c-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive ...Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers.
Dwarf spheroidal galaxies are dark matter dominated systems, and as such, ideal for indirect dark matter searches. If dark matter decays into high-energy photons in the dwarf galaxies, they will be a ...good target for current and future generations of x-ray and gamma-ray telescopes. By adopting the latest estimates of density profiles of dwarf galaxies in the Milky Way, we revise the estimates dark matter decay rates in dwarf galaxies; our results are more robust, but weaker than previous estimates. Applying these results, we study the detectability of dark matter decays with x-ray and very-high-energy gamma-ray telescopes, such as eROSITA, XRISM, Athena, HAWC, and CTA. Our projection shows that all of these x-ray telescopes will be able to critically assess the claim of the 7 keV sterile neutrino decays from stacked galaxy clusters and nearby galaxies. For TeV decaying dark matter, we can constrain its lifetime to be longer than ∼ 1027– 1028 s . We also make projections for future dwarf galaxies that would be newly discovered with the Vera Rubin Observatory Legacy Survey of Space and Time, which will further improve the expected sensitivity to dark matter decays both in the keV and PeV mass ranges.
Abstract
We present a Monte Carlo–based population synthesis study of fast radio burst (FRB) dispersion and scattering focusing on the first catalog of sources detected with the Canadian Hydrogen ...Intensity Mapping Experiment Fast Radio Burst (CHIME/FRB) project. We simulate intrinsic properties and propagation effects for a variety of FRB population models and compare the simulated distributions of dispersion measures and scattering timescales with the corresponding distributions from the CHIME/FRB catalog. Our simulations confirm the results of previous population studies, which suggested that the interstellar medium of the host galaxy alone (simulated based on the NE2001 model) cannot explain the observed scattering timescales of FRBs. We therefore consider additional sources of scattering, namely, the circumgalactic medium (CGM) of intervening galaxies and the circumburst medium whose properties are modeled based on typical Galactic plane environments. We find that a population of FRBs with scattering contributed by these media is marginally consistent with the CHIME/FRB catalog. In this scenario, our simulations favor a population of FRBs offset from their galaxy centers over a population that is distributed along the spiral arms. However, if the models proposing the CGM as a source of intense scattering are incorrect, then we conclude that FRBs may inhabit environments with more extreme properties than those inferred for pulsars in the Milky Way.
Limited efforts have been made to transform electrical discharge machining to a green and sustainable machining process. Current electric discharge machining (EDM) processes use hydrocarbon or ...synthetic-based dielectric fluids. These fluids emit harmful vapors when they break down, raising concerns for machine operators and for the environment. Biodiesel (BD) has similar properties as conventional dielectric and it can be used in place of conventional dielectric fluids. This research aims to study the effects of biodiesel dielectric in EDM process, especially in micromachining. Experiments are carried out in both low and high energy settings, on bulk metallic glass (BMG) and titanium alloy (Ti-6Al-4 V) using 200-μm-diameter electrodes. Canola BD and sunflower BD are compared against conventional dielectric in terms of material removal rate and tool wear ratio. The experimental evidence showed that both canola and sunflower BD are able to outperform conventional dielectric, and thus suggesting that BD has the potential to replace conventional dielectric as to provide a more sustainable machining process in the future.
Organosulfur compounds are important components of secondary organic aerosols (SOA). While the Aerodyne high-resolution time-of-flight aerosol mass spectrometer (AMS) has been extensively used in ...aerosol studies, the response of the AMS to organosulfur compounds is not well-understood. Here, we investigated the fragmentation patterns of organosulfurs and inorganic sulfates in the AMS, developed a method to deconvolve total sulfate into components of inorganic and organic origins, and applied this method in both laboratory and field measurements. Apportionment results from laboratory isoprene photooxidation experiment showed that with inorganic sulfate seed, sulfate functionality of organic origins can contribute ∼7% of SOA mass at peak growth. Results from measurements in the Southeastern U.S. showed that 4% of measured sulfate is from organosulfur compounds. Methanesulfonic acid was estimated for measurements in the coastal and remote marine boundary layer. We explored the application of this method to unit mass-resolution data, where it performed less well due to interferences. Our apportionment results demonstrate that organosulfur compounds could be a non-negligible source of sulfate fragments in AMS laboratory and field data sets. A reevaluation of previous AMS measurements over the full range of atmospheric conditions using this method could provide a global estimate/constraint on the contribution of organosulfur compounds.
Abstract
Background
Consideration of circulating biomarkers for risk stratification in heart failure (HF) is recommended, but the influence of atrial fibrillation (AF) on prognostic performance of ...many markers is unclear. We investigated the influence of AF on the prognostic performance of circulating biomarkers in HF.
Methods
N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide, C-type natriuretic peptide (CNP), NT-proCNP, high-sensitivity troponin-T, high-sensitivity troponin-I, mid-regional-propeptide adrenomedullin, co-peptin, growth differentiation factor-15, soluble Suppressor of Tumorigenicitiy (sST2), galectin-3, and procalcitonin plasma concentrations were measured in a prospective, multicenter study of adults with HF. AF was defined as a previous history of AF, and/or presence of AF/flutter on baseline 12-lead electrocardiogram. The primary outcome was the composite of HF-hospitalization or all-cause mortality at 2 years.
Results
Among 1099 patients (age 62 ± 12years, 28% female), 261(24%) patients had AF. Above-median concentrations of all biomarkers were independently associated with increased risk of the primary outcome. Significant interactions with AF were detected for galectin-3 and sST2. In considering NT-proBNP for additive risk stratification, sST2 (adjusted hazard ratio AHR1.85, 95%confidence interval C.I. 1.17-2.91) and galectin-3 (AHR1.85, 95%C.I. 1.09-2.45) were independently associated with increased primary outcome only in the presence of AF. The prognostic performance of sST2 was also stronger in AF for all-cause mortality (AF: AHR2.82, 95%C.I. 1.26-6.21; non-AF: AHR1.78, 95% C.I. 1.14-2.76 without AF), while galectin-3 predicted HF-hospitalization only in AF (AHR1.64, 95%C.I. 1.03-2.62).
Conclusions
AF modified the prognostic utility of selected guideline-endorsed HF-biomarkers. Application of markers for prognostic purposes in HF requires consideration of the presence or absence of AF.
Clinical trial registration
ACTRN12610000374066
Background and Purpose
Cigarette smoke is a major cause for chronic obstructive pulmonary disease (COPD). Andrographolide is an active biomolecule isolated from the plant Andrographis paniculata. ...Andrographolide has been shown to activate nuclear factor erythroid‐2‐related factor 2 (Nrf2), a redox‐sensitive antioxidant transcription factor. As Nrf2 activity is reduced in COPD, we hypothesize that andrographolide may have therapeutic value for COPD.
Experimental Approach
Andrographolide was given i.p. to BALB/c mice daily 2 h before 4% cigarette smoke exposure for 1 h over five consecutive days. Bronchoalveolar lavage fluid and lungs were collected for analyses of cytokines, oxidative damage markers and antioxidant activities. BEAS‐2B bronchial epithelial cells were exposed to cigarette smoke extract (CSE) and used to study the antioxidant mechanism of action of andrographolide.
Key Results
Andrographolide suppressed cigarette smoke‐induced increases in lavage fluid cell counts; levels of IL‐1β, MCP‐1, IP‐10 and KC; and levels of oxidative biomarkers 8‐isoprostane, 8‐OHdG and 3‐nitrotyrosine in a dose‐dependent manner. Andrographolide promoted inductions of glutathione peroxidase (GPx) and glutathione reductase (GR) activities in lungs from cigarette smoke‐exposed mice. In BEAS‐2B cells, andrographolide markedly increased nuclear Nrf2 accumulation, promoted binding to antioxidant response element (ARE) and total cellular glutathione level in response to CSE. Andrographolide up‐regulated ARE‐regulated gene targets including glutamate‐cysteine ligase catalytic (GCLC) subunit, GCL modifier (GCLM) subunit, GPx, GR and heme oxygenase‐1 in BEAS‐2B cells in response to CSE.
Conclusions
Andrographolide possesses antioxidative properties against cigarette smoke‐induced lung injury probably via augmentation of Nrf2 activity and may have therapeutic potential for treating COPD.
The cell biology of bone metabolism Datta, H K; Ng, W F; Walker, J A ...
Journal of clinical pathology,
05/2008, Volume:
61, Issue:
5
Journal Article
Peer reviewed
Contrary to the commonly held misconception, bone is a relatively dynamic organ that undergoes significant turnover as compared to other organs in the body. This review details how complex ...intercellular signalling, between the osteoprogenitor cells and mature osteoblasts, osteocytes and osteoclasts, regulates and balances activities of bone cells during remodelling and growth. Both systemic, as well as local autocrine and paracrine factors are discussed. A number of recent important advances in cell biology of bone have led to a new paradigm in understanding of the subject. In this regard, the interaction between the immune system and bone cells is of particular interest, leading to the emergence of a new discipline termed osteoimmunology. The role of lymphocytes and a number of key cytokines in the regulation of osteoclastogenesis and osteoblast function is critically examined. The intracellular signalling regulating key cellular pathways involved in cell differentiation and activity are outlined. The emerging evidence of osteocytes as mechanosensors as well as regulators of mineralisation is discussed.
Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common ...comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8
T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.
PDF
