Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells

BACKGROUND: Arachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX) pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2). Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells. METHODS: Three colorectal cancer cell lines (HCA7, HT-29 & LoVo) expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor) and rofecoxib (COX-2 selective) on prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA) content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay. RESULTS: COX inhibitors suppressed PGE(2) production but enhanced LTB(4) secretion in COX-2 expressing cell lines (P <0.001). The level of COX-2 expression in colorectal cancer cells did not significantly influence the anti-proliferative and pro-apoptotic effects of COX inhibitors due to the shunting mechanism. CONCLUSIONS: This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors

Inducing apoptosis of human colon cancer cells by an IGF-I D domain analogue peptide

Background: The resistance of tumour cells to apoptosis is a major contributor to the limited effectiveness of chemotherapies. Insulin-like growth factor I (IGF-I) has potential to protect cancer cells from variety of apoptotic challenges. This study was carried out to investigate the effect of a novel IGF-I receptor antagonist on apoptosis in colon cancer cells.Results: We have designed and synthesised a novel antagonist of IGF-I receptor. The effect of this antagonist on human colon cancer cell proliferation was examined by a non-radioactive assay; the apoptosis was revealed by determining the activities of cellular caspases3/7, 8 and 9. The apoptosis pathways were investigated by examining the levels of pro-apoptosis proteins with Western blotting. Following 40 hours treatment with the novel antagonist peptide, colon cancer cell Caspase 3/7 activities increased 2-7 times; Caspase 8 activities increased 2-5 times and Caspase 9 increased 1.2-1.6 times. The proliferation of cancer cell was inhibited by 14-15%. The data showed that the antagonist induced colon cancer cell apoptosis and inhibited cancer cell proliferation. The different changes of Caspase 3/7, 8 and 9 activities suggested that the extrinsic pathways may play a major role in the antagonist peptide-induced apoptosis.Conclusion: This is the first report on this novel antagonist to induce human colon cancer cell apoptosis and inhibit cancer cell proliferation. These results suggest that IGF-I receptor antagonists may have the potential to be developed as a novel therapy for colon cancers in the future

Superconductivity in Co-doped LaFeAsO

Here we report the synthesis and basic characterization of LaFe1-xCoxAsO for several values of x. The parent phase LaFeAsO orders antiferromagnetically (TN ~ 145 K). Replacing Fe with Co is expected to both electron dope the system and introduce disorder in the FeAs layer. For x = 0.05 antiferromagnetic order is destroyed and superconductivity is observed at Tconset = 11.2 K. For x = 0.11 superconductivity is observed at Tc(onset) = 14.3 K, and for x = 0.15 Tc = 6.0 K. Superconductivity is not observed for x = 0.2 and 0.5, but for x = 1, the material appears to be ferromagnetic (Tc ~ 56 K) as judged by magnetization measurements. We conclude that Co is an effective dopant to induce superconductivity. Somewhat surprisingly, the system appears to tolerate considerable disorder in the FeAs planes.Comment: 19 pages, 9 figure

Thermoelectric Figure of Merit of Strongly Correlated Superlattice Semiconductors

We solved the Anderson Lattice Hamiltonian to get the energy bands of a strongly correlated semiconductor by using slave boson mean field theory. The transport properties were calculated in the relaxation-time approximation,and the thermoelectric figure of merit was obtained for the strongly correlated semiconductor and its superlattice structures. We found that at room temperature $ZT$ can reach nearly 2 for the quantum wire lattice structure.We believe that it is possible to find high values of thermoelectric figure of merit from strongly correlated semiconductor superlattice systems.Comment: 4 pages, 3 figure

Does Doxycycline work in synergy with cisplatin and oxaliplatin in colorectal cancer?

Background: In recent years, apart from antibacterial properties, doxycycline is reported to have cytotoxic and anti-proliferative actions in various cancers including colorectal cancer. Colorectal cancer constitutes one of the most common cancers in the western population. Apart from surgery, chemotherapy plays crucial role in the treatment of colorectal cancer. Cisplatin and oxaliplatin are most commonly used platinum compounds for the cancer chemotherapy. This study has looked for any impact of doxycycline on the cytotoxic effects of platinum compounds in colorectal cancer including its mechanisms of actions.Methods: HT 29 colorectal cancer cells were used for this study. These cells were treated with cisplatin and oxaliplatin with or without doxycycline treatment. The caspase 3 gene expression was quantitated by gel electrophoresis and qualitated by real time polymerase chain reactions. The caspase 3 activity was assessed in HT 29 cells with fluorescence kit.Results: The results revealed increased caspase 3 gene expressions and activities in HT 29 cells treated with cisplatin, oxaliplatin and doxycycline; however the combination of doxycycline with cisplatin and oxaliplatin did not report increased caspase 3 gene expressions and activity compared to cisplatin and oxaliplatin alone.Conclusion: We concluded that doxycycline has role in apoptosis induction in the colorectal cancer. However, it did not show any synergy with platinum compounds in the colorectal cancer cells. This study also pointed towards possible caspase-independent actions of doxycycline with cisplatin and oxaliplatin. However, further work is required to underpin the mechanisms of actions of doxycycline

Galaxy Zoo: The Environmental Dependence of Bars and Bulges in Disc Galaxies

We present an analysis of the environmental dependence of bars and bulges in disc galaxies, using a volume-limited catalogue of 15810 galaxies at z<0.06 from the Sloan Digital Sky Survey with visual morphologies from the Galaxy Zoo 2 project. We find that the likelihood of having a bar, or bulge, in disc galaxies increases when the galaxies have redder (optical) colours and larger stellar masses, and observe a transition in the bar and bulge likelihoods, such that massive disc galaxies are more likely to host bars and bulges. We use galaxy clustering methods to demonstrate statistically significant environmental correlations of barred, and bulge-dominated, galaxies, from projected separations of 150 kpc/h to 3 Mpc/h. These environmental correlations appear to be independent of each other: i.e., bulge-dominated disc galaxies exhibit a significant bar-environment correlation, and barred disc galaxies show a bulge-environment correlation. We demonstrate that approximately half (50 +/- 10%) of the bar-environment correlation can be explained by the fact that more massive dark matter haloes host redder disc galaxies, which are then more likely to have bars. Likewise, we show that the environmental dependence of stellar mass can only explain a small fraction (25 +/- 10%) of the bar-environment correlation. Therefore, a significant fraction of our observed environmental dependence of barred galaxies is not due to colour or stellar mass dependences, and hence could be due to another galaxy property. Finally, by analyzing the projected clustering of barred and unbarred disc galaxies with halo occupation models, we argue that barred galaxies are in slightly higher-mass haloes than unbarred ones, and some of them (approximately 25%) are satellite galaxies in groups. We also discuss implications about the effects of minor mergers and interactions on bar formation.Comment: 20 pages, 18 figures; references updated; published in MNRA

IGF-I activates caspases 3/7, 8 and 9 but does not induce cell death in colorectal cancer cells

Background: Colorectal cancer is the third most common cancer in the western world. Chemotherapy is often ineffective to treat the advanced colorectal cancers due to the chemoresistance. A major contributor to chemo-resistance is tumour-derived inhibition or avoidance of apoptosis. Insulin-like growth factor I (IGF-I) has been known to play a prominent role in colorectal cancer development and progression. The role of IGF-I in cancer cell apoptosis is not completely understood.Methods: Using three colorectal cancer cell lines and one muscle cell line, associations between IGF-I and activities of caspase 3/7, 8 and 9 have been examined; the role of insulin-like growth factor I receptor (IGF-IR) in the caspase activation has been investigated.Results: The results show that exogenous IGF-I significantly increases activity of caspases 3/7, 8 and 9 in all cell lines used; blocking IGF-I receptor reduce IGF-I-induced caspase activation. Further studies demonstrate that IGF-I induced caspase activation does not result in cell death. This is the first report to show that while IGF-I activates caspases 3/7, 8 and 9 it does not cause colorectal cancer cell death.Conclusion: The study suggests that caspase activation is not synonymous with apoptosis and that activation of caspases may not necessarily induce cell death

A Molecular Epidemiological Study of var Gene Diversity to Characterize the Reservoir of Plasmodium falciparum in Humans in Africa

BACKGROUND: The reservoir of Plasmodium infection in humans has traditionally been defined by blood slide positivity. This study was designed to characterize the local reservoir of infection in relation to the diverse var genes that encode the major surface antigen of Plasmodium falciparum blood stages and underlie the parasite's ability to establish chronic infection and transmit from human to mosquito. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the molecular epidemiology of the var multigene family at local sites in Gabon, Senegal and Kenya which differ in parasite prevalence and transmission intensity. 1839 distinct var gene types were defined by sequencing DBLα domains in the three sites. Only 76 (4.1%) var types were found in more than one population indicating spatial heterogeneity in var types across the African continent. The majority of var types appeared only once in the population sample. Non-parametric statistical estimators predict in each population at minimum five to seven thousand distinct var types. Similar diversity of var types was seen in sites with different parasite prevalences. CONCLUSIONS/SIGNIFICANCE: Var population genomics provides new insights into the epidemiology of P. falciparum in Africa where malaria has never been conquered. In particular, we have described the extensive reservoir of infection in local African sites and discovered a unique var population structure that can facilitate superinfection through minimal overlap in var repertoires among parasite genomes. Our findings show that var typing as a molecular surveillance system defines the extent of genetic complexity in the reservoir of infection to complement measures of malaria prevalence. The observed small scale spatial diversity of var genes suggests that var genetics could greatly inform current malaria mapping approaches and predict complex malaria population dynamics due to the import of var types to areas where no widespread pre-existing immunity in the population exists

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe