The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA ...Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3' untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism.
HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse ...spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1.
Display omitted
•HNRNPA2B1 interacts with UAGG in 3′ UTRs to affect alternative polyadenylation•HNRNPA2B1 affects alternative splicing of ALS-associated D-amino acid oxidase•HNRNPA2B1 D290V causes widespread splicing changes in fibroblasts and motor neurons•ALS mutant motor neurons display abnormal molecular and cellular stress responses
HNRNPA2B1 is associated with neurodegeneration, but its role in the nervous system and effects of mutations are unclear. Martinez et al. discover HNRNPA2B1-dependent alternative splicing and polyadenylation in spinal cord. Stressed mutant motor neurons exhibit abnormal molecular responses and aggregation.
Patients undergoing arthroplasty require appropriate postsurgical pain relief. Analgesia is typically achieved through bolus doses of short-acting local anesthetics and with oral analgesics such as ...opiates, which are associated with systemic side effects. By formulating an injectable thermosensitive gelling system containing lidocaine, sustained and local delivery can be achieved following a single administration.
Poloxamer-based thermosensitive gelling formulations were prepared. Altering the weight ratios of poloxamers affected the sol-to-gel transition temperature, mechanical and rheological properties and
drug release. Desirable formulations gelled between 28 and 33°C providing sustained release of lidocaine over 48 h.
Thermosensitive gelling systems are promising for sustained drug release following patient administration and may be beneficial in addressing postoperative pain.
There have been few randomized control trials comparing the incidence of stent fracture and primary patency among different self-expanding nitinol stents to date. The SMART™ CONTROL stent (Cordis ...Corp, Miami Lakes, Florida, United States) has a peak-to-valley bridge and inline interconnection, whereas the COMPLETE™-SE stent (Medtronic Vascular, Santa Rosa, California, United States) crowns have been configured to minimize crown-to-crown interaction, increasing the stent's flexibility without compromising radial strength. Further, the 2011 ESC (European society of cardiology) guidelines recommend that dual antiplatelet therapy with aspirin and a thienopyridine such as clopidogrel should be administered for at least one month after infrainguinal bare metal stent implantation. Cilostazol has been reported to reduce intimal hyperplasia and subsequent repeat revascularization. To date, there has been no randomized study comparing the safety and efficacy of two different antiplatelet regimens, clopidogrel and cilostazol, following successful femoropopliteal stenting.
The primary purpose of our study is to examine the incidence of stent fracture and primary patency between two different major representative self-expanding nitinol stents (SMART™ CONTROL versus COMPLETE™-SE) in stenotic or occlusive femoropopliteal arterial lesion. The secondary purpose is to examine whether there is any difference in efficacy and safety between aspirin plus clopidogrel versus aspirin plus cilostazol for one month following stent implantation in femoropopliteal lesions. This is a prospective, randomized, multicenter trial to assess the efficacy of the COMPLETE™-SE versus SMART™ CONTROL stent for provisional stenting after balloon angioplasty in femoropopliteal arterial lesions. The study design is a 2x2 randomization design and a total of 346 patients will be enrolled. The primary endpoint of this study is the rate of binary restenosis in the treated segment at 12 months after intervention as determined by catheter angiography or duplex ultrasound.
This trial will provide powerful insight into whether the design of the COMPLETE™-SE stent is more fracture-resistant or effective in preventing restenosis compared with the SMART™ CONTROL stent. Also, it will determine the efficacy and safety of aspirin plus clopidogrel versus aspirin plus cilostazol in patients undergoing stent implantation in femoropopliteal lesions.
Registered on 2 April 2012 with the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier# NCT01570803).
We introduce a rapid and low-temperature laser annealing process of roll-to-roll (R2R) printed metal nanoparticle (NP) ink on a polymer substrate as an alternative to the conventional thermal ...annealing process using expensive and time consuming lengthy furnace. Due to the confined heating induced by the focused laser, R2R printed Ag NP film is selectively turned into a continuous conductive film without heating the whole substrate. As a result, the damage on the underlying polymer substrate, as well as the processing time required for the annealing, is significantly reduced by the laser annealing compared to the conventional thermal annealing. The resultant laser annealed Ag NP film also exhibits superior electrical and mechanical properties in comparison to the thermal annealed sample. The laser annealed Ag NP film is further applied to the flexible supercapacitor as the current collector in order to confirm the excellence of laser annealed Ag NP film in the fabrication of practical devices.
Fiber-reinforced composites are not chemical compounds but physical mixtures of fiber and matrix, and the constituents are bonded together. Therefore, it is natural and essential to adopt a full ...microscopic model and directly analyze the model with no assumptions for local deformation or local loading conditions, in order to understand and predict not only the averaged or homogenized behaviors but also the detailed microscopic behaviors of composite structures. However, in spite of the necessity, full microscopic models of composite structures have rarely been dealt with, mainly because of their difficulties arising in the actual computation of the finite element model with immense degree of freedoms.
In this work, to overcome the difficulties and analyze full microscopic models of composite structures, an efficient parallel multifrontal solver, which can utilize distributed computing resources unlimitedly, is developed and applied to the Direct Numerical Simulation (DNS) of composite structures. Using the developed code, feasibility studies are carried out to observe whether or not the proposed solver is adequate for the DNS of composite structures, such as in parallel performance and others. As an example of DNS, virtual experiments are carried out, where material constants are directly obtained through DNS. Comparisons with previous experimental and theoretical results show the promising possibility that the present virtual experiments by the DNS of composite structures can be an alternative way to obtain material constants without expensive real experiments. Additionally, a microscopic model with defects is also analyzed and compared with a perfect model to validate the potential of the DNS in dealing with irregularity of microscopic models of composite structures coming from imperfection. The examples show the future direction of analysis and design of composite structures as well as the usefulness of the proposed DNS methodology.
The aim of this study was to evaluate the feasibility of using (18)F 3'-deoxy-3'-fluorothymidine (FLT) positron emission tomography (PET) for the diagnosis and grading of brain tumors.
The patient ...population comprised 26 patients (15 males, 11 females) with brain tumors (n=18) or nontumorous lesions (n=8). 2-(18)Ffluoro-2-deoxy-D: -glucose (FDG) and FLT PET images were obtained using a dedicated PET scanner 1 h after the injection of 370 MBq of FDG or FLT. Uptake of FDG and FLT by the lesions was visually and semiquantitatively assessed in comparison with normal brain tissue.
Of 26 brain lesions, four showed increased FDG uptake compared with normal gray matter (grade 5). These four lesions showed intensely increased FLT uptake and were all high-grade tumors. Twenty-two lesions with similar (grade 4) or decreased (grades 1-3) FDG uptake compared with normal gray matter showed variable pathology. Among the 18 brain tumors, FLT PET showed increased uptake in all 12 high-grade tumors but FDG uptake was variable. In 22 brain lesions with similar or decreased uptake compared with normal gray matter on FDG PET, the sensitivity and specificity of FLT PET for the diagnosis of brain tumor were 79% (11/14) and 63% (5/8), respectively. The uptake ratios of 14 brain tumors on FLT PET were significantly higher than the lesion to gray matter ratios (p=0.012) and lesion to white matter ratios (p=0.036) of FDG uptake and differed significantly between high (5.1+/-2.6) and low (2.1+/-1.1) grade tumors (p=0.029). In nine gliomas, FLT uptake was significantly correlated with the Ki-67 proliferation index (rho=0.817, p=0.007).
These findings indicate that FLT PET is useful for evaluating tumor grade and cellular proliferation in brain tumors. It displayed high sensitivity and good contrast in evaluating brain lesions that showed similar or decreased uptake compared with normal gray matter on FDG PET. FLT PET, however, did not appear to be sufficiently useful for differentiating tumors from nontumorous lesions.
Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA ...foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43 , or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.
Current nanoparticle (NP) drug carriers mostly depend on the enhanced permeability and retention (EPR) effect for selective drug delivery to solid tumors. However, in the absence of a persistent EPR ...effect, the peritumoral endothelium can function as an access barrier to tumors and negatively affect the effectiveness of NPs. In recognition of the peritumoral endothelium as a potential barrier in drug delivery to tumors, poly(lactic‐co‐glycolic acid) (PLGA) NPs are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands. QA‐decorated NPs (QA‐NP) interact with human umbilical vein endothelial cells expressing E‐/P‐selectins and induce transient increase in endothelial permeability to translocate across the layer. QA‐NP reach selectin‐upregulated tumors, achieving greater tumor accumulation and paclitaxel (PTX) delivery than polyethylene glycol‐decorated NPs (PEG‐NP). PTX‐loaded QA‐NP show greater anticancer efficacy than Taxol or PTX‐loaded PEG‐NP at the equivalent PTX dose in different animal models and dosing regimens. Repeated dosing of PTX‐loaded QA‐NP for two weeks results in complete tumor remission in 40–60% of MDA‐MB‐231 tumor‐bearing mice, while those receiving control treatments succumb to death. QA‐NP can exploit the interaction with selectin‐expressing peritumoral endothelium and deliver anticancer drugs to tumors to a greater extent than the level currently possible with the EPR effect.
To overcome the endothelial barrier when accessing tumors, polymeric nanoparticles (NPs) are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands, via polydopamine. The QA‐decorated NPs interact with selectin‐overexpressing endothelial cells and induce a transient increase in endothelial permeability to translocate across the endothelial layer. The QA‐NPs reach selectin‐upregulated tumors, achieving greater tumor accumulation and paclitaxel delivery than polyethylene glycol‐decorated NPs.
To determine whether the tumor volume reduction rate (TVRR) measured using three-dimensional region-of-interest magnetic resonance volumetry correlates with the pathologic tumor response after ...preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer.
The study included 405 patients with locally advanced rectal cancer (cT3-T4) who had undergone preoperative CRT and radical proctectomy. The tumor volume was measured using three-dimensional region-of-interest magnetic resonance volumetry before and after CRT but before surgery. We analyzed the correlation between the TVRR and the pathologic tumor response in terms of downstaging and tumor regression grade (TRG). Downstaging was defined as ypStage 0-I (ypT0-T2N0M0), and the TRG proposed by Dworak et al. was used.
The mean TVRR was 65.0% +/- 22.3%. Downstaging and complete regression occurred in 167 (41.2%) and 58 (14.3%) patients, respectively. The TVRRs according to ypT classification (ypT0-T2 vs. ypT3-T4), ypN classification (ypN0 vs. ypN1-N2), downstaging (ypStage 0-I vs. ypStage II-III), good regression (TRG 3-4 vs. TRG 1-2), and complete regression (TRG 4 vs. TRG 1-3) were all significantly different (p <.05). When the TVRR was categorized into three groups (<60%, 60-80%, and >80%), the rates of ypT0-T2, ypN0, downstaging, and good regression were all significantly greater for patients with a TVRR of >or=60%, as was the complete regression rate for patients with a TVRR >80% (p <.05).
The TVRR measured using three-dimensional region-of-interest magnetic resonance volumetry correlated significantly with the pathologic tumor response in terms of downstaging and TRG after preoperative CRT for locally advanced rectal cancer.
PDF
![[18F]3'-deoxy-3'-fluorothym...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1619-7070/small "[18F]3'-deoxy-3'-fluorothymidine PET for the diagnosis and grading of brain tumors")
