3,674 research outputs found
Demonstration of new possibilities of multilayer technology on resistive microstrip/ microdot detectors
The first successful attempts to optimize the electric field in Resistive
Microstrip Gas Chamber and resistive microdot detectors using additional field
shaping strips located inside the detector substrate are describedComment: Presented at the RD-51 mmini week, CERN, June 201
Overcoming Resistance to Natural Killer Cell Based Immunotherapies for Solid Tumors
Despite advances in the diagnostic and therapeutic modalities, the prognosis of several solid tumor malignancies remains poor. Different factors associated with solid tumors including a varied genetic signature, complex molecular signaling pathways, defective cross talk between the tumor cells and immune cells, hypoxic and immunosuppressive effects of tumor microenvironment result in a treatment resistant and metastatic phenotype. Over the past several years, immunotherapy has emerged as an attractive therapeutic option against multiple malignancies. The unique ability of natural killer (NK) cells to target cancer cells without antigen specificity makes them an ideal candidate for use against solid tumors. However, the outcomes of adoptive NK cell infusions into patients with solid tumors have been disappointing. Extensive studies have been done to investigate different strategies to improve the NK cell function, trafficking and tumor targeting. Use of cytokines and cytokine analogs has been well described and utilized to enhance the proliferation, stimulation and persistence of NK cells. Other techniques like blocking the human leukocyte antigen-killer cell receptors (KIR) interactions with anti-KIR monoclonal antibodies, preventing CD16 receptor shedding, increasing the expression of activating NK cell receptors like NKG2D, and use of immunocytokines and immune checkpoint inhibitors can enhance NK cell mediated cytotoxicity. Using genetically modified NK cells with chimeric antigen receptors and bispecific and trispecific NK cell engagers, NK cells can be effectively redirected to the tumor cells improving their cytotoxic potential. In this review, we have described these strategies and highlighted the need to further optimize these strategies to improve the clinical outcome of NK cell based immunotherapy against solid tumors
New perspectives on the molecular basis of the interaction between oxygen homeostasis and iron metabolism
Oxygen and iron are two elements closely related from a (bio)chemical point of view. Moreover, they share the characteristic of being indispensable for life, while also being potentially toxic. Therefore, their level is strictly monitored, and sophisticated pathways have evolved to face variations in either element. In addition, the expression of proteins involved in iron and oxygen metabolism is mainly controlled by a complex interplay of proteins that sense both iron levels and oxygen availability (ie, prolyl hydroxylases, hypoxia inducible factors, and iron regulatory proteins), and in turn activate feedback mechanisms to re-establish homeostasis. In this review, we describe how cells and organisms utilize these intricate networks to regulate responses to changes in oxygen and iron levels. We also explore the role of these pathways in some pathophysiological settings
Ironing out Macrophage Immunometabolism
Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism
Innovations in Human Stem Cell Research: A Holy Grail for Regenerative Medicine
Stem cells are unspecialized cells capable of renewing themselves and giving rise to differentiated and specialized cell subtypes. There are two general categories of stem cells, i.e., pluripotent stem cells capable of differentiation into any cell type in the human body and multipotent adult stem cells maintaining tissue homeostasis in postnatal life. Investigations in both these categories of stem cells have expanded our knowledge on human organogenesis and tissue regeneration and have suggested potential therapeutic functions of stem cells in regenerative medicine. The advent of induced pluripotent stem cell (iPSC) technology a decade ago further revolutionized stem cell biology and has given rise to the translation of stem cell-based therapies. This chapter will summarize some of the exciting progress and challenges in the applications of iPSC-derived stem cells and adult stem cells and the potential of translational and clinical research of these stem cells in regenerative medicine
A humanized orthotopic mouse model for preclinical evaluation of immunotherapy in Ewing sarcoma
The advent of novel cancer immunotherapy approaches is revolutionizing the treatment for cancer. Current small animal models for most cancers are syngeneic or genetically engineered mouse models or xenograft models based on immunodeficient mouse strains. These models have been limited in evaluating immunotherapy regimens due to the lack of functional human immune system. Development of animal models for bone cancer faces another challenge in the accessibility of tumor engraftment sites. Here, we describe a protocol to develop an orthotopic humanized mouse model for a bone and soft tissue sarcoma, Ewing sarcoma, by transplanting fresh human cord blood CD34+ hematopoietic stem cells into young NSG-SGM3 mice combined with subsequent Ewing sarcoma patient derived cell engraftment in the tibia of the humanized mice. We demonstrated early and robust reconstitution of human CD45+ leukocytes including T cells, B cells, natural killer cells and monocytes. Ewing sarcoma xenograft tumors successfully orthotopically engrafted in the humanized mice with minimal invasive procedures. We validated the translational utility of this orthotopic humanized model by evaluating the safety and efficacy of an immunotherapy antibody, magrolimab. Treatment with magrolimab induces CD47 blockade resulting in significantly decreased primary tumor growth, decreased lung metastasis and prolonged animal survival in the established humanized model. Furthermore, the humanized model recapitulated the dose dependent toxicity associated with the CD47 blockade as observed in patients in clinical trials. In conclusion, this orthotopic humanized mouse model of Ewing sarcoma represents an improved platform for evaluating immunotherapy in bone and soft tissue sarcoma, such as Ewing sarcoma. With careful design and optimization, this model is generalizable for other bone malignancies
Impact of deep convection in the tropical tropopause layer in West Africa: in-situ observations and mesoscale modelling
We present the analysis of the impact of convection on the composition of the tropical tropopause layer region (TTL) in West-Africa during the AMMA-SCOUT campaign. Geophysica M55 aircraft observations of water vapor, ozone, aerosol and CO2 show perturbed values at altitudes ranging from 14 km to 17 km (above the main convective outflow) and satellite data indicates that air detrainment is likely originated from convective cloud east of the flight. Simulations of the BOLAM mesoscale model, nudged with infrared radiance temperatures, are used to estimate the convective impact in the upper troposphere and to assess the fraction of air processed by convection. The analysis shows that BOLAM correctly reproduces the location and the vertical structure of convective outflow. Model-aided analysis indicates that in the outflow of a large convective system, deep convection can largely modify chemical composition and aerosol distribution up to the tropical tropopause. Model analysis also shows that, on average, deep convection occurring in the entire Sahelian transect (up to 2000 km E of the measurement area) has a non negligible role in determining TTL composition
Aerosols in the tropical and subtropical UT/LS: in-situ measurements of submicron particle abundance and volatility
Processes occurring in the tropical upper troposphere and lower stratosphere (UT/LS) are of importance for the global climate, for the stratospheric dynamics and air chemistry, and they influence the global distribution of water vapour, trace gases and aerosols. The mechanisms underlying cloud formation and variability in the UT/LS are of scientific concern as these still are not adequately described and quantified by numerical models. Part of the reasons for this is the scarcity of detailed in-situ measurements in particular from the Tropical Transition Layer (TTL) within the UT/LS. In this contribution we provide measurements of particle number densities and the amounts of non-volatile particles in the submicron size range present in the UT/LS over Southern Brazil, West Africa, and Northern Australia. The data were collected in-situ on board of the Russian high altitude research aircraft M-55 "Geophysica" using the specialised COPAS (COndensation PArticle counting System) instrument during the TROCCINOX (Araçatuba, Brazil, February 2005), the SCOUT-O3 (Darwin, Australia, December 2005), and SCOUT-AMMA (Ouagadougou, Burkina Faso, August 2006) campaigns. The vertical profiles obtained are compared to those from previous measurements from the NASA DC-8 and NASA WB-57F over Costa Rica and other tropical locations between 1999 and 2007. The number density of the submicron particles as function of altitude was found to be remarkably constant (even back to 1987) over the tropical UT/LS altitude band such that a parameterisation suitable for models can be extracted from the measurements. At altitudes corresponding to potential temperatures above 430 K a slight increase of the number densities from 2005/2006 results from the data in comparison to the 1987 to 2007 measurements. The origins of this increase are unknown. By contrast the data from Northern hemispheric mid latitudes do not exhibit such an increase between 1999 and 2006. Vertical profiles of the non-volatile fraction of the submicron particles were also measured by a COPAS channel and are presented here. The resulting profiles of the non-volatile number density fraction show a pronounced maximum of 50% in the tropical TTL over Australia and West Africa. Below and above this fraction is much lower attaining values of 10% and smaller. In the lower stratosphere the fine particles mostly consist of sulphuric acid which is reflected in the low numbers of non-volatile residues measured by COPAS. Without detailed chemical composition measurements the reason for the increase of non-volatile particle fractions cannot yet be given. The long distance transfer flights to Brazil, Australia and West-Africa were executed during a time window of 17 months within a period of relative volcanic quiescence. Thus the data measured during these transfers represent a "snapshot picture" documenting the status of a significant part of the global UT/LS aerosol (with sizes below 1 μm) at low concentration levels 15 years after the last major (i.e., the 1991 Mount Pinatubo) eruption. The corresponding latitudinal distributions of the measured particle number densities are also presented in this paper in order to provide input on the UT/LS background aerosol for modelling purposes
Morphology of the tropopause layer and lower stratosphere above a tropical cyclone : a case study on cyclone Davina (1999)
During the APE-THESEO mission in the Indian Ocean the Myasishchev Design Bureau stratospheric research aircraft M55 Geophysica performed a flight over and within the inner core region of tropical cyclone Davina. Measurements of total water, water vapour, temperature, aerosol backscattering, ozone and tracers were made and are discussed here in comparison with the averages of those quantities acquired during the campaign time frame. Temperature anomalies in the tropical tropopause layer (TTL), warmer than average in the lower part and colder than average in the upper TTL were observed. Ozone was strongly reduced compared to its average value, and thick cirrus decks were present up to the cold point, sometimes topped by a layer of very dry air. Evidence for meridional transport of trace gases in the stratosphere above the cyclone was observed and perturbed water distribution in the TTL was documented. The paper discuss possible processes of dehydration induced by the cirrus forming above the cyclone, and change in the chemical tracer and water distribution in the lower stratosphere 400–430 K due to meridional transport from the mid-latitudes and link with Davina. Moreover it compares the data prior and after the cyclone passage to discuss its actual impact on the atmospheric chemistry and thermodynamics
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