Tyrosine kinases (TKs) play an important role in pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Aberrant activity of TKs has been implicated in several ...types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to interfere with the activity of deregulated kinases. These TKIs are remarkably effective in the treatment of various human cancers including head and neck, gastric, prostate and breast cancer and several types of leukemia. However, these TKIs are transported out of the cell by ATP-binding cassette (ABC) transporters, resulting in development of a characteristic drug resistance phenotype in cancer patients. Interestingly, some of these TKIs also inhibit the ABC transporter mediated multi drug resistance (MDR) thereby; enhancing the efficacy of conventional chemotherapeutic drugs. This review discusses the clinically relevant TKIs and their interaction with ABC drug transporters in modulating MDR.
Two short (< 2 s) γ-ray bursts (GRBs) have recently been localized and fading afterglow counterparts detected. The combination of these two results left unclear the nature of the host galaxies of the ...bursts, because one was a star-forming dwarf, while the other was probably an elliptical galaxy. Here we report the X-ray localization of a short burst (GRB 050724) with unusual γ-ray and X-ray properties. The X-ray afterglow lies off the centre of an elliptical galaxy at a redshift of z = 0.258 (ref. 5), coincident with the position determined by ground-based optical and radio observations. The low level of star formation typical for elliptical galaxies makes it unlikely that the burst originated in a supernova explosion. A supernova origin was also ruled out for GRB 050709 (refs 3, 31), even though that burst took place in a galaxy with current star formation. The isotropic energy for the short bursts is 2-3 orders of magnitude lower than that for the long bursts. Our results therefore suggest that an alternative source of bursts-the coalescence of binary systems of neutron stars or a neutron star-black hole pair-are the progenitors of short bursts.
In immersed friction stir welding (FSW), the workpiece is fully immersed in the water during welding. Thermal numerical model development of air and immersed FSW is carried out using ...three-dimensional heat transfer model. FSW joints were produced in AA2014-T6 plate using different backing plates like mild steel, asbestos, and copper in both air and immersed conditions. K-type thermocouples are used to measure the temperature profile at different locations on the workpiece during air and immersed FSW. Commercially available software ANSYS is used to develop thermal numerical model using temperature-dependent material properties of AA2014-T6. The coefficient of friction between a tool and plate has been considered constant throughout the analysis for the simplification for both air and immersed conditions. Simulation results obtained both for air and immersed FSW are in good agreement with those obtained experimentally. It is observed that diffusivity of backing plate affects the temperature of weld region. It is also observed that higher tensile strength and microhardness attained for the joints produced using mild steel backing plate in immersed FSW compared with other backing plates for the same weld parameters.
In the present investigation, the influence of addition of the rare earth element samarium (Sm) in different concentrations (0, 0.1, 0.3, 0.5, 0.7 and 0.9wt.%) on the microstructure and tensile ...properties of the Al-Si-Cu 319 alloy have been evaluated. Microstructural constituents such as SDAS of α-Al and characteristics of eutectic silicon particles were observed by optical microscopy. It was concluded from the findings that Sm addition reduces the size of secondary dendrite arm spacings (SDAS) and altered the morphology of the eutectic silicon particles from needle-like to lamellar and smaller segments. The tensile properties of the Al-Si-Cu 319 alloy improved with the concentration of Sm. It was found that the highest tensile properties were obtained at 0.7wt.% addition of Sm, i.e., 55.5% higher than unmodified 319 alloy. With the further addition of the Sm above 0.7wt.%, it does not improve the tensile properties of the alloy. This can be attributed to the precipitation of the brittle and needle like quaternary Sm-rich intermetallic compounds observed through Scanning electron microscopy.
Stress is a major risk factor for the development of mood and anxiety disorders; elucidation of novel approaches to mitigate the deleterious effects of stress could have broad clinical applications. ...Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress. Here we show that acute foot-shock stress induces a transient anxiety state measured 24 h later using the light-dark box assay and novelty-induced hypophagia test. Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. FAAH inhibition does not significantly affect anxiety-like behaviors in non-stressed mice. Moreover, whole brain anandamide levels are reduced 24 h after acute foot-shock stress and are negatively correlated with anxiety-like behavioral measures in the light-dark box test. These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition. These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.
Summary
Cardiac arrest in the peri‐operative period is rare but associated with significant morbidity and mortality. Current reporting systems do not capture many such events, so there is an ...incomplete understanding of incidence and outcomes. As peri‐operative cardiac arrest is rare, many hospitals may only see a small number of cases over long periods, and anaesthetists may not be involved in such cases for years. Therefore, a large‐scale prospective cohort is needed to gain a deep understanding of events leading up to cardiac arrest, management of the arrest itself and patient outcomes. Consequently, the Royal College of Anaesthetists chose peri‐operative cardiac arrest as the 7th National Audit Project topic. The study was open to all UK hospitals offering anaesthetic services and had a three‐part design. First, baseline surveys of all anaesthetic departments and anaesthetists in the UK, examining respondents' prior peri‐operative cardiac arrest experience, resuscitation training and local departmental preparedness. Second, an activity survey to record anonymised details of all anaesthetic activity in each site over 4 days, enabling national estimates of annual anaesthetic activity, complexity and complication rates. Third, a case registry of all instances of peri‐operative cardiac arrest in the UK, reported confidentially and anonymously, over 1 year starting 16 June 2021, followed by expert review using a structured process to minimise bias. The definition of peri‐operative cardiac arrest was the delivery of five or more chest compressions and/or defibrillation in a patient having a procedure under the care of an anaesthetist. The peri‐operative period began with the World Health Organization ‘sign‐in’ checklist or first hands‐on contact with the patient and ended either 24 h after the patient handover (e.g. to the recovery room or intensive care unit) or at discharge if this occured earlier than 24 h. These components described the epidemiology of peri‐operative cardiac arrest in the UK and provide a basis for developing guidelines and interventional studies.
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