Exploratory modeling: Extracting causality from complexity

On 22 May 2011 a massive tornado tore through Joplin, Mo., killing 158 people. With winds blowing faster than 200 miles per hour, the tornado was the most deadly in the United States since modern record keeping began in the 1950s. ©2014. American Geophysical Union. All Rights Reserved

Large Scale Matrix Degradation by Stromal Cells Independent of Invadopodia

Invadopodia are actin-rich structures at the base of many neoplastic cells that sequester matrix metalloproteases that act to degrade the surrounding stroma to facilitate the invasive process. Conventional invadopodia are dependent upon Src kinase and the large GTPase dynamin 2 (Dyn 2). Whether invadopodia are the only mechanism by which cells degrade matrix is unclear. We have observed that cells of mesenchymal origin degrade matrix in an unique way different from tumor cells. The HYPOTHESIS of this study is that fibroblasts, and other cells of mesenchymal origin, degrade matrix by a mechanism distinct from that of epithelial-based tumor cells. The CONCLUSION is that stromal cells degrade matrix by a novel mechanism distinct from traditional invadopodia

Stromal Fibroblasts Facilitate Cancer Cell Invasion by a Novel Invadopodia-Independent Matrix Degradation Process

Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process utilizes complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42, or Dyn2. Rather, inhibition of Dyn2 causes a dramatic upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization, and regulated by disparate molecular mechanisms

Activity of high-dose epirubicin combined with gemcitabine in advanced non-small-cell lung cancer: a multicenter phase I and II study

The aim of the study was to evaluate efficacy and tolerance of epirubicin and gemcitabine as first-line chemotherapy in patients with advanced non-small-cell lung cancer. A phase I study was performed with the combination of escalating doses of epirubicin intravenously on day 1 and a fixed dose of gemcitabine on days 1 and 8 of a 21-day cycle. Eighteen patients were included in the phase I part of the study before the maximum tolerated dose was found. Dose-limiting toxicity was febrile neutropenia. The phase II part of the study was continued with epirubicin 100 mg m−2on day 1 and gemcitabine 1125 mg m−2on days 1 and 8 of a 21-day cycle. Forty-three chemotherapy-naive patients were included. The median age of the patients was 60 years (range 26–75). Most patients (74%) were in stage IV. Granulocytopenia CTC grade 4 occurred in 32.5% and thrombocytopenia grade 4 in 11.6% of cycles. Febrile neutropenia occurred in six patients. Non-haematological toxicity was mainly mucositis CTC grade 2 and 3 in 35% of patients. The tumour response rate was 49% (95% confidence interval (CI) 35–63%). The median survival time for the patients was 42 weeks (95% CI 13–69). © 2000 Cancer Research Campaig

First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial

The purpose of our study was to compare progression-free survival and quality of life (QOL) after cisplatin-gemcitabine (CG) or epirubicin-gemcitabine (EG) in chemotherapy-naive patients with unresectable non-small-cell lung cancer. Patients (n = 240) were randomised to receive gemcitabine 1125 mg m(-2) (days 1 and 8) plus either cisplatin 80 mg m(-2) (day 2) or epirubicin 100 mg m(-2) (day 1) every 3 weeks for a maximum of five cycles. Eligible patients had normal organ functions and Eastern Cooperative Oncology Group performance status less than or equal to2. QOL was measured with European Organisation for Research and Treatment of Cancer QLQ-C30 and LC13 questionnaires. There were no significant differences in median progression-free survival (CG 26 weeks, EG 23 weeks), median overall survival (CG 43 weeks, EG 36 weeks), or tumour response rates (CG 46%, EG 36%). Toxicity was mainly haematologic. In the EG arm granulocytopenia occurred more frequently, leading to more febrile neutropenia. Also, elevation of serum transaminases, mucositis, fever, and decline in LVEF were more common in the EG arm. In the CG arm, more patients experienced elevated serum creatinine levels, sensory neuropathy, nausea, and vomiting. Global QOL was not different in both arms. Progression-free survival, overall survival, response rate, and QOL were not different between both arms; however, overall toxicity was more severe in the EG arm

Massive Peatland Carbon Banks Vulnerable to Rising Temperatures

Peatlands contain one-third of the world’s soil carbon (C). If destabilized, decomposition of this vast C bank could accelerate climate warming; however, the likelihood of this outcome remains unknown. Here, we examine peatland C stability through five years of whole-ecosystem warming and two years of elevated atmospheric carbon dioxide concentrations (eCO2). Warming exponentially increased methane (CH4) emissions and enhanced CH4 production rates throughout the entire soil profile; although surface CH4 production rates remain much greater than those at depth. Additionally, older deeper C sources played a larger role in decomposition following prolonged warming. Most troubling, decreases in CO2:CH4 ratios in gas production, porewater concentrations, and emissions, indicate that the peatland is becoming more methanogenic with warming. We observed limited evidence of eCO2 effects. Our results suggest that ecosystem responses are largely driven by surface peat, but that the vast C bank at depth in peatlands is responsive to prolonged warming

Peatland Initiation, Carbon Accumulation, and 2 ka Depth in the James Bay Lowland and Adjacent Regions

Copyright © 2014 University of Colorado at Boulder, Institute of Arctic and Alpine ResearchPeatlands surrounding Hudson and James Bays form the second largest peatland complex in the world and contain major stores of soil carbon (C). This study utilized a transect of eight ombrotrophic peat cores from remote regions of central and northern Ontario to quantify the magnitude and rate of C accumulation since peatland initiation and for the past 2000 calendar years before present (2 ka). These new data were supplemented by 17 millennially resolved chronologies from a literature review covering the Boreal Shield, Hudson Plains, and Taiga Shield bordering Hudson and James Bays. Peatlands initiated in central and northern Ontario by 7.8 ka following deglaciation and isostatic emergence of northern areas to above sea level. Total C accumulated since inception averaged 109.7 ± (std. dev.) 36.2 kg C m–2. Approximately 40% of total soil C has accumulated since 2 ka at an average apparent rate of 20.2 ± 6.9 g C m–2 yr–1. The 2 ka depths correlate significantly and positively with modern gridded climate estimates for mean annual precipitation, mean annual air temperature, growing degree-days > 0 °C, and photosynthetically active radiation integrated over days > 0 °C. There are significantly shallower depths in permafrost peatlands. Vertical peat accumulation was likely constrained by temperature, growing season length, and photosynthetically active radiation over the last 2 ka in the Hudson Bay Lowlands and surrounding regions.US National Science Foundatio

Discovery of novel heart rate-associated loci using the Exome Chip

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate