Ceramide 1-phosphate (C1P) is a bioactive sphingolipid metabolite first shown to regulate cell growth and death. Subsequent studies revealed that C1P was a potent stimulator of cytosolic ...phospholipase A2 (cPLA2) with ensuing release of arachidonic acid and prostaglandin biosynthesis. The latter findings placed C1P on the list of pro-inflammatory metabolites. More recently, C1P was found to potently stimulate cell migration, an action that is associated to diverse physiological effects, as well as to inflammatory responses and tumor dissemination. The implication of C1P in inflammation has gained further interest in the last few years due to the discovery that it can exert anti-inflammatory actions in some cell types and tissues. In particular, C1P has been demonstrated to inhibit pro-inflammatory cytokine release and blockade of the pro-inflammatory transcription factor NF-κB in some cell types, as well as to reduce airway inflammation and lung emphysema. The present review is focused on novel aspects of C1P regulation of cell migration and the impact of C1P as novel anti-inflammatory agent.
Ceramide 1-phosphate (C1P) is a phosphosphingolipid with potent biological activities. It promotes cell growth and survival, and is a key regulator of cell migration. Both C1P and the enzyme that catalyzes its biosynthesis, ceramide kinase, are implicated in inflammatory responses. Although C1P has pro-inflammatory properties, it reduces pulmonary emphysema and exerts anti-inflammatory actions in the lung. Synthetic C1P analogs may be promising tools to treat lung inflammation.
•Ceramide 1-phosphate (C1P) is mitogenic and antiapoptotic.•C1P promotes cell migration and invasion.•C1P can be pro- or anti-inflammatory depending on cell type.
To demonstrate the efficacy of the anti-interleukin-6 receptor monoclonal antibody tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy (GO).
Double-masked ...randomized clinical trial.
Setting and Participants: Thirty-two adults with moderate-to-severe corticosteroid-resistant GO from 10 medical centers in Spain were randomized (1:1). Intervention: Randomization to either 8 mg/kg body weight tocilizumab or placebo administered intravenously at weeks 0, 4, 8, and 12, and follow-up for an additional 28 weeks. Main Outcomes and Measures: The primary outcome was the proportion of patients with a change from baseline to week 16 of at least 2 in the clinical activity score (CAS).
The primary outcome was met by 93.3% (95% confidence interval CI 70.1%-98.8%) of the patients receiving tocilizumab and 58.8% (36%-78.3%) receiving placebo (P = .04; odds ratio, 9.8 CI 1.3-73.2). A significant difference was also observed in the proportion of patients achieving a CAS < 3 (86.7% CI 62.1%-96.2% vs 35.2% CI 17.3%-58.7%, P = .005; OR 11.9 CI 2.1-63.1) at week 16. Additionally, a larger proportion of patients with improvement in the European Group on GO–proposed composite ophthalmic score at week 16 (73.3% CI 48%-89.1% vs 29.4% CI 13.2%-53.1%; P = .03), and exophthalmos size change from baseline to week 16 (-1.5 -2.0 to 0.5 mm vs 0.0 -1.0 to 0.5 mm; P = .01) were seen with tocilizumab. One patient experienced a moderate increase in transaminases at week 8; another had an acute pyelonephritis at week 32 in the tocilizumab-treated group.
Tocilizumab offers a meaningful improvement in activity and severity in corticosteroid-resistant GO. This trial justifies further studies to characterize the role of tocilizumab in GO.
α‐Brominated ketones and aldehydes, with two adjacent electrophilic carbon atoms, are highly valuable synthetic intermediates in organic synthesis, however, their synthesis from unsymmetrical ketones ...is very challenging, and current methods suffer from low selectivity. We present a new, reliable, and efficient method for the synthesis of α‐bromocarbonyl compounds in excellent yields and with excellent selectivities. Starting from allylic alcohols as the carbonyl precursors, the combination of a 1,3‐hydrogen shift catalyzed by iridium(III) with an electrophilic bromination gives α‐bromoketones and aldehydes in good to excellent yields. The selectivity of the process is determined by the structure of the starting allylic alcohol; thus, α‐bromoketones formally derived from unsymmetrical ketones can be synthesized in a straightforward and selective manner.
Synthon shuffle: An efficient and high‐yielding synthetic route to prepare α‐bromoketones and aldehydes is presented (see scheme, Cp*=pentamethylcyclopentadienyl). The method relies on 1,3‐hydrogen shift/bromination of allylic alcohols catalyzed by IrIII complexes. The products are obtained in excellent yields and as single constitutional isomers.
A mild base-catalyzed strategy for the isomerization of allylic alcohols and allylic ethers has been developed. Experimental and computational investigations indicate that transition metal catalysts ...are not required when basic additives are present. As in the case of using transition metals under basic conditions, the isomerization catalyzed solely by base also follows a stereospecific pathway. The reaction is initiated by a rate-limiting deprotonation. Formation of an intimate ion pair between an allylic anion and the conjugate acid of the base results in efficient transfer of chirality. Through this mechanism, stereochemical information contained in the allylic alcohols is transferred to the ketone products. The stereospecific isomerization is also applicable for the first time to allylic ethers, yielding synthetically valuable enantioenriched (up to 97% ee) enol ethers.
Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism ...provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible for its biosynthesis, ceramide kinase (CERK), are well established regulators of cell growth and survival in normal, as well as malignant cells through stress-regulated signaling pathways. This metabolite also promotes cell survival, which has been associated with the feedback regulation of other antitumoral sphingolipids or second messengers. C1P also regulates cancer cell invasion and migration of different types of cancer, including lung, breast, pancreas, prostate, or leukemia cells. More recently, CERK and C1P have been implicated in the control of inflammatory responses. The present review provides an updated view on the important role of CERK/C1P in the regulation of cancer cell growth, survival, and dissemination.
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•Synergistic effects can be induced by adding Pt to Ru/Al2O3 catalysts prepared by wet impregnation and reduced by H2CO3.•Reduction by H2CO3 led to metallic species, whereas oxides ...were formed after H2 activation, notably on monometallic solids.•The addition of Pd or Pt seems to have promoted the reduction of Ru also inhibiting its oxidation on bimetallic catalysts.•The preparation method under mild conditions led to catalysts with small metallic particles and narrow size distribution.
Catalytic hydrogenation of aromatic compounds is of great interest due to environmental aspects and the wide range of industrial processes involving such reaction. In this context, the present work aims to study the influence of Pd or Pt addition on the performance of Ru/Al2O3 based catalysts for toluene hydrogenation in liquid phase. For this, catalysts were prepared by wet impregnation from chlorinated precursors and reduced in liquid phase by formaldehyde (H2CO). After impregnation, a part of the catalysts were activated ex situ at 573K or in situ at 523K under H2. The studied solids were characterized by N2 physisorption, SEM+EDX, TEM, XPS and TPR techniques. Catalytic tests were conducted in a slurry Parr reactor at 373K under constant H2 pressure of 5MPa. Results show that solids reduction by H2CO led to metallic species, while the activation treatments form oxides and decrease the catalytic activity. The initial reaction rate of non-activated monometallic catalysts follows the order: Ru/Al2O3≫Pd/Al2O3≈Pt/Al2O3. A synergistic effect on the activity of Ru/Al2O3 based catalysts is induced by the Pt addition.
Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available ...biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.
A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.
Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio HR, 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).
The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.
This paper analyses the extent to which local land supply is the result of strategic interaction among nearby local governments. In a setting of limited tax instruments to raise revenues and ...interjurisdictional competition for mobile residents, municipal authorities are provided with the economic incentives to convert land from rural to urban uses, hence promoting urban growth. Using data on a large sample of Spanish municipalities for the period 2003-11 and a modified Cournot-style competition model, we report evidence in support of this hypothesis. The results suggest that local incumbents do not make policy decisions in isolation, and reaction functions arise because the mobile tax base reacts to the regulatory measures that modify land uses in each municipality.
In this article, a wave propagation model is presented as the first step in the development of a new type of transluminal procedure for performing elastography. Elastography is a medical imaging ...modality for mapping the elastic properties of soft tissue. The wave propagation model is based on a Kelvin Voigt Fractional Derivative (KVFD) viscoelastic wave equation, and is numerically solved using a Finite Difference Time Domain (FDTD) method. Fractional rheological models, such as the KVFD, are particularly well suited to model the viscoelastic response of soft tissue in elastography. The transluminal procedure is based on the transmission and detection of shear waves through the luminal wall. Shear waves travelling through the tissue are perturbed after encountering areas of altered elasticity. These perturbations carry information of medical interest that can be extracted by solving the inverse problem. Scattering from prostate tumours is used as an example application to test the model. In silico results demonstrate that shear waves are satisfactorily transmitted through the luminal wall and that echoes, coming from reflected energy at the edges of an area of altered elasticity, which are feasibly detectable by using the transluminal approach. The model here presented provides a useful tool to establish the feasibility of transluminal procedures based on wave propagation and its interaction with the mechanical properties of the tissue outside the lumen.
In this paper we study how the visual animation of a self-avatar can be artificially modified in real-time in order to generate different haptic perceptions. In our experimental setup, participants ...could watch their self-avatar in a virtual environment in mirror mode while performing a weight lifting task. Users could map their gestures on the self-animated avatar in real-time using a Kinect. We introduce three kinds of modification of the visual animation of the self-avatar according to the effort delivered by the virtual avatar: 1) changes on the spatial mapping between the user's gestures and the avatar, 2) different motion profiles of the animation, and 3) changes in the posture of the avatar (upper-body inclination). The experimental task consisted of a weight lifting task in which participants had to order four virtual dumbbells according to their virtual weight. The user had to lift each virtual dumbbells by means of a tangible stick, the animation of the avatar was modulated according to the virtual weight of the dumbbell. The results showed that the altering the spatial mapping delivered the best performance. Nevertheless, participants globally appreciated all the different visual effects. Our results pave the way to the exploitation of such novel techniques in various VR applications such as sport training, exercise games, or industrial training scenarios in single or collaborative mode.
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