Utilization of Fluorescent Chemosensors to Quantify Pb2+ in Aqueous Media

Currently the detection of environmental lead samples requires time and material intensive methods. Recently, through the development of small fluorescent lead sensors, it may be possible to detect lead in the environment quickly and efficiently. A specific fluorescent chemosensor, Leadglow (LG), has shown promise in detecting low levels of lead in a rapid manner with little sample preparation or training. Leadglow and a naphthalene derivative were successfully synthesized and purified. The lead binding properties of Leadglow and the naphthalene derivative were studied and optimized. The use of Leadglow on several portable devices was also studied

Examining Gentle Rivalry: Decision-Making in Blockchain Systems

The blockchain comes with the promise of being a disruptive technology with the potential for novel ways of interaction in a wide range of applications. Although scholarly interest in the technology is growing, a comprehensive analysis of blockchain applications from a governance perspective lacks to date. This research pays special attention to the governance of blockchain systems and illustrates core governance decisions on 15 blockchain implementations from four application domains. Additionally, this research sheds light on changes brought by the blockchain in terms of governance. Based on academic literature, semi-structured-interviews with representatives from those companies, and content analysis of grey literature, different blockchain governance decisions have been derived and their enactment described. The identification of those enriches the scarce body of knowledge on blockchain-based implementations with a better understanding of how key governance decisions are enacted

Titanium Dioxide as Energy Storage Material: A Review on Recent Advancement

With the increased attention on sustainable energy, a novel interest has been generated towards construction of energy storage materials and energy conversion devices at minimum environmental impact. Apart from the various potential applications of titanium dioxide (TiO2), a variety of TiO2 nanostructure (nanoparticles, nanorods, nanoneedles, nanowires, and nanotubes) are being studied as a promising materials in durable active battery materials. The specific features such as high safety, low cost, thermal and chemical stability, and moderate capacity of TiO2 nanomaterial made itself as a most interesting candidate for fulfilling the current demand and understanding the related challenges towards the preparation of effective energy storage system. Many more synthetic approaches have been adapted to design different nanostructures for improving the electronic conductivity of TiO2 by combining with other materials such as carbonaceous materials, conducting polymers, metal oxides etc. The combination can be done through incorporating and doping methods to synthesize TiO2-based anodic materials having more open channels and active sites for lithium and/or sodium ion transportation. The present chapter contained a broad literature and discussion on the synthetic approaches for TiO2-based anodic materials for enhancing the lithium ion batteries (LIBs) and sodium ion batteries (SIBs) performance. Based on lithium storage mechanism and role of anodic material, we could conclude on future exploitation development of titania and titania based materials as energy storage materials

Combined BRAFV600E- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer

Anaplastic (ATC) and refractory papillary thyroid cancer (PTC) lack effective treatments. Inhibition of either oncogenic BRAF or SRC has marked anti-tumor effects in mouse models of thyroid cancer, however, neither drug induces notable apoptosis. Here we report that the SRC-inhibitor dasatinib further sensitizes BRAFV600E-positive thyroid cancer cells to the BRAFV600E-inhibitor PLX4720. Combined treatment with PLX4720 and dasatinib synergistically inhibited proliferation and reduced migration in PTC and ATC cells. Whereas PLX4720 did not induce robust apoptosis in thyroid cancer cells, combined treatment with dasatinib induced apoptosis in 4 of 6 lines. In an immunocompetent orthotopic mouse model of ATC, combined PLX4720 and dasatinib treatment significantly reduced tumor volume relative to PLX4720 treatment alone. Immune cell infiltration was increased by PLX4720 treatment and this effect was maintained in mice treated with both PLX4720 and dasatinib. Further, combined treatment significantly increased caspase 3 cleavage in vivo relative to control or either treatment alone. In conclusion, combined PLX4720 and dasatinib treatment induces apoptosis, increases immune cell infiltration and reduces tumor volume in a preclinical model of ATC, suggesting that the combination of these FDA-approved drugs may have potential for the treatment of patients with ATC or refractory PTC

Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways

Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAFV600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAFV600E inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis

The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAF

Background: While the development of new treatments for aggressive thyroid cancer has advanced in the last 10 years, progress has trailed headways made with other malignancies. A lack of reliable authenticated human cell lines and reproducible animal models is one major roadblock to preclinical testing of novel therapeutics. Existing xenograft and orthotopic mouse models of aggressive thyroid cancer rely on the implantation of highly passaged human thyroid carcinoma lines in immunodeficient mice. Genetically engineered models of papillary and undifferentiated (anaplastic) thyroid carcinoma (PTC and ATC) are immunocompetent; however, slow and stochastic tumor development hinders high-throughput testing. Novel models of PTC and ATC in which tumors arise rapidly and synchronously in immunocompetent mice would facilitate the investigation of novel therapeutics and approaches. Methods: We characterized and utilized mouse cell lines derived from PTC and ATC tumors arising in genetically engineered mice with thyroid-specific expression of endogenous BrafV600E/WTand deletion of either Trp53 (p53) or Pten. These murine thyroid cancer cells were transduced with luciferase- and GFP-expressing lentivirus and implanted into the thyroid glands of immunocompetent syngeneic B6129SF1/J mice in which the growth characteristics were assessed. Results: Large locally aggressive thyroid tumors form within one week of implantation. Tumors recapitulate their histologic subtype, including well-differentiated PTC and ATC, and exhibit CD3+, CD8+, B220+, and CD163+ immune cell infiltration. Tumor progression can be followed in vivo using luciferase and ex vivo using GFP. Metastatic spread is not detected at early time points. Conclusions: We describe the development of the next generation of murine orthotopic thyroid cancer models. The implantation of genetically defined murine BRAF-mutated PTC and ATC cell lines into syngeneic mice results in rapid and synchronous tumor formation. This model allows for preclinical investigation of novel therapeutics and/or therapeutic combinations in the context of a functional immune system

Risk of acute appendicitis in and around pregnancy: a population-based cohort study from England

Objective: To determine the absolute and relative risk of acute appendicitis during the antepartum and postpartum periods compared with the time outside pregnancy among women of childbearing age. Background: Acute appendicitis is the most common nonobstetric surgical emergency during pregnancy. Estimates of the incidence of acute appendicitis in pregnancy remain imprecise and inconsistent. Methods: All potential fertile women aged 15 to 44 years registered within Clinical Practice Research Datalink with linkages to the Hospital Episodes Statistics between 1997 and 2012 were identified. Absolute rates of acute appendicitis were calculated during the antepartum and postpartum periods and were compared with the time outside pregnancy in terms of incidence rate ratio (IRR) using a Poisson regression model. Results: Among 1,624,804 women, there were 362,219 pregnancies resulting in live or stillbirths. Compared with the time outside pregnancy, the rate of acute appendicitis was 35% lower during the antepartum period [IRR, 0.65; 95% confidence interval (CI), 0.55–0.76], with the lowest rate reported during the third trimester (IRR, 0.47; 95% CI, 0.35–0.64) for all ages; no increased risk of acute appendicitis was observed in the postpartum period compared with the time outside pregnancy among women aged 15 to 34 years but an 84% increased risk for women older than 35 years (IRR, 1.84; 95% CI, 1.18–2.86). The highest and lowest rates of negative appendectomy were encountered in the second and the third trimesters, respectively. Conclusions: Pregnant women are less likely to be diagnosed with acute appendicitis than nonpregnant women, with the lowest risk reported during the third trimester

Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP

The success of pancreatic β-cells transplantation to treat type 1 diabetes has been hindered by massive β-cell dysfunction and loss of β-cells that follows the procedure. Hypoxia-mediated cell death has been considered one of the main difficulties that must be overcome for transplantation to be regarded as a reliable therapy. Here we have investigated the mechanisms underlying β-cell death in response to hypoxia (1% O2). Our studies show that mouse insulinoma cell line 6 (Min6) cells undergo apoptosis with caspase-3 activation occurring as early as 2 h following exposure to hypoxia. Hypoxia induces endoplasmic reticulum stress in Min6 cells leading to activation of the three branches of the unfolded protein response pathway. In response to hypoxia the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) is upregulated. The important role of CHOP in the apoptotic process was highlighted by the rescue of Min6 cells from hypoxia-mediated apoptosis observed in CHOP-knockdown cells. Culturing isolated pancreatic mouse islets at normoxia showed intracellular hypoxia with accumulation of hypoxia-inducible factor-1α and upregulation of CHOP, the latter one occurring as early as 4 h after isolation. Finally, we observed that pancreatic islets of type 2 db/db diabetic mice were more hypoxic than their counterpart in normoglycemic animals. This finding indicates that hypoxia-mediated apoptosis may occur in type 2 diabetes