We report on the first direct comparisons of microtearing turbulence simulations to experimental measurements in a representative high bootstrap current fraction (f_{BS}) plasma. Previous studies of ...high f_{BS} plasmas carried out in DIII-D with large radius internal transport barriers (ITBs) have found that, while the ion energy transport is accurately reproduced by neoclassical theory, the electron transport remains anomalous and not well described by existing quasilinear transport models. A key feature of these plasmas is the large value of the normalized pressure gradient, which is shown to completely stabilize conventional drift-wave and kinetic ballooning mode instabilities in the ITB, but destabilizes the microtearing mode. Nonlinear gyrokinetic simulations of the ITB region performed with the cgyro code demonstrate that the microtearing modes are robustly unstable and capable of driving electron energy transport levels comparable to experimental levels for input parameters consistent with the experimental measurements. These simulations uniformly predict that the microtearing mode fluctuation and flux spectra extend to significantly shorter wavelengths than the range of linear instability, representing significantly different nonlinear dynamics and saturation mechanisms than conventional drift-wave turbulence, which is also consistent with the fundamental tearing nature of the instability. The predicted transport levels are found to be most sensitive to the magnetic shear, rather than the temperature gradients more typically identified as driving turbulent plasma transport.
We present a nonperturbative lattice calculation of the form factors which contribute to the amplitudes for the radiative decays P → ℓνℓγ, where P is a pseudoscalar meson and ℓ is a charged lepton. ...Together with the nonperturbative determination of the corrections to the processes P → ℓνℓ due to the exchange of a virtual photon, this allows accurate predictions at O(αem) to be made for leptonic decay rates for pseudoscalar mesons ranging from the pion to the Ds meson. We are able to separate unambiguously and nonpertubatively the pointlike contribution, from the structure-dependent, infrared-safe, terms in the amplitude. The fully nonperturbative O(a) improved calculation of the inclusive leptonic decay rates will lead to the determination of the corresponding Cabibbo-Kobayashi-Maskawa matrix elements also at O(αem). Prospects for a precise evaluation of leptonic decay rates with emission of a hard photon are also very interesting, especially for the decays of heavy D and B mesons for which currently only model-dependent predictions are available to compare with existing experimental data.
miRNAs are small non-coding RNAs of ~24 nt that can block mRNA translation and/or negatively regulate its stability. There is a large body of evidence that dysregulation of miRNAs is a hallmark of ...cancer. miRNAs are often aberrantly expressed and their function is linked to the regulation of oncogenes and/or tumor suppressor genes involved in cell signaling pathway. miR-221 and miR-222 are two highly homologous microRNAs, whose upregulation has been recently described in several types of human tumors. miR-221/222 have been considered to act as oncogenes or tumor suppressors, depending on tumor system. Silencing oncomiRs or gene therapy approaches, based on re-expression of miRNAs that are down-regulated in cancer cells, could represent a novel anti-tumor approach for integrated cancer therapy. Here we will review the role of miR-221/222 in cancer progression and their use as prognostic and therapeutic tools in cancer.
Standard of care for cancer is commonly a combination of surgery with radiotherapy or chemoradiotherapy. However, in some advanced cancer patients this approach might still remaininefficient and may ...cause many side effects, including severe complications and even death. Oncolytic viruses exhibit different anti-cancer mechanisms compared with conventional therapies, allowing the possibility for improved effect in cancer therapy. Chemotherapeutics combined with oncolytic viruses exhibit stronger cytotoxic responses and oncolysis. Here, we have investigated the systemic delivery of the oncolytic adenovirus and paclitaxel encapsulated in extracellular vesicles (EV) formulation that, in vitro, significantly increased the transduction ratio and the infectious titer when compared with the virus and paclitaxel alone. We demonstrated that the obtained EV formulation reduced the in vivo tumor growth in animal xenograft model of human lung cancer. Indeed, we found that combined treatment of oncolytic adenovirus and paclitaxel encapsulated in EV has enhanced anticancer effects both in vitro and in vivo in lung cancer models. Transcriptomic comparison carried out on the explanted xenografts from the different treatment groups revealed that only 5.3% of the differentially expressed genes were overlapping indicating that a de novo genetic program is triggered by the presence of the encapsulated paclitaxel: this novel genetic program might be responsible of the observed enhanced antitumor effect. Our work provides a promising approach combining anticancer drugs and viral therapies by intravenous EV delivery as a strategy for the lung cancer treatment.
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Extracellular vesicles (EVs), are naturally occurring cargo delivery tools with the potential to be used as drug vehicles of single agents or combination therapies. We previously demonstrated that ...human lung cancer cell-derived EVs could be used for the systemic delivery of oncolytic virus (OVs) and chemotherapy drugs such as paclitaxel (PTX), leading to enhanced anti-tumor effects in nude mice. In the current work, we evaluated the biodistribution of EVs by using bioluminescence and fluorescence imaging technologies, thus proving the ability of these EVs-formulations to specifically target the neoplasia, while leaving other body tissues unaffected. Moreover, in vivo imaging of NFκB activation in an immunocompetent reporter mouse model allowed to demonstrate the selective ability of EVs to induce tumor-associated inflammatory reactions, which are characterized by immunogenic cell death and CD3+/CD4+/CD8+ T-cell infiltration. While EVs have the potential to induce a systemic immune reaction by pro-inflammatory cytokines, our study provides compelling evidences of a localized inflammatory effect in the peritumoral area. Collectively, our findings strongly support the systemic administration of EVs formulations with OVs alone or in combination with chemotherapy agents as a novel strategy aimed at treating primary and metastatic cancers.
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Non-small cell lung cancer (NSCLC) accounts for ∼80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 ...and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy.
Divertor detachment offers a promising solution to the challenge of plasma-wall interactions for steady-state operation of fusion reactors. Here, we demonstrate the excellent compatibility of ...actively controlled full divertor detachment with a high-performance (β
~ 3, H
~ 1.5) core plasma, using high-β
(poloidal beta, β
> 2) scenario characterized by a sustained core internal transport barrier (ITB) and a modest edge transport barrier (ETB) in DIII-D tokamak. The high-β
high-confinement scenario facilitates divertor detachment which, in turn, promotes the development of an even stronger ITB at large radius with a weaker ETB. This self-organized synergy between ITB and ETB, leads to a net gain in energy confinement, in contrast to the net confinement loss caused by divertor detachment in standard H-modes. These results show the potential of integrating excellent core plasma performance with an efficient divertor solution, an essential step towards steady-state operation of reactor-grade plasmas.
Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. To define novel ...pathways that regulate susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma, we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant glioma cells, levels of different miRs are increased, and in particular, miR-30b/c and -21. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. T98G-sensitive cells treated with miR-21 or -30b/c become resistant to TRAIL. Furthermore, we demonstrate that miR-30b/c and miR-21 target respectively the 3' untranslated region of caspase-3 and TAp63 mRNAs, and that those proteins mediate some of the effects of miR-30 and -21 on TRAIL resistance, even in human glioblastoma primary cells and in lung cancer cells. In conclusion, we show that high expression levels of miR-21 and -30b/c are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets for TRAIL resistance in glioma.
We present a determination of the ratio of kaon and pion leptonic decay constants in isosymmetric QCD (ISOQCD), fK/fπ, making use of the gauge ensembles produced by the Extended Twisted Mass ...Collaboration with Nf = 2 + 1 + 1 flavors of Wilson-clover twisted-mass quarks, including configurations close to the physical point for all dynamical flavors. The simulations are carried out at three values of the lattice spacing ranging from ∼ 0.068 to ∼ 0.092 fm with linear lattice size up to L ~ 5.5 fm. The scale is set by the particle data group (PDG) value of the pion decay constant, ... , at the ISOQCD pion point, ... , obtaining for the gradient-flow scales the values w 0 = 0.17383 (63) fm, ... and t0/w0 = 0.11969 (62) fm. The data are analyzed within the framework of SU(2) chiral perturbation theory without resorting to the use of renormalized quark masses. At the ISOQCD kaon point ... we get (fK/fπ) ISO QCD = 1.1995 (44), where the error includes both statistical and systematic uncertainties. Implications for the Cabibbo-Kobayashi-Maskawa matrix element |Vus| and for the first-row Cabibbo-Kobayashi-Maskawa unitarity are discussed.(ProQuest: … denotes formulae omitted.)
The transition from a human diet based exclusively on wild plants and animals to one involving dependence on domesticated plants and animals beginning 10,000 to 11,000 y ago in Southwest Asia set ...into motion a series of profound health, lifestyle, social, and economic changes affecting human populations throughout most of the world. However, the social, cultural, behavioral, and other factors surrounding health and lifestyle associated with the foraging-to-farming transition are vague, owing to an incomplete or poorly understood contextual archaeological record of living conditions. Bioarchaeological investigation of the extraordinary record of human remains and their context from Neolithic Çatalhöyük (7100–5950 cal BCE), a massive archaeological site in south-central Anatolia (Turkey), provides important perspectives on population dynamics, health outcomes, behavioral adaptations, interpersonal conflict, and a record of community resilience over the life of this single early farming settlement having the attributes of a protocity. Study of Çatalhöyük human biology reveals increasing costs to members of the settlement, including elevated exposure to disease and labor demands in response to community dependence on and production of domesticated plant carbohydrates, growing population size and density fueled by elevated fertility, and increasing stresses due to heightened workload and greater mobility required for caprine herding and other resource acquisition activities over the nearly 12 centuries of settlement occupation. These changes in life conditions foreshadow developments that would take place worldwide over the millennia following the abandonment of Neolithic Çatalhöyük, including health challenges, adaptive patterns, physical activity, and emerging social behaviors involving interpersonal violence.
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