Aims
Aggressive meningioma remains incurable with neither chemo‐ nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving ...the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression.
Methods
Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression‐free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked‐down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM‐Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)‐pretreated or control IOMM‐Lee cells were implanted subcutaneously in nude mice.
Results
FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of β‐catenin, cyclin D1, p21, interleukin‐8, vascular endothelial growth factor‐A, PLAU, and epithelial‐to‐mesenchymal transition‐related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model.
Conclusions
Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.
The computing demands of future data-intensive applications will greatly exceed the capabilities of current electronics, and are unlikely to be met by isolated improvements in transistors, data ...storage technologies or integrated circuit architectures alone. Instead, transformative nanosystems, which use new nanotechnologies to simultaneously realize improved devices and new integrated circuit architectures, are required. Here we present a prototype of such a transformative nanosystem. It consists of more than one million resistive random-access memory cells and more than two million carbon-nanotube field-effect transistors-promising new nanotechnologies for use in energy-efficient digital logic circuits and for dense data storage-fabricated on vertically stacked layers in a single chip. Unlike conventional integrated circuit architectures, the layered fabrication realizes a three-dimensional integrated circuit architecture with fine-grained and dense vertical connectivity between layers of computing, data storage, and input and output (in this instance, sensing). As a result, our nanosystem can capture massive amounts of data every second, store it directly on-chip, perform in situ processing of the captured data, and produce 'highly processed' information. As a working prototype, our nanosystem senses and classifies ambient gases. Furthermore, because the layers are fabricated on top of silicon logic circuitry, our nanosystem is compatible with existing infrastructure for silicon-based technologies. Such complex nano-electronic systems will be essential for future high-performance and highly energy-efficient electronic systems.
Summary
Background
Aspirin‐intolerant asthma (AIA) refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin or other non‐steroidal ...anti‐inflammatory drugs (NSAIDs). Angiotensin I‐converting enzyme (ACE), a membrane‐bound peptidase present in the lung, plays a pivotal role in the metabolism of the endogenous peptides involved in the pathogenesis of asthma.
Methods
We screened a Korean asthma cohort (581 asthmatics including 81 aspirin‐intolerant asthmatics and 231 aspirin‐tolerant asthmatics, and 181 normal controls) for four single nucleotide polymorphisms (SNPs; −262 A>T and −115 T>C in the 5′‐flanking region and +5467 T>C Pro450Pro and+11860 A>G Thr776Thr in the coding region) and one ins/del (+21288 CT) in the ACE gene.
Results
None of the SNPs or haplotypes showed any association with the development of asthma, but they were significantly associated with the risk of AIA. Logistic regression indicated that the frequency of the rare alleles of −262 A>T and −115 T>C was higher in subjects with AIA than in subjects with aspirin‐tolerant asthma (ATA) (P=0.003–0.01, P corr=0.015–0.05). Subjects homozygous for the rare alleles of −262 A>T and −115 T>C showed a greater decline in forced expiratory volume in 1 s (FEV1) after aspirin provocation than those homozygous for the common alleles (P<0.05). A luciferase reporter assay indicated that ACE promoters containing the rare −262 A>T allele possessed lower activity than did those containing the common allele (P=0.009). In addition, ACE promoters bearing the rare −115 T>C allele had no luciferase activity. DNA–protein binding assays revealed a band containing the ACE promoter region (including −262 A) and a protein complex.
Conclusion
The −262 A>T polymorphism in the promoter of the ACE gene is associated with AIA, and the rare allele of −262 A>T may confer aspirin hypersensitivity via the down‐regulation of ACE expression.
Membrane proteins, including G protein-coupled receptors (GPCRs), present a challenge in studying their structural properties under physiological conditions. Moreover, to better understand the ...activity of proteins requires examination of single molecule behaviors rather than ensemble averaged behaviors. Force–distance curve-based AFM (FD-AFM) was utilized to directly probe and localize the conformational states of a GPCR within the membrane at nanoscale resolution based on the mechanical properties of the receptor. FD-AFM was applied to rhodopsin, the light receptor and a prototypical GPCR, embedded in native rod outer segment disc membranes from photoreceptor cells of the retina in mice. Both FD-AFM and computational studies on coarse-grained models of rhodopsin revealed that the active state of the receptor has a higher Young’s modulus compared to the inactive state of the receptor. Thus, the inactive and active states of rhodopsin could be differentiated based on the stiffness of the receptor. Differentiating the states based on the Young’s modulus allowed for the mapping of the different states within the membrane. Quantifying the active states present in the membrane containing the constitutively active G90D rhodopsin mutant or apoprotein opsin revealed that most receptors adopt an active state. Traditionally, constitutive activity of GPCRs has been described in terms of two-state models where the receptor can achieve only a single active state. FD-AFM data are inconsistent with a two-state model but instead require models that incorporate multiple active states.
A
bstract
Limits on the cross section for weakly interacting massive particles (WIMPs) elastic scattering on nuclei in NaI(Tl) detectors at the Yangyang Underground Laboratory are obtained from a ...2967.4 kg·day data exposure. The nuclei recoiling from the scattering process are identified by the pulse shape of the scintillation light signals that they produce. The data are consistent with a no nuclear-recoil hypothesis, and WIMP-mass-dependent 90% confidence-level upper-limits are set on WIMP-nuclei elastic scattering cross sections. These limits partially exclude the DAMA/LIBRA allowed region for WIMP-sodium interactions with the same NaI(Tl) target material. The 90% confidence level upper limit on the WIMP-nucleon spin-independent cross section is 3.26×10
−4
pb for a WIMP mass of 10 GeV/c
2
.
Aims/hypothesis
Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 ...has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM).
Methods
We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an
ob/ob
mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor κB (NF-κB), extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro.
Results
Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated
ob/ob
mice. Macrophage populations (F4/80
+
and F4/80
+
CD11b
+
CD11c
+
cells), as well as the expression and production of IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated
ob/ob
mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated
ob/ob
mice. NF-κB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated
ob/ob
mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM.
Conclusions/interpretation
We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and ...safety of vandetanib 300 mg daily in this patient population.
This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0–2. The primary endpoint was the objective response rate.
A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35–71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.
Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
The purpose of this study was to investigate the prevalence of sarcopenia and to examine its impact on patients with degenerative lumbar spinal stenosis (DLSS).
This case-control study included two ...groups: one group consisting of patients with DLSS and a second group of control subjects without low back or neck pain and related leg pain. Five control cases were randomly selected and matched by age and gender (n = 77 cases and n = 385 controls) for each DLSS case. Appendicular muscle mass, hand-grip strength, sit-to-stand test, timed up and go (TUG) test, and clinical outcomes, including the Oswestry Disability Index (ODI) scores and the EuroQol EQ-5D were compared between the two groups.
The prevalence of sarcopenia, as defined by hand-grip strength, was significantly higher in the DLSS group (24%) when compared with the age- and gender-matched control group (12%) (p = 0.004). In the DLSS group, the sarcopenia subgroup demonstrated inferior results for the TUG test and ODI scores when compared with the non-sarcopenia subgroup (p = 0.006 and p = 0.039, respectively) after adjusting for age and gender.
This study demonstrated a higher prevalence of sarcopenia in patients with DLSS and highlighted its negative effect on clinical outcomes. Cite this article: Bone Joint J 2016;98-B:1093-8.
We compared late thoracic radiotherapy (TRT) with early TRT in the treatment of limited-disease small-cell lung cancer (LD-SCLC).
Patients with LD-SCLC received four cycles of etoposide plus ...cisplatin every 21 days. Patients were randomly assigned to receive either TRT administered concurrently with the first cycle (early TRT) or the third cycle (late TRT) of chemotherapy. The primary end point was complete response rate.
Two hundred twenty-two patients were randomly assigned. Late TRT was not inferior to early TRT in terms of the complete response rate (early versus late; 36.0% versus 38.0%). Other efficacy measures including overall survival median, 24.1 versus 26.8 months; hazard ratio (HR) 0.90; 95% CI 0.18–1.62 and progression-free survival (median, 12.4 versus 11.2 months; HR 1.10; 95% CI 0.37–1.84) were not different between two arms. No statistical difference was noted in the pattern of treatment failures. However, neutropenic fever occurred more commonly in the early TRT arm than the late TRT arm (21.6% versus 10.2%; P = 0.02).
In LD-SCLC treatment, TRT starting in the third cycle of chemotherapy seemed to be noninferior to early TRT, and had a more favorable profile with regard to neutropenic fever.
Collisionless shocks can be produced as a result of strong magnetic fields in a plasma flow, and therefore are common in many astrophysical systems. The Weibel instability is one candidate mechanism ...for the generation of sufficiently strong fields to create a collisionless shock. Despite their crucial role in astrophysical systems, observation of the magnetic fields produced by Weibel instabilities in experiments has been challenging. Using a proton probe to directly image electromagnetic fields, we present evidence of Weibel-generated magnetic fields that grow in opposing, initially unmagnetized plasma flows from laser-driven laboratory experiments. Three-dimensional particle-in-cell simulations reveal that the instability efficiently extracts energy from the plasma flows, and that the self-generated magnetic energy reaches a few percent of the total energy in the system. This result demonstrates an experimental platform suitable for the investigation of a wide range of astrophysical phenomena, including collisionless shock formation in supernova remnants, large-scale magnetic field amplification, and the radiation signature from gamma-ray bursts.
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