and induction of cell apoptosis. Meanwhile, tumor growth was delayed in established subcutaneous gliomas in nude mice treated with Notch1 siRNA in vivo. These results suggest that Notch1 plays an important oncogenic role in the development and progression of astrocytic gliomas. Furthermore, knockdown of Notch1 expression by siRNA simultaneously downregulated the expression of EGFR and the important components of its downstream pathways, including PI3K, p-AKT, K-Ras, cyclin D1 and MMP9, indicating the crosstalk and interaction of Notch and EGFR signaling pathways.     

Homozygous familial hypercholesterolemia in China: Genetic and clinical characteristics from a real-world,multi-center,cohort study

BackgroundThere is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia.ObjectiveTo define the characteristics of phenotypic and genetic HoFH probands from mainland China.MethodsWe collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test.ResultsA total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH.ConclusionsThis report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH.     

Immune activation after intraventricular hemorrhage

ObjectivesIntraventricular hemorrhage (IVH) is a subtype of stroke which has high mortality and morbidity, while comprehensive mechanism investigations and effective therapies are still in great need. Plenty of studies have shown that inflammation after stroke plays a critical role in disease outcomes. However, the inflammation after IVH remains unclear. This study aims to observe the immune response after IVH, thus providing therapeutic targets for IVH treatments.Materials and methodsIVH was induced by autologous blood infusion model in SD rats. Totally 588 rats were assigned either in the sham or IVH group. T2* lesion and hemoglobin quantities, ventricular volume, brain edema, ventricular wall damage, blood-brain-barrier (BBB) continuity and immune response were observed by magnetic resonance image (MRI), hematoxylin-eosin staining (HE), Evans Blue, flow cytometry (FACS), and enzyme-linked immunosorbent assay (ELISA) at baseline, 6 h, 1 d, 3 d, 7 d, 14 d after surgery.ResultsWe found that ventricular volume enlargement occurred hours after IVH and peaked at 3 d after IVH, then mildly reduced till 14 d. Similar changes happened in brain edema, ventricular wall damage and BBB leakage. Immune cells and cytokines in the central nervous system and peripheral blood also increased after IVH and experienced similar trends as ventricular enlargement. T2* lesion and hemoglobin degradation occurred 6 h after IVH and kept decreasing till 14 d after IVH.ConclusionsOur investigation illustrates that immune response exists after IVH, which may have a close relationship with disease outcomes. These results may provide promising immune related clues for mechanism and intervention studies in IVH.     

Diagnostic accuracy of MR vessel wall imaging at 2 weeks to predict morphological healing of vertebral artery dissection

ObjectivesThe spontaneous healing of non-hemorrhagic intracranial vertebral artery dissection (VAD) may be associated with the stabilization of intramural hematoma (IMH). We previously suggested that the signal intensity of IMH increases until approximately 2 weeks in VAD with spontaneous healing. We herein investigated the diagnostic accuracy of the signal intensity of IMH at 2 weeks to predict the spontaneous healing of VAD.MethodsFrom April 2017 to April 2021, we prospectively investigated patients with non-hemorrhagic VAD who underwent vessel wall imaging (VWI). Morphological healing of VAD was evaluated by MR angiography three months after its onset. The relative signal intensity (RSI) of IMH against the posterior cervical muscle on VWI was calculated. Univariate and multivariate analyses were performed on factors associated with the spontaneous healing of VAD among patient baseline data, vascular morphology at the diagnosis, and RSI parameters.ResultsForty-eight patients (23 men and 25 women; mean age: 51 years, range: 34-73 years) with 50 non-hemorrhagic VAD were included in the present study. Spontaneous healing was observed in 28 VAD (56%). RSI two weeks after the onset of VAD (RSI_2w) and morphological feature such as the string sign were associated with spontaneous healing, respectively. The multivariate logistic regression analysis identified RSI_2w as an independent predictive factor of spontaneous healing (OR: 7.3; 95% CI, 1.9-28, p = 0.004). The cut-off value for RSI_2w to predict spontaneous healing was 1.22 (AUC = 0.90, sensitivity: 91%, specificity: 82%).ConclusionRSI_2w predicted the spontaneous healing of non-hemorrhagic VAD 3 months after its onset.     

Tongue cancer treatment and oncological outcomes: The role of glossectomy classification

BackgroundNowadays surgery remains the gold standard of treatment for tongue cancer. Via a more clear and precise terminology, the glossectomy classification by Ansarin et al. facilitates shared communication between surgeons, allowing comparison between published research and improving surgical practice and patient care. To establish the association of glossectomies, according to their classification by Ansarin et al. with overall survival (OS), disease-free survival (DSF), and cause-specific survival (CSS) in tongue cancer, we conducted a systemic retrospective study on 300 consecutive patients affected by primary oral tongue cancer and treated with surgery at the European Institute of Oncology, IRCCS (IEO).MethodsThree hundred patients with tongue squamous cell carcinoma and treated at the Division of Otorhinolaryngology and Head and Neck Surgery of the European Institute of Oncology, IRCCS were cataloged according to the glossectomy classification. OS, DFS, and CSS were compared by surgical treatments.ResultsOS-5yrs was 80% for the type I glossectomy group, 75% for type II, 65% for type III, and 35% for type IV-V. DFS-5yrs was 74%, 60%, 55%, and 27%, respectively for I, II, III, and IV-V glossectomy group; CSS-5yrs was 82%, 80%, 72%, and 48%, respectively for I, II, III, and IV-V glossectomy group (p < 0.01).ConclusionsThis study confirmed that the application of the glossectomy classification was statistically correlated with patients' oncological outcomes.     

The Cost-Effectiveness of Intermediate-Acting,Long-Acting,Ultralong-Acting,and Biosimilar Insulins for Type 1 Diabetes Mellitus: A Systematic Review

ObjectivesThe incidence of type 1 diabetes mellitus is increasing every year requiring substantial expenditure on treatment and complications. A systematic review was conducted on the cost-effectiveness of insulin formulations, including ultralong-, long-, or intermediate-acting insulin, and their biosimilar insulin equivalents.MethodsMEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, HTA, and NHS EED were searched from inception to June 11, 2021. Cost-effectiveness and cost-utility analyses were included if insulin formulations in adults (≥ 16 years) with type 1 diabetes mellitus were evaluated. Two reviewers independently screened titles, abstracts, and full-text articles, extracted study data, and appraised their quality using the Drummond 10-item checklist. Costs were converted to 2020 US dollars adjusting for inflation and purchasing power parity across currencies.ResultsA total of 27 studies were included. Incremental cost-effectiveness ratios ranged widely across the studies. All pairwise comparisons (11 of 11, 100%) found that ultralong-acting insulin was cost-effective compared with other long-acting insulins, including a long-acting biosimilar. Most pairwise comparisons (24 of 27, 89%) concluded that long-acting insulin was cost-effective compared with intermediate-acting insulin. Few studies compared long-acting insulins with one another.ConclusionsLong-acting insulin may be cost-effective compared with intermediate-acting insulin. Future studies should directly compare biosimilar options and long-acting insulin options and evaluate the long-term consequences of ultralong-acting insulins.