Chromosomal rearrangements of
resulting in gene fusions (
gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers. Typically,
gene fusions involve both ...inter- and intrachromosomal fusions of the 5' regions of a variety of genes with the 3' regions of
genes leading to TRK fusion proteins with constitutive, ligand-independent activation of the intrinsic tyrosine kinase. The incidence of
gene fusions can range from the majority of cases in certain rare cancers to lower rates in a wide range of more common cancers. Two small-molecule TRK inhibitors have recently received regulatory approval for the treatment of patients with solid tumors harboring
gene fusions, including the selective TRK inhibitor larotrectinib and the TRK/ROS1/ALK multikinase inhibitor entrectinib. In this review, we consider the practicalities of detecting tumors harboring
gene fusions, the pharmacologic properties of TRK inhibitors currently in clinical development, the clinical evidence for larotrectinib and entrectinib efficacy, and possible resistance mechanisms.
The detection of ensembles of spins under ambient conditions has revolutionized the biological, chemical and physical sciences through magnetic resonance imaging1 and nuclear magnetic resonance2, 3. ...Pushing sensing capabilities to the individual-spin level would enable unprecedented applications such as single-molecule structural imaging; however, the weak magnetic fields from single spins are undetectable by conventional far-field resonance techniques4. In recent years, there has been a considerable effort to develop nanoscale scanning magnetometers5, 6, 7, 8, which are able to measure fewer spins by bringing the sensor in close proximity to its target. The most sensitive of these magnetometers generally require low temperatures for operation, but the ability to measure under ambient conditions (standard temperature and pressure) is critical for many imaging applications, particularly in biological systems. Here we demonstrate detection and nanoscale imaging of the magnetic field from an initialized single electron spin under ambient conditions using a scanning nitrogen-vacancy magnetometer. Real-space, quantitative magnetic-field images are obtained by deterministically scanning our nitrogen-vacancy magnetometer 50 nm above a target electron spin, while measuring the local magnetic field using dynamically decoupled magnetometry protocols. We discuss how this single-spin detection enables the study of a variety of room-temperature phenomena in condensed-matter physics with an unprecedented combination of spatial resolution and spin sensitivity.
PD (Parkinson's disease) is characterized by the selective and progressive loss of DA neurons (dopaminergic neurons) in the substantia nigra. Inflammation and activation of microglia, the resident ...innate immune cell in the brain, have been strongly linked to neurodegenerative diseases, such as PD. Microglia can respond to immunological stimuli and neuronal death to produce a host of toxic factors, including cytokines and ROS (reactive oxygen species). Microglia can also become persistently activated after a single stimulus and maintain the elevated production of both cytokines and ROS, long after the instigating stimulus is gone. Current reports suggest that this chronic microglial activation may be fuelled by either dying/damaged neurons or autocrine and paracrine signals from local glial cells, such as cytokines. Here, we review proposed mechanisms responsible for chronic neuroinflammation and explain the interconnected relationship between deleterious microglial activation, DA neuron damage and neurodegenerative disease.
Magnetic resonance imaging (MRI) has revolutionized biomedical science by providing non-invasive, three-dimensional biological imaging. However, spatial resolution in conventional MRI systems is ...limited to tens of micrometres, which is insufficient for imaging on molecular scales. Here, we demonstrate an MRI technique that provides subnanometre spatial resolution in three dimensions, with single electron-spin sensitivity. Our imaging method works under ambient conditions and can measure ubiquitous 'dark' spins, which constitute nearly all spin targets of interest. In this technique, the magnetic quantum-projection noise of dark spins is measured using a single nitrogen-vacancy (NV) magnetometer located near the surface of a diamond chip. The distribution of spins surrounding the NV magnetometer is imaged with a scanning magnetic-field gradient. To evaluate the performance of the NV-MRI technique, we image the three-dimensional landscape of electronic spins at the diamond surface and achieve an unprecedented combination of resolution (0.8 nm laterally and 1.5 nm vertically) and single-spin sensitivity. Our measurements uncover electronic spins on the diamond surface that can potentially be used as resources for improved magnetic imaging. This NV-MRI technique is immediately applicable to diverse systems including imaging spin chains, readout of spin-based quantum bits, and determining the location of spin labels in biological systems.
To cite this article: Hong S-W, Kim M-R, Lee E-Y, Kim JH, Kim Y-S, Jeon SG, Yang J-M, Lee B-J, Pyun B-Y, Gho YS, Kim Y-K. Extracellular vesicles derived from Staphylococcus aureus induce atopic ...dermatitis-like skin inflammation. Allergy 2011; 66: 351-359. ABSTRACT: Background: Recently, we found that Staphylococcus aureus produces extracellular vesicles (EV) that contain pathogenic proteins. Although S. aureus infection has been linked with atopic dermatitis (AD), the identities of the causative agents from S. aureus are controversial. We evaluated whether S. aureus-derived EV are causally related to the pathogenesis of AD. Methods: Extracellular vesicles were isolated by the ultracentrifugation of S. aureus culture media. The EV were applied three times per week to tape-stripped mouse skin. Inflammation and immune dysfunction were evaluated 48 h after the final application in hairless mice. Extracellular vesicles-specific IgE levels were measured by ELISA in AD patients and healthy subjects. Results: The in vitro application of S. aureus EV increased the production of pro-inflammatory mediators (IL-6, thymic stromal lymphopoietin, macrophage inflammatory protein-1α, and eotaxin) by dermal fibroblasts. The in vivo application of S. aureus EV after tape stripping caused epidermal thickening with infiltration of the dermis by mast cells and eosinophils in mice. These changes were associated with the enhanced cutaneous production of IL-4, IL-5, IFN-γ, and IL-17. Interestingly, the serum levels of S. aureus EV-specific IgE were significantly increased in AD patients relative to healthy subjects. Conclusion: These results indicate that S. aureus EV induce AD-like inflammation in the skin and that S. aureus-derived EV are a novel diagnostic and therapeutic target for the control of AD.
Airway diseases such as chronic rhinosinusitis, asthma, and chronic obstructive pulmonary disorder are characterized by inflammation and remodeling. Among inflammatory and extracellular matrix ...regulatory cytokines, transforming growth factor‐beta (TGF‐β) stands central, as it possesses both important immunomodulatory and fibrogenic activities, and should be considered a key for understanding inflammation and remodeling processes. This review will briefly summarize the recent findings on the role of TGF‐β1, from the view points of inflammation and remodeling, and discuss the role of TGF‐β in the upper and lower airway diseases. This may reveal new perspectives in the understanding of airway inflammation and remodeling processes and may open innovative treatment strategies for the regulation of TGF‐β1.
Pristine and Ce doped TiO2 nanoparticles were fabricated for toxic pollutants removal from wastewater. Pristine, 2% Ce and 4% Ce doped TiO2 photocatalysts were produced via hydrothermal route. 4% Ce ...doped TiO2 exhibited 2.41 eV bandgap which is smaller than pure TiO2. The morphology was also investigated and it was established that doping of Ce ions enhanced the surface roughness and reduced the particle size. The surface area was characterized through BET analysis and 4% Ce–TiO2 possess higher surface with large pore diameter which helped the photocatalytic activity. The prepared photocatalysts were investigated on reduction of pollutants from wastewater under visible light. Higher efficiency was obtained for 4% Ce–TiO2 photocatalyst for both model pollutants. The “k” value possessed was also higher for the doped TiO2 catalyst. These analysis reports the optimum level of ceria doping to enhance morphology, surface area and it increased activity than bare TiO2. 4% Ce–TiO2 will be the potential candidate for efficient wastewater management. The 4% Ce doped TiO2 photocatalyst provided 77% and 88% on reducing MB and RhB dyes. The dopant has developed higher surface area, morphology and good recombination rate which reduced the toxic pollutants and changed the wastewater to reuse.
•4% Ce–TiO2 possess higher surface with large pore diameter.•4% Ce–TiO2 explored higher efficiency for both model pollutants.•The “k” value possessed was also higher for the doped TiO2 catalyst.•4% Ce–TiO2 will be the potential candidate for efficient wastewater management.
Background
Many surgical instruments have been replaced with powered devices in open gastrointestinal and laparoscopic surgery. The production of smoke as a result of vaporization of surgical tissue ...is inevitable, and exposure to surgical smoke is a long‐standing concern. These vapours are potentially hazardous to patients and surgical teams. The present research was designed to compare various surgical devices to determine whether viable cells exist in their surgical smoke.
Methods
The search for viable cells in surgical smoke was conducted using both in vitro and in vivo experiments. Various cancers were cauterized with electrocautery, radiofrequency ablation and ultrasonic scalpels, and the resulting surgical smoke was aspirated with Transwell® membrane; viable cells were sought in the surgical smoke. In an in vivo experiment, samples of SCC7 were cauterized with an ultrasonic scalpel and the sediment from the rinsed Transwell® membrane liquid after centrifugation was injected subcutaneously into the lower back of mice.
Results
Viable cells were found only in the smoke from ultrasonic scalpels (in all 25 samples taken 5 cm from the cautery; 2 of 25 samples at 10 cm). Viable cells in the surgical smoke from ultrasonic scalpels implanted in mice grew in 16 of 40 injection sites. Histological and biochemical analyses revealed that these cancer cells were identical to the cancer cells cauterized by the ultrasonic scalpel.
Conclusion
Viable tumour cells are produced in the surgical smoke from tumour dissection by ultrasonic scalpel.
Surgical relevance
Surgical smoke is a byproduct of dissection using a number of powered devices. Hazards to operating room personnel and patients are unclear.
This study has shown that use of an ultrasonic dissection device can produce smoke that contains viable tumour cells.
Although the model is somewhat artificial, a theoretical risk exists, and measures to evacuate surgical smoke efficiently are important.
Surgical smoke is potentially hazardous
Several different binders for high temperature proton exchange membrane fuel cell (PEMFC) were tested to investigate the effects of binder properties on cell performance. The cell voltage values ...measured with electrodes with PTFE binders are compared to that obtained with electrode with PBI or polyurethane binders. The electrodes that used PBI and polyurethane binders showed Tafel slopes of 87 mV/decade, and the values were lower than the Tafel slope measured from Teflon containing electrodes which showed the Tafel slope value of 100 mV/decade. Pt utilization also showed dependence on the kind of binders used in the electrodes. When PTFE or polyurethane binder was used, Pt utilization of 15% was measured. The PBI binder was found to reduce Pt utilization, and 10% of catalyst utilization was measured. The changes in Tafel slope, Pt utilization, η
ohm
affected cell performance, and it was found that the electrodes with polyurethane binder showed the highest cell voltage among the tested binders with the cell voltage of 0.619V @ 0.2 A/cm
2
. Binder properties also affected cell life time. By increasing Teflon content in the electrode, it was possible to operate cells for a longer period.
Alzheimer's disease (AD) is the most common form of dementia affecting the elderly population today; however, there is currently no accurate description of the etiology of this devastating disorder. ...No single factor has been demonstrated as being causative; however, an alternative co-factors theory suggests that the interaction of multiple risk factors is responsible for AD. We have used this model, in combination with the original cholinergic hypothesis of AD to propose a "new" cholinergic hypothesis that we present in this review. This new version takes into account recent findings from the literature and our reports of removal of medial septum cholinergic projections to the hippocampus reduces both behavioural and anatomical plasticity, resulting in greater cognitive impairment in response to secondary insults (stress, injury, disease, etc.). We will first summarize the experimental results and discuss some potential mechanisms that could explain our results. We will then present our 'new' version of the cholinergic hypothesis and how it relates to the field of AD research today. Finally we will discuss some of the implications for treatment that arise from this model and present directions for future study.
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