LNCipedia 5 : towards a reference set of human long non-coding RNAs

While long non-coding RNA (lncRNA) research in the past has primarily focused on the discovery of novel genes, today it has shifted towards functional annotation of this large class of genes. With thousands of lncRNA studies published every year, the current challenge lies in keeping track of which lncRNAs are functionally described. This is further complicated by the fact that lncRNA nomenclature is not straightforward and lncRNA annotation is scattered across different resources with their own quality metrics and definition of a lncRNA. To overcome this issue, large scale curation and annotation is needed. Here, we present the fifth release of the human lncRNA database LNCipedia (https://lncipedia.org). The most notable improvements include manual literature curation of 2482 lncRNA articles and the use of official gene symbols when available. In addition, an improved filtering pipeline results in a higher quality reference lncRNA gene set

Three year outcome of the Covered Endovascular Reconstruction of the Aortic Bifurcation (CERAB) technique for aortoiliac occlusive disease

Objective:The objective of the current study was to demonstrate the three year outcome of the CERAB technique for the treatment of extensive aortoiliac occlusive disease (AIOD). Methods:Between February 2009 and July 2016, all patients treated with the CERAB technique for AIOD were identified in the local databases of two centers and analyzed. Demographics and lesion characteristics were scored. Follow-up (FU) consisted of clinical assessment, duplex ultrasound and ankle brachial indices (ABI). Patency rates and clinically driven target lesion revascularization (CD-TLR) were calculated by Kaplan-Meier analysis. Results: 130 patients (69 male and 61 female) were treated of which 68% patients were diagnosed with intermittent claudication and 32% suffered from critical limb ischemia. The vast majority (89%) were TASC-II D lesions and the remaining were TASC-II B and C (both 5%). Median follow-up was 24 months (range 0-67 months). The technical success rate was 97% and 67% of cases were performed completely percutaneously. The ABI improved significantly from 0.65 plusminus 0.22 preoperatively to 0.88 plusminus 0.15 after the procedure. The 30-day minor and major complication rate was 33% and 7%. The median hospital stay was 2 days (range 1-76 days). At 1 and 3-years FU 94% and 96% of the patients clinically improved at least 1 Rutherford category (2% and 0% unchanged, 4% and 4% worsened). Limb salvage rate at 1-year was 98% and 97% at three year follow-up. Primary, primary-assisted and secondary patency was 86%/91%/97% at 1-year, 84%/89%/97% at 2-year and 82%/87%/97% at 3-year FU. Freedom from CD-TLR was 87% at 1-year and 86% at both 2 and 3-year FU. Conclusions:The CERAB technique is a safe and feasible technique for the treatment of extensive aortoiliac occlusive disease with good three year results regarding patency and clinical improvement

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction

Advances in the clinical management of pediatric B cell Acute Lymphoblastic Leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL

Intelligent hydrogel design: Towards more performing hydrogel processing

Despite their highly attractive properties, 3D printing of hydrogel materials can be rather challenging. Herein, we present a novel hydrogel material that can be easily processed into three-dimensional scaffolds using different 3D printing technologies. An acrylate-terminated, urethane-based PEG was prepared by reacting PEG 2000 with isophorone diisocyanate (IPDI) and monoacrylated PEG (336 g/mol) in a 1:2:2 molar ratio (WO 2017/005613 A1). For melt 3D-printing, pure polymer was used (Tm 38°C). For bioprinting, a 50 wt% solution with 3 wt% Laponite was used. Please click Additional Files below to see the full abstract

Equal performance of aspiration and stent retriever thrombectomy in daily stroke treatment

BACKGROUND: Mechanical thrombectomy with stent retrievers has proved to be safe and effective in endovascular treatment of acute ischemic stroke. Direct aspiration has shown revascularization rates comparable to those of stent retrievers in the recent ASTER and COMPASS trials. However, the efficacy of aspiration in routine clinical practice has not yet been shown. OBJECTIVE: To show that aspiration has clinical and technical outcomes equal to those of stent retriever thrombectomy in daily clinical practice. METHODS: We analysed data of patients with a large vessel occlusion of the anterior circulation registered in the Dutch MR CLEAN Registry between March 2014 and June 2016. Primary outcome was functional outcome measured with the modified Rankin Scale (mRS) score. Secondary outcomes were reperfusion grade, periprocedural complication rate, and procedure duration. Association of treatment technique with functional outcome was estimated with univariable and multivariable ordinal logistic regression analysis and expressed as a common OR (cOR) for a shift towards better outcome on the mRS. RESULTS: As first-line treatment, 207 of 1175 patients (17.6%) were treated with direct aspiration, and 968 (82.4%) by a stent retriever. We observed no differences in functional outcome (adjusted cOR=1.020 (95% CI 0.68 to 1.52)) and periprocedural complications. Successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b) was similar. Duration of the procedure was shorter with aspiration (57 min (IQR 35-73) vs 70 min (IQR 47-95), p<0.0001). CONCLUSION: Direct aspiration shows clinical outcomes equal to those of stent retriever thrombectomy in our large multicenter real-life cohort. We found no difference in complication rates and shorter procedure times for aspiration

Importance of Occlusion Site for Thrombectomy Technique in Stroke:Comparison Between Aspiration and Stent Retriever

BACKGROUND AND PURPOSE: Thrombectomy with stent retriever and direct aspiration are equally effective in the endovascular treatment of anterior circulation acute ischemic stroke. We report efficacy and safety of initial treatment technique per occlusion segment.METHODS: For this study, we analyzed data from the MR CLEAN Registry, a prospective, observational study in all centers that perform endovascular therapy in the Netherlands. We used ordinal logistic regression analysis to compare clinical and technical results of first line direct aspiration treatment with that of stent retriever thrombectomy stratified for occlusion segment. Primary outcome measure was functional outcome at 3 months. Secondary outcome measures included reperfusion grade expressed as the extended Thrombolysis in Cerebral Infarction score, periprocedural complication risk, time to reperfusion, and mortality.RESULTS: Of the 2282 included patients, 1658 (73%) were initially treated with stent retriever and 624 (27%) with aspiration. Four hundred sixty-two patients had an occlusion of the intracranial part of the carotid artery, 1349 of the proximal middle cerebral artery, and 471 of the distal parts of the middle cerebral artery. There was no difference in functional outcome between aspiration and stent retriever thrombectomy (odds ratio, 1.0 [95% CI, 0.9-1.2]) in any of the occlusion segments (P value for interaction=0.2). Reperfusion rate was higher in the aspiration group (odds ratio, 1.4 [95% CI, 1.1-1.6]) and did not differ between occlusion segments (P value for interaction=0.6). Procedure times were shorter in the aspiration group (minutes 50 versus 65 minutes; P&lt;0.0001). There was no difference in periprocedural complications or mortality.CONCLUSIONS: In unselected patients with anterior circulation infarcts, we observed equal functional outcome of aspiration and stent retriever thrombectomy in all occlusion segments. When aspiration was the first line treatment modality, reperfusion rates were higher and procedure times shorter in all occlusion segments.</p

Aspiration Versus Stent Retriever Thrombectomy for Posterior Circulation Stroke

BACKGROUND AND PURPOSE: Whereas a clear benefit of endovascular treatment for anterior circulation stroke has been established, randomized trials assessing the posterior circulation have failed to show efficacy. Previous studies in anterior circulation stroke suggest that advanced thrombectomy devices were of great importance in achieving clinical benefit. Little is known about the effect of thrombectomy techniques on outcomes in posterior circulation stroke. In this study, we compare first-line strategy of direct aspiration to stent retriever thrombectomy for posterior circulation stroke. METHODS: We analyzed data of patients with a posterior circulation stroke who were included in the Multicentre Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry between March 2014 and December 2018, a prospective, nationwide study, in which data were collected from consecutive patients who underwent endovascular treatment for ischemic stroke in the Netherlands. We compared patients who underwent first-line aspiration versus stent retriever thrombectomy. Primary outcome was functional outcome according to the modified Rankin Scale. Secondary outcomes were reperfusion grade, complication rate, and procedure duration. Associations between thrombectomy technique and outcome measures were estimated with multivariable ordinal logistic regression analyses. RESULTS: Overall, 71 of 205 patients (35%) were treated with aspiration, and 134 (65%) with stent retriever thrombectomy. Patients in the aspiration group had a lower pc-ASPECTS on baseline computed tomography, and general anesthesia was more often applied in this group. First-line aspiration was associated with better functional outcome compared with stent retriever thrombectomy (adjusted common odds ratio for a 1-point improvement on the modified Rankin Scale 1.94 [95% CI, 1.03-3.65]). Successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2B) was achieved more often with aspiration (87% versus 73%, P=0.03). Symptomatic hemorrhage rates were comparable (3% versus 4%). Procedure times were shorter in the aspiration group (49 versus 69 minutes P<0.001). CONCLUSIONS: In this retrospective nonrandomized cohort study, our findings suggest that first-line aspiration is associated with a shorter procedure time, better reperfusion, and better clinical outcome than stent retriever thrombectomy in patients with ischemic stroke based on large vessel occlusion in the posterior circulation

Association of thrombus density and endovascular treatment outcomes in patients with acute ischemic stroke due to M1 occlusions

PURPOSE: We aimed to study the association of non-contrast CT (NCCT) thrombus density with procedural and clinical outcomes in patients with acute ischemic stroke who underwent endovascular treatment (EVT). Since thrombus density is associated with thrombus location, we focused on M1 occlusions only.METHODS: Patients with available thin-slice (&lt; 2.5 mm) NCCT were included from a nationwide registry. Regression models were used to assess the relation between thrombus density (per Hounsfield unit [HU]) and the following outcomes. For reperfusion grade, adjusted common odds ratios (acOR) indicated a 1-step shift towards improved outcome per HU increase in thrombus density. For the binary outcomes of first-pass reperfusion (first-pass extended thrombolysis in cerebral infarction [eTICI] 2C-3, FPR), functional independence [90-day modified Rankin Scale (mRS) score of 0-2] and mortality), aORs were reported. Adjusted β coefficients (aβ) were reported for 24-h NIHSS and procedure duration in minutes. Outcome differences between first-line treatment devices (stent retriever versus aspiration) were assessed with interaction terms.RESULTS: In 566 patients with M1 occlusions, thrombus density was not associated with reperfusion (acOR 1.01, 95% CI 0.99-1.02), FPR (aOR 1.01, 95% CI 0.99-1.03), mortality (aOR 0.98, 95% CI 0.95-1.00), 24-h NIHSS (aβ - 0.7%, 95% CI - 1.4-0.2), or procedure duration (aβ 0.27, 95% CI - 0.05-0.58). In multivariable analysis, thrombus density was associated with functional independence (aOR 1.02, 95% CI 1.00-1.05). No interaction was found between thrombus density and first-line treatment device for any outcome.CONCLUSION: In patients with M1 occlusions, thrombus density was not clearly associated with procedural and clinical outcomes after EVT.</p

Sex differences in clot, vessel and tissue characteristics in patients with a large vessel occlusion treated with endovascular thrombectomy

Introduction: To improve our understanding of the relatively poor outcome after endovascular treatment (EVT) in women we assessed possible sex differences in baseline neuroimaging characteristics of acute ischemic stroke patients with large anterior vessel occlusion (LVO). Patients and methods: We included all consecutive patients from the MR CLEAN Registry who underwent EVT between 2014 and 2017. On baseline non-contrast CT and CT angiography, we assessed clot location and clot burden score (CBS), vessel characteristics (presence of atherosclerosis, tortuosity, size, and collateral status), and tissue characteristics with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Radiological outcome was assessed with the extended thrombolysis in cerebral infarction score (eTICI) and functional outcome with the modified Rankin Scale score (mRS) at 90 days. Sex-differences were assessed with multivariable regression analyses with adjustments for possible confounders. Results: 3180 patients were included (median age 72 years, 48% women). Clots in women were less often located in the intracranial internal carotid artery (ICA) (25%vs 28%, odds ratio (OR) 0.85;95% confidence interval: 0.73–1.00). CBS was similar between sexes (median 6, IQR 4–8). Intracranial (aOR 0.73;95% CI:0.62–0.87) and extracranial (aOR 0.64;95% CI:0.43–0.95) atherosclerosis was less prevalent in women. Vessel tortuosity was more frequent in women in the cervical ICA (aOR 1.89;95% CI:1.39–2.57) and women more often had severe elongation of the aortic arch (aOR 1.38;95% CI:1.00–1.91). ICA radius was smaller in women (2.3vs 2.5 mm, mean difference 0.22;95% CI:0.09–0.35) while M1 radius was essentially equal (1.6vs 1.7 mm, mean difference 0.09;95% CI:−0.02–0.21). Women had better collateral status (⩾50% filling in 62%vs 53% in men, aOR 1.48;95% CI:1.29–1.70). Finally, ASPECT scores were equal between women and men (median 9 in both sexes, IQR 8–10vs 9–10). Reperfusion rates were similar between women and men (acOR 0.94;95% CI:0.83–1.07). However, women less often reached functional independence than men (34%vs 46%, aOR 0.68;95% CI:0.53–0.86). Discussion and conclusion: On baseline imaging of this Dutch Registry, men and women with LVO mainly differ in vessel characteristics such as atherosclerotic burden, extracranial vessel tortuosity, and collateral status. These sex differences do not result in different reperfusion rates and are, therefore, not likely to explain the worse functional outcome in women after EVT.</p

Progression of ductal carcinoma in situ to invasive breast cancer: comparative genomic sequencing

Several models have been described as potential mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC). The aim of our study was to increase our understanding of DCIS progression by using massive parallel sequencing of synchronous DCIS and IBC. We included patients with synchronous DCIS and IBC (n = 4). Initially, IBC and normal tissue were subjected to whole exome sequencing. Subsequently, targeted sequencing was performed to validate those tumor-specific variants identified by whole exome sequencing. Finally, we analyzed whether those specific variants of the invasive component were also present in the DCIS component. There was a high genomic concordance between synchronous DCIS and IBC (52 out of 92 mutations were present in both components). However, the remaining mutations (40 out of 92) were restricted to the invasive component. The proportion of tumor cells with these mutations was higher in the invasive component compared to the DCIS component in a subset of patients. Our findings support the theory that the progression from DCIS to IBC could be driven by the selection of subclones with specific genetic aberrations. This knowledge improves our understanding of DCIS progression, which may lead to the identification of potential markers of progression and novel therapeutic targets in order to develop a more personalized treatment of patients with DCIS