Atrial fibrillation is associated with anterior predominant white matter lesions in patients presenting with embolic stroke

Objective

High white matter hyperintensity (WMH) burden is commonly found on brain MRI among patients with atrial fibrillation (AF). However, whether the link between AF and WMH extends beyond a common vascular risk factor profile is uncertain. We sought to determine whether AF relates to a distinct WMH lesion pattern which may suggest specific underlying pathophysiological relationships.

Methods

We retrospectively analysed a cohort of consecutive patients presenting with embolic stroke at an academic hospital and tertiary referral centre between March 2010 and March 2014. In total, 234 patients (53% female, 74% anterior circulation infarction) fulfilled the inclusion criteria and were included in the analyses. WMH lesion distribution was classified according to previously defined categories. Multivariable logistic regression analysis was performed to determine variables associated with AF within 90 days of index hospital discharge.

Results

Among included patients, 114 had AF (49%). After adjustment for the CHA₂DS₂-VASc score (congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, prior stroke/TIA (doubled), vascular disease, age 65–74 years, sex category (female)) score, WMH lesion burden as assessed on the Fazekas scale, embolic stroke pattern, infarct distribution and pertinent interaction terms, AF was significantly associated with presence of anterior subcortical WMH patches (OR 3.647, 95% CI 1.681 to 7.911, p=0.001).

Conclusions

AF is associated with specific WMH lesion pattern among patients with embolic stroke aetiology. This suggests that the link between AF and brain injury extends beyond thromboembolic complications to include a cardiovasculopathy that affects the brain and can be detected and characterised by WMH.

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MicroRNA-211 expression is down-regulated and associated with poor prognosis in human glioma

Abstract

Accumulating evidence has supported the role of microRNAs in the initiation and development of malignant tumors. MicroRNA-211 (miR-211), which was reported to involve in diverse physiological activities in several cancers, was investigated for its expression in human glioma and adjacent normal brain tissues, as well as its correlation with patient prognosis. Glioma tissues and adjacent normal brain tissues were obtained from 82 patients who underwent surgical resection, and quantitative real-time polymerase chain reaction was performed to assess the expression level of miR-211. Here, we found that miR-211 was significantly decreased in glioma tissues compared with adjacent normal brain tissues (glioma, 3.52 ± 0.14 vs. normal, 4.96 ± 0.17, p < 0.001), and inversely associated with ascending WHO classification (grade III–IV, 3.16 ± 0.21 vs. grade I–II, 4.22 ± 0.26, p < 0.001). Then, the correlation of miR-211 with clinicopathological factors was investigated by Pearson’s Chi square test, indicating that miR-211 might be a potential biomarker to predict the malignant status of glioma. Further, Kaplan–Meier curves with log-rank analysis were carried out to determine the relationship between miR-211 expression level and the overall survival rate of glioma patients. Our data showed that there was a close correlation between down-regulated miR-211 and shorter survival time in 82 patients (p = 0.026). Finally, the multivariate Cox regression analysis indicated that WHO grade (HR = 2.437, 95% CI 1.251–4.966, p = 0.007), KPS (HR = 2.215, 95% CI 1.168–4.259, p = 0.016), and miR-211 expression level (HR = 3.614, 95% CI 2.152–6.748, p < 0.001) were considered as independent risk factors for glioma prognosis. These results suggested that lower miR-211 expression might be a marker for poor prognosis of glioma patients.

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The ratio of HLA-DR and VNN2 + expression on CD14 + myeloid derived suppressor cells can distinguish glioblastoma from radiation necrosis patients

Abstract

Glioblastoma (GBM) is the most aggressive and lethal type of brain cancer with a median survival of less than two years even following aggressive treatment (Stupp et al., N Engl J Med 352:987–996, 2005). Among the many challenges in treating patients with this devastating disease is the ability to differentiate Magnetic Resonance Imaging (MRI) images that appear following radiation therapy, often termed “radiation necrosis” from true GBM recurrence. Radiation necrosis (RN) and GBM are very difficult to distinguish and currently only a brain biopsy can conclusively differentiate these pathologies. In the present study, we introduce a differential diagnostic approach using a newly identified Myeloid-Derived Suppressor Cell (MDSC) biomarker, vascular non-inflammatory molecule 2 (VNN2⁺), in combination with expression of traditional HLA-DR on peripheral blood CD14⁺ monocytes isolated from GBM and/or RN patients. We performed proof-of-principle experiments confirming the sensitivity and specificity of this approach based upon the combined expression levels of HLA-DR and VNN2 among CD14⁺ Mo-MDSC, which we called the DR-Vanin Index or DVI. The DVI was able to distinguish GBM from RN patients with a high degree of certainty (n = 18 and n = 6 respectively; p = 0.0004). This novel, quick and inexpensive blood-based liquid biopsy could potentially replace invasive brain biopsies in differentiating GBM from RN patients using a minimally-invasive technique.

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Long non-coding RNA MALAT1 promotes proliferation and suppresses apoptosis of glioma cells through derepressing Rap1B by sponging miR-101

Abstract

Long non-coding RNAs (lncRNAs) have been recently shown to be dysregulated and closely related to several cancers. Here, we aimed to elucidate the function and the possible molecular mechanisms of lncRNA Metastasis-associated lung Adenocarcinoma transcript-1 (MALAT1) in human glioma. Quantitative real-time PCR (qRT-PCR) was used to detect the expressions of MALAT1, miR-101 and Rap1B mRNA in U251 and U87 cells. The protein level of Rap1B was examined by western blot assays. Moreover, the proliferation and apoptosis of U251 and U87 cells were determined by CCK-8 assay and flow cytometry analysis, respectively. Additionally, the targets of miR-101 were identified by target prediction and luciferase reporter assays. The results demonstrated that MALAT1 and Rap1B were upregulated, while miR-101 expression was downregulated in glioma cell lines U251 and U87. MALAT1 and Rap1B knockdown could inhibit proliferation and induce apoptosis of glioma cells. Moreover, MALAT1 promoted the Rap1B expression by sponging miR-101 in U251 and U87 cells. Furthermore, miR-101 downregulation or Rap1B overexpression reversed the proliferation inhibitory and apoptosis induction of glioma cell lines caused by MALAT1 knockdown. Taken together, MALAT1 promotes proliferation and suppresses apoptosis of glioma cells through derepressing Rap1B by sponging miR-101. The present study elucidates a novel MALAT1-miR-101-Rap1B regulatory axis in glioma, contributing to a better understanding of the glioma pathogenesis and providing a promising therapeutic target for glioma patients.

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Complement in renal transplantation: The road to translation

Publication date: Available online 27 May 2017
Source:Molecular Immunology
Author(s): Neeltina M. Jager, Felix Poppelaars, Mohamed R. Daha, Marc A. Seelen
Renal transplantation is the treatment of choice for patients with end-stage renal disease. The vital role of the complement system in renal transplantation is widely recognized. This review discusses the role of complement in the different phases of renal transplantation: in the donor, during preservation, in reperfusion and at the time of rejection. Here we examine the current literature to determine the importance of both local and systemic complement production and how complement activation contributes to the pathogenesis of renal transplant injury. In addition, we dissect the complement pathways involved in the different phases of renal transplantation. We also review the therapeutic strategies that have been tested to inhibit complement during the kidney transplantation. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition for the treatment of brain death-induced renal injury, renal ischemia-reperfusion injury and acute rejection. We conclude that it is expected that in the near future, complement-targeted therapeutics will be used clinically in renal transplantation. This will hopefully result in improved renal graft function and increased graft survival.



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Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro

Abstract

Lymphovascular invasion (LVI), encompassing blood and lymphatic vessel invasion, is an important event in tumourigenesis. Macrophages within the tumour microenvironment are linked to the presence of LVI and angiogenesis. This study investigates the role of macrophage-derived, caspase-1-dependent interleukin-1beta (IL-1β) in an in vitro model of LVI. IL-1β significantly augmented the adhesion and transmigration of breast cancer cell lines MCF7 and MDA-MB-231 across endothelial cell barriers. MDA-MB-231 and MCF7 showed a higher percentage of adhesion to lymphatic endothelial cells than blood endothelial cells following endothelial cell IL-1β stimulation (P < 0.001 and P < 0.0001, respectively). Supernatants from activated macrophages increased the adhesion of tumour cells to lymphatic and blood endothelium. Secretion of IL-1β was caspase-1 dependent, and treatment with caspase-1 inhibitor reduced IL-1β production by 73% and concomitantly reduced tumour cell adhesion to levels obtained with resting macrophages. Transmigration of MDA-MB-231 cells across blood and lymphatic endothelial monolayers was significantly increased following IL-1β stimulation. Furthermore, supernatants from activated macrophages increased transmigration of MDA-MB-231 cells across endothelial monolayers, which was abolished by caspase-1 inhibition. IL-1β stimulation of tumour cells significantly increased their migratory ability and a significant increase in migration was observed when MDA-MB-231 cells were stimulated with macrophage conditioned media (two of three donors). Results demonstrate that macrophage production of IL-1β plays an important role in the migration of breast cancer cells and their adhesion to, and transmigration across, blood and lymphatic endothelial cells. Results suggest that IL-1β may play a role in the adhesion to lymphatic endothelial cells in particular.

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CD45RA − Foxp3 high regulatory T cells have a negative impact on the clinical outcome of head and neck squamous cell carcinoma

Abstract

Background

Although regulatory T cells (Tregs) are thought to play an important role in immune suppression, their clinical significance in head and neck squamous cell carcinoma (HNSCC) is unclear. A recent study reported Tregs could be divided into functional subsets based on the expression of CD45RA and Foxp3.

Method

The frequency of circulating Treg subsets was analyzed in patients with HNSCC and compared with the frequency in patients with benign tumors. The association of Treg subsets with the frequency of lymphocyte subsets, status of progression, clinical course, and prognosis were also examined.

Results

The frequency of CD4⁺Foxp3⁺ Tregs was comparable between HNSCC patients and age-matched benign tumor patients; however, CD45RA⁻Foxp3^high Tregs were significantly increased in HNSCC patients, in particular those with advanced stage tumors. The high frequency of CD45RA⁻Foxp3^high Tregs correlated with a poor prognosis and the low frequency of CD45RA⁻Foxp3^high Tregs before treatment showed a better clinical outcome, even in patients with advanced stage tumors. CD45RA⁻Foxp3^high Treg numbers were decreased after intensive treatments; however, Treg numbers recovered in the early stages of recurrent cases, even before the clinical manifestation.

Conclusion

CD45RA⁻Foxp3^high Tregs are associated with the clinical course of HNSCC and might be a new target for treatment and an early marker of tumor recurrence in HNSCC patients.

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