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A novel gold-catalyzed cycloisomerization/[2 + 1]cycloaddition/rearrangement of enyne-amides and sulfur ylides is reported. This strategy enables rapid and efficient construction of a series of α-pyrone derivatives.

A highly efficient [4 + 1] annulation of sulfur ylide salts and o-sulfonamido aldimines for construction of valuable 2,3-disubstituted indolines is reported. It is worth noting that indoles could also be synthesized by this cascade reaction.

Developmental sevoflurane exposure leads to widespread neuronal cell death known as sevoflurane-induced neurotoxicity (SIN). Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL)-driven necroptosis plays an important role in cell fate. Previous research has shown that inhibition of RIPK1 activity alone did not attenuate SIN. Since RIPK3/MLKL signaling could also be activated by Z-DNA/RNA binding protein 1 (ZBP1), the present study was designed to investigate whether ZBP1-mediated and RIPK3/MLKL-driven necroptosis is involved in SIN through in vitro and in vivo experiments. We found that sevoflurane priming triggers neuronal cell death and LDH release in a time-dependent manner. The expression levels of RIPK1, RIPK3, ZBP1 and membrane phosphorylated MLKL were also dramatically enhanced in SIN. Intriguingly, knockdown of RIPK3, but not RIPK1, abolished MLKL-mediated neuronal necroptosis in SIN. Additionally, inhibition of RIPK3-mediated necroptosis with GSK'872, rather than inhibition of apoptosis with zVAD, significantly ameliorated SIN. Further investigation showed that sevoflurane treatment causes mitochondrial DNA (mtDNA) release into the cytosol. Accordingly, ZBP1 senses cytosolic mtDNA and consequently activates RIPK3/MLKL signaling. This conclusion was reinforced by the evidence that knockdown of ZBP1 or depleting mtDNA with ethidium bromide remarkably improved SIN. Finally, the administration of the RIPK3 inhibitor GSK'872 relieved sevoflurane-induced spatial and emotional disorders without influence on locomotor activity. Altogether, these results illustrate that ZBP1 senses cytosolic mtDNA to induce RIPK3/MLKL-driven necroptosis in SIN. Elucidating the role of necroptosis in SIN will provide new insights into understanding the mechanism of anesthetic exposure in the developing brain.

Background: Admission hyperglycemia is a predictor of poor prognosis after ischemic stroke (IS). Previous studies have found that admission hyperglycemia was related to clopidogrel high on-treatment platelet reactivity (HTPR) in diabetic patients with myocardial infarction. However, reports on associations between admission hyperglycemia and clopidogrel HTPR remain scarce in IS patients. In this study, we assessed the correlation between admission hyperglycemia and clopidogrel HTPR in patients with IS. Methods: In this retrospective study, we included IS patients who were treated with clopidogrel for at least 5 days. Thromboelastography (TEG) was used to evaluate the platelet function. Clopidogrel HTPR was defined if adenosine diphosphate (ADP)-induced platelet fibrin clot strength (MAADP)> 47 mm. Otherwise, it would be defined as clopidogrel normal on-treatment platelet reactivity (NTPR). Two groups were divided according to admission glucose of 7.8 mmol/L, consistent with previous studies on admission hyperglycemia. The independent risk factors of clopidogrel HTPR were assessed by multivariate logistic regression analysis. Results: A total of 147 patients were evaluated, and 42(28.57%) of patients were identified as clopidogrel HTPR. In the hyperglycemia group (admission glucose level ≥7.8mmol/L), 40.38% patients were defined as clopidogrel HTPR, which was significantly higher than in the normoglycemia group (22.11%, admission glucose level

Рассматривается дефокусирующее модифицированное комплексное уравнение коротких импульсов. Преобразование Дарбу для этого уравнения строится с помощью преобразования взаимности и получающегося после преобразования ассоциированного уравнения коротких импульсов. В качестве приложения представлены многосолитонные решения с темными солитонами, задающиеся в форме отношения определителей.

An atroposelectively diversity-oriented synthetic strategy was developed for the divergent synthesis of axially chiral heterocycles through organocatalytic asymmetric intramolecular annulation of a...

Suppl. Table 1. Histology, age, gender, diagnosis, site of CSF draws, longitudinal # and IDH1/2 mutation status of 84 tumor samples analyzed. Highlighted in 'yellow' are CSF samples that tested positive for IDH1 mutant staining, while their DNA indicated WT IDH.

Suppl. Table 2. CSF and Matching Tissues Available for the Study Suppl. Table 3. Metabolite concentrations in the three cohorts (t-test Statistics) Suppl. Table 4. Site-specific thresholds for D-/L-2HG Suppl. Table 5. Information about site-specific accuracy for D-2HG Suppl. Table 6. Tumor tissue sample demographics tested in parallel by MS and NMR

Purpose: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene.Experimental Design: We developed a mass spectrometry (MS)–based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients. Three independent cohorts of patients were analyzed, comprising a total of 176 samples derived from 84 patients. The levels of D- and L-2HG were used to stratify patients into IDH wild-type or IDH-mutated groups using an empirically obtained threshold of 0.69 μmol/L.Results: Using this platform, a greater than 17-fold mean increase in D-2HG was observed in the CSF of patients with IDH mutant versus wild-type gliomas. The means for the D-2HG levels in CSF were 0.427 μmol/L in wild-type and 7.439 μmol/L in mutant groups. The C statistic for the receiver operator curve was 0.938, with 84% sensitivity, 90% specificity, and 89% accuracy to detect D-2HG. The levels of D- and L-2HG in CSF from wild-type patients varied by location of CSF draw (cisternal > ventricular > lumbar).Conclusions: Our findings demonstrate that the CSF of patients harboring IDH mutant gliomas contain increased levels of D-2HG, which can be reliably detected with a MS-based platform. Clin Cancer Res; 22(24); 6256–65. ©2016 AACR.

Supplementary Figures 1-3 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Figure Legends 1-7 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Figure Legends 1-2 from Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates In vivo Angiogenesis through a CD36-Dependent Mechanism

The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONP; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma, both in vitro and in vivo, after convection-enhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P < 0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell–containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P < 0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87ΔEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED. Cancer Res; 70(15); 6303–12. ©2010 AACR.

Supplementary Figure 2 from Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates In vivo Angiogenesis through a CD36-Dependent Mechanism

Supplementary Note from Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates In vivo Angiogenesis through a CD36-Dependent Mechanism

Supplementary Figure 7 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Figure 1 from Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates In vivo Angiogenesis through a CD36-Dependent Mechanism

Supplementary Methods from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Figure 4 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Figure 6 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Figure 5 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Background: Ischemic stroke seriously threatens human health because of high rates of morbidity, mortality and disability. This study compared the effects of nicotinamide adenine dinucleotide (NAD+) and butylphthalide (NBP) on in vitro and in vivo ischemic stroke models.Methods: Transient middle cerebral artery occlusion/reperfusion (t-MCAO/R) model was established in mice, and the cultured primary cortical neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cerebral infarct volume, neurobehavioral indices, antioxidant activity, ATP level and lactic acid content were determined. The neuroprotective effects of NAD+ or NBP were compared using sirtuin inhibitor niacinamide (NAM).Results: Intraperitoneal injection of NBP within 4 h or intravenous injection of NAD+ within 1 h after t-MCAO/R significantly reduced the volume of infarcts, cerebral edema, and neurological deficits. Administration of NAD+ and NBP immediately after t-MCAO/R in mice showed similar neuroprotection against acute and long-term ischemic injury. Both NAD+ and NBP significantly inhibited the accumulation of MDA and H2O2 and reduced oxidative stress. NAD+ was superior to NBP in inhibiting lipid oxidation and DNA damage. Furthermore, although both NAD+ and NBP improved the morphology of mitochondrial damage induced by ischemia/reperfusion, NAD+ more effectively reversed the decrease of ATP and increase of lactic acid after ischemia/reperfusion compared with NBP. NAD+ but not NBP treatment significantly upregulated SIRT3 in the brain, but the sirtuin inhibitor NAM could abolish the protective effect of NAD+ and NBP by inhibiting SIRT1 or SIRT3.Conclusions: These results confirmed the protective effects of NAD+ and NBP on cerebral ischemic injury. NBP and NAD+ showed similar antioxidant effects, while NAD+ had better ability in restoring energy metabolism, possibly through upregulating the activity of SIRT1 and SIRT3. The protection provided by NBP against cerebral ischemia/reperfusion may be achieved through SIRT1.