Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The ...Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia.
Macrophages can reversibly polarize into multiple functional subsets depending on their micro-environment. Identification and understanding the functionality of these subsets is relevant for the ...study of immune‑related diseases. However, knowledge about canine macrophage polarization is still in its infancy. In this study, we polarized canine monocytes using GM-CSF/IFN- γ and LPS towards M1 macrophages or M-CSF and IL-4 towards M2 macrophages and compared them to undifferentiated monocytes (M0). Polarized M1 and M2 macrophages were thoroughly characterized for morphology, surface marker features, gene profiles and functional properties. Our results showed that canine M1-polarized macrophages obtained a characteristic large, roundish, or amoeboid shape, while M2-polarized macrophages were smaller and adopted an elongated spindle-like morphology. Phenotypically, all macrophage subsets expressed the pan-macrophage markers CD14 and CD11b. M1-polarized macrophages expressed increased levels of CD40, CD80 CD86 and MHC II, while a significant increase in the expression levels of CD206, CD209, and CD163 was observed in M2-polarized macrophages. RNAseq of the three macrophage subsets showed distinct gene expression profiles, which are closely associated with immune responsiveness, cell differentiation and phagocytosis. However, the complexity of the gene expression patterns makes it difficult to assign clear new polarization markers. Functionally, undifferentiated -monocytes, and M1- and M2- like subsets of canine macrophages can all phagocytose latex beads. M2-polarized macrophages exhibited the strongest phagocytic capacity compared to undifferentiated monocytes- and M1-polarized cells. Taken together, this study showed that canine M1 and M2-like macrophages have distinct features largely in parallel to those of well-studied species, such as human, mouse and pig. These findings enable future use of monocyte derived polarized macrophages particularly in studies of immune related diseases in dogs.
Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and ...reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events.
This meta-analysis included studies from the 2006 Cochrane meta-analysis, studies published/updated since the 2006 Cochrane report, and unpublished trial data from Amgen and Centocor Ortho Biotech. The 60 studies analysed (15 323 patients) were conducted in the settings of chemotherapy/radiochemotherapy, radiotherapy only treatment or anaemia of cancer. Data were summarised using odds ratios (ORs) with 95% confidence intervals (CIs).
Results indicated that ESA use did not significantly affect mortality (60 studies: OR=1.06; 95% CI: 0.97-1.15) or disease progression (26 studies: OR=1.01; 95% CI: 0.90-1.14), but increased the risk for venous-thromoboembolic events (44 studies: OR=1.48; 95% CI: 1.28-1.72).
Though this meta-analysis showed no significant effect of ESAs on survival or disease progression, prospectively designed, future randomised clinical trials will further examine the safety and efficacy of ESAs when used according to the revised labelling information.
Land evapotranspiration (ET) estimates are available from several global data sets. Here, monthly global land ET synthesis products, merged from these individual data sets over the time periods ...1989–1995 (7 yr) and 1989–2005 (17 yr), are presented. The merged synthesis products over the shorter period are based on a total of 40 distinct data sets while those over the longer period are based on a total of 14 data sets. In the individual data sets, ET is derived from satellite and/or in situ observations (diagnostic data sets) or calculated via land-surface models (LSMs) driven with observations-based forcing or output from atmospheric reanalyses. Statistics for four merged synthesis products are provided, one including all data sets and three including only data sets from one category each (diagnostic, LSMs, and reanalyses). The multi-annual variations of ET in the merged synthesis products display realistic responses. They are also consistent with previous findings of a global increase in ET between 1989 and 1997 (0.13 mm yr−2 in our merged product) followed by a significant decrease in this trend (−0.18 mm yr−2), although these trends are relatively small compared to the uncertainty of absolute ET values. The global mean ET from the merged synthesis products (based on all data sets) is 493 mm yr−1 (1.35 mm d−1) for both the 1989–1995 and 1989–2005 products, which is relatively low compared to previously published estimates. We estimate global runoff (precipitation minus ET) to 263 mm yr−1 (34 406 km3 yr−1) for a total land area of 130 922 000 km2. Precipitation, being an important driving factor and input to most simulated ET data sets, presents uncertainties between single data sets as large as those in the ET estimates. In order to reduce uncertainties in current ET products, improving the accuracy of the input variables, especially precipitation, as well as the parameterizations of ET, are crucial.
Emergent phenomena, including superconductivity and magnetism, found in the two-dimensional electron liquid (2-DEL) at the interface between the insulators lanthanum aluminate (LaAlO3) and strontium ...titanate (SrTiO3) distinguish this rich system from conventional 2D electron gases at compound semiconductor interfaces. The origin of this 2-DEL, however, is highly debated, with focus on the role of defects in the SrTiO3, while the LaAlO3 has been assumed perfect. Here we demonstrate, through experiments and first-principle calculations, that the cation stoichiometry of the nominal LaAlO3 layer is key to 2-DEL formation: only Al-rich LaAlO3 results in a 2-DEL. Although extrinsic defects, including oxygen deficiency, are known to render LaAlO3/SrTiO3 samples conducting, our results show that in the absence of such extrinsic defects an interface 2-DEL can form. Its origin is consistent with an intrinsic electronic reconstruction occurring to counteract a polarization catastrophe. This work provides insight for identifying other interfaces where emergent behaviours await discovery.
TOPoS Bonifacio, P.; Monaco, L.; Salvadori, S. ...
Astronomy and astrophysics (Berlin),
07/2021, Letnik:
651
Journal Article
Recenzirano
Odprti dostop
Context.
The goal of the Turn-Off Primordial Stars survey (TOPoS) project is to find and analyse turn-off (TO) stars of extremely low metallicity. To select the targets for spectroscopic follow-up at ...high spectral resolution, we relied on low-resolution spectra from the Sloan Digital Sky Survey (SDSS).
Aims.
In this paper, we use the metallicity estimates we obtained from our analysis of the SDSS spectra to construct the metallicity distribution function (MDF) of the Milky Way, with special emphasis on its metal-weak tail. The goal is to provide the underlying distribution out of which the TOPoS sample was extracted.
Methods.
We made use of SDSS photometry,
Gaia
photometry, and distance estimates derived from the
Gaia
parallaxes to derive a metallicity estimate for a large sample of over 24 million TO stars. This sample was used to derive the metallicity bias of the sample for which SDSS spectra are available.
Results.
We determined that the spectroscopic sample is strongly biased in favour of metal-poor stars, as intended. A comparison with the unbiased photometric sample allows us to correct for the selection bias. We selected a sub-sample of stars with reliable parallaxes for which we combined the SDSS radial velocities with
Gaia
proper motions and parallaxes to compute actions and orbital parameters in the Galactic potential. This allowed us to characterise the stars dynamically, and in particular to select a sub-sample that belongs to the
Gaia
-Sausage-Enceladus (GSE) accretion event. We are thus also able to provide the MDF of GSE.
Conclusions.
The metal-weak tail derived in our study is very similar to that derived in the H3 survey and in the Hamburg/ESO Survey. This allows us to average the three MDFs and provide an error bar for each metallicity bin. Inasmuch as the GSE structure is representative of the progenitor galaxy that collided with the Milky Way, that galaxy appears to be strongly deficient in metal-poor stars compared to the Milky Way, suggesting that the metal-weak tail of the latter has been largely formed by accretion of low-mass galaxies rather than massive galaxies, such as the GSE progenitor.
The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal ...translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.
Context. Due to an ill-depicting model of the convective layers below the photosphere in 1D stellar models (structural contribution) and/or a misrepresentation of the coupling between convection and ...oscillations (modal contribution), a well-known deviation appears between observed and theoretical frequencies, which grows towards high frequencies; the so-called surface effects. While satisfying solutions have been found regarding the structural contribution, the accurate modeling of the modal effect still represents a challenge. Alongside the frequency, the interaction between convection and oscillations also impacts the damping rate of the modes and forms an important part of the driving mechanism behind the stellar oscillations of low-mass stars. With increasing observational capabilities at our disposal with Kepler and TESS, shortcomings in modeling constitute the main limitation to accurate seismic probing of solar-like and red giant stars. Aims. We present the formalism of an approach that changes the current paradigm by addressing three-dimensional space. This new formalism consists in an original nonadiabatic 3D time-dependent convection model for asteroseismology. Methods. We aim to keep the entire 3D structure of the astrophysical flow in these superficial layers in order to fully account for the nature of turbulence in our model via the use of advanced hydrodynamic simulation. We use the perturbative approach and introduce a spectral decomposition approach that results in an entirely new formalism describing standing waves in 3D. This formalism is set to solve the quasi-radial global nonadiabatic oscillation equations in a full 3D framework. Results. Based on physical assumptions, we establish an eigenvalue problem describing the 3D quasi-radial global nonadiabatic stellar oscillation. We also provide a prescription for its numerical resolution alongside a proposed iteration method for our formalism. Finally, we derive the peculiar 3D work integral and establish the expression of the damping rate. We show how our formalism offers the possibility to probe the complex structure of stars and is able to precisely locate regions of the driving and damping of the modes as well as their physical origin.
The hydrogen-rich outer layers of massive stars can be removed by interactions with a binary companion. Theoretical models predict that this stripping produces a population of hot helium stars of ~2 ...to 8 solar masses (
), however, only one such system has been identified thus far. We used ultraviolet photometry to identify potential stripped helium stars then investigated 25 of them using optical spectroscopy. We identified stars with high temperatures (~60,000 to 100,000 kelvin), high surface gravities, and hydrogen-depleted surfaces; 16 stars also showed binary motion. These properties match expectations for stars with initial masses of 8 to 25
that were stripped by binary interaction. Their masses fall in the gap between subdwarf helium stars and Wolf-Rayet stars. We propose that these stars could be progenitors of stripped-envelope supernovae.
The incidence of venous thromboembolism (VTE) is more than 1 per thousand annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma ...(MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with < or = 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.
PDF
