Onset of the aerobic nitrogen cycle during the Great Oxidation Event

The rise of oxygen on the early Earth (about 2.4 billion years ago)1 caused a reorganization of marine nutrient cycles2, 3, including that of nitrogen, which is important for controlling global primary productivity. However, current geochemical records4 lack the temporal resolution to address the nature and timing of the biogeochemical response to oxygenation directly. Here we couple records of ocean redox chemistry with nitrogen isotope (15N/14N) values from approximately 2.31-billion-year-old shales5 of the Rooihoogte and Timeball Hill formations in South Africa, deposited during the early stages of the first rise in atmospheric oxygen on the Earth (the Great Oxidation Event)6. Our data fill a gap of about 400 million years in the temporal 15N/14N record4 and provide evidence for the emergence of a pervasive aerobic marine nitrogen cycle. The interpretation of our nitrogen isotope data in the context of iron speciation and carbon isotope data suggests biogeochemical cycling across a dynamic redox boundary, with primary productivity fuelled by chemoautotrophic production and a nitrogen cycle dominated by nitrogen loss processes using newly available marine oxidants. This chemostratigraphic trend constrains the onset of widespread nitrate availability associated with ocean oxygenation. The rise of marine nitrate could have allowed for the rapid diversification and proliferation of nitrate-using cyanobacteria and, potentially, eukaryotic phytoplankton

DADOS-Survey: an open-source application for CHERRIES-compliant Web surveys

BACKGROUND: The Internet has been increasingly utilized in biomedical research. From online searching for literature to data sharing, the Internet has emerged as a primary means of research for many physicians and scientists. As a result, Web-based surveys have been employed as an alternative to traditional, paper-based surveys. We describe DADOS-Survey, an open-source Web-survey application developed at our institution that, to the best of our knowledge, is the first to be compliant with the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). DADOS-Survey was designed with usability as a priority, allowing investigators to design and execute their own studies with minimal technical difficulties in doing so. RESULTS: To date, DADOS-Survey has been successfully implemented in five Institutional Review Board-approved studies conducted by various departments within our academic center. Each of these studies employed a Web-survey design as their primary methodology. Our initial experience indicates that DADOS-Survey has been used with relative ease by each of the investigators and survey recipients. This has been further demonstrated through formal and field usability testing, during which time suggestions for improvement were incorporated into the software design. CONCLUSION: DADOS-Survey has the potential to have an important role in the future direction of Web-survey administration in biomedical research. This CHERRIES-compliant application is tailored to the emerging requirements of quality data collection in medicine

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

Abstract PD03-01: Significant Reduction of Triple-Negative Breast Cancers in Diabetic Women on Metformin

Abstract Background: Diabetes is an increasingly prevalent chronic disease. Many of these patients may develop breast cancer (BC). A meta-analysis by Larsson (2007)demonstrated that diabetic women have an increased risk (RR: 1.2) of BC particularly for estrogen receptor positive (ER+) subtypes (RR: 1.22). However, a recent study by Bodmer (2010) showed that women on long-term metformin have a reduced incidence of BC (OR 0.44, 95% CI 0.24-0.82). Metformin has antiproliferative effects on BC based on studies using proliferative marker Ki67. BC patients on metformin have better cancer-specific survival based on Landman (2010). We hypothesize that when compared to other diabetic medications; including exogenous insulin and other oral hypoglycemics; metformin specifically reduces the incidence of triple negative BCs (TNBC or ER-/PR-/Her2-). Methods: We conducted a retrospective chart review of an unselected cohort of patients who underwent surgical interventions for their primary BC to correlate the history of pre-existing diabetes and metformin use to the BC subtypes based on the immunohistochemistry of the surgical specimens. P-values were calculated using Chi-square and Fisher exact tests. Results: There were 99 TNBC in the 1005 patients reviewed. Of the 90 diabetic patients, none of the 44 patients took metformin had TNBC, compared to 7 of the 46 diabetic patients not taking metformin had TNBC (0% vs. 15.2% p=0.007). Discussion: Studies that examined the incidence of BC in diabetics were not able to differentiate the effects of various diabetic treatments on the subtypes of BC. The reported increase in ER+ BC in diabetics is likely multifactorial but may be attributed to the proliferative effects of hyperinsulinemia. Interesting, of all the diabetic medications, Bodmer (2010) reported only metformin reduced the incidence of BC. In this study, we reported a statistical significant reduction in the incidence of TNBC. In fact, in our study population, there was no TNBC in patients who took metformin. Hirsch (2009) reported a selective inhibition of BC stem cells with metformin. Of interest, many studies have shown that BC stem cells were ER-/PR-/Her2-. This study supports the view that the phenotype of the BCs can be influenced by drug. At this point, we cannot differentiate if metformin can “protect” patients from developing TNBC, or “convert” TNBC to other subtypes of BC, further study is underway to address this question. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-01.</jats:p

Abstract PD03-05: Analysis of tumour cell signaling in response to neoadjuvant metformin in women with early stage breast cancer.

Abstract Background: The anti-diabetic drug metformin, commonly used to treat type 2 diabetes due to its ability to reduce circulating glucose and insulin, has emerged as a potential anti-cancer agent. Observational studies have reported decreased cancer incidence and mortality in diabetics receiving metformin. Metformin's ability to reduce insulin may be particularly important for breast cancer (BC) because hyperinsulinemia is an adverse prognostic factor and most cells express the insulin receptor (IR). The anti-cancer effects of metformin are associated with both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMPK and an inhibition of mTOR signalling, while indirect effects are mediated by reductions in circulating insulin levels, leading to reduced IR-activated PI3K signalling. We conducted a neoadjuvant, single arm, “window of opportunity” trial examining the clinical and biological effects of metformin on thirty-nine locoregional BC patients awaiting definitive surgery. Methods: Non-diabetic women with newly diagnosed, untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until surgery. Fasting blood and tumour samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, while IHC analysis of tumours was used to characterize cellular markers before and after metformin. Specifically, IR levels and the phosphorylation status of proteins involved in AMPK and PI3K/AKT/mTOR signalling, including AMPK (T172) and AKT (S473), were examined. Results: 39 patients with a mean age of 51 years received metformin for a median of 18 days (range 13–40) with minor GI toxicities. The clinical effects (previously reported) included significant (p &amp;lt; 0.05) decreases in body mass index (−0.5 kg/m2), weight (−1.2 kg), glucose (−0.14 mM) and HOMA (an estimate of insulin resistance, −0.21), and a decrease in insulin (−4.7 pmol/L) that approached significance (p = 0.0686). Ki67 staining in tumour tissue decreased significantly and TUNEL increased significantly. Levels of IR expression decreased significantly (from 4.39 to 3.82, p = 0.0375) as did the phosphorylation status of AKT (S473) and AMPK (T172) (from 9.82 to 7.08, p = &amp;lt;0.0001; from 6.2 to 5.1, p = 0.0034, respectively). Conclusions: Metformin impact was consistent with beneficial anti-cancer effects. Reduced AKT phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. Assessment of additional factors in BC cells, including OCT1 expression (required for metformin uptake), and the phosphorylation of ACC (a marker of AMPK activation), is underway and will be reported. Integrated analysis of these factors combined with the physiological and molecular data described above will further enhance understanding of metformin action in the clinical setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-05.</jats:p