THE METABOLOMIC EFFECTS OF METFORMIN ON COLON CANCER

Metformin is an oral biguanide that is prescribed to over 120 million people worldwide for the treatment of conditions including type II diabetes mellitus, polycystic ovarian syndrome, and gestational diabetes. This hypoglycemic agent is rapidly emerging as a potential cost-effective anti-oncogenic agent. Over the past decade multiple epidemiologic studies have consistently associated metformin with decreased cancer incidence and cancer-related mortality. More recently numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to the proposal of numerous clinical trials to better understand this drug and its mechanism of action. Previously experts believed metformin primarily targeted AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, but more recent data suggest the impact of metformin has a multi-faceted impact on various metabolic pathways. Current understanding of the potential anti-cancer effects of metformin raises the intriguing possibility of a duality of action, suggesting that metformin has the ability to act directly on a tumor while also indirectly lowering insulin levels in the host. This complexity creates challenges in determining the true impact of this drug in the clinical and translational setting. Despite an increase in investment, only one in every 10 new molecular therapeutic agents that enters clinical development receives approval from the Food and Drug Administration. This warrants a demand for better designed clinical trials with more elegant and robust analyses of relevant primary endpoints to determine which targeted therapies are cost-effective, and more importantly which agents will provide the best care for our patients. Stable isotope resolved metabolomics (SIRM) is a powerful tool capable of robust analyses that can address these questions. Using these capabilities we have determined that metformin does significantly impact cellular metabolism by shifting colon cancer cells into glycolytic overdrive, ultimately leading to decreased proliferation and protein synthesis in cancer cells. This study contributes to the literature and implores that we continue to elucidate the full potential of this drug, especially in the setting of personalized medicine where select patients may receive maximal benefit from this agent

News Stories of Intimate Partner Violence: An Experimental Examination of Participant Sex, Perpetrator Sex, and Violence Severity on Seriousness, Sympathy, and Punishment Preferences

This study experimentally examines the effects of participant sex, perpetrator sex, and severity of violence on perceptions of intimate partner violence (IPV) seriousness, sympathy toward the victim, and punishment preferences for the perpetrator. Participants (N = 449) were randomly assigned to a condition, exposed to a composite news story, and then completed a survey. Ratings of seriousness of IPV for stories with male perpetrators were significantly higher than ratings of seriousness for stories with female perpetrators. Men had significantly higher sympathy for female victims in any condition than for male victims in the weak or strong severity of violence conditions. Men’s sympathy for male victims in the fatal severity of violence condition did not differ from their sympathy for female victims. Women had the least sympathy for female victims in the weak severity condition and men in the weak or strong severity conditions. Women reported significantly higher sympathy for female victims in the strong and fatal severity of violence conditions. Women’s ratings of sympathy for male victims in the fatal severity of violence condition were statistically indistinguishable from any other group. Participants reported stronger punishment preferences for male perpetrators and this effect was magnified among men. Theoretical implications are presented with attention provided to practical considerations about support for public health services

Spectral identification and quantification of salts in the Atacama Desert

This work was part-funded by a Research Incentive Grant from The Carnegie Trust (REF: 70335) and a Royal Society of Edinburgh Research Fellowship to C. Cousins. J, Harris acknowledges funding from STFC (consolidated grant ST/N000528/1).Salt minerals are an important natural resource. The ability to quickly and remotely identify and quantify salt deposits and salt contaminated soils and sands is therefore a priority goal for the various industries and agencies that utilise salts. The advent of global hyperspectral imagery from instruments such as Hyperion on NASA’s Earth-Observing 1 satellite has opened up a new source of data that can potentially be used for just this task. This study aims to assess the ability of Visible and Near Infrared (VNIR) spectroscopy to identify and quantify salt minerals through the use of spectral mixture analysis. The surface and near-surface soils of the Atacama Desert in Chile contain a variety of well-studied salts, which together with low cloud coverage, and high aridity, makes this region an ideal testbed for this technique. Two forms of spectral data ranging 0.35 – 2.5 μm were collected: laboratory spectra acquired using an ASD FieldSpec Pro instrument on samples from four locations in the Atacama desert known to have surface concentrations of sulfates, nitrates, chlorides and perchlorates; and images from the EO-1 satellite’s Hyperion instrument taken over the same four locations. Mineral identifications and abundances were confirmed using quantitative XRD of the physical samples. Spectral endmembers were extracted from within the laboratory and Hyperion spectral datasets and together with additional spectral library endmembers fed into a linear mixture model. The resulting identification and abundances from both dataset types were verified against the sample XRD values. Issues of spectral scale, SNR and how different mineral spectra interact are considered, and the utility of VNIR spectroscopy and Hyperion in particular for mapping specific salt concentrations in desert environments is established. Overall, SMA was successful at estimating abundances of sulfate minerals, particularly calcium sulfate, from both hyperspectral image and laboratory sample spectra, while abundance estimation of other salt phase spectral end-members was achieved with a higher degree of error.Publisher PD

Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin

AbstractThe establishment of relative size of organs and structures is paramount for attaining final form and function of an organism. Importantly, variation in the proportions of structures frequently underlies adaptive change in morphology in evolution and maybe a common mechanism underlying selection. However, the mechanism by which growth is integrated within tissues during development to achieve proper proportionality is poorly understood. We have shown that signaling by potassium channels mediates coordinated size regulation in zebrafish fins. Recently, calcineurin inhibitors were shown to elicit changes in zebrafish fin allometry as well. Here, we identify the potassium channelkcnk5bas a key player in integrating calcineurin’s growth effects, in part through regulation of the cytoplasmic C-terminus of the channel. We propose that the interaction between Kcnk5b and calcineurin acts as a signaling node to regulate allometric growth. Importantly, we find that this regulation is epistatic to inherent mechanisms instructing overall size as inhibition of calcineurin is able to bypass genetic instruction of size as seen insofand wild-type fins, however, it is not sufficient to re-specify positional memory of size of the fin. These findings integrate classic signaling mediators such as calcineurin with ion channel function in the regulation of size and proportion during growth.</jats:p

Identification of early gene expression changes in primary cultured neurons treated with topoisomerase I poisons.

Topoisomerase 1 (TOP1) poisons like camptothecin (CPT) are currently used in cancer chemotherapy but these compounds can have damaging, off-target effects on neurons leading to cognitive, sensory and motor deficits. To understand the molecular basis for the enhanced sensitivity of neurons to CPT, we examined the effects of compounds that inhibit TOP1-CPT, actinomycin D (ActD) and β-lapachone (β-Lap)-on primary cultured rat motor (MN) and cortical (CN) neurons as well as fibroblasts. Neuronal cells expressed higher levels of Top1 mRNA than fibroblasts but transcript levels are reduced in all cell types after treatment with CPT. Microarray analysis was performed to identify differentially regulated transcripts in MNs in response to a brief exposure to CPT. Pathway analysis of the differentially expressed transcripts revealed activation of ERK and JNK signaling cascades in CPT-treated MNs. Immediate-early genes like Fos, Egr-1 and Gadd45b were upregulated in CPT-treated MNs. Fos mRNA levels were elevated in all cell types treated with CPT; Egr-1, Gadd45b and Dyrk3 transcript levels, however, increased in CPT-treated MNs and CNs but decreased in CPT-treated fibroblasts. These transcripts may represent new targets for the development of therapeutic agents that mitigate the off-target effects of chemotherapy on the nervous system

Does Crime Trigger Genetic Risk for Type 2 Diabetes in Young Adults? A G x E Interaction Study Using National Data

Background Living in neighborhoods perceived as disordered exacerbates genetic risk for type 2 diabetes (T2D) among older adults. It is unknown whether this gene-neighborhood interaction extends to younger adults. The present study aims to investigate whether crime, an objectively measured indicator of neighborhood disorder, triggers genetic risk for T2D among younger adults, and whether this hypothesized triggering occurs through exposure to obesity. Methods Data were from the Wave I (2008) National Longitudinal Study of Adolescent to Adult Health. A standardized T2D polygenic score was created using 2014 GWAS meta-analysis results. Weighted mediation analyses using generalized structural equation models were conducted in a final sample of 7606 adults (age range: 25–34) to test the overall association of T2D polygenic scores with T2D, and the mediating path through obesity exposure in low, moderate, and high county crime-rate groups. Age, sex, ancestry, educational degree, household income, five genetic principal components, and county-level concentrated advantage and population density were adjusted. Results The overall association between T2D polygenic score and T2D was not significant in low-crime areas (p = 0.453), marginally significant in moderate-crime areas (p = 0.064), and statistically significant in high-crime areas (p = 0.007). The mediating path through obesity was not significant in low or moderate crime areas (ps = 0.560 and 0.261, respectively), but was statistically significant in high-crime areas (p = 0.023). The indirect path through obesity accounted for 12% of the overall association in high-crime area. Conclusion A gene-crime interaction in T2D was observed among younger adults, and this association was partially explained by exposure to obesity

Organic layer formation and sorption of U(vi) on acetamide diethylphosphonate-functionalized mesoporous silica.

Acetamide diethylphosphonate (AcPhos)-functionalized silica has been shown to have a high affinity for U(vi) in pH 2-3 nitric acid. Previous work with AcPhos-functionalized silica has focused on actinide and lanthanide extraction under various conditions, but has shown poor reproducibility in the functionalization process. For this work, four AcPhos-functionalized SBA-15 materials were synthesized and evaluated based on their U(vi) sorption capacity and their stability in nitric acid. Materials synthesized using pyridine as a basic catalyst were shown to form a greater fraction of polymeric structures at the silica surface, which correlated with higher structural integrity upon contact with acidic solutions. Single-pulse 31P and 1H NMR spectra of these materials show evidence of phosphonic acid groups, as well as hydrogen-bonding interactions either between ligands or with the silica surface. Additionally, these materials were found to have significantly higher U(vi) sorption capacities and Keq values than the materials synthesized without pyridine, most likely due to the ion-exchange properties of the phosphonic acid groups. The 31P-31P DQ-DRENAR NMR technique was used to compare the average strength of dipolar coupling interactions between phosphorus atoms for the four materials. Because the strength of dipolar coupling interactions depends on the number and proximity of neighboring spins, this technique provides information about the average density of ligands on the surface. The conventional functionalization procedure yielded materials with the lowest average surface ligand density, while those using extended reaction times and the pyridine base catalyst yielded materials with higher surface ligand densities

Polysaccharide utilization loci and nutritional specialization in a dominant group of butyrate-producing human colonic Firmicutes

Acknowledgements The Rowett Institute of Nutrition and Health (University of Aberdeen) receives financial support from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS). POS is a PhD student supported by the Scottish Government (RESAS) and the Science Foundation Ireland, through a centre award to the APC Microbiome Institute, Cork, Ireland. Data Summary The high-quality draft genomes generated in this work were deposited at the European Nucleotide Archive under the following accession numbers: 1. Eubacterium rectale T1-815; CVRQ01000001–CVRQ0100 0090: http://www.ebi.ac.uk/ena/data/view/PRJEB9320 2. Roseburia faecis M72/1; CVRR01000001–CVRR010001 01: http://www.ebi.ac.uk/ena/data/view/PRJEB9321 3. Roseburia inulinivorans L1-83; CVRS01000001–CVRS0 100 0151: http://www.ebi.ac.uk/ena/data/view/PRJEB9322Peer reviewedPublisher PD

Temperature Induces Significant Changes in Both Glycolytic Reserve and Mitochondrial Spare Respiratory Capacity in Colorectal Cancer Cell Lines

Thermotherapy, as a method of treating cancer, has recently attracted considerable attention from basic and clinical investigators. A number of studies and clinical trials have shown that thermotherapy can be successfully used as a therapeutic approach for various cancers. However, the effects of temperature on cancer bioenergetics have not been studied in detail with a real time, in a microplate, label-free detection approach. This study investigate how changes in temperature affect the bioenergetics characteristics (mitochondrial function and glycolysis) of three colorectal cancer (CRC) cell lines utilizing the Seahorse XF96 technology. Experiments were performed at 32°C, 37°C and 42°C using assay medium conditions and equipment settings adjusted to produce equal oxygen and pH levels ubiquitously at the beginning of all experiments. The results suggest that temperature significantly changes multiple components of glycolytic and mitochondrial function of all cell lines tested. Under hypothermia conditions (32°C), the extracellular acidification rates (ECAR) of CRC cells were significantly lower compared to the same basal ECAR levels measured at 37°C. Mitochondrial stress test for SW480 cells at 37°C vs 42°C demonstrated increased proton leak while all other OCR components remained unchanged (similar results were detected also for the patient-derived xenograft cells Pt.93). Interestingly, the FCCP dose response at 37°C vs 42°C show significant shifts in profiles, suggesting that single dose FCCP experiments might not be sufficient to characterize the mitochondrial metabolic potential when comparing groups, conditions or treatments. These findings provide valuable insights for the metabolic and bioenergetic changes of CRC cells under hypo- and hyperthermia conditions that could potentially lead to development of better targeted and personalized strategies for patients undergoing combined thermotherapy with chemotherapy

Prevalence of chronic kidney disease in adults in England: comparison of nationally representative cross-sectional surveys from 2003 to 2016

Objectives: To identify recent trends in chronic kidney disease (CKD) prevalence in England and explore their association with changes in sociodemographic, behavioural and clinical factors. Design: Pooled cross-sectional analysis.Setting: Health Survey for England 2003, 2009/2010 combined, and 2016.Participants: 17,663 individuals (aged 16+) living in private households.Primary and secondary outcome measures: Prevalence of estimated glomerular filtration rate (eGFR