40 research outputs found

    Ets-1 Is Essential for Connective Tissue Growth Factor (CTGF/CCN2) Induction by TGF-β1 in Osteoblasts

    Get PDF
    Ets-1 controls osteoblast differentiation and bone development; however, its downstream mechanism of action in osteoblasts remains largely undetermined. CCN2 acts as an anabolic growth factor to regulate osteoblast differentiation and function. CCN2 is induced by TGF-β1 and acts as a mediator of TGF-β1 induced matrix production in osteoblasts; however, the molecular mechanisms that control CCN2 induction are poorly understood. In this study, we investigated the role of Ets-1 for CCN2 induction by TGF-β1 in primary osteoblasts.We demonstrated that Ets-1 is expressed and induced by TGF-β1 treatment in osteoblasts, and that Ets-1 over-expression induces CCN2 protein expression and promoter activity at a level similar to TGF-β1 treatment alone. Additionally, we found that simultaneous Ets-1 over-expression and TGF-β1 treatment synergize to enhance CCN2 induction, and that CCN2 induction by TGF-β1 treatment was impaired using Ets-1 siRNA, demonstrating the requirement of Ets-1 for CCN2 induction by TGF-β1. Site-directed mutagenesis of eight putative Ets-1 motifs (EBE) in the CCN2 promoter demonstrated that specific EBE sites are required for CCN2 induction, and that mutation of EBE sites in closer proximity to TRE or SBE (two sites previously shown to regulate CCN2 induction by TGF-β1) had a greater effect on CCN2 induction, suggesting potential synergetic interaction among these sites for CCN2 induction. In addition, mutation of EBE sites prevented protein complex binding, and this protein complex formation was also inhibited by addition of Ets-1 antibody or Smad 3 antibody, demonstrating that protein binding to EBE motifs as a result of TGF-β1 treatment require synergy between Ets-1 and Smad 3.This study demonstrates that Ets-1 is an essential downstream signaling component for CCN2 induction by TGF-β1 in osteoblasts, and that specific EBE sites in the CCN2 promoter are required for CCN2 promoter transactivation in osteoblasts

    Extra-Intestinal Manifestations of Familial Adenomatous Polyposis

    Get PDF
    Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which results from a germ line mutation in the APC (adenomatous polyposis coli) gene. FAP is characterized by the formation of hundreds to thousands of colorectal adenomatous polyps. Although the development of colorectal cancer stands out as the most prevalent complication, FAP is a multisystem disorder of growth. This means, it is comparable to other diseases such as the MEN syndromes, Von Hippel-Lindau disease and neurofibromatosis. However, the incidence of many of its clinical features is much lower. Therefore, a specialized multidisciplinary approach to optimize health care—common for other disorders—is not usually taken for FAP patients. Thus, clinicians that care for and counsel members of high-risk families should have familiarity with all the extra-intestinal manifestations of this syndrome. FAP-related complications, for which medical attention is essential, are not rare and their estimated lifetime risk presumably exceeds 30%. Affected individuals can develop thyroid and pancreatic cancer, hepatoblastomas, CNS tumors (especially medulloblastomas), and various benign tumors such as adrenal adenomas, osteomas, desmoid tumors and dental abnormalities. Due to improved longevity, as a result of better prevention of colorectal cancer, the risk of these clinical problems will further increase

    Evaluation of lung MDCT nodule annotation across radiologists and methods

    Get PDF
    RATIONALE AND OBJECTIVES: Integral to the mission of the National Institutes of Health–sponsored Lung Imaging Database Consortium is the accurate definition of the spatial location of pulmonary nodules. Because the majority of small lung nodules are not resected, a reference standard from histopathology is generally unavailable. Thus assessing the source of variability in defining the spatial location of lung nodules by expert radiologists using different software tools as an alternative form of truth is necessary. MATERIALS AND METHODS: The relative differences in performance of six radiologists each applying three annotation methods to the task of defining the spatial extent of 23 different lung nodules were evaluated. The variability of radiologists’ spatial definitions for a nodule was measured using both volumes and probability maps (p-map). Results were analyzed using a linear mixed-effects model that included nested random effects. RESULTS: Across the combination of all nodules, volume and p-map model parameters were found to be significant at P < .05 for all methods, all radiologists, and all second-order interactions except one. The radiologist and methods variables accounted for 15% and 3.5% of the total p-map variance, respectively, and 40.4% and 31.1% of the total volume variance, respectively. CONCLUSION: Radiologists represent the major source of variance as compared with drawing tools independent of drawing metric used. Although the random noise component is larger for the p-map analysis than for volume estimation, the p-map analysis appears to have more power to detect differences in radiologist-method combinations. The standard deviation of the volume measurement task appears to be proportional to nodule volume

    The golden age of wasted TVs: Regaining precious metals and critical raw materials from low and medium grade PCBs within the EU, including a technical case study for FDP TVs and monitors

    No full text
    In recent decades Europe has been increasing its demand and consumption of electronics. This has in turn resulted in major outflows of waste electronics (WEEE) that are usually not properly dealt with. This is especially the case for low to medium grade printed circuit boards (PCBs) which unlike higher grade electronics such as computers are currently not profitable to recycle. Therefore this thesis, as a part of the Peacoc project, investigated the low energy separation methods roll sorting, magnetic separation and magnetic density separation to concentrate the precious and critical metals found in the components of these discarded PCBs. The resulting secondary material flows were then evaluated on their impact in the EU from a material and energetical perspective.The roll sorter was able to significantly increase the concentrations of the precious metal rich target components (Central processing units, IC chips and transistors, MLCC + Ta capacitors, Small transistors and IC chips and Connectors of plastic with golden pins). The machine sorted the feed into multiple width sizes (&lt; 3.0, 3.0 - 5.0, 5.0 - 7.0 and &gt; 7.0 mm) of which all except &gt; 7.0 were used for further processing, increasing the overall grade from 18.66 to 42.61 wt%. This was further increased by the magnetic separator (lightly and non magnetic fractions for &lt; 3.0 mm and only the non magnetic fraction for 3.0 - 7.0 mm) to 53.69 wt% and magnetic density separation (only for non magnetic 5.0 - 7.0 mm)to 66.23 wt%. Recovery for all target categories was near 100% with the exception of Connectors of plastic with golden pins as these were too large for the roll sorter to sort.The thesis also took a broader approach by employing a dynamic material flow analysis to determine the low to medium grade PCBs and their accompanying precious metal flows in the EU. The expected metal flows were low (∼4%) compared to the EU’s overall demand in 2020 and expected to decrease over the years due to miniaturisation (decreasing size and weight) of the components. Furthermore, only around 36.68 wt% of the maximum precious metal flows were expected to be captured due to low collection rates of WEEE and small loses in separation and metallurgical recovery. Nonetheless, a sizeable fraction of the EU’s electronics sector’s demand (over 10%) could be supplied. These results were confirmed by modelling different future scenarios, a Monte-Carlo uncertainty and sensitivity analysis of the model.Lastly, the thesis explored the topic of critical raw materials (CRMs) and the direct energy requirements of Peacoc’s recovery system. It was found that beryllium, antimony, platinum and palladium were the only CRMs that had any significant potential to supply the EU (9.13% for beryllium, 1.58% for antimony,1.32% for platinum and 4.02% for palladium). If only looking at the electronics sector this was also the case for cobalt and vanadium. The newly captured secondary precious metals were shown to require significantly less energy to produce, around an order of magnitude, compared to primary production but were similar to other recycling pathways. Furthermore, the majority of energy was required during metallurgical recovery showing a potential for further mechanical concentration during separation.In conclusion it can be stated that the separation technologies (roll sorting, magnetic separation and magnetic density separation) are effective methods for separating the components of low to medium grade PCBs. However, their impact on the circularity and energetical footprint of the whole EU are expected to be small.PeacocIndustrial Ecolog

    Closing the mass-balance of pyroprobe research regarding biomass fast pyrolysis

    No full text
    Presently, the majority of the worlds energy supply is dependent on fossil fuels. As these fuels area limited resource and have significant negative side effects, the way humanity uses these is unsustainable and other sources of energy have to be found. One of these sustainable energy sources is plant-derived biomass. However, biomass cannot be efficiently used in its natural form and needs to be converted to other products through processes such as pyrolysis and gasification. Pyrolysis will be the focus of this thesis, as fast pyrolysis of Miscanthus is studied for the BRISK 2 project at Process &amp; Energy (TU Delft). However, the current setup used for pyrolysis research does not provide a complete mass-closure of the experiments, with only 80% of the total mass accounted for in the char, tar and gaseous yields. In order to improve this closure, four different methods were developed and investigated during this thesis. All of the pyrolysis experiments were performed in a Pyroprobe 5200. The pyrolysis parameters were comparable to fast pyrolysis, with a high heating rate of 600°C/s, a low residence time of 10 s and a Final Pyrolysis Temperature between 600°C and 1000°C. The objective of the first adjustment was to improve the purge flow stability, reduce the amount of blockages in the system and increase the accuracy of the experiments. The flow meter, controlling the purge flow, was replaced with a mass-flow controller and a tube in the setup was simplified and shortened. No further blockages were observed and the total mass-closure improved on average by 7.85 wt% over the temperature range of 600-1000°C, with an increase at every temperature. The second considered element was the homogeneity of the biomass. Two biomass feedstocks were investigated, the first feedstock consisted of inhomogeneous pellets grinded down to a size less than 80μm, while the second type was homogenized biomass of a size of less than 200μm. Both biomass types performed comparably to each other and better than the previous data collected with the setup. At 600°C the inhomogeneous biomass performed better, while at 700°C the homogeneous biomass gave a higher yield. The last two experimental series both focused on gravimetrically measuring the tars collected in the condenser of the setup, which was not gravimetrically measured before. The first of these methods removed the condenser in favour of a direct capture in a quartz trap. This gave a maximum yield increase of 1.14 wt% at 700°C. However, concerns of contaminating the gas mixture with tars arose, therefore this method was not investigated at higher temperatures. In the second technique, the 2ml of isopropanol in the condenser was evaporated from a glass Petri dish, leaving the tars behind. This method was explored over a larger temperature range (600-1000°C), yet only provided a maximum increase of 1.5 wt% at 1000°C, while giving significant fluctuations between experiments. Thus proving that neither of these methods is a suitable way of gravimetrically measuring the condenser.Molecular Science and Technolog

    Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: A prespecified secondary analysis of a randomized controlled clinical trial

    No full text
    Aims: To evaluate the effects of separate and combined use of the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin and the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on measures of kidney function. Methods: In this prespecified secondary analysis of the DECREASE trial, we enrolled 66 obese patients with type 2 diabetes in a 16-week randomized double-blind placebo-controlled clinical trial to investigate the effects of dapagliflozin and exenatide twice daily, alone or in combination, versus placebo on 24-hour urinary albumin:creatinine ratio (UACR), creatinine and cystatin C-estimated glomerular filtration rate (GFR) and kidney injury molecule-1:creatinine ratio (KIM-1:Cr). Results: At week 16, the mean UACR change from baseline was −39.6% (95% confidence interval [CI] −58.6, −11.9; P = 0.001) in the combined exenatide-dapagliflozin group, −18.1% (95% CI −43.1, 18.0; P = 0.278) in the dapagliflozin group, −15.6% (95% CI −41.4, 21.6; P = 0.357) in the exenatide group and − 11.0% (95% CI −39.8, 31.5; P = 0.552) in the placebo group. Compared to placebo, UACR difference at week 16 in the exenatide-dapagliflozin group was −32.2% (95% CI −60.7, 16.9; P = 0.159). Effects were similar in 37 participants who were using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at baseline. Compared to placebo, in the exenatide-dapagliflozin group, an acute dip in estimated GFR was observed with creatinine-estimated GFR (−4.0 mL/min/1.73 m2 [95% CI −9.3, 1.2]; P = 0.129) and cystatin C-estimated GFR (−10.4 mL/min/1.73 m2 [95% CI −14.9, −5.8]; P < 0.001). The mean KIM-1:Cr difference in the combined treatment arm versus placebo was −43.8% (95% CI −73.5, 18.9; P = 0.129). Conclusion: This prespecified secondary analysis suggests that combined therapy with exenatide and dapagliflozin may have synergistic effects on markers of kidney function compared to either therapy alone or placebo in obese patients with type 2 diabetes
    corecore