Apoptotic and chemotherapeutic properties of iron(III)-salophene in an ovarian cancer animal model

The cytotoxicity of organometallic compounds iron(III)-, cobalt(III)-, manganese(II)-, and copper(II)-salophene (-SP) on platinum-resistant ovarian cancer cell lines was compared. Fe-SP displayed selective cytotoxicity (IC 50 at ∼1 μM) against SKOV-3 and OVCAR-3 cell lines while Co-SP caused cytotoxic effects only at higher concentrations (IC50 at 60 ?M) and Cu-SP effects were negligible. High cytotoxicity of Mn-SP (30-60 μM) appeared to be nonspecific because the Mn-chloride salt reduced cell viability similarly. The effect of Fe-SP at 1 μM proved to be ovarian cancer cell selective when compared to a panel of cell lines derived from different tumors. The first irreversible step in the induction of cell death by Fe-SP occurred after 3 hrs as indicated by the mitochondrial transmembrane potential (ΔΨm) and was mainly linked to apoptotic, not necrotic events. To evaluate the toxicity of Fe-SP in vivo we conducted an acute toxicity study in rats. The LD 50 of Fe-SP is >2000 mg/kg orally and >5.5 mg/kg body weight by intraperitoneal injection. An ovarian cancer animal model showed that the chemotherapeutic relevant dose of Fe-SP in rats is 0.5-1 mg/kg body weight. The present report suggests that Fe-SP is a potential therapeutic drug to treat ovarian cancer. © 2009 Lange et al, publisher and licensee Dove Medical Press Ltd

Nudging Cooperation in a Crowd Experiment

We examine the hypothesis that driven by a competition heuristic, people don't even reflect or consider whether a cooperation strategy may be better. As a paradigmatic example of this behavior we propose the zero-sum game fallacy, according to which people believe that resources are fixed even when they are not. We demonstrate that people only cooperate if the competitive heuristic is explicitly overridden in an experiment in which participants play two rounds of a game in which competition is suboptimal. The observed spontaneous behavior for most players was to compete. Then participants were explicitly reminded that the competing strategy may not be optimal. This minor intervention boosted cooperation, implying that competition does not result from lack of trust or willingness to cooperate but instead from the inability to inhibit the competition bias. This activity was performed in a controlled laboratory setting and also as a crowd experiment. Understanding the psychological underpinnings of these behaviors may help us improve cooperation and thus may have vast practical consequences to our society.Fil: Niella, Tamara. Universidad Torcuato di Tella; ArgentinaFil: Stier, Nicolas. Universidad Torcuato di Tella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sigman, Mariano. Universidad Torcuato di Tella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

On Glauber modes in Soft-Collinear Effective Theory

Gluon interactions involving spectator partons in collisions at hadronic machines are investigated. We find a class of examples in which a mode, called Glauber gluons, must be introduced to the effective theory for consistency.Comment: 19 pages, three figures. Uses JHEP3.cl

Toe clearance and velocity profiles of young and elderly during walking on sloped surfaces

Background Most falls in older adults are reported during locomotion and tripping has been identified as a major cause of falls. Challenging environments (e.g., walking on slopes) are potential interventions for maintaining balance and gait skills. The aims of this study were: 1) to investigate whether or not distributions of two important gait variables [minimum toe clearance (MTC) and foot velocity at MTC (VelMTC)] and locomotor control strategies are altered during walking on sloped surfaces, and 2) if altered, are they maintained at two groups (young and elderly female groups). Methods MTC and VelMTC data during walking on a treadmill at sloped surfaces (+3°, 0° and -3°) were analysed for 9 young (Y) and 8 elderly (E) female subjects. Results MTC distributions were found to be positively skewed whereas VelMTC distributions were negatively skewed for both groups on all slopes. Median MTC values increased (Y = 33%, E = 7%) at negative slope but decreased (Y = 25%, E = 15%) while walking on the positive slope surface compared to their MTC values at the flat surface (0°). Analysis of VelMTC distributions also indicated significantly (p < 0.05) lower minimum and 25th percentile (Q1) values in the elderly at all slopes. Conclusion The young displayed a strong positive correlation between MTC median changes and IQR (interquartile range) changes due to walking on both slopes; however, such correlation was weak in the older adults suggesting differences in control strategies being employed to minimize the risk of tripping

Centimeter-long electron transport in marine sediments via conductive minerals

© 2015 International Society for Microbial Ecology All rights reserved. Centimeter-long electron conduction through marine sediments, in which electrons derived from sulfide in anoxic sediments are transported to oxygen in surficial sediments, may have an important influence on sediment geochemistry. Filamentous bacteria have been proposed to mediate the electron transport, but the filament conductivity could not be verified and other mechanisms are possible. Surprisingly, previous investigations have never actually measured the sediment conductivity or its basic physical properties. Here we report direct measurements that demonstrate centimeter-long electron flow through marine sediments, with conductivities sufficient to account for previously estimated electron fluxes. Conductivity was lost for oxidized sediments, which contrasts with the previously described increase in the conductivity of microbial biofilms upon oxidation. Adding pyrite to the sediments significantly enhanced the conductivity. These results suggest that the role of conductive minerals, which are more commonly found in sediments than centimeter-long microbial filaments, need to be considered when modeling marine sediment biogeochemistry

Iron(III)-Salophene: An Organometallic Compound with Selective Cytotoxic and Anti-Proliferative Properties in Platinum-Resistant Ovarian Cancer Cells

Background: In this pioneer study to the biological activity of organometallic compound Iron(III)-salophene (Fe-SP) the specific effects of Fe-SP on viability, morphology, proliferation, and cell-cycle progression on platinum-resistant ovariancancer cell lines were investigated. Methodology/Principal Findings: Fe-SP displayed selective cytotoxicity against SKOV-3 and OVCAR-3 (ovarian epithelial adenocarcinoma) cell lines at concentrations between 100 nM and 1 μM, while the viability of HeLa cells (epithelial cervix adenocarcinoma) or primary lung or skin fibroblasts was not affected. SKOV-3 cells in contrast to fibroblasts after treatment with Fe-SP revealed apparent hallmarks of apoptosis including densely stained nuclear granular bodies within fragmented nuclei, highly condensed chromatin and chromatin fragmentation. Fe-SP treatment led to the activation of markers of the extrinsic (Caspase-8) and intrinsic (Caspase-9) pathway of apoptosis as well as of executioner Caspase-3 while PARP-1 was deactivated. Fe-SP exerted effects as an anti-proliferative agent with an IC50 value of 300 nM and caused delayed progression of cells through S-phase phase of the cell cycle resulting in a complete S-phase arrest. When intra-peritoneally applied to rats Fe-SP did not show any systemic toxicity at concentrations that in preliminary trials were determined to be chemotherapeutic relevant doses in a rat ovarian cancer cell model. Conclusion/Significance: The present report suggests that Fe-SP is a potent growth-suppressing agent in vitro for cell lines derived from ovarian cancer and a potential therapeutic drug to treat such tumors in viv

Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0–29.2%) among child contacts, 4.8% (95% CI, 3.0–7.7%) among adult contacts, 5.0% (95% CI, 1.6–14.5%) among migrants and 4.8% (95% CI, 1.5–14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal–external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82–0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide

Cocaine-induced renal infarction: report of a case and review of the literature

BACKGROUND: Cocaine abuse has been known to have detrimental effects on the cardiovascular system. Its toxicity has been associated with myocardial ischemia, cerebrovascular accidents and mesenteric ischemia. The pathophysiology of cocaine-related renal injury is multifactorial and involves renal hemodynamic changes, alterations in glomerular matrix synthesis, degradation and oxidative stress, and possibly induction of renal atherogenesis. Renal infarction as a result of cocaine exposure, however, is rarely reported in the literature. CASE PRESENTATION: A 48 year-old male presented with a four-day history of severe right flank pain following cocaine use. On presentation, he was tachycardic, febrile and had severe right costovertebral angle tenderness. He had significant proteinuria, leukocytosis and elevated serum creatinine and lactate dehydrogenase. Radiographic imaging studies as well as other screening tests for thromboembolic events, hypercoagulability states, collagen vascular diseases and lipid disorders were suggestive of Cocaine-Induced Renal Infarction (CIRI) by exclusion. CONCLUSION: In a patient with a history of cocaine abuse presenting with fevers and flank pain suggestive of urinary tract infection or nephrolithiasis, cocaine-induced renal infarction must be considered in the differential diagnosis. In this article, we discuss the prior reported cases of CIRI and thoroughly review the literature available on this disorder. This is important for several reasons. First, it will allow us to discuss and elaborate on the mechanism of renal injury caused by cocaine. In addition, this review will demonstrate the importance of considering the diagnosis of CIRI in a patient with documented cocaine use and an atypical presentation of acute renal injury. Finally, we will emphasize the need for a consensus on optimal treatment of this disease, for which therapy is not yet standardized

Isothiocyanate NB7M causes selective cytotoxicity, pro-apoptotic signalling and cell-cycle regression in ovarian cancer cells

The present report identifies indole-3-ethyl isothiocyanate NB7M as a potent cytotoxic agent with selective activity against cell lines derived from various tumour types. Ovarian cancer cell lines showed sensitivity to NB7M (60–70% cytotoxicity at 2.5 μM), in contrast to control cells (TCL-1 and HTR-8; IC50 ∼15 μM). In a screen performed by the National Cancer Institute (NCI) (NCI60 cancer cell-line assay) NB7M (NSC746077) reduced growth up to 100% with an IC50 between 0.1 and 10 μM depending on the cell line studied. Using SKOV-3 ovarian cancer cells as a model, mechanisms of cytotoxicity were analysed. NB7M caused hallmarks of apoptosis such as PARP-1 deactivation, chromatin condensation, DNA nicks, activation of caspases-9, -8, -3, loss of mitochondrial transmembrane depolarisation potential and upregulation of pro-apoptotic mitogen activated protein kinases (p38, SAP/JNK). NB7M downregulated phosphorylation of prosurvival kinases (PI-3K, AKT, IKKα), transcription factor NF-κB, and expression of DNA-Pk and AXL receptor tyrosine kinase. Subcytotoxic doses of NB7M inhibited DNA synthesis, caused G1-phase cell-cycle arrest and upregulated p27 expression. The present report suggests that NB7M is a selective cytotoxic agent in vitro for cell lines derived from ovarian and certain other tumours. In addition, NB7M acts as a growth/cell-cycle-suppressing agent and may be developed as a potential therapeutic drug to treat ovarian cancer

Activation of Methanogenesis in Arid Biological Soil Crusts Despite the Presence of Oxygen

Methanogenesis is traditionally thought to occur only in highly reduced, anoxic environments. Wetland and rice field soils are well known sources for atmospheric methane, while aerated soils are considered sinks. Although methanogens have been detected in low numbers in some aerated, and even in desert soils, it remains unclear whether they are active under natural oxic conditions, such as in biological soil crusts (BSCs) of arid regions. To answer this question we carried out a factorial experiment using microcosms under simulated natural conditions. The BSC on top of an arid soil was incubated under moist conditions in all possible combinations of flooding and drainage, light and dark, air and nitrogen headspace. In the light, oxygen was produced by photosynthesis. Methane production was detected in all microcosms, but rates were much lower when oxygen was present. In addition, the δ13C of the methane differed between the oxic/oxygenic and anoxic microcosms. While under anoxic conditions methane was mainly produced from acetate, it was almost entirely produced from H2/CO2 under oxic/oxygenic conditions. Only two genera of methanogens were identified in the BSC-Methanosarcina and Methanocella; their abundance and activity in transcribing the mcrA gene (coding for methyl-CoM reductase) was higher under anoxic than oxic/oxygenic conditions, respectively. Both methanogens also actively transcribed the oxygen detoxifying gene catalase. Since methanotrophs were not detectable in the BSC, all the methane produced was released into the atmosphere. Our findings point to a formerly unknown participation of desert soils in the global methane cycle